67th Meeting

Thursday, June 7, 2001

8:15 a.m.

Holiday Inn Bethesda Versailles Ballroom

8120 Wisconsin Avenue Bethesda, Maryland




Stacy Nerenstone, M.D., Chair

Karen M. Templeton-Somers, Ph.D., Executive



Kathy S. Albain, M.D.

Douglas W. Blayney, M.D. John T. Carpenter, Jr., M.D. Stephen George, Ph.D.

David P. Kelsen, M.D.

Donna Przepiorka, M.D., Ph.D. Bruce G. Redman, D.O.

Victor M. Santana, M.D. George W. Sledge, Jr., M.D. Sarah A. Taylor, M.D.

Jody L. Pelusi, F.N.P., Ph.D., Consumer Representative


Steven D. Averbuch, M.D.

Carl F. Dixon

Robert Erwin

Ruth Linden, Ph.D. Jan Platner

Robert Spiegel, M.D.


Dr. Robert Temple Dr. Richard Pazdur Dr. Grant Williams Dr. Patricia Keegan

Ms. Patricia Delaney





Call to Order and Opening Remarks 4

Stacy Nerenstone, M.D., Chair

Introduction of the Committee 4

Conflict of Interest Statement:

Karen M. Templeton-Somers, Ph.D. 6

Open Public Hearing

Karen F. Doran - Greenup, Kentucky 8

Susan L. Weiner, The Children's Cause 13

Helen Schiff - SHARE 18

Lurdes Queimado, M.D./Ph.D. (Letter read

by Karen M. Templeton-Somers, Ph.D.) 22

Sally Cooper (Letter read by Karen M.

Templeton-Somers, Ph.D.) 26

Single Patient Use of Non-Approved Oncology Drugs

and Biologics


Summary of Regulatory and Industry Considerations

Grant Williams, M.D. 35

Summary of the Ethical Considerations

Sarah Taylor, M.D. 50

Perspective from the Patient Advocacy Community

Jody Pelusi, F.N.P., Ph.D. 58

ODAC Discussants

Sarah Taylor, M.D. 84

Jody Pelusi, F.N.P., Ph.D. 89

Committee Discussion 90


4 1 P R O C E E D I N G S

2 Call to Order and Opening Remarks

3 DR. NERENSTONE: Good morning. First of

4 all, I would like to thank everyone for coming to

5 ODAC. This morning we are going to be discussing

6 the single patient use of non-approved oncology

7 drugs and biologicals.

8 I would like to start with the

9 introduction of the committee, and if we could go

10 around and have everybody state their name and

11 where they are from into the microphone for the

12 record, please. We will start with Dr. Averbuch.

13 Introduction of the Committee

14 DR. AVERBUCH: Steve Averbuch,

15 Astra/Zeneca Pharmaceuticals.

16 DR. SPIEGEL: Bob Spiegel,

17 Schering-Plough.

18 DR. LINDEN: Ruth Linden, UC/San Francisco

19 and UC/Berkeley, University of California.

20 MS. PLATNER: Jan Platner, National Breast

21 Cancer Coalition.

22 MR. ERWIN: Robert Erwin, Marti Nelson

23 Cancer Research Foundation.

24 DR. BLAYNEY: Doug Blayney, Wilshire

25 Oncology Medical Group. Pasadena, California.


5 1 DR. KELSEN: Dave Kelsen, Sloan-Kettering,

2 New York.

3 DR. PELUSI: Jody Pelusi, Phoenix Indian

4 Medical Center and the Consumer Rep.

5 DR. TAYLOR: Sarah Taylor, University of

6 Kansas.

7 DR. NERENSTONE: I am Stacy Nerenstone,

8 Medical Oncology, Hartford Hospital.


10 Executive Secretary to the committee, FDA.

11 DR. GEORGE: Stephen George, Duke

12 University.

13 DR. SLEDGE: George Sledge, Indiana

14 University.

15 DR. REDMAN: Bruce Redman, University of

16 Michigan.

17 DR. PRZEPIORKA: Donna Przepiorka, Cell

18 and Gene Therapy, Baylor College of Medicine,

19 Houston.

20 DR. CARPENTER: John Carpenter, University

21 of Alabama at Birmingham.

22 DR. ALBAIN: Kathy Albain, Medical

23 Oncology, Loyola University, Chicago.

24 DR. WEISS: Karen Weiss, Center for

25 Biologics, FDA.


6 1 DR. WILLIAMS: Grant Williams, Center for

2 Drugs, FDA.

3 MS. DELANEY: Pattie Delaney, Office of

4 Special Health Issues, Cancer Liaison Program, FDA.

5 DR. PAZDUR: Richard Pazdur, FDA.

6 DR. TEMPLE: Bob Temple, Office Director,

7 OD-1, FDA.

8 DR. NERENSTONE: Thank you. Dr.

9 Templeton-Somers will now discuss the Conflict of

10 Interest Statement.

11 Conflict of Interest Statement

12 DR. TEMPLETON-SOMERS: The following

13 announcement addresses the issue of conflict of

14 interest with regard to this meeting and is made a

15 part of the record to preclude even the appearance

16 of such at this meeting.

17 Since the issue to be discussed by the

18 committee at this meeting will not have a unique

19 impact on any particular firm or product, but

20 rather may have widespread implications with

21 respect to an entire class of products,

22 in accordance with 18 U.S.C. Section 208(b),

23 waivers have been granted to all members and

24 consultants who have reported interests in any

25 pharmaceutical companies.


7 1 A copy of these waiver statements may be

2 obtained by submitting a written request to the

3 FDA's Freedom of Information Office, Room 12A-30 of

4 the Parklawn Building.

5 With respect to the FDA's invited guests,

6 there are reported affiliations which we believe

7 should be made public to allow the participants to

8 objectively evaluate their comments.

9 Ruth Linden, Ph.D., would like to disclose

10 for the record that she has provided consulting

11 services for MGI Pharma regarding the development

12 of an expanded access program. This service was

13 provided January 2001 through February 2001 and may

14 resume in the future. Her views on expanded access

15 are described in the paper she presented at the

16 December 2000 meeting of the Oncologic Drugs

17 Advisory Committee.

18 Robert Erwin would like to disclose that

19 he is founder, shareholder, and full-time employee

20 of a large scale biology corporation. The firm is

21 conducting research in medical fields including

22 oncology.

23 Robert Spiegel, M.D., would like to

24 disclose that he is the Senior Vice President of

25 Medical Affairs and Chief Medical Officer of


8 1 Schering-Plough.

2 Steven Averbuch, M.D., would like to

3 disclose that he is Senior Medical Director,

4 Oncology, of Astra/Zeneca Pharmaceuticals and holds

5 stock in Astra/Zeneca, Merck, and 3-Dimensional

6 Pharmaceuticals.

7 In the event that the discussions involve

8 any other products or firms not already on the

9 agenda for which an FDA participant has a financial

10 interest, the participants are aware of the need to

11 exclude themselves from such involvement, and their

12 exclusion will be noted for the record.

13 With respect to all other participants, we

14 ask in the interest of fairness that they address

15 any current or previous involvement with any firm

16 whose products they may wish to comment upon.

17 Thank you.

18 Open Public Hearing

19 DR. NERENSTONE: We would like to start

20 the next part, which is the open public hearing.

21 Karen Doran.

22 MS. DORAN: Good morning. I wish to thank

23 the FDA for giving me another opportunity to

24 address the Oncologic Drug Advisory Committee about

25 the Gene Therapy Clinical Trial. For those who


9 1 were not in attendance at the December 2000

2 meeting, let me briefly explain why I am here

3 today.

4 My mother, Hazel Doran, had been approved

5 to participate in the Gene Therapy Clinical Trial

6 at the University of Pennsylvania in Philadelphia.

7 She was well informed of the risks and benefits and

8 decided gene therapy was her only hope in her fight

9 against mesothelioma, a deadly form of lung cancer.

10 My mother was a non-smoker and was exposed

11 to asbestos as a young adult. Upon the death of a

12 young man from Arizona who was undergoing gene

13 therapy, the FDA put a hold on any further gene

14 therapy clinical trials. This prevented my mother

15 from her only chance at a possible cure, and as we

16 waited hopefully for her treatment to begin, over a

17 three-month period, mother did not partake of any

18 type of cancer therapy.

19 We finally found out about gene therapy

20 being put on hold through the news media. No one

21 at the medical center informed us of this momentous

22 decision.

23 I am here today as an advocate for

24 patients considering any clinical trial, the right

25 to decisions, choice, and being informed.


10 1 Consider for a moment that you have a

2 loved one missing in action during a war. You may

3 never know if they are dead or alive. This is how

4 my family feels. We will never know if the Gene

5 Therapy Clinical Trial would have saved or extended

6 my mother's life. That question will stay with us

7 for the rest of our lives.

8 My mother was willing to take this chance,

9 not only for herself, but for others, as well. She

10 had hoped in addition to keeping her alive that

11 medical science would also learn something from her

12 gene therapy treatment that in turn might save

13 someone else's life. That is why it is so

14 important that those wanting to be a part of any

15 clinical trial should have the opportunity to do

16 so.

17 It is hard for me to understand how

18 someone could decide to halt a clinical trial when

19 there have been proven benefits and it is the only

20 hope for a terminally ill person, like my mother.

21 My mother, age 72 at the time, was active and

22 involved with her family and community. She was

23 determined to live.

24 When I spoke in December, someone said

25 they could not understand how I could make this


11 1 presentation so soon after my mother's death. It

2 is because of my mother that I have this strength.

3 She instilled in me the right to stand up for what

4 you believe. My family and I believe that cancer

5 patients, along with their physicians, should have

6 the right to decide if a clinical trial is right

7 for them.

8 Isn't everything we do in life a trial?

9 At one point, taking an aspirin was a trial as well

10 as chemotherapy.

11 My family and I, on behalf of my mother,

12 Hazel Doran, strongly encourage the Gene Therapy

13 Clinical Trial to be reinstated. When a person is

14 told they are going to die and that they might

15 benefit from a clinical trial, they should have a

16 choice.

17 When my mother was told she could not

18 participate in this Gene Therapy Clinical Trial,

19 all hope was taken from her. We could see an

20 immediate change in her outlook on fighting this

21 horrible disease. Even though mom put up a

22 tremendous effort, she was finally defeated by the

23 cancer because someone took away her right to

24 decide what treatment options she had.

25 In the last remaining months of my mom's


12 1 life, there was very little we could do for her.

2 However, one bright spot was her 72nd birthday.

3 Have you ever given a birthday party for someone

4 who is dying? It was probably the best thing we

5 could have done for mom. It gave her friends the

6 opportunity to visit her, wish her a happy

7 birthday, and that is how they now remember my

8 mother - in a very positive manner celebrating

9 another year of life.

10 Please consider carefully when deciding if

11 this Gene Therapy Clinical Trial should be

12 permitted to begin at the University of

13 Pennsylvania in Philadelphia. Think of my mother

14 and think of someone else's loved one and the only

15 possible hope that they have in fighting this rare

16 deadly form of lung cancer.

17 Please consider carefully that this

18 decision could mean someone celebrating another

19 birthday with their family. My mother's birthday

20 passed this year - we honored her by placing

21 flowers on her grave. We would have rather placed

22 them in her hands.

23 Please consider the right for a patient to

24 decide what is best for them when fighting deadly

25 disease. Your decision may help prevent another


13 1 family from spending the rest of their lives asking

2 What If?

3 Thank you.

4 DR. NERENSTONE: Thank you very much, Ms.

5 Doran.

6 Susan Weiner.

7 MS. WEINER: Thank you for the opportunity

8 to speak to the FDA Oncologic Drug Advisory

9 Committee on this important issue.

10 I am Susan Weiner, President and Founder

11 of the Children's Cause, a patient and family led

12 education and advocacy group dedicated to improving

13 outcomes for childhood cancer. I was also the

14 mother of Adam Weiner, who lived and died with a

15 brain tumor.

16 I addressed this group briefly in December

17 and am grateful for the chance to speak again. At

18 that time, I emphasized the Children's Cause

19 position on single patient use in children, that it

20 should be unnecessary. We argued for the ideal

21 that there should be a comprehensive, tightly

22 organized, and proactive national clinical trials

23 program through the Children's Oncology Group, so

24 that any child with cancer might qualify for an

25 open trial.


14 1 Single patient use of non-approved drugs

2 represents a special threat in pediatric oncology

3 because treatment outside of a clinical trial is

4 not consistent with the high quality care that has

5 saved so many children's lives. It is also a

6 threat because children with cancer are a precious

7 and scarce resource from which we must learn how to

8 improve treatment for others.

9 I support this position because I believe

10 it is best for children struggling with cancer and

11 those yet to be diagnosed, but I wanted to speak

12 today about what so-called compassionate use was

13 like from my own personal perspective, to highlight

14 the conflict from the other side. It is still very

15 difficult for me to talk publicly about my son

16 Adam's experience even these many years later, so

17 forgive me.

18 Adam was never expected to live beyond his

19 brain tumor diagnosis in infancy, but live he did

20 until he was nearly 14 years old. Three months

21 before Adam died, he experienced among other things

22 status epilepticus. For many, many days he had

23 constant uncontrollable seizures. His doctors from

24 one of the nation's best academic medical centers

25 discussed applying for what they called


15 1 compassionate use of a drug that might stop the

2 seizures. A few days later they told me that it

3 was not possible for him to have access to this

4 experimental anticonvulsant.

5 I neither knew what made him eligible nor

6 ineligible, nor what process was necessary to

7 obtain the drug. The impact was clear, however,

8 hope of ending this nightmare had been introduced

9 with language that conveyed sensitivity to our

10 desperate circumstances, only to be withdrawn for

11 reasons that were not clear, and when access that

12 could be considered compassionate was no longer

13 possible, all hope and options were gone.

14 The issues of language, terminology,

15 consistency, and communication were at the heart of

16 much of the misunderstanding and distress that

17 parents and patients have about access to new drugs

18 in clinical research. The unfortunate term

19 "compassionate use" needs to be dispensed with

20 entirely. FDA documents no long use the phrase,

21 but it still appears in the NCI document on

22 non-research use of investigational agents.

23 The phrase persists among physicians and

24 families as a code phrase for our best hope, but it

25 is a misnomer. There are other terms in current


16 1 use in FDA and NCI materials that need replacing

2 and clarification.

3 For example, FDA's background materials

4 for this meeting cite investigational use versus

5 treatment use of investigational drug. Treatment

6 presumes that a drug is known to be therapeutic.

7 Drugs considered for single patient use are all

8 investigational and therefore have unknown

9 therapeutic effect.

10 Clinical trials are also always

11 investigational, research, and not treatment,

12 according to the consent forms that we sign. So,

13 how can giving an investigational drug with unknown

14 therapeutic effect be treatment when it is used for

15 a single patient, but not treatment when it is used

16 in the context of a clinical trial?

17 Clearly, there is need for linguistic

18 overhaul both at the FDA and the NCI in the

19 description of single patient use. Beyond

20 terminology, however, FDA and NCI need to adopt

21 open and consistent rules and policies on single

22 patient use.

23 The National Cancer Institute sets the

24 policies, standards, and procedures for the conduct

25 of clinical trials through the National Pediatric


17 1 Cooperative Groups. If these are indeed the best

2 ethical and scientific strategies to guide

3 children's access to new oncology drugs, then, they

4 should apply equally to access through clinical

5 trials, special exception, and single patient use

6 for children.

7 For families seeking care, clarity,

8 consistency, and access to information in this

9 complex domain are vital to making sound and

10 rational decisions for our children. Accordingly,

11 we make the following recommendations.

12 FDA and NCI should coordinate efforts to

13 develop a common, nonvalue-laden set of terms with

14 clear and precise definitions to describe single

15 patient use. FDA and NCI should develop

16 consistent, open, and publicly accessible policies

17 about single patient use. Such an approach can

18 avoid unequal access to new drugs and help preserve

19 the clinical trial system.

20 To implement these changes, FDA and NCI

21 should coordinate a communication strategy for

22 print and electronic materials to educate and

23 change public and professional perception about

24 so-called compassionate use.

25 We applaud the FDA for holding these


18 1 meetings and for allowing an in-depth look at these

2 important issues.

3 Thank you.

4 DR. NERENSTONE: Thank you very much for

5 your thoughtful comments.

6 Helen Schiff.

7 MS. SCHIFF: Good morning. My name is

8 Helen Schiff. I have no conflict of interest. I

9 am a member of SHARE, a self-help group for women

10 with breast or ovarian cancer based in New York

11 City.

12 Today, I am speaking for SHARE members who

13 have graduated from Project LEAD, a breast cancer

14 advocacy training course. We meet monthly to

15 discuss controversial issues facing women with

16 breast cancer. I will present the evolution of our

17 group's thinking on access to unproven drugs at

18 three long intense meetings.

19 At our first meeting, most members of our

20 group expressed total disbelief at the idea that

21 advocates could be against single patient

22 protocols, how could SHARE deny a dying woman the

23 right to an unproven drug, SHARE should not close

24 off any avenues of hope even false hope.

25 About one-third of our 20-member group


19 1 have metastatic breast cancer. At our next meeting

2 we discussed the importance of not doing anything

3 that would undermine the clinical trial system. We

4 were all aware of the high dose chemotherapy

5 fiasco, how lives can needlessly be cut short and

6 how valuable time in which treatment advances can

7 be made is wasted when experimental treatment is

8 given outside of trials.

9 Still, the majority of our group felt that

10 there must be a way to allow the use of unproven

11 drugs that would not undercut the clinical trial

12 system.

13 Next, we saw a videotape of a Sixty Minute

14 segment which interviewed two women with advanced

15 colon cancer. Both were trying to get the

16 experimental drug C225. Neither of them qualified

17 for the clinical trial. The both spent hours

18 searching online, writing letters, and calling

19 influential people.

20 In the end, the woman who devised the

21 strategy of phoning the president of the drug

22 company before his secretary was there to screen

23 his calls got the drug. The woman who wrote to the

24 President of the United States did not.

25 Jane Sawyer, a member of our LEAD group,


20 1 who had been metastatic for four years sent me a

2 note saying I am convinced. She said it was

3 painful to watch what those women went through.

4 The results were unfair. I would rather be in a

5 lottery.

6 Most of us then agreed that single patient

7 protocols are anything but compassionate. They are

8 very unfair and arbitrary and discriminate against

9 people who are not highly educated or well

10 connected.

11 At our final meeting, we came to a

12 consensus that the real problem was with the

13 clinical trial system itself. We need more high

14 quality trials using novel agents. We need more

15 access and faster enrollment. We need to test

16 drugs in earlier stages of disease and later stages

17 of disease, and in case of the new biologics, with

18 and without chemotherapy.

19 We think any attempt to use access to

20 unproven drugs is a way around the shortcomings of

21 the clinical trial system will ultimately be a huge

22 disservice to cancer survivors because trials are

23 the only way to know if a new drug is better, no

24 different, or worse than the standard of care.

25 We agreed that expanded access, not single


21 1 patient protocol, is the only fair way to provide

2 access to unproven drugs and that it should be

3 encouraged only: one, when the drug has

4 exceptional promise due to very strong evidence in

5 humans, not just good PR or elegant-sounding

6 hypotheses; two, when it has a good safety profile;

7 and, three, when the person does not qualify for

8 any other high-quality trial.

9 A member of SHARE, who is an ovarian

10 cancer survivor, at our meeting argued against this

11 proposal, stating that ovarian cancer patients have

12 fewer choices and need broader access to unproven

13 drugs.

14 Speaking for myself, from what I know

15 about Gleevec, that is a good example of the kind

16 of exceptional drug we are talking about that

17 should be, and was, made available by expanded

18 access. I can't think of any others including

19 Herceptin, that would fit into that category.

20 Gleevec's use, first in trials of CML

21 leukemia and then for a rare form of intestinal

22 cancer, speaks to the question raised by those with

23 less common cancers. More and more we are looking

24 at therapies, not by organ, breast, ovary, colon,

25 et cetera, but by mutation, HER2, ras, EGFR, et


22 1 cetera.

2 Isn't it more rational and compassionate

3 to set up different trials in other cancers with

4 the same mutation than to give it to people who

5 have little chance of benefiting from it? Isn't it

6 more rational if extra drug is available to set up

7 trials in later or early stages of disease, so we

8 can actually learn something?

9 Are the drug companies being forced to

10 give out unproven drugs for fear of bad PR, like

11 the insurance companies were forced to pay for

12 high-dose chemotherapy outside of trials?

13 We have too few people entering clinical

14 trials. FDA and ODAC need to formulate a policy

15 that will not undercut the clinical trial system.

16 That is what is best for the interest of present

17 and future cancer patients.

18 This is a statement of SHARE's Project

19 Lead group. SHARE itself is still formulating its

20 position.

21 DR. NERENSTONE: Thank you very much.

22 The next comments will be in the form of a

23 letter from Dr. Queimado. Dr. Templeton-Somers

24 will be reading.

25 DR. TEMPLETON-SOMERS: This letter is from


23 1 Lurdes Queimado, who is a lymphoma advocate.

2 "Dear Sirs and Madams: I am a founding

3 member of the Lymphoma Action Alliance, an advocacy

4 group created to help lymphoma patients gain access

5 to the best and least toxic cancer treatments -

6 when they are most likely to be effective.

7 Professionally, I am an M.D./Ph.D., working full

8 time in cancer research.

9 In low-grade Non-Hodgkin's lymphoma

10 patients, chemotherapy and/or radiotherapy are

11 relatively effective in temporarily reducing the

12 patient's tumor burden. However, these therapies

13 do not cure the disease, nor do they increase the

14 overall survival. Therefore, chemotherapy and/or

15 radiotherapy should not be considered standard

16 treatments for this disease.

17 Indeed, this fact is recognized by every

18 lymphoma specialist. For example, Dr. Dan Long,

19 working at the NCI, wrote recently, "A patient with

20 follicular lymphoma might hear from his or her

21 physician treatment recommendations ranging from

22 high-dose chemotherapy with stem cell

23 transplantation to doing nothing and every

24 gradation in between.

25 Patients with low-grade non-Hodgkin's


24 1 lymphoma understand the significant short- and

2 long-term risks associated with chemotherapy and

3 radiation, which include secondary malignancies,

4 myelosuppression, organ dysfunction (cardiac,

5 pulmonary and endocrine), neuropsychological

6 effects, and degraded quality of life.

7 They know that the benefits will be

8 short-lived and that repeated and increasingly less

9 effective retreatments will be needed to control

10 the disease. Based on this, patients with

11 low-grade NHL often seek clinical trials as

12 front-line therapy, but they often find that these

13 trials are closed to previously untreated patients.

14 Single patient exemptions are also systematically

15 refused for these patients.

16 The reasons for this may be the widely

17 accepted belief that all cancer patients should

18 first receive the standard therapies and only when

19 these therapies fail should they look for a

20 clinical trial. It is illogical to apply this rule

21 to low-grade NHL patients for the following

22 reasons:

23 1. The approved therapies are not

24 curative.

25 2. Approved therapies have known and


25 1 serious short- and long-term side effects.

2 3. These therapies can cause permanent

3 damage, undermining the patient's ability to

4 benefit from emerging therapies, such as vaccines

5 and monoclonal antibodies.

6 4. Emerging therapies often attack

7 specific targets and are less toxic.

8 5. Standard therapies can be used later

9 if needed.

10 Many thousands of low-grade NHL patients

11 are diagnosed every year. The majority of these

12 patients, based on the survival statistics, should

13 be treated in clinical trials. Since these

14 patients cannot be absorbed by the available

15 clinical trials, they should be granted single

16 patient exemptions in order to access the most

17 promising treatments. However, as described above,

18 they are generally refused admission into studies

19 because they have not yet received all possible

20 standard therapies first.

21 It is urgent that the FDA, working with

22 activists and patients, develop policies to

23 facilitate expanded access and single patient INDs

24 while assuring that meaningful data is collected.

25 It is also urgent that incentives are developed to


26 1 assure that drug companies will be willing to

2 participate in expanded access and single patient

3 INDs.

4 Finally, since cancer is a

5 life-threatening disease, expanded access and

6 single patient INDs should be made available as

7 soon as a drug has been proven safe and has shown

8 efficacy, as was done with AIDS drugs over ten

9 years ago. Thank you.

10 Lurdes Queimado, M.D./Ph.D., Lymphoma

11 Advocate."

12 A copy of her statement is available at

13 the reception desk out there for those in the

14 audience who want to see it, and she does have

15 references cited.

16 The second letter was received late last

17 evening from Sally Cooper of NABCO.

18 "Dear ODAC Committee Members: Good

19 morning. I am the Director of Information Services

20 for the National Alliance of Breast Cancer

21 Organizations, a national nonprofit information and

22 education resource since 1986.

23 I personally have no financial interest in

24 any pharmaceutical, biotech, medical device, or

25 trial management company, but NABCO does receive


27 1 unrestricted educational grants from several

2 pharmaceutical companies.

3 In addition to my current position, I also

4 bring some perspective from 11 years of working in

5 the HIV/AIDS epidemic, often directly on issues of

6 early access to investigational agents.

7 In that capacity, I have worked with the

8 FDA, numerous companies and researchers on single

9 agent access, treatment INDs, and the design,

10 delivery and publicizing of a number of expanded

11 access programs for people living with HIV and

12 AIDS. I would like to thank you all for providing

13 us with this opportunity to speak and thank you as

14 well for taking the time and effort to initiate a

15 broad discussion about this confusing area.

16 I would like to start with two

17 observations.

18 One. Something that has always dogged

19 these discussions is a lack of data. We tend

20 towards anecdotes and seemingly common-sense

21 statements, but without data, no ethnographic or

22 detailed qualitative research about who is getting

23 early access and why, who chooses and who refuses

24 to go in a trial in the face of expanded access;

25 how many INDs are granted for what indications;


28 1 what useful data has been collected through

2 expanded access programs, et cetera.

3 The missing data is worrisome. It can be

4 problematic to develop policy without an

5 evidence-based understanding of what has been

6 happening. The solution may not work well, or

7 worse, it may result in unwanted ramifications that

8 no one was able to foresee without a better initial

9 understanding.

10 Thus, before any significant change in the

11 current policy is enacted, we would ask for some

12 quantitative and qualitative research to better

13 understand what is truly problematic in this arena,

14 and what is not.

15 Two. It is very important conceptually to

16 separate expanded access programs from single

17 patient compassionate use. For example, there is

18 little data but much concern that expanded access

19 may interfere with trial accrual. However, it is

20 inconceivable that the small number of individuals

21 getting compassionate use could seriously interfere

22 with accrual, especially in light of the relatively

23 small sized trials in advanced cancers.

24 One major difference is that expanded

25 access is a program. Single patient compassionate


29 1 use is not a program. It is simply a mechanism or

2 opportunity that companies, clinicians and patients

3 sometimes use. Whether and how much we want to

4 turn it into a process should be carefully thought

5 out, as real questions of flexibility may be

6 compromised.

7 When looking at single patient

8 compassionate use, several areas of concern stand

9 out.

10 One area is the possibility of causing

11 more harm than good. These are investigational

12 agents being offered to patients with advanced

13 disease who have run out of conventional treatment

14 options. Some argue what's the point since there

15 is little reason, honestly, to expect much benefit

16 in this setting? Doesn't the possibility of harm

17 outweigh any possible good? What is the good faith

18 in this?

19 In addition, how can we be sure that

20 patients really understand the possibility of harm

21 here? How good is the informed consent process

22 when the stakes are so high, and so little is known

23 about the compound? As noted, this situation may

24 be worsened by the existence of embargoed

25 information that would be useful for the clinician


30 1 and patient to know - although this is something

2 surely we can fix with confidentiality agreements

3 and the like.

4 Well, the folks who testified in December

5 answered these questions rather well, I think -

6 individuals with serious illness or rare diseases

7 going about their lives, hoping for the possibility

8 of extending their lives further, often having

9 already paid their dues in one or more clinical

10 trials - not exactly the picture of desperate,

11 ill-informed people believing in a miracle cure.

12 I think the FDA has widely kept this door

13 open in the face of extreme complexity of illness,

14 and recognizing an ethical need not to simply close

15 off all access. We do not know what may come down

16 the pike, we cannot anticipate what someone may

17 need access to, and rather than pretend to, this

18 mechanism was created to allow for a discussion

19 when the possibility arises that this may be a

20 source of treatment.

21 Single patient access is not a program,

22 but a negotiation because so much is not known

23 either about the drug or how it may work in an

24 individual patient. This discussion serves an

25 important purpose, as a sort of discovery phase in


31 1 which all players can decide whether it is worth

2 going forward or not.

3 This leads to another issue - equity.

4 Others have discussed this at length and it is

5 clearly already high on the FDA's list of concerns.

6 We also lack data about this, and I would caution

7 those who assume that it is solely the well

8 connected who succeed in this area.

9 Facing a terminal diagnosis can have a

10 profound energizing effect on families and

11 individuals, and a number of folks fight for early

12 access who would never have thought about doing

13 anything like this before. It can be a deep

14 educational and politicizing experience. But it is

15 clearly unfair how randomly compassionate use

16 occurs.

17 One solution calls for better public

18 education (including for clinicians) about the

19 existence and procedures of this mechanism.

20 However, increased public awareness will only ease

21 some but not much of the current inequity.

22 Compassionate use is a time-consuming,

23 negotiated process that few medical centers will be

24 able to offer. With our multi-tiered health care

25 system, this means that folks with excellent


32 1 insurance or resources may have this access, and

2 others with fewer resources probably will not.

3 Another approach to the problem of equity

4 is to recognize that right now, too much is being

5 asked of the compassionate use mechanism. Far too

6 often, it's the only early access option, and

7 filling in when expanded access programs should be

8 considered.

9 Equity issues can and should be earnestly

10 addressed through other early access mechanisms,

11 such as expanded access and parallel track

12 programs, administered through multiple venues such

13 as the VA and public hospital systems, with

14 national IRBs and shared staffing support, when the

15 nature of the Phase II data, drug supply, safety

16 and toxicity data and disease condition warrant

17 such distribution. These options have been used in

18 HIV, so we know they are possible. With many new

19 compounds in the pipeline, it's time to make a

20 broader social commitment to fair expanded access

21 programs when prudent and feasible.

22 Finally, one area that we can all improve

23 in is our communication with patients. It's time

24 to let patients know what's going on. The doctor

25 who fails to get the IRB paperwork in, the company


33 1 reluctant or unable to release drug, the FDA unsure

2 of how to figure out the safety/efficacy profile,

3 the community-based program overly excited by a

4 press release - we are all part of the problem when

5 we fail to tell patients our plans, our mistakes,

6 what we really can do and what we can't.

7 It is always much easier to hear the truth

8 and cope with it than get stonewalled. There are

9 real supply problems, real safety issues, serious

10 efficacy questions and always the real problem of

11 time and resources to get things done well.

12 The more information that flows, the more

13 we work together on building functional expanded

14 access - the less resonant all the media hype will

15 be. The recent 60 Minutes piece would have been

16 very different if the company in question had early

17 on held community meetings and made an effort to

18 address a natural and understandable phenomena;

19 folks interested in trying their drug had very

20 limited options otherwise.

21 Single patient compassionate access serves

22 as an important source of hope and sometimes

23 access. It's an imperfect, necessary bridge

24 between our urgently important but contradictory

25 twin social goals of developing effective therapies


34 1 and providing care for the individuals that we as a

2 society have failed to find answers for yet.

3 What I learned from the HIV epidemic was

4 that we can't simply choose one goal over the

5 other, but must face squarely the challenge of

6 trying to accomplish both. It's time as a society

7 to learn to be more realistic about what emerging

8 therapies can offer us, which in turn will enhance

9 the effectiveness of the informed consent process.

10 At the same time, we can also communicate

11 better, all the players, so that where possible

12 patients will be able to see and experience a

13 society that is committed to providing equitable

14 early access when prudent and possible. That

15 brings us full circle to hope, that very human of

16 emotions, which sustains all of us.

17 Thank you very much. Sally Cooper,

18 Director, NABCO Information Services."

19 DR. NERENSTONE: Thank you, Karen.

20 I would like to turn now to the Summary of

21 Regulatory and Industry Considerations.

22 Dr. Williams is going to lead the

23 discussion.

24 Single Patient Use of Non-Approved

25 Oncology Drugs and Biologics


35 1 Introduction

2 Summary of Regulatory and Industry Considerations

3 Grant Williams, M.D.

4 DR. WILLIAMS: Madam Chairman, Committee

5 Members, ladies and gentlemen: In the next 20

6 minutes I will summarize presentations made by

7 speakers from FDA, from the pharmaceutical industry

8 at our last session on treatment use of

9 investigational drugs.

10 [Slide.]

11 You will have to excuse the title. After

12 that last speaker, I still have treatment in there,

13 and unless we can come up with another name, I

14 guess it is going to stay there for now.

15 [Slide.]

16 First, I will review the regulatory

17 background that I presented for FDA, then,

18 summarize the points on single patient use of

19 investigational drugs made by Dr. Robert Spiegel

20 from Schering-Plough, and finally, I will summarize

21 the presentation on expanded access made by Dr.

22 Gerard Kennealey from Astra/Zeneca.

23 We are very appreciative to Dr. Spiegel

24 and Dr. Kennealey for providing such an instructive

25 and honest view of how treatment use of


36 1 investigational drugs affects the pharmaceutical

2 industry, and for providing us with ideas of how

3 this process might be improved.

4 [Slide.]

5 Again, the objectives for this meeting are

6 to educate the public on the issues surrounding the

7 treatment use of experimental cancer drugs and,

8 especially for this meeting, to get advice and

9 input of when it is appropriate for FDA to allow

10 experimental drugs to be used for treatment use of

11 individual cancer patients.

12 Note that FDA has only a partial role,

13 that is, defining the rough boundaries within which

14 treatment use is appropriate. From discussions we

15 heard from patients, discussions which were echoed

16 by a TV spot on 60 Minutes about compassionate use

17 a few weeks ago, it is clear there are other issues

18 that are very important to patients, such as when

19 should a company provide access to experimental

20 treatment and how should the drug be distributed,

21 so that patients are treated fairly.

22 We believe that these issues should be

23 addressed in a consensus conference in the near

24 future, a conference to include representatives

25 from the two main parties - the pharmaceutical


37 1 industry and cancer patients and their advocacy

2 groups.

3 We believe that the Food and Drug

4 Administration and the National Cancer Institute

5 can play important roles in facilitating this

6 dialogue. When everyone agrees upon a set of norms

7 for treatment use of experimental drugs, both

8 patients and industry will benefit.

9 So, there is the framework for today.

10 Today, we are asking when should FDA allow

11 treatment use of experimental drugs.

12 [Slide.]

13 First, I want to review a few definitions

14 that we talked about last time. All use of

15 experimental drugs is regulated by FDA under an

16 IND. An IND is an Investigational New Drug

17 application.

18 There are several individuals involved in

19 the process of an IND. First, there is the IND

20 sponsor. The sponsor is the individual company or

21 institution that assumes responsibility for

22 overseeing the study, for assuring that the

23 regulations are followed, and for reporting to FDA

24 on the progress of the study. The sponsor may or

25 may not be the manufacturer of the drug.


38 1 Next, there is the investigator. The

2 investigator is that individual that actually

3 performs the trial or administers the drug, and at

4 times, and quite often in these circumstances, at

5 least with single patient INDs, the investigator

6 and the sponsor are the same person.

7 [Slide.]

8 The usual purpose of an IND is to allow

9 for clinical investigations to determine whether a

10 drug is safe and effective. If findings from the

11 studies are favorable, the sponsor will then submit

12 all of the data from these investigations to the

13 FDA to determine whether the drug an be approved

14 for marketing. In this way, the drug becomes

15 widely available to the American public.

16 The FDA strongly endorses participation in

17 clinical trials because it is in the best interest

18 of the American public. It is in their best

19 interest to determine whether a drug is safe and

20 effective. Individual patients also benefit by

21 participating in clinical trials.

22 The best treatments available are selected

23 for these trials. However, there are times when it

24 may be appropriate to make an investigational drug

25 available primarily for treatment rather than for


39 1 the usual purpose of investigating safety and

2 effectiveness.

3 [Slide.]

4 The terminology surrounding the treatment

5 use of experimental drugs can be confusing because

6 the regulations do not explicitly describe all of

7 the practices. Different terms are frequently used

8 for the same practices. Treatment use of

9 experimental drugs may be divided into two main

10 groups - single patient treatment use and expanded

11 access treatment use, but these are not terms or

12 programs described in the regulations. They are

13 just useful descriptive terms.

14 Expanded access refers to multiple

15 patients being treated under a single protocol.

16 Single patient use, individual protocols or

17 treatment plans are drawn up for each patient.

18 [Slide.]

19 Historically, there have been several

20 different methods for providing expanded access.

21 In the cancer area, since the 1970s, NCI has worked

22 with the FDA to provide investigational drug under

23 a mechanism called Group C. This mechanism was

24 only for drugs provided by NCI.

25 In 1987, FDA developed an official program


40 1 described in the regulations called the treatment

2 IND. That was for patients for any

3 life-threatening disease, not just for cancer.

4 Both of these mechanisms, Group C and treatment

5 IND, are formal mechanisms for drugs that are very

6 advanced in their development, usually within

7 months of being marketed.

8 Over the years, expanded access protocols

9 have also been approved for promising drugs under

10 industry sponsorship, and not at the stage of

11 development that qualifies for a treatment IND.

12 Later, when I describe Dr. Kennealey's

13 presentation, I will discuss one of those programs.

14 [Slide.]

15 Now, I will describe single patient use.

16 Basically, with single patient use, the sponsor or

17 physician requests to use drug. The drug supplier

18 decides whether to offer drug for treatment use,

19 the sponsor proposes a plan or a protocol, and then

20 FDA decides whether to allow it.

21 There are two mechanisms for handling

22 single patient use. In the first mechanism, the

23 single patient IND, a new sponsor files a separate

24 IND, and that sponsor often is an investigator.

25 In the second mechanism, called the single


41 1 patient use exception, there is already an existing

2 IND, there is an existing sponsor, and an

3 investigational protocol. With single patient

4 exception mechanism, a patient who is ineligible

5 for investigational protocol is treated under a

6 plan that usually is a slight modification of the

7 existing protocol. The same IND and the same

8 sponsor are used, and this is a more efficient

9 mechanism for single patient treatment.

10 Obviously, the single patient mechanism of

11 providing drug is the most laborious for all

12 involved - for the patient, for the physician, the

13 company, and for the FDA. However, this approach

14 does provide the greatest individual oversight, and

15 so it is appropriate for areas where difficult

16 individual judgments must be made.

17 [Slide.]

18 So, what are the legal requirements?

19 Legal requirements for single patient use are

20 basically the same as those for any IND. There

21 must be a drug manufacturer that will supply the

22 drug, there must be a sponsor that reports to FDA,

23 there must be an adequately trained investigator,

24 there must be informed consent, and there must be

25 IRB approval. Then, there must be concurrence by


42 1 FDA that there is sufficient evidence supporting

2 the drug's efficacy and safety to allow treatment

3 in that individual patient.

4 [Slide.]

5 The following are items that FDA considers

6 in evaluating treatment use of experimental drugs:

7 Evidence of drug activity and toxicity, other

8 treatment options for the patient's cancer, whether

9 the sponsor is conducting trials needed for

10 marketing drug, and whether the proposed protocol

11 is likely to interfere with clinical studies needed

12 to approve whether the drug is safe and effective.

13 In the next slide, I would like to expand

14 on the first two points because these points form

15 the basis for today's FDA questions to the

16 committee.

17 [Slide.]

18 The first important question is what

19 evidence do we have about the drug's effect in

20 people. One aspect of this question is to consider

21 the stage of drug development, do we have data from

22 Phase I, Phase II, Phase III studies, and then what

23 do the data show, for instance, what is the

24 response rate and what are the toxicities.

25 Second, is there effective therapy for the


43 1 patient's cancer, and if so, how effective is it.

2 For diseases where there is no standard therapy or

3 where a standard therapy is not satisfactory, FDA

4 has usually permitted single patient use if the

5 data suggest that the treatment is relatively safe.

6 Evaluating these points requires clinical

7 judgment, and we look forward to the committee's

8 discussion to assist us in making these judgments.

9 [Slide.]

10 At our meeting in December, we heard an

11 excellent overview of industry concerns about

12 treatment use of experimental drugs from two

13 physicians who work for pharmaceutical firms - Dr.

14 Robert Spiegel from Schering-Plough and Dr. Gerard

15 Kennealey from Astra/Zeneca Pharmaceuticals. I

16 want to briefly discuss points they made.

17 [Slide.]

18 Here are some of the concerns about

19 treatment use of experimental drugs. First, there

20 may be a limited drug supply early in drug

21 development especially with some kinds of drugs.

22 Drugs from these batches are scarce and are very

23 expensive. Then, at some point in development,

24 companies must decide whether the drug is showing

25 enough promise to justify large Phase III studies


44 1 and then to convert from small batch manufacturing

2 to large commercial manufacturing.

3 Before a company converts to commercial

4 production, it may be unreasonable for the oncology

5 community to expect them to provide large amount of

6 drug for treatment use.

7 Next, there is the concern over

8 competition between expanded access programs and

9 the regulatory programs that will lead to drug

10 approval. Competition can be either for patients

11 entering trials or for internal company resources.

12 Most expanded access programs exclude patients who

13 are eligible for their Phase III regulatory trials

14 to minimize this first concern.

15 Competition for company resources may

16 occur at multiple levels, for example, in the

17 packaging and shipping departments. The process of

18 individualized packing and shipping of drug for

19 single patient use on an emergent basis can be very

20 disruptive to departments that are organized to

21 pack and ship drug in a scheduled manner for

22 clinical trials.

23 Another worry is that use in a less

24 controlled setting will lead to more adverse

25 reactions, raising potential safety concerns.


45 1 Lastly, industry seems to learn little

2 about drug from single patient use. It is possible

3 that something may be learned from expanded

4 protocols, however.

5 [Slide.]

6 Next, Dr. Spiegel shared with us the

7 complexity of the process of single patient use

8 from the daily working experience in a company.

9 First, there is the initial contact where the

10 family or doctor tries to find the right person in

11 the company to begin the dialogue, sometimes

12 involving an extensive process of telephone tag.

13 Ultimately, the project physician talks to

14 the patient's oncologist. Next, the patient

15 synopsis is submitted, FDA paperwork is submitted,

16 and a protocol must be approved by FDA and by an

17 IRB. Then, there are internal approval steps and

18 the drug must be packaged and shipped.

19 [Slide.]

20 In addition, there are follow-up

21 responsibilities including collection of adverse

22 reaction reports, summarizing these adverse reports

23 at intervals for FDA annual reports, and retrieving

24 unused drug. Also, if a patient appears to be

25 benefiting from drug, the company may need to


46 1 supply drug to the patients for a prolonged period

2 of time.

3 So, I think we can see that committing to

4 a program of supplying drug on a patient-by-patient

5 basis is no small step for a company to consider.

6 It could mean commitment of considerable resources.

7 [Slide.]

8 Dr. Spiegel suggested that we consider

9 easing the burden of reporting for patients

10 receiving drug under treatment use by only

11 requiring collection of data from unexpected or

12 serious adverse events. In reply, I think this is

13 something that we could consider at times, but it

14 would be on a case-by-case basis.

15 [Slide.]

16 The next industry speaker, Dr. Kennealey,

17 addressed expanded access, that is, a procedure

18 that allows multiple patients to be given

19 experimental drug according to a carefully defined

20 protocol.

21 As suggested by Dr. Kennealey, here are

22 the conditions that may affect whether one needs to

23 consider offering an expanded access protocol.

24 First, when there are early studies in humans

25 showing promising results. Second, in those common


47 1 tumors where patients regularly run out of

2 treatment options, and finally, realistically, in

3 circumstances when one expects many requests for

4 treatment use will come in, such as for drugs that

5 are widely discussed in the media.

6 [Slide.]

7 Dr. Kennealey described experience with an

8 expanded access program at Astra/Zeneca for a new

9 drug to treat lung cancer, and he offered this as

10 an example of a system that seemed to have worked

11 fairly well.

12 The first step was to make a commitment, a

13 commitment to the process and to dedicate resources

14 needed to make it succeed. A team dedicated to the

15 project was created. A contract research

16 organization was hired to handle day-to-day

17 matters, such as collecting forms, getting IRB

18 approval, and processing data.

19 There was careful networking with

20 important parties, such as FDA and advocacy groups.

21 A single informed consent was carefully developed,

22 and an important feature was the determination

23 there would be firm rules about entry with no

24 exceptions made on the basis of persistence or

25 political position.


48 1 In order to prevent interference in the

2 process of getting the drug to market, patients

3 were excluded who were eligible for clinical trials

4 that would support FDA approval. Eligibility was

5 restricted to the disease where the most promising

6 activity was shown.

7 Next, the data collection requirements had

8 to be addressed. In this case, because there were

9 only 300 patients who had been treated with the

10 drug in any trials, the company decided to collect

11 fairly detailed safety data in the expanded access

12 program.

13 One issue that was not a problem in this

14 particular program was drug shortage, however, this

15 is an important issue that will often need to be

16 addressed.

17 So, these were the problems addressed in

18 the Astra/Zeneca expanded access experience.

19 [Slide.]

20 One of the questions Dr. Kennealey asked

21 FDA to address was how these data from expanded

22 access protocols might be used when the company

23 submits a new drug application and whether these

24 data could decrease the time to NDA submission.

25 Of course, specifics vary from protocol to


49 1 protocol, but these are some of the generalizations

2 I would suggest.

3 First, the most important data to collect

4 are clearly those on adverse reactions, especially

5 serious events and unexpected new toxicities.

6 Other data are probably seldom very useful in this

7 setting, that is, with a single-arm study where

8 conditions vary widely from patient to patient, and

9 where physicians are less experienced at collecting

10 data and may not have the same support staff for

11 assuring high quality data.

12 Finally, it does not seem likely that

13 expanded access will speed NDA submission and

14 approval for cancer drugs because usually the rate

15 limiting step in this process is collection of data

16 on effectiveness, data that will usually come from

17 clinical trials. To speed this process, we need

18 more patients in clinical trials.

19 [Slide.]

20 However, sometimes it might be reasonable

21 to try to answer some limited questions in expanded

22 access protocols. For instance, sometimes

23 additional populations are treated in expanded

24 access that are not studied in clinical trials, and

25 we can evaluate the frequency of adverse reactions


50 1 in this population versus what we have in the

2 clinical trial, or we might consider doing some

3 more simple randomized studies in this setting,

4 comparing two doses of investigational drug where

5 patients could be assured they were getting drug,

6 and evaluating very simple safety or efficacy

7 endpoints, such as survival.

8 So, that is a summary of the regulatory

9 overview and of the two industry talks that we had

10 from Dr. Spiegel and Dr. Kennealey, and I don't

11 know if we are taking questions now.

12 DR. NERENSTONE: I think we have time for

13 questions from the committee for Dr. Williams.

14 [No response.]

15 DR. NERENSTONE: Thank you very much.

16 Dr. Taylor will give us a summary of the

17 ethical considerations.

18 Summary of Ethical Considerations

19 Sarah Taylor, M.D.

20 DR. TAYLOR: Good morning. My first

21 statement will be a disclaimer. I am not a medical

22 ethicist, I am a medical oncologist and a

23 palliative care physician dealing a lot with

24 end-of-life issues, so I do deal a lot with ethics.

25 What I was asked to do was to summarize


51 1 what was presented at our last meeting on ethical

2 issues. I have added a few of my own comments

3 because I come to this as a physician, as a patient

4 advocate, and as a family member. My family has

5 had cancer, as well. So, I think you will have to

6 accept a few of my own comments, as well as this

7 summary.

8 The first speaker was Dr. Sugarman, and he

9 chose to give us a background or a framework for

10 ethics and try to teach us the language of ethics

11 because there are a lot of different words that

12 aren't used in every-day language.

13 His point was that the off-study use of

14 these experimental drugs was really kind of

15 in-between medical ethics and research ethics. In

16 my own mind, I think research ethics should be

17 basically the same as medical ethics and in many

18 ways they are similar, and we will talk a little

19 bit about that.

20 If we look at the history of some of

21 medical ethics, which is the first intersection

22 that we have, it goes back, at least the first

23 written word, is with Hippocrates, and which

24 Hippocrates is telling us that we are to do good as

25 physicians.


52 1 The Scottish took this a little further in

2 the centuries after that, and they made it a moral

3 obligation that physicians were to be the trustee

4 for the patient and were to hold the good of the

5 patient in their hands and to do good for the

6 patient.

7 As time went on, life got more complex.

8 We got more machines like dialysis machines. We

9 got more artificial hearts. We got a lot of

10 different complex things, and the idea of doing

11 good for the patient wasn't as easy to define. So,

12 other ways of looking at medical ethics were

13 developed, talked about, and taught.

14 One of these which he presented was a

15 four-principle look at medical ethics, and he gave

16 four principles that are in this look. The first

17 is autonomy, the second beneficence, the third

18 maleficence, and the fourth is justice.

19 If you look at the first, which is

20 autonomy, that is our patient right. That is our

21 right to say I don't want treatment. That is our

22 right to say you are not to touch me or give me a

23 treatment without my permission. In a sense, it is

24 a type of informed consent.

25 The second principle, which is


53 1 beneficence, many people feel should be and should

2 remain the first principle, and that is to do good,

3 and that is what we are here for is to help the

4 patient and to do good.

5 Sometimes that principle in itself can

6 conflict with that autonomy because autonomy means

7 that I define for myself what is good for me, and

8 when we look at beneficence, the physician is

9 having to look at me and try to decide for me what

10 is good, and so there may be conflict within this

11 which leads us to other ethical issues.

12 Then, if we look at non-maleficence, that

13 is basically what patients expect of us. I think

14 they are very shocked to think that this would even

15 have to be a rule, and that is that we will do no

16 harm. Sometimes that is very complex when you are

17 dealing with seriously ill patients, when you are

18 dealing with very toxic therapies, bone marrow

19 transplants, chemotherapies, and even some of the

20 genetic therapies that can cause death.

21 Last is justice. Justice is a way of

22 looking at equal access. I think this has been

23 identified in today's talk as a major problem in

24 this off-study use of investigational agents.

25 So, looking at all of those as our way of


54 1 looking at medical ethics, we go on to look at what

2 is research ethics. Unfortunately, instead of

3 those researchers using their medical ethics, our

4 research ethics come out of a lot of scandal.

5 Unfortunately, there were lots of bad

6 things happened, not just in Nazi Germany, but also

7 in the good old United States in which patients at

8 Tuskegee and elderly patients and retarded patients

9 have had research done on them without the

10 appropriate ethical informed consent.

11 So, out of this we have come upon various

12 regulatory agencies within our government and

13 within the FDA, we have come up with various rules

14 at looking at research ethics.

15 One of those summaries has come up with

16 that we will have again three principles, the first

17 being respect for the patient or shall we call it

18 autonomy, the second being beneficence, we are

19 going to do good with the corollary being we won't

20 do bad, and the third being that of justice or

21 looking out for equal access for all patients.

22 Again, our world has changed, and as

23 science chances, society has changed. Whereas,

24 there was a lot of uproar and upset and feeling

25 that physicians should have protected us from the


55 1 thalidomide babies and protected us from being

2 injected with cancer cells on a study without

3 informed consent, more and more you see in society

4 that the patients are demanding more autonomy and

5 in that asking for more access to these new drugs

6 before it is known whether they are effective or

7 not.

8 Because of that, I think that is why we

9 are having more of these conferences because life

10 is just plain more complex.

11 I think we are still dealing, and what we

12 have to remember is we are still dealing with

13 vulnerable populations. The vulnerable population

14 is the people that are sick and their families, and

15 they are fighting for their lives, and it is the

16 most vulnerable position we can be in. We are more

17 desperate in those times, more unable to listen and

18 sometimes to understand the complexities of the

19 treatments we are being offered. I think that puts

20 the burden on the physician in terms of again

21 informed consent and communication.

22 The other aspect that has been alluded to

23 here, that is defined as therapeutic misconception,

24 and I find this a lot in my patient population -

25 well, let's take this experimental treatment, it


56 1 must work. If it's experimental, it must be great.

2 Unfortunately, as a former Phase I

3 researcher, I know that when I wrote those Phase I

4 trials, the objectives of my trials were

5 scientific. I would be wonderfully happy if they

6 also were therapeutic and if my patient responded,

7 but the objectives of the trial were not that of

8 therapy. The objectives of the trial were

9 obtaining a baseline of data about that particular

10 agent, so that I could go on and learn further

11 information about it.

12 I think that therapeutic misconception is

13 not just a misconception for patients. As you can

14 see by the way we use the terminology, that we are

15 going to use these experimental drugs as

16 treatments. We don't know that they are treatments

17 until they are effective.

18 I think that what these things hopefully

19 emphasize, the vulnerability and the therapeutic

20 misconception is that we have to do a lot on that

21 autonomy side and providing informed consent. When

22 you are dealing with folks who are sick, that can

23 be very difficult.

24 Dr. Linden also presented at that meeting

25 in December, and she gave a very nice summary of


57 1 her work with a group of activists and to obtaining

2 expanded access to the drug Herceptin. It was a

3 nice history of that, I am not going to go through

4 that.

5 She made some other important points, I

6 think. Some have been brought up earlier today,

7 and I won't go into a whole lot, but we don't have

8 data in terms of how many people apply, who gets

9 it, why do they get it, and why don't others get

10 it.

11 I know for a fact from my practice that

12 because I used expanded access protocols, I get a

13 lot of patients whose docs didn't know or wouldn't

14 take the time to go through the process to get an

15 expanded access protocol or to call to get offset

16 use of a drug, so I think that is important that we

17 know the basics, that we know some of the

18 statistics. I am not sure that I know whether we

19 can get all of them, because I do know, it was on

20 the 60 Minute program here, people who know people

21 get drugs in other than the usual fashion.

22 I think that white paper could then be

23 used as she suggested, to have a conference in

24 which we might try to look at ways to make access

25 easier, to make our systems and our policies


58 1 easier, and most importantly, we need to make these

2 systems and policies available in terms of

3 education of the public that they are there.

4 I know that frequently when I call

5 referring physicians and tell them that these drugs

6 are available if they will just make the call or

7 sign the papers, they are very surprised, so it

8 isn't just a matter of educating parents, it is a

9 matter of educating the public as to what the FDA

10 and the NCI and the drug companies have all made

11 available to us if we will take the time and

12 trouble to do that.

13 Thank you.

14 DR. NERENSTONE: Are there any questions

15 from the Committee?

16 [No response.]

17 DR. NERENSTONE: Thank you.

18 Dr. Pelusi will then address the

19 perspective from the patient advocacy community.

20 Perspective from the Patient Advocacy Community

21 Jody Pelusi, F.N.P., Ph.D.

22 DR. PELUSI: Good morning and thank you,

23 Madam Chairman, for allowing me to speak.

24 I come to you today as the Consumer Rep on

25 the ODAC Committee, and I would like to give you a


59 1 little bit of my background because I think that

2 becomes important in terms of how I got a lot of

3 this information and again what I see in my

4 every-day practice.

5 I am an oncology nurse practitioner with

6 more than 25 years' experience in oncology, mostly

7 in rural settings and in settings with people who

8 are dubbed underserved and minority populations.

9 I have worked with clinical trials in

10 terms of community clinical trials, and I have also

11 been the family member of numerous family people

12 who have had cancer and have gone through this

13 process as well with them.

14 [Slide.]

15 I want to thank all the individuals,

16 organizations, and agencies which shared a lot of

17 thoughts with me and their experiences regarding

18 this issue. Over the last couple months I have

19 been trying to get a lot of input from people to

20 say what do you think about this, because as a

21 consumer rep, we want to represent what the true

22 feelings are in the community.

23 [Slide.]

24 What came to mind time and time again and

25 what came up, not only in the presentations that


60 1 were given last time by community members, but also

2 this time, as well as all of my interactions, is

3 that we all have the same goal. We have the same

4 goal that all individuals must have equal access to

5 culturally competent, quality cancer care

6 throughout the disease trajectory, and what that

7 means is it includes clinical trials at all phases

8 of the disease process, and it is not just clinical

9 trials in terms of treatment, but also in cancer

10 control and in prevention.

11 [Slide.]

12 When we look at what was said last time in

13 December, and we look at what was said today, we

14 hear many different world views, and I just want to

15 go through them and recap what are the themes that

16 we hear, because it makes a difference when we have

17 to decide where do we need to go with this.

18 What we heard from community is that they

19 wanted the truth about outcome of their disease,

20 and they wanted to know what is known about the new

21 drugs that may be available to them. We need the

22 truth.

23 People said they did not want false hope

24 from the media or the health care system, but

25 realistic guidance. People stated that they wanted


61 1 to know how to make the process of clinical trials

2 and the single patient use program more

3 user-friendly. They wanted to be able to do all

4 that they could individually as a patient and as a

5 family member.

6 [Slide.]

7 We also heard that they wanted to have a

8 choice, to take what may be considered a risk,

9 given as much information that was available in

10 relation to the new treatment. People wanted to

11 learn about cancer and treatment options. People

12 want to contribute to society as a whole by being

13 part of the process, and we heard that again today.

14 They want to have a say in the process, and they

15 want the process to be fair and ethical.

16 [Slide.]

17 So, when you put all that together and you

18 listen and you listen, clinical trials still are

19 believed to be the very best avenue of obtaining

20 safe and effective treatment. The question becomes

21 do we need more programs to look at single patient

22 use or do we go back before that and say why aren't

23 more people in clinical trials.

24 When I talked to a lot of individuals,

25 what I heard were the stories about access into


62 1 clinical trials, and I think that that is where I

2 want to spend some time this morning sharing with

3 you things that we really need to look at because

4 people really do want to be in clinical trials.

5 People do realize that there is a very, very low

6 rate of participation in clinical trials.

7 People also believe that the single

8 patient use is necessary in cancer care, but not in

9 all cases, and that there should be criteria. So,

10 let's take a look at the whole issue in terms of

11 clinical trials and how that really impacts this

12 whole issue of should or if we decide about single

13 patient use, things that we really need to

14 consider.

15 [Slide.]

16 It seems to be that we really need to look

17 at the system of clinical trials in the process, we

18 need to look at the environment in terms of media,

19 we need to look at health care providers, we need

20 to look at patients and families and communities as

21 a whole.

22 [Slide.]

23 In terms of the system, why aren't people

24 in clinical trials? I can tell you from a

25 community person, from a community nurse, this is


63 1 very hard because there is delays in the referral

2 process that negates someone's ability to be

3 offered a clinical trial.

4 With the health care system the way it is

5 set up, with the HMOs, with the plans that are out

6 there, many times people wait two and three months

7 to get referred to even medical oncology. Many

8 times that is past the deadline, if you will, in

9 terms of how long out you can be before you can be

10 eligible for a trial.

11 I have heard time and time again from many

12 of the research centers we are sitting there

13 waiting, we want to see these patients, we are

14 waiting for approval.

15 Now, referrals sometimes cannot

16 necessarily be so convenient. I can tell you in a

17 small area, we have four institutions very capable

18 of doing research, they do it all the time, and why

19 are patients being referred two and three hours

20 away to different settings, and it is based on

21 contracts.

22 Many of our patient who are day workers

23 cannot take off work to drive two and three hours

24 to get the consult to get in the trial, and then on

25 a routine basis, take off time to go down to get


64 1 the clinical trial someplace else when it is

2 available right in their own hometown.

3 The other issue is when are we available,

4 if you will, to give treatments. Many of the

5 patients I work with, I do evening hours, we do

6 weekend hours because our day workers are migrant

7 farm workers, are Native American patients can only

8 come at certain times, and if we are not open, they

9 are not even going to take the treatment, so we

10 really have to look at the process in terms of how

11 do we get and treat patients in a very ethical way

12 in terms of are we really accessible to them.

13 The referral process may not always be

14 available. Maybe what many people don't realize is

15 when we look at the Indian Health System, there is

16 a whole group of people who don't even have access

17 to referral services.

18 As you know, the IHS is funded by the

19 Federal Government. Congress decides how much they

20 are going to get. On a regular basis, the last

21 five years, they have been 60 percent funded. That

22 means 40 percent underfunded.

23 So, if we don't have oncology services

24 within the Indian Health System, that means you

25 have to refer out. If you only have X number of


65 1 dollars for referrals, how does that referral get

2 made? Who makes that decision?

3 We have what we call kind of a life and

4 limb committee that meets on a weekly basis, who

5 gets those dollars and who doesn't.

6 What is also interesting is you only have

7 and are eligible for referral services if your

8 tribe is in the service unit where the services are

9 being offered, so if you are from Oklahoma and you

10 happen to live in Phoenix, sure, you can come and

11 get all the direct services you want from the

12 medical center there, Indian Medical Center, but if

13 you have to be referred out, you are not eligible

14 for referral services.

15 So, again, when we look at a population

16 such as Native Americans, and you look to say,

17 sure, they have the lowest incidence of cancer,

18 they also have the highest mortality. When you say

19 who is the most under-represented in clinical

20 trials, it is our Native American population. So,

21 again, it is not that people don't want treatment

22 and don't want to be in trials, it's the process

23 itself.

24 Then, we look at our uninsured. Many

25 times they are not considered for trial because


66 1 there is a perception out there that there will be

2 a lack of compliance. They don't have insurance,

3 they don't have the money that may be required to

4 meet all the requirements in a clinical trial.

5 [Slide.]

6 In the system itself, the minority and

7 underserved population, there truly is a disconnect

8 between research and the community. Language

9 barriers, world view barriers, previous history

10 regarding clinical trials, and the time and the

11 resource barriers in making the efforts to get to

12 those communities.

13 I think that we have to look very closely

14 at this, and so does industry. When we start to

15 look at the development of clinical trials, where

16 is the community voice in the development of that?

17 If you wonder why people have a hard time with

18 informed consents, and you wonder why can't they

19 come on this particular regime, have we looked at

20 the true day-to-day issues?

21 If we had community members actually

22 helping us design the trials, we are going to have

23 better buy-in. You are going to see people

24 actually talk in their communities about this. Let

25 me give you an example.


67 1 I was recently approached by an elders

2 group. The elders group had been asked--they are a

3 group of elderly Native Americans--to look at a

4 clinical trial. It was a prevention trial for

5 prostate cancer.

6 They were handed, literally handed the

7 trial and said can you look over this. That was

8 their introduction of here, we want you to

9 participate. They came to us, which we are not

10 those particular individuals' health care

11 providers, because we were an Indian System.

12 What they asked of us, "Is this a good

13 thing or is this a bad thing?" You know, we have

14 kind of been used in the past. We felt

15 uncomfortable with how it was presented to us.

16 What they were asking is we need more education,

17 how do we make good choices about what is out there

18 and about should we partner or not with university

19 settings.

20 So, it is not that people aren't

21 interested, it is how we approach. So, again,

22 where is this in the very beginning of clinical

23 trials?

24 [Slide.]

25 When we look at the media, I can tell you


68 1 every person I talked to made a comment about the

2 media, and they made it in a comment of saying we

3 really need to know what the reality is, what are

4 truly the issues, and not sensationalism.

5 But the other thing that came up time and

6 time again is that many times in the media, what we

7 are seeing is that community is really versing, if

8 you will, either the health care system or, you

9 know, it's the FDA against the community, when, in

10 reality, this is all of us working together for an

11 outcome of better cancer treatments.

12 So, the question is, is why is that

13 allowed to happen and how again do we partner

14 collectively to address the issue that we are all

15 trying to get to. We cannot be at ends with each

16 other, and we have to really look at that in terms

17 of how do you move forward, and with media having

18 such great access, why not use it to the best of

19 the ability when we talk about education. We can

20 use that medium, if you will, to provide good

21 education about what really exists.

22 [Slide.]

23 When we look at health care providers and

24 health care teams, as was mentioned this morning,

25 we all have to look at each one of us and say what


69 1 can we do better. Do we truly articulate the

2 disease process? At the time of diagnosis, all we

3 hear is the word "cancer," but do we really

4 understand as time goes by what is going on in

5 terms of disease process, and do we plan for the

6 future.

7 The question is, is why do we wait until

8 the last minute to say, oh, we need this or we need

9 that? There are very few times when we really

10 don't understand that disease trajectory. We have

11 a pretty good idea from the get-go where are we

12 going with this disease.

13 If we need time to look at single patient

14 use, we have that time. We also have time to

15 really talk about quality palliative care and

16 end-of-life care. Many patients have been treated,

17 treated, treated, and then we say there is nothing

18 else to give you unless it's an experimental drug.

19 The question is, is there is stuff to give you, and

20 the problem is, is people don't understand that

21 there is excellent palliative care out there, and

22 that is treatment, if you will, for that stage of

23 the disease process.

24 Do we develop a plan with the patient and

25 family which demonstrates our continued commitment


70 1 to care? My question to all of the providers in

2 the room, and I have to ask myself when I see new

3 patients, is do I just give a treatment plan that

4 says we are going to give you this drug, this many

5 times, and how often we are going to give it, or do

6 we really say how are we going to get you through

7 this disease, and it is not just the treatment, it

8 is everything else that goes in.

9 We need treatment plans that are

10 all-inclusive, if you will, of going through the

11 process, not just one aspect.

12 [Slide.]

13 The other question that we have to ask

14 ourselves as providers, if we fail the first-line

15 treatments, do we consider second-line treatment

16 part of clinical trials, how are we determining

17 these outcomes, and that was brought up more and

18 more times to the researchers and to the industry,

19 do we develop from the get-go an arm that looks at

20 those who do not qualify, those patients who may be

21 advanced stage, who have already failed.

22 I think that has already been mentioned by

23 some of the suggestions, is do we go ahead and

24 already set that criteria upfront, so that there

25 are some guidelines, if you will, or some outcomes


71 1 of knowing what are the outcomes in patients who

2 are already advanced or who are different than

3 those who are typically in the clinical trials.

4 Do we look at the system setting up

5 studies that would already have built in manpower

6 for this or do we need to look at something more

7 globally in terms of a 1-800 number to help screen

8 calls?

9 When that 60 Minutes program ran, one of

10 the clinic managers called me and said to me I had

11 to bring in another nurse just to man the phones

12 because the phone calls were coming in to their

13 clinic was why didn't I know about this research,

14 why haven't you offered it to me.

15 So, she had to literally bring in more

16 manpower when indeed, in fact, is there a 1-800

17 number, so that individuals, physicians can call

18 and say what is available in terms of expanded

19 access, and that that system is really funded by

20 all versus each company having to do it on their

21 own.

22 Is there screenings that can be set up for

23 such a call center, if you will, to see, indeed,

24 can they move forward to the next step. Again,

25 what I think we have heard, even today, is many


72 1 times we get bogged down, if you will, because

2 everybody is doing it individually and it is not

3 being done collectively.

4 Also, in terms of our rural health

5 providers, and also in our urban settings, maybe we

6 are not educated enough in terms of clinical

7 trials, expanded access, and single patient use.

8 Again, what efforts do we need to make to make sure

9 we all understand, just as Dr. Taylor said, what

10 really is available out there.

11 Many rural people, especially providers,

12 don't have the time nor the resources to really

13 pursue this process. They may not have the

14 experience to do it either, so the question is an

15 IRB, that doesn't necessarily have to be in one

16 particular place, is there something global that

17 can be done for certain aspects of clinical trials,

18 and I think there is.

19 When we look at patients and families, I

20 think we really have to look at the whole issue of

21 perceptions, knowledge, beliefs, and values, what

22 are definitions of health and illness, and how does

23 that impact the process.

24 We have talked before here about quality

25 of life and how that goes into many of our studies,


73 1 and we have yet to see that that really is a

2 criteria for studies - do we need to begin to look

3 at that.

4 The informed consent. Many people have

5 talked about autonomy today and that that is the

6 reason for informed consent, that that person makes

7 the decision. I will challenge you to say that

8 with many people and many people who are coming to

9 this country, it is not an autonomous decision, it

10 is a family decision, and our informed consents are

11 not set up that way.

12 I can tell you that where I work, it is a

13 family decision. Family members all want to sign

14 the form, and it usually isn't the patient who

15 makes the final decision, it is a consensus

16 decision, and we are going to see more and more

17 people looking at that.

18 So, we are going to have to look at that,

19 as well, in terms of informed consent. Many

20 patients and families want to be involved in the

21 process, and again, the challenge is when do we

22 involve them.

23 Many families--and we heard it again

24 today--are responsible for coordinating the care

25 and many times without training or guidance. That


74 1 is why people are so passionate about saying I want

2 to do everything I can because they want to make

3 sure they do the very best.

4 None of us can fault anybody for that, but

5 where is the guidance and where is the training.

6 [Slide.]

7 Single patient use. After talking to a

8 lot of people, a lot of agencies, a lot of groups,

9 this is what I heard in terms of general consensus.

10 There needs to be single patient use available for

11 patients who may not have access to routine

12 clinical trials or special circumstantial issues

13 exist.

14 Again, there are people who could be in

15 clinical trials, but cannot get through the process

16 to get to them. However, there needs to be a

17 single clearinghouse where one can go for

18 information about availability and process.

19 [Slide.]

20 What happens--and I have asked this

21 question--what happens when there is standard

22 curable therapy available? People said in their

23 minds the only reason to use single use would be if

24 there was something very specific to an ethical,

25 religious, or circumstantial reason that they could


75 1 not undergo such therapies.

2 [Slide.]

3 When no standard therapy exists and all

4 previous treatments have failed, this could be

5 considered for single patient use, but all other

6 options need to be explored, and that includes

7 palliative care measures. They need good

8 education, and that is what they are saying,

9 sometimes I don't realize I have anything else or

10 that I don't have to say I have to do something,

11 and that they don't have to feel guilty about not

12 doing something.

13 Trials initially have set criteria for

14 those individuals. We really need to look at who

15 really gets these, what is their performance

16 status, are they even able to undergo some of these

17 new therapies, and what and when should

18 interventions be started, and what and when should

19 they be stopped.

20 Many people still feel that when you start

21 something, you have got to keep going, and there

22 are many indications when then is when we do more

23 harm.

24 We also heard again that nobody wants to

25 interfere with the clinical trials process.


76 1 [Slide.]

2 What about standard therapy when standard

3 therapy provides substantial prolongation, but not

4 curative? People still felt, the majority of

5 people felt that standard therapy really should be

6 utilized, but what needed to be considered is

7 perhaps a cohort to include in that next phase of

8 if indeed that drug was approved and felt to be

9 safe, can we go back and use that group of patients

10 to say they were treated with standard therapy, it

11 wasn't curative, here we are now, can we use it in

12 them.

13 [Slide.]

14 So, what we really need and what was

15 really said is we need to address the barriers to

16 the systems of clinical trials itself, the access

17 to the clinical care, the timeliness to referrals,

18 the support of families and providers for this

19 process, more organized approach if we are going to

20 use single use, collaborations with community,

21 media, health care providers, and research, more

22 attention to, if you will, informed consent

23 process, so it is reflective of all communities,

24 and to look at the same in terms of the IRB

25 process.


77 1 [Slide.]

2 Dr. Gil Friedell is somebody who I highly

3 respect. He has done more for the Appalachian poor

4 than anybody else I know, and he always says this

5 at every ICC meeting, Intercultural Cancer Council

6 meeting. He says the issues as well as the

7 solutions come from the community, and I really

8 think that that is true. All of what we are

9 talking about happens at a community level.

10 [Slide.]

11 As communities try to address health

12 issues, and they do it by themselves in terms of

13 what expectations are, what they have, we really

14 need to look at all the stakeholders in the

15 community, and we need to sort out roles and

16 responsibilities, and what we are going to find in

17 clinical trials is it is going to vary from

18 community to community, how we get the word out,

19 how we get the buy-in, and we are really going to

20 have to look at it from a community perspective.

21 Patients are really tired of having people

22 come in and say here, I have this, take it, and not

23 be part of the process. So, we really need to look

24 at community-based education and research.

25 If you haven't read the article by Israel,


78 1 on community-based research, that was published in

2 Public Health in 1999, I would ask every one of you

3 to read that. Community-based research is not an

4 easy thing to do, but it gets us faster to where we

5 want to go, and it means partnering with community,

6 with media, with health care providers from the

7 get-go, and it really means that we have to do

8 community-based outreach in terms of education.

9 Communities, patients want to be involved

10 and they want to be a partner in the process. They

11 are asking that they get more information, so that

12 they can have a better understanding, and I think

13 we heard this again by everybody that presented

14 this morning. They want to help facilitate the

15 process, they are not here to slow it down.

16 They want the knowledge. So, whether the

17 researchers come and go, or we come and go as

18 providers, that the community still has the

19 knowledge to carry on in terms of health.

20 [Slide.]

21 They were really want to ensure that they

22 are involved in informed consent, and they want the

23 informed consents to be culturally competent. They

24 want the IRB process to be culturally competent,

25 and they want to make sure that all cultures are


79 1 reflected in clinical trials.

2 [Slide.]

3 So, in summary, our goals are all the same

4 - equal access to culturally relevant, quality

5 cancer care through all stages of the disease, and

6 it has to be a partnership.

7 Thank you.

8 DR. NERENSTONE: Does anyone have any

9 questions for Dr. Pelusi?

10 DR. TEMPLE: Early on, you described the

11 sort of general principle, I guess which would be

12 called justice, that there should be equal access

13 to therapies throughout the development process.

14 How do you fit that with the observation

15 that the early trials are obviously smaller and

16 more limited? Sometimes justice has been

17 translated to say that people shouldn't be excluded

18 within the community, that they should have access,

19 but you can't have Phase I studies that cover the

20 whole nation or at least not easily.

21 How do you translate that?

22 DR. PELUSI: I think what I was referring

23 to, Dr. Temple, is when we look throughout the

24 phases of disease, what I am looking at is do we

25 have even prevention trials available across the


80 1 board to people.

2 When you are looking at Phase I/Phase II,

3 I think the question becomes is if indeed people

4 want to participate, are they going to be able to

5 participate? No, you are not going to be able to

6 have them all around, but is there a system

7 involved that can support that?

8 So, if indeed you have somebody who wants

9 to be in a Phase I trial, they may not be able to

10 travel to another state to get that, and if

11 insurance, you know, if they don't have insurance,

12 how are they going to be supported to participate?

13 That is a question that we have to ask

14 ourselves, is there a support system set up that

15 they can participate if they want. Most people

16 really want access, to be really honest what you

17 hear from communities, they want to be able to have

18 what everybody else has in terms of standard of

19 care.

20 In many communities, standard of care is

21 not available.

22 DR. TEMPLE: That is sort of what I am

23 asking about. A Phase I study is likely to be done

24 in one or a small number of institutions. The

25 company plainly is not ready to support thousands


81 1 of people, and you probably wouldn't want that

2 because you don't know enough about the drug, so

3 how do you translate the equal access to the early

4 stages?

5 DR. PELUSI: To the early stages of the

6 trials process, again, if you are struggling to get

7 patients into the trials in all phases, and you are

8 especially looking at trying to get minority

9 populations in, you are going to have to support

10 them somehow, and the question becomes are we, if

11 we want people in clinical trials, willing to

12 support them in terms of transportation, in terms

13 of housing for that, and that may be part that has

14 to be built in.

15 Again, that is the only way we are going

16 to get people into trials, and they are going to

17 have to say, you know, do they even know that they

18 are available. Many people may not want to be in

19 Phase I studies, but do they want to be in Phase II

20 studies, do they want to be in Phase III studies?

21 Perhaps. But again, many people don't participate

22 because they don't have the ability to travel.

23 Many times it means if you are poor, you

24 don't have access to that if you chose to

25 participate. Many times you don't even know that


82 1 that exists.

2 The question also that goes with that is

3 do they understand what Phase I is, is it something

4 that they want to participate in, have they been

5 educated into what it is that a Phase I study does.

6 You know, are we looking to see is an entity really

7 basically, does it have any activity, what are the

8 potential side effects, not what it is against.

9 Again, basic education at the community

10 levels can't be done necessarily by us. It needs

11 to be done by community members. I think what you

12 are starting to see, that is coming out in kind of

13 a rough form from some of the special population

14 grants, is that what we are seeing is communities

15 actually want to be the ones that decide how

16 education will be done within their communities,

17 but they want the knowledge from the researchers,

18 they want the knowledge from the experts, if you

19 will, but they want to deliver it in their

20 communities.

21 So, when you talk about access, again, we

22 have to ask ourselves who do we want in trials, and

23 if we truly say that we want to make sure everybody

24 is represented in trials, we are going to have to

25 say what are the barriers to the trial and did we


83 1 build it in, in terms of resources to get people

2 in.

3 DR. NERENSTONE: Any other questions?

4 Yes, sir.

5 DR. REDMAN: A question, and it is

6 probably more on the ethical, and maybe Dr. Taylor

7 can respond to this, but I sort of get a sense from

8 some of the community speakers and others that

9 there seems to be--and I guess this deals with

10 patient autonomy, the right to refuse therapy--when

11 or is it an inalienable right that a patient has

12 access to investigational agents? I mean is that

13 written somewhere that everybody has to have access

14 to investigational agents?

15 DR. TAYLOR: I think if you look at what

16 the write about justice, it is more along the lines

17 of what Dr. Temple alluded to. You have to have,

18 it is felt in our country, and it is certainly not

19 felt in others, that we should all have access to

20 the same medical care when it is relevant, and

21 there are some times when it is not going to be

22 relevant, you are going to not be willing to give

23 your time to fly to California to take a Phase I

24 agent or you are not going to have the disease that

25 it is even reasonable to treat it. You have to set


84 1 certain parameters. It is not always relevant that

2 everybody--I don't think that I should be able to

3 demand to go take a Phase I drug as a non-cancer or

4 non-ill patient.

5 So, I think that you have to look in a

6 relevant way. We don't have equal access to even

7 standard of care in this country, and whether we

8 should or not, only those people that have lots of

9 money are going to be able to tell us because that

10 is where I think it is. We don't have equal

11 access. You see it in your practice every day.

12 Whereas my patients without insurance may

13 not go in a trial, it may be because they have to

14 keep working, and they can't even come in at night

15 to my 24-hour-a-day clinic because they have to

16 keep working and they can't participate.

17 So, I don't think there is anywhere that

18 says everybody should get to be on a Phase I trial,

19 but I think that you shouldn't be excluded for

20 other than relevant reasons.

21 DR. NERENSTONE: We are going to have

22 further discussion after the break. We will take

23 the break now and be back at five after 10:00.

24 [Recess.]

25 ODAC Discussants


85 1 Sarah Taylor, M.D.

2 DR. NERENSTONE: Dr. Taylor has been kind

3 enough to volunteer or was drafted to lead off this

4 discussion.

5 Sarah.

6 DR. TAYLOR: We have heard from a lot of

7 different aspects, and I am going to talk to you

8 from my different hats that I wear about this

9 issue. Primarily, I think that we will try to

10 drift back to the off-study use for individual

11 patients as an issue, and not access to medical

12 care, as I was told that is a huge issue.

13 As a physician, I wear a number of

14 different hats. Number one is I am an oncologist,

15 and as an oncologist, I have a number of cancer

16 patients who come to me today seeking treatments.

17 Issues that I have within my own practice in doing

18 this are that if I am going to use a drug off-label

19 or off-study, that I, number one, have to know

20 about it, and there are a lot of physicians who are

21 not in my position in which I go to meetings and

22 have that luxury of having a group that will cover

23 while I am out trying to learn new information.

24 I am in a large city where many times the

25 meetings are held. I also have the luxury that I


86 1 have a National Cancer Institute grant that pays

2 for data management, and what I manage to do is use

3 that data management to help me keep records of

4 those patients for whom I call and seek the

5 individual INDs or for whom I get expanded access.

6 Now, if I were an oncologist in private

7 practice, some do belong to community-based

8 research organizations, but many don't, and so as a

9 physician who is not in my position, I would be

10 concerned about the cost, not only my time in terms

11 of calling and arranging it, but my having to pay a

12 nurse to keep the records, pharmacists to mix the

13 drug, all of which I am not going to get any

14 reimbursement for, and I may have to come up with

15 the cost for that.

16 So, I think that as we talk about these

17 issues, one aspect is the physician side, is cost

18 and time that they have to put into it.

19 I think that as an oncologist, it is very

20 important that I educate, just as we talked about,

21 in terms of that misconception that because it is

22 an experimental drug, it is going to be better.

23 With my scientist hat on, I have done an

24 awful lot of studies that were very negative, and I

25 have to say that as a scientist, I look at the


87 1 studies and I realize how few responses there are,

2 and I feel that it is important that patients

3 really know that. At one time, the NCI screened

4 40,000 drugs in a year, and we certainly don't have

5 40,000 drugs on the market. I think that that is

6 an important part of it.

7 As a palliative care physician, I have to

8 tell you that many times people come to me with

9 end-of-life issues which should have been addressed

10 far earlier than that last week of life, and that

11 sometimes, as physicians, when we are not willing

12 or able to give the bad news and to give the truth

13 about the fact that the majority of people on a

14 Phase I trial are not going to respond, are not

15 going to have a clinical benefit, and that perhaps

16 you need to look at other issues, such as do you

17 want to go visit your daughter now, should we be

18 looking at other issues in your life.

19 Hopefully, all of you who do Phase I

20 trials and Phase II trials are controlling that

21 pain anyway. We don't want to be not controlling

22 symptoms, but symptoms need to be controlled. I

23 think that often, as Jody alluded to, people feel

24 that the only treatment has to be an active

25 anti-cancer treatment. Certainly, as a palliative


88 1 care physician, I find it very offensive that

2 sometimes my pain and symptom management is not

3 considered treatment because indeed it is a

4 treatment thing.

5 So, I would hope that as people seek these

6 new agents, that we also keep them well informed

7 about the palliative care issues and the realities

8 of it.

9 Now, as a patient and a family member, I

10 also understand a number of things in terms of the

11 hope, and I have seen people who weren't supposed

12 to respond to a drug, and that drug isn't on the

13 market respond to a Phase I drug and actually have

14 a complete remission. Those are anecdotes, but

15 they are things that people hold onto and things

16 that keep them looking for other issues. So, I

17 would note that.

18 I think that another aspect of industry

19 that was not emphasized today, but which I am aware

20 of, is that as they do expanded access on

21 individual patient treatments or use of their drug,

22 they are spending a lot of money, and money may be

23 a real bad word in a lot of ways, but when that

24 industry has to spend that money in that way, I

25 think they have to look at how they are spending it


89 1 and whether they are going to get data back that

2 will help the public to know what the drug is going

3 to do and whether it is going to be effective,

4 whether it will be an effective use of their money

5 or whether it will be more money spent that will

6 just increase the cost of the new drugs.

7 So, I am throwing into the argument here

8 that we have many issues both from industry and

9 physician, and actually from patients who spend a

10 lot of time and effort taking treatment.

11 DR. NERENSTONE: Dr. Pelusi.

12 Jody Pelusi, F.N.P., Ph.D.

13 DR. PELUSI: I was asked to only give four

14 lines. In summary, just to probably hit the four

15 biggest points that I see, is I think that we all

16 hear what people want is to make sure that they get

17 honest, real information about the disease process

18 and about true reality about what is available to

19 treat their cancer. Again, it needs to be

20 inclusive of not only drug therapy, but palliative

21 care.

22 Also, when we look at this, we hear time

23 and time again nobody wants to slow down the

24 clinical trials process, that we feel that that is

25 the standard, if you will, to truly put effective


90 1 and safe drugs on the market.

2 So, when we begin to look at what should

3 we do with expanded access or special patient use,

4 that in no way do we ever want to slow down the

5 clinical trials process.

6 Third, we hear that there needs to be

7 education in terms of patients understanding the

8 issue of patient use and expanded use, as well as

9 the medical community.

10 Fourth, I think that everybody is saying

11 right now, because the system isn't perfect, that

12 single patient use is yes, indeed, something that

13 we need to look at, it may evolve over time, but

14 yet there should be criteria, so that we know that

15 it is safe and effective, and that may be to look

16 at what phase of the study does it become

17 available.

18 Last but not least, again, people just

19 want access, to be able to say that I am receiving

20 quality care in whatever form that may be.

21 Thank you.

22 Committee Discussion

23 DR. NERENSTONE: I would like to open it

24 up to the committee now for discussion, and I am

25 going to take the chairwoman's prerogative, and I


91 1 don't want to reiterate, I think our two leaders

2 made very good and important points. I just want

3 to reiterate very briefly.

4 One, I think patient education is

5 extraordinarily important and what patients'

6 expectations are of these treatments. It makes me

7 very nervous to hear speakers today talk about

8 experimental treatment as the only potential for

9 cure for their family member.

10 Most of these drugs are not going to cure

11 anyone. Most of these drugs, even if they are the

12 most effective we can hope, we are talking about

13 increasing people's lives by months, not years, and

14 that is in the most effective drugs that are now

15 used upfront, when they are used in the second,

16 third, and fourth line setting, they have very

17 minimal activity even when we know they are

18 effective.

19 The other issue is that performance status

20 adherence. I think it is wrong to give patients

21 chemotherapy as they are dying. I think that it is

22 wrong for patients to expect that they should be

23 getting chemotherapy as they are dying.

24 If patients should not be getting standard

25 therapy because they are no longer of an adequate


92 1 performance status, they should certainly not be

2 getting experimental treatment where you know there

3 is no likelihood of any benefit to the patient, and

4 only very severe toxicity.

5 So, I think these are really very

6 important things for patient education.

7 Now, I would like to open it up to the

8 rest of the committee.

9 Dr. Blayney.

10 DR. BLAYNEY: Thank you. In considering

11 the discussion and reading the material and

12 reviewing what we heard in December, I have four

13 points perhaps in my role as adviser to the FDA.

14 I think clearly in this country, the

15 autonomy of the patient and that conflict between

16 physician and patient autonomy has been settled on

17 the side of the patient, and I think we all

18 recognize that that is the way things should

19 continue to be and we should respect whenever

20 possible the autonomy of the patient.

21 Secondly, if we had a frictionless system,

22 we would not be having this discussion today. If

23 the time from a biologic event, meaning giving a

24 drug and observing the effect of that drug, to when

25 that event was recorded, verified, acted upon, and


93 1 a decision was made to approve that drug for

2 marketing was very short, this discussion would in

3 large measure be a much smaller issue.

4 I commend the Agency with the quick

5 approval of Gleevec, and I think not only can that

6 be viewed to your credit, but I would hope that you

7 would learn and work with your drug sponsors and us

8 in the practice community to learn how we can make

9 that more of a common occurrence rather than

10 something that is deserving of comment because it

11 is so out of the ordinary.

12 Thirdly, I think that in your discussions

13 with PhRMA, you need to encourage them to be

14 proactive and think about a planned access program

15 as part of their drug development process,

16 especially if the sponsor is planning a big media

17 campaign in advance of drug approval, as we have

18 seen with a lot of the drugs that I suspect we will

19 be considering over the next few years, they need

20 to factor an expanded access program into their

21 drug development mechanism.

22 Second to last, the semantic issue has

23 been touched on. I think the compassionate use

24 needs to disappear from various publications, and

25 also as a semantic issue, I think palliative care


94 1 or some other term that is acceptable to patients,

2 you should put into your vocabulary of ways that

3 patients can consider active treatment or

4 compassionate use treatment of experimental agents,

5 that palliative care many times is a much better

6 option for these patients.

7 Finally, I must say that I am encouraged

8 that the pediatric advocate from whom we heard this

9 morning, and the pediatric, which my understanding

10 is as close to a frictionless clinical trial system

11 as we have, where they have a very high

12 participation in clinical trials in pediatric

13 patients, came to the view, which is largely my

14 view, that the individual use or individual trial

15 should be a mechanism that is used as minimally as

16 possible, so as not to impede drug development.

17 DR. NERENSTONE: Mr. Erwin.

18 MR. ERWIN: One thing that seems to come

19 through in a lot of the comments is the need for

20 information, and there has been a focus on patient

21 education, but I think at another level, a more

22 systematic approach to gathering information could

23 be extremely helpful.

24 We have heard from people with varied

25 experiences in many different types of cancer.


95 1 Frequently, there is not a great deal of

2 communication across those interest groups, and the

3 experiences with everything from expanded access in

4 the HIV community to attempts at individual access

5 in certain rare forms of cancer has generated a lot

6 of what is frequently dismissed as anecdotal

7 results.

8 Given the now almost two decades of

9 history of various types of attempts to gain access

10 to innovative promising new therapies, whether it

11 goes back to early devices or more recent

12 biologics, I think that given that the FDA is going

13 to be a center of focus for a lot of this going

14 forward, it would make sense without it becoming

15 yet another unfunded mandate or some kind of

16 approach to be taken to create a high quality,

17 systematic review of the experience across all of

18 these different disease sectors, and what is the

19 conclusion or conclusions that can be drawn in a

20 much more sort of academic or objective manner in

21 compiling this information and looking at what has

22 worked and what has not worked.

23 In particular, I think one part of that

24 analysis might be what has worked and what has not

25 worked when it turned out that the device, the


96 1 intervention, or the drug was, in fact effective,

2 was ultimately approved, was there benefit in an

3 expanded access program, was there life extension

4 that is statistically valid, was there benefit in

5 even individual access.

6 There have been some I think important

7 distinctions drawn between expanded access and

8 individual patient INDs, but with all of this

9 discussion of anecdotes, personal histories,

10 emotion, fairness, it seems to me that the

11 overwhelming need for policy decisions or even fair

12 conclusions on justice could benefit a great deal

13 from that kind of a systematic analysis.

14 DR. NERENSTONE: Ms. Platner.

15 MS. PLATNER: While there is certainly a

16 consensus in the room that no one wants to

17 undermine the clinical trial system, I don't think

18 that in any way implies that folks wouldn't like to

19 change the clinical trial system and improve the

20 clinical trial system.

21 I think that looking at the whole issue of

22 single patient INDs, we can go through various

23 scenarios about when it may be appropriate in this

24 circumstance but not that circumstance, and maybe

25 if the situation in this but not that, and I think


97 1 in the end, there is no way, no matter what you do

2 with single patient INDs, that you can ever

3 actually make that fair, equitable, or

4 compassionate, and in the end, effective in any way

5 in dealing with the issues that all of these raise.

6 So, I think it is really time to move

7 beyond that and recognize it as a mechanism that is

8 really not effective and really doesn't work, and

9 look at the clinical trial system itself and how to

10 address issues and maybe look at more trials in

11 late stage disease although in cancer there are

12 many, many trials in metastatic cancer, there are

13 not many trials that deal with later stage disease

14 that look at expanded access, and maybe some other

15 mechanisms for treatments that are very, very

16 promising, and that is not most treatments.

17 But I think it is really time to move

18 beyond this because in the end, I don't think this

19 mechanism will ever address effectively the issues

20 we want to address, and it just simply will never

21 be fair and equitable.

22 DR. NERENSTONE: Dr. Temple.

23 DR. TEMPLE: I just want to provide a

24 little bit of historical background, and it is

25 relevant to these things. One of the reasons the


98 1 treatment IND mechanism--and I realize there is

2 some question of whether it should be called

3 treatment IND, but leave that aside--was developed

4 was a perception that the way things were when

5 drugs did look promising, when there was a certain

6 amount of evidence of effectiveness, who got into

7 the various programs of expanded access that

8 existed was capricious and depended on who you knew

9 and whether your doctor was wired in.

10 The program was designed to make

11 information more widely available, so that it

12 wasn't only for the aficionados and their patients.

13 I have to say to the extent that expanded access--I

14 am talking now about relatively late expanded

15 access--is not using that mechanism and is being

16 sort of local and not using the treatment IND or

17 the Group C equivalent, it is undermining the

18 desire to have it be widely known and fair, and

19 that seems important to me, because one of the

20 things that impressed me most is how infuriating it

21 must be to not know what the rules are for getting

22 whatever you want and being confused about it.

23 So, whether it should be called something

24 different could be discussed also, but having a

25 public determination that this will be available in


99 1 this kind of expanded access in the form of a

2 treatment IND or something like that seems an

3 important part of being fair.

4 That, of course, doesn't solve the early

5 individual patient problems at all, but I have one

6 thought I wanted to ask people about.

7 When somebody gets an idea, when a

8 physician gets an idea that a drug might work in a

9 tumor that isn't currently under study, that is a

10 little like a sort of dispersed Phase I study

11 and/or it's a pilot study or something, and while

12 it gets called compassionate use or something else

13 like that, it really seems to me it is more similar

14 to a Phase I study, but of a somewhat different

15 kind.

16 Those things seem to me less troubling if

17 they are individual because nobody expects that

18 those are going to happen in every part of the

19 country. There will be a certain number of people

20 who, because of interest, want to do something that

21 is not part of the system that the drug company has

22 already set up.

23 It is when those start to become frequent

24 and numerous--that's the same word--more frequent

25 that you start to get the question of who is


100 1 entitled and who is not, and it is at that point

2 that companies ideally would start thinking about

3 whether they want to have a formal program and

4 incorporate this into their trial.

5 So, it seems important to me to separate,

6 take a try at this tumor that hasn't been studied

7 before with all of the many other circumstances

8 that lead to individual patient uses which do seem

9 to bring questions of capriciousness to the fore.

10 DR. NERENSTONE: Bob, I don't want to

11 argue semantics with the FDA, but really, don't you

12 mean a dispersed Phase II, because they are not

13 varying the dose, they are just studying it in a

14 different tumor type?

15 DR. TEMPLE: I will buy that.

16 DR. NERENSTONE: The only reason I say

17 that, I think the implications are significant

18 because that implies that you have a dose that is

19 being studied in someone in a Phase II manner. It

20 is not a dose that we haven't had some experience

21 with.

22 DR. TEMPLE: That is fair. I stand

23 corrected. But conceptually, that seems different

24 from the desire for people all over the country to

25 take a last shot in a desperate case and they don't


101 1 fit any of the protocols. Those are the things

2 that raise all kinds of questions of

3 capriciousness, and as many people have pointed

4 out, there ought to be a plan for dealing with

5 those, but someone, somewhere wants to try this

6 drug in a different tumor, that doesn't seem to

7 raise too novel issues, that sort of in some ways

8 happens all the time. This is more like a case

9 where the company isn't directing it, but that's

10 okay, they are not all-knowing.

11 DR. NERENSTONE: Ms. Linden.

12 DR. LINDEN: I would like to respond to a

13 couple of comments that have been made around the

14 table and also mentioned this morning and also at

15 the December hearing.

16 First, I would like to respond to Ms.

17 Platner regarding equity and justice, and that this

18 is the time to move on from focusing on those

19 issues. I am afraid--or I am not afraid--I

20 actually view those issues differently as a

21 bioethicist.

22 The way that I view them is that equity

23 and justice are ideals toward which we strive and

24 in any arena, whether it is experimental therapies

25 or democracy or what have you, we never accomplish


102 1 fully our ideals. We use them as beacons toward

2 which we are guided.

3 I would also like to respond to a comment

4 that Mr. Erwin made, as well as Dr. Williams, in

5 part of the discussion last December that has

6 really stayed with me over these past five or so

7 months, and that is the issue of communication.

8 Dr. Williams this morning

9 proposed--perhaps "proposed" is too hard a

10 version--suggested the possibility of a consensus

11 conference at some point to lay a framework for the

12 issues of treatment INDs and expanded access. I

13 think that is a wonderful idea, but I do believe

14 that we are very far from a time when it would be

15 appropriate to hold such a conference.

16 Bob Erwin's comment about communication, I

17 think is extraordinarily important, and the sort of

18 communication that I am most concerned about is of

19 the sort that was mentioned at the hearing last

20 December, and that is communication between and

21 among industry, PhRMA and its constituent members,

22 large pharmaceutical companies, and small biotech

23 start-ups, community members, activists, consumers,

24 physicians, the FDA, the NCI, HMOs, which have a

25 rather significant role in those communities where


103 1 they are dominant providers and how clinical trials

2 are enrolled.

3 I hope that the call for meetings where

4 these various stakeholders can get together and

5 begin to talk about their concerns, the fiscal

6 concerns that you mentioned, Dr. Taylor a few

7 moments ago, so that we can really begin to hear

8 each other and find out what our points of

9 agreement are, what our common ground is, and where

10 we have fundamental disagreements. That is not

11 going to happen at a consensus conference. A

12 consensus conference is for down the road in my

13 view.

14 Thank you.

15 DR. NERENSTONE: Mr. Dixon.

16 MR. DIXON: Yes. We have gone around and

17 around once again on this information and access,

18 and justice and equity point, and I would like to

19 remind everyone that we do have a statutory basis

20 for a clinical trials' database, which is largely

21 ignored by industry involved in FDA-related trials.

22 I would hope that this group would suggest

23 strongly to the agency that it work more

24 aggressively with industry to assure that those

25 trials are available on a database, so that


104 1 patients can find out about them wherever they

2 live. I think this would go a long way towards

3 answering some of these access questions.

4 I also think that if all cancer trials at

5 the FDA were within one office, so there were

6 similar rules across the board, that that would

7 also be a big step forward.

8 Thank you.

9 DR. NERENSTONE: Dr. Albain.

10 DR. ALBAIN: I do think, though, in

11 relation to the concept of a consensus conference

12 and national dialogue, that we are in a new era,

13 though, with our new agents, our molecular targeted

14 therapies, and, in fact, we are now seeing trials

15 open and close in 6 to 8 months with expanded

16 access trials opening before the investigators know

17 even the toxicity profile of the agent.

18 So, I think it is clearly necessary that

19 we rapidly reach some consensus about how at least

20 an expanded trial process should proceed

21 nationally.

22 DR. NERENSTONE: Dr. Sledge.

23 DR. SLEDGE: After hearing so many

24 wonderful discussions here, it is hard to add a

25 whole lot, but just three points, if I could.


105 1 First, the issue of justice. I mean in

2 essence in this very wonderful philosophical

3 discussion, we are basically talking about two very

4 different concepts of justice.

5 One is sort of utilitarian justice of, you

6 know, the greatest good for the greatest number,

7 which would suggest that justice is best served by

8 getting a drug onto the market as quickly as

9 possible, and therefore doing the best trials as

10 quickly as possible, and anything that holds it up

11 will delay justice for the majority.

12 The other form of justice, of course, is

13 individual justice, what can we do best for the

14 individual.

15 These really are very different concepts

16 of justice, we have got to recognize that.

17 Second, from a scientific standpoint,

18 leaving aside the issue of expanded access, which I

19 don't think is what we are discussing here, but

20 rather the use of single patient use setting, can

21 we get anything scientific out of single use

22 indications? My bias is no. My bias is no

23 because, first, the physicians who are involved in

24 the system as a rule of thumb are not clinical

25 researchers, and they are not used to or very good


106 1 at collecting clinical research data.

2 The patients, as a group, tend to be very

3 poorly characterized, and therefore, even the

4 adverse event data that you get out of these single

5 use indications I think is highly flawed and is

6 confounded by the patient's underlying disease in

7 most cases.

8 Is it possible that we might be able to

9 get some signal data from an efficacy standpoint in

10 terms of rare tumors? There, I suspect, yes, it is

11 possible. Certainly, if one looks at the history

12 of, say, a treatable cancer like testicular cancer,

13 where actually the initial signals did come out of

14 Phase I programs, and out of individual patients

15 responding remarkably well in a rare tumor, I think

16 it is at least possible that there may be at least

17 some potential for getting that sort of data.

18 Third, is a toxicity issue. We have

19 talked a lot about informing patients, but the

20 truth of the matter is that for drugs in early

21 development, we really don't have much to tell

22 patients about the drugs.

23 Talking about issues of informed consent

24 with patients with a drug that has only been

25 through a Phase I trial or very early Phase II


107 1 trial is pretty nonsensical, to tell the truth.

2 Most of the time we just simply don't know anything

3 about the range of activity of the drug, and we

4 truly don't know very much about the toxicity of

5 the drug. Most of the scary side effects that we

6 end up discussing with patients down the road, we

7 learn as a result of large Phase III trials rather

8 than Phase I and Phase II trials.

9 So, my bias is that a lot of the

10 bureaucracy that surrounds single use is pretty

11 much wasted bureaucracy. The sending of a protocol

12 to an Institutional Review Board, you know, the

13 informed consent discussions that go around this, I

14 think by and large really are done primarily for

15 lawyers rather than for patients. I am truly not

16 sure how much they benefit the average patient.

17 DR. NERENSTONE: Again, I have a question,

18 a point of information. Somebody raised a question

19 about centralizing the database for patient access

20 to trials.

21 Would someone comment about PDQ and

22 whether that has expanded access protocols listed

23 on that, does anyone know?

24 MS. DELANEY: We request that the

25 companies list their expanded access protocols in


108 1 the PDQ. Compliance with PDQ, in general, though,

2 has been very poor, as Carl Dixon said. There are

3 currently 1,850 clinical trials in the PDQ

4 database, and the number of industry-sponsored

5 trials in that database, the highest it ever got

6 was 200, and it is now going down again in spite of

7 the law that was passed.

8 So, this is the single largest place that

9 a patient can find out about an ongoing trial or if

10 they are not eligible for an expanded access

11 protocol that may be in there, they certainly can

12 find out about another trial they might be eligible

13 for, the compliance with it has been poor to

14 miserable.

15 DR. NERENSTONE: So, maybe one of the

16 suggestions can be that because the mechanism

17 exists, that drug companies should be encouraged--I

18 don't know if we can say required--to comply with

19 that in terms of helping them with their accrual,

20 as well as patient information about existing

21 studies. Because the mechanism does exist, we

22 shouldn't have to reinvent the wheel.

23 Other comments?

24 MR. DIXON: If I could just supplement

25 that, the statute on that particular database says


109 1 that they shall comply, so it is not a question of

2 whether industry wants to do it or not, the

3 database is there. It is just that they are not

4 doing it.

5 DR. NERENSTONE: Could you please

6 introduce yourself for the members of the

7 committee?

8 MS. TOIGO: I will. I am Terry Toigo.

9 Part of the law that Carl Dixon is referring to is

10 a section of the Food and Drug Modernization Act,

11 Section 113. FDA developed guidance and put out

12 guidance about a year ago. We will have another

13 guidance document available very shortly that will

14 tell sponsors how to get their trials into

15, which is the database that the

16 government developed to respond to Section 113 of


18 So, that will clear up any--we have

19 already given guidance on which trials need to be

20 put in that database. This will tell industry how

21 to get the trials into the database. It is

22 required, it is a law.

23 The reason they are not doing it--Dr.

24 Temple asked me how come companies are not doing

25 it--Congress passed a law, we are developing


110 1 guidance. We needed to get a mechanism in place

2 for companies to submit their trials, and that has

3 been now developed.

4 DR. NERENSTONE: Dr. Redman.

5 DR. REDMAN: Again, I am probably just

6 going to reiterate what Dr. Sledge said, you know,

7 there seem to be two issues here. The one that I

8 came prepared to discuss, I guess was the access to

9 investigational agents, not therapies, outside the

10 context of a clinical trial.

11 I think that process, that access does

12 co-opt the clinical trial, not that that person is

13 not being put on a clinical trial, but the fact is

14 you are making an assumption that the clinical

15 trial is through and you know the answer, and there

16 is some therapeutic benefit.

17 I really think that is a fallacy, and I

18 tend to agree that the whole process of single

19 patient use or access to an investigational agent

20 is a lot of waste of time, both at the regulatory

21 level and at the physician level, and there is no

22 information that is gained from that.

23 Some of the other comments, though, are

24 dealing with better access to clinical trials, and

25 I do agree, and there have been meetings at the


111 1 NCI, at CTEP, regarding this process. I think that

2 process definitely needs improvement, but I don't

3 think this committee is going to improve it.

4 DR. NERENSTONE: Dr. Linden.

5 DR. LINDEN: In response to the comment,

6 the clarification of the regs for the database, as

7 with any requirement, requirements don't hold a lot

8 of water unless there is enforcement, and I wonder

9 if there is or will be enforcement of entering

10 trials and updating information as it is

11 appropriate. That seems to me that it would be

12 quite essential.

13 DR. NERENSTONE: Mr. Erwin.

14 MR. ERWIN: Leaving the broader questions

15 of clinical trial design and expanded access and

16 just going back to individual access for a moment,

17 I think there is an additional perspective to

18 consider, and that is the hope by a lot of

19 scientists, and certainly families and patients,

20 that newer technologies will lead to more

21 efficacious products and the sometimes very

22 reasonable hope that what an individual is trying

23 to get access will, in fact, turn out to be one of

24 those.

25 For example, had it been necessary,


112 1 although I guess in many cases it wasn't, for an

2 individual to attempt to get access to Gleevec,

3 there is a good chance it would have been

4 beneficial, at least with the data that is

5 currently available today.

6 So, as more and more targeted therapies,

7 as they have been called, come along, the

8 importance to an individual of individual access

9 might actually increase.

10 I think that the mechanism that is in

11 place now, which the FDA very infrequently blocks,

12 where an individual's physician and a company can

13 choose to voluntarily provide individual access,

14 certainly works sometimes, and what we are talking

15 about is how to, one, make it fairer, to make it

16 perhaps less complex, perhaps streamline it, but

17 more importantly, to integrate it into the broader

18 context of the two forms of justice that Dr. Sledge

19 referred to.

20 The additional perspective I think we

21 ought to keep in mind is that the drive by families

22 and individuals to survive a disease like cancer is

23 going to go on no matter what policy decisions we

24 make, and, in fact, if individual access were

25 completely blocked, there would still be consistent


113 1 persistent attempts at access to something.

2 In fact, in the United States right now,

3 patients can get access through the legal clinical

4 trials mechanism, drugs that most of us in this

5 room probably believe do not work, and for which

6 those patients pay thousands of dollars in full

7 compliance with FDA regulations or at least close

8 to full compliance, and many of us consider those

9 particular kinds of trials to be fraud, but they

10 happen to fit within the legal framework that has

11 been set up.

12 Alternative therapies are another whole

13 category. People fly overseas for all sorts of

14 bizarre treatments. So, that demand and that drive

15 for a cure, as unreasonable as it may be, needs to

16 constantly be factored back into the decisions that

17 are made, particularly when there is an attempt to

18 provide guidance and education, because they are

19 not going to go away and in the face of advancing

20 technology, that hope will continually be fueled

21 whether it is false or not.

22 DR. NERENSTONE: Dr. Spiegel.

23 DR. SPIEGEL: Listening, I would concur

24 with some other speakers that there seem to be a

25 lot of issues on the table including general access


114 1 to clinical trials, participation in either the

2 government or there are many--I think there are

3 still some around that are trying to make public

4 databases and for-profit companies that have some

5 very clever ideas about how to overcome some of the

6 issues that have been raised with the government

7 databases and providing a third party who could

8 screen patients for companies who could post their

9 trials, but I think that is a different consensus

10 conference.

11 What I wanted to mention was I think both

12 in the December meeting and on 60 Minutes, but what

13 we have heard is probably a very appropriate level

14 of frustration that it is hard for people to

15 penetrate both Big Pharma and little biotech

16 companies to understand what stage drugs are at and

17 whether any single patient exemption is available.

18 I am certainly taking home something that

19 we could all do is to just challenge our own public

20 relations departments to see if our web sites or

21 800 numbers could be more clear, so that people

22 could even get a fast answer, that we do not at

23 this time have a compassionate use or an expanded

24 access program for any indication for a drug if it

25 is at a very early stage of development, just to


115 1 give people answers, so they don't feel they have

2 to keep knocking on doors.

3 I would like to raise a different issue,

4 though, and I guess I would ask Dr. George or

5 maybe, I know Dr. Temple has thought about this

6 often, is just to go to the concept of equipoise

7 that we apply when we do a clinical trial, we

8 convince ourselves that it is ethical to randomize

9 to standard therapy versus experimental because

10 nobody knows the answer, that one arm of the trial

11 is better than another.

12 But somehow when it comes to a

13 compassionate use, we seem to be saying if I am

14 doing a trial that has 25 inclusion and exclusion

15 criteria, and a patient is not eligible, but I am

16 doing the trial to find out if it works in that

17 disease, somehow I should be considering

18 compassionately that somebody whose creatinine is

19 too high or had too many prior therapies should

20 have access to compassionate use when there is

21 really no evidence, you know, by the usual criteria

22 of evidence, that it is likely to work. So, I

23 don't know if our statisticians or people who have

24 thought about clinical trial development would want

25 to comment in that.


116 1 DR. GEORGE: A brief comment. There is

2 one issue that you brought up obliquely there is

3 the issue of eligibility criteria in clinical

4 trials, which is something else off the topic here,

5 but I guess it is relevant in some indirect ways,

6 that I think it is true in cancer particularly that

7 the eligibility criteria are often too rigid.

8 That is, there are too many eligibility

9 criteria. That, of course, then leads to the

10 situation of people saying, well, not many people

11 are entered on clinical trials in cancer, and one

12 of the reasons is they are not eligible for the

13 clinical trials that are available. I mean there

14 are trials that are there, but they can't get on

15 them because they have a long list of eligibility

16 criteria.

17 But it is just the issue of whether, then,

18 not meeting the eligibility criteria, why people

19 seek these compassionate use or whatever we call

20 them mechanisms is just a human one, I think.

21 DR. NERENSTONE: Dr. Williams.

22 DR. WILLIAMS: You may wonder why we

23 titled this single patient use. It was really to

24 try to focus on the questions we asked here, which

25 is the dilemma that we are often faced with, is


117 1 when should we say no, the FDA say no, you know,

2 according to following the guidelines and law that

3 there is there isn't adequate safety and efficacy

4 to allow this person to receive the drug. That is

5 our responsibility.

6 I think many of the questions we are

7 hearing addressed, but what we do need to address

8 in the future and may or may not be our

9 responsibility, but I would like to make sure we

10 have time to ask--I think we have good groundwork

11 for it--but the questions about when should we

12 absolutely say no, when is it basically, I would

13 say, unethical or unwise or unsafe for us to allow

14 use.

15 The only reason we put single patient use

16 is because it avoids the likelihood it is going to

17 interfere with the trial or all these different

18 issues that industry might be concerned with, the

19 cost, et cetera, and more, in the time remaining,

20 perhaps focus on when should FDA say no, and then

21 in the future, we hope that there will be a process

22 where we can address some of these other issues.

23 DR. TAYLOR: I would like to make a

24 comment to answer yours, but also about what was

25 said earlier about frustration. I think what I see


118 1 as much as frustration about not being able to get

2 an answer is frustration about dying. I think that

3 is the whole basis of a lot of this is frustration

4 about dying and the realities of medicine and what

5 man can do and what God can do.

6 I do think that that is part of what I am

7 talking about in terms of patient education. I may

8 not know what the toxicity of that Phase I drug is,

9 but I do know the likelihood of response based upon

10 other Phase I trials, and I have to be frank and

11 honest about what man can do, and that is a very

12 important part of this whole thing.

13 A lot of this is dealing with the

14 frustration of dying and our inadequacies in

15 medical care.

16 I would like to go back. I think that I

17 would agree, that I think that a patient whose

18 performance status is so poor that we don't

19 consider them able to tolerate or to respond to

20 standard curative therapy would be a very reason

21 not to agree to provide that type of drug.

22 I also have a very hard time saying that

23 we are going to give Phase I agents out when we

24 have not even obtained a dose level that we know

25 could be used in a safe fashion. I think in that


119 1 setting that we do give, as you alluded to, with

2 your equipoise, we do give the implication that we

3 think this drug is better and before the trial is

4 done. We don't have the trial done, and we imply

5 by allowing that, that we know it is better.

6 We don't know it is better, we just don't

7 know, and it is a big zero in the column as opposed

8 to a 10 percent response or a 20 percent response

9 from the standard things.

10 DR. NERENSTONE: Why don't we then ask for

11 Dr. Williams, focus our discussion more

12 specifically on the questions, and we can further

13 have discussion under that framework that might be

14 more specific to what the FDA needs us to

15 accomplish this morning.

16 I am going to just go to the Questions to

17 the Committee. I think that we have had extensive

18 discussion about just to very briefly the FDA is

19 seeking advice from us in its role of assessing the

20 risk-to-benefit ratio of treatment use with an

21 experimental drug in an individual patient, and

22 when determining the apparent risk-to-benefit

23 ratio, the following are important considerations:

24 How thoroughly has the drug been studied

25 in humans?


120 1 What do the preliminary results from these

2 studies suggest about the safety and efficacy (or

3 activity) of the drug?

4 What are the other therapeutic options

5 available to the patient?

6 They feel that those are questions that

7 need to be in the context of those kinds of issues.

8 I would like to go to our first Questions

9 to the Committee.

10 For each of the following clinical

11 scenarios describing standard therapy, please

12 discuss the following question:

13 The FDA receives a request from an

14 investigator to use Drug X under a single patient

15 IND. The commercial sponsor of Drug X has granted

16 permission for the investigator to use the drug and

17 also has provided written permission for FDA to

18 refer to the commercial IND, so that has all been

19 taken care of. The patient's medical history is

20 outlined in each of the scenarios below.

21 The investigator states that the patient

22 is aware of the benefits of standard therapy but

23 wants to receive investigational treatment with

24 Drug X instead. The patient is ineligible or

25 unable to participate in a clinical trial using


121 1 Drug X.

2 When would single patient treatment with

3 Drug X be appropriate?

4 They would like us to discuss it in the

5 context of the drug's stage of development, the

6 level of efficacy and toxicity that would be

7 acceptable in the following standard therapy cases.

8 So, that is setting the scenario.

9 The first is there is no standard therapy

10 available, and essentially metastatic--I guess you

11 mean extensive--non-small-cell lung cancer that has

12 received all available therapy.

13 I think that probably we need to talk

14 about what phase the drug is in, Phase I, Phase,

15 II, Phase III, as to when that would be

16 appropriate, so each of these.

17 The first would be Phase I. Would it be

18 appropriate for a patient to receive a Phase I drug

19 with non-small-cell lung cancer after all available

20 therapy has been exhausted?

21 Discussion from the committee?

22 DR. WILLIAMS: Dr. Nerenstone, we are not

23 really asking for votes on these. We really would

24 just prefer to get discussion.

25 DR. NERENSTONE: I will lead off. I would


122 1 say no. I think in any of these scenarios, a Phase

2 I drug is really not appropriate for widespread or

3 even limited single patient use. We have no idea

4 of the toxicity. How can you even do an informed

5 consent if you not only don't know the drug dose,

6 but have no idea of the toxicity.

7 So, I would say because of lack of data,

8 informed consent becomes meaningless and therefore,

9 the potential to do extraordinary harm remains

10 high, the benefit remains most likely very low.

11 So, I would say pretty much under no circumstances

12 do I think a Phase I drug should be given out for

13 single patient IND, single patient exemption.

14 Dr. Kelsen.

15 DR. KELSEN: I agree. I was thinking

16 about this. If it is truly an experimental drug in

17 Phase I, it is not a combination of conventional

18 agents being used in a Phase I trial, which gets a

19 little tricky, so if I put that aside for a minute,

20 and it is really a new drug, you are at Level 2 or

21 Level 3, you have no idea of the toxicity, you have

22 only treated three or four patients, maybe up to

23 six, to provide that outside of a carefully,

24 carefully supervised trial would make me very

25 uneasy.


123 1 DR. WILLIAMS: As a devil's advocate,

2 there is an informed consent in your Phase I trial,

3 and for that patient it is okay, but you are saying

4 since you don't have a controlled setting, that

5 would be another--

6 DR. KELSEN: Right, obviously. There is

7 two settings this happens in. You are the

8 investigator at the center doing the Phase I trial.

9 The patient is not eligible. The level is not

10 open, which is even more difficult, they are

11 eligible, but the level is not open.

12 But you know very, very little about that

13 drug. That would make me very uneasy, make me

14 extremely uneasy. The patient is not at your

15 center. They read the PDQ. They understand there

16 is Drug X that is being studied in New York or

17 California or wherever, and they want to receive

18 that drug from a physician who is not even involved

19 in the study. I think that is really a bad idea.

20 DR. NERENSTONE: Dr. Przepiorka.

21 DR. PRZEPIORKA: I would have to agree

22 that anything that has not been studied or is still

23 in Phase I or just completed Phase I and going to

24 Phase II, should not be used in a single individual

25 patient.


124 1 I don't disagree with the terminology

2 "treatment IND." I think that pretty much says it

3 exactly the way we intend it to be. It is not a

4 single patient experiment. It is a single patient

5 treatment. So, in the interest of time, I would

6 actually suggest that we not even entertain Phase 0

7 or Phase I drugs in the rest of the scenarios.

8 DR. NERENSTONE: Is that the feeling of

9 the committee? Mr. Erwin.

10 MR. ERWIN: I think it is useful to draw a

11 distinction between single patient exception and a

12 single patient IND, because that also addresses the

13 confidence of the investigator and the quality with

14 which that patient will be treated.

15 DR. WILLIAMS: You are suggesting that it

16 might be acceptable at a Phase I center for someone

17 who didn't fit on the protocol, that they might

18 consider treating them off that protocol, is that

19 what you are suggesting?

20 MR. ERWIN: Yes, that is my suggestion.

21 DR. NERENSTONE: Why, I guess is my

22 question, why would you consider doing that?

23 DR. KELSEN: We should be very careful

24 about that because the parameters for a Phase I

25 trial usually involve very small groups of people


125 1 at each level, and it is a very common scenario to

2 say, you know, you talked to me about Phase I

3 studies and you told me that you might be opening

4 another level, and it is not, but I did fit the

5 criteria and I want to go into that. I could

6 imagine that having a level of 20 people in no time

7 flat without really knowing all the side effects.

8 MR. ERWIN: I would agree that it requires

9 care, but in this case, a single patient exception

10 to the study, you have got the primary investigator

11 who is running the Phase I study, who may be the

12 physician involved. You have got the patient, you

13 have got the IRB. There are multiple levels of

14 decisionmaking in this case which have all gone

15 positive.

16 My suggestion is that you don't need

17 broader government involvement in that decision.

18 At that point, you have got enough competent people

19 who have said yes, I want to do it. It comes back

20 to that issue of patient autonomy.

21 DR. KELSEN: It implies that a patient can

22 say I understand that the study is not open, I

23 understand you don't know very much at all about

24 this drug, you have only treated the first few

25 patients, but I want you to treat me, and you could


126 1 have that situation, you could have a number of

2 patients who are requesting that therapy when you

3 know very little.

4 DR. TAYLOR: You don't have true informed

5 consent because your informed consent for the Phase

6 I trial says I am not doing this for a therapeutic

7 benefit, I am doing this to find the side effects,

8 and that is not the same as doing it for treatment.

9 The objectives of a Phase I trial are to

10 determine the MTD and the toxicity of that drug,

11 and by treating that patient off of the study, you

12 don't succeed in getting your objectives, and the

13 patient, in my opinion, is being treated with

14 something that therapeutically, has a very little

15 chance of responding, and they are not

16 understanding that.

17 DR. SLEDGE: I can't accept that. You

18 have to differentiate between why we do Phase I

19 trials and why patients go on Phase I trials.

20 DR. TAYLOR: I don't disagree, but I think

21 you still have to--

22 DR. SLEDGE: I mean the idea that a

23 patient goes on a Phase I trial without any hope of

24 therapeutic intent is ridiculous.

25 DR. TAYLOR: And I don't do it without any


127 1 hope of therapeutic intent, but I think the

2 realities of it or the objectives of that trial are

3 not for therapeutic benefit at that point.

4 DR. SLEDGE: I am well aware that that is

5 your objective, it is not the patient's objective.

6 DR. NERENSTONE: Dr. Redman.

7 DR. REDMAN: Basically, this is for Dr.

8 Kelsen with Mr. Erwin. Having reviewed off-site

9 Phase I trials, what you are suggesting, many

10 investigators have had their trials pulled for

11 doing that. It is inappropriate, it is unethical,

12 and not within the rights of the patient to demand

13 treatment on an investigational trial outside the

14 confines of that trial.

15 We are talking about allowing Phase I. I

16 mean I can go all the way up to Phase III and say

17 no.

18 DR. NERENSTONE: Dr. Albain.

19 DR. ALBAIN: I think we have the real

20 potential of doing harm. That has been alluded to,

21 and we cannot allow patients in these early Phase I

22 trials that are designed very deliberately with

23 rigid eligibility criteria to protect the patient.

24 We don't know the metabolism. You know,

25 the creatinine criteria may be very, very


128 1 appropriate, and you put someone on with a

2 creatinine of 2, you could kill them.

3 DR. NERENSTONE: I think that the FDA,

4 that the take-home message that I see is that there

5 may be a real division between the medical

6 community and the non-medical community over this

7 issue, and I do think that the medical community,

8 many of whom around this table have been involved

9 in Phase I research, is struck by how potentially

10 harmful this could be.

11 In our role as physician, someone pointed

12 out how research treating a group of people under

13 research and treating patients individually

14 sometimes come into conflict. Our fear is that in

15 this particular case, it is the physicians who are

16 worried about doing harm, and the non-physicians

17 who perhaps don't understand our fear of doing harm

18 to the extent that we are--I don't want to say

19 horrified at this idea--but certainly strongly

20 against Phase I drugs being released.

21 DR. WILLIAMS: I think that was a very

22 good discussion, and it will be useful.

23 DR. NERENSTONE: Again, with the standard

24 patient with metastatic non-small-cell lung cancer,

25 what about a Phase II agent? Discussion.


129 1 DR. KELSEN: This is a little trickier

2 because this happens also a great deal where there

3 is an agent that is under study in a given disease

4 for which we now know perhaps a good bit about

5 toxicity. It may be a multicenter trial where

6 there is information from a number of

7 investigators, so that you have a better feel for

8 the dose and the schedule. You know it well enough

9 to go forward, and you are already beginning to see

10 preliminary activity.

11 Now, you have made even maybe a

12 preliminary report in some meeting, not necessarily

13 an open meeting, which very rapidly begins to

14 disseminate, and you have a patient who has no

15 options, would ordinarily be a candidate for the

16 study, but they have something that withholds from

17 the study, which is not felt to be a safety issue,

18 or the study, even worse, has now filled its

19 accrual in that particular center, and the patient

20 says, you know, I know that this drug is working in

21 22.5 percent of patients for Temple, and I would

22 like access to this agent in my disease for which

23 you have exhausted all the conventional options,

24 and we face that every day.

25 DR. WILLIAMS: What about some patients


130 1 treated, but no activity, or just the first few

2 patients have been treated?

3 DR. KELSEN: I think that is very

4 important. So, even within Phase II, I guess the

5 suggestion is even within Phase II, there are

6 gradations as to when treating a patient with

7 single patient use, it becomes more reasonable and

8 less reasonable, and I agree with the implication

9 that I have treated three people, I haven't a clue.

10 DR. WILLIAMS: I would like to hear the

11 discussion. Is it just you need to know it is safe

12 based on Phase I, or is it that you have to show

13 some activity? Where do you find it reasonable or

14 not reasonable?

15 DR. KELSEN: I am speaking personally for

16 myself. I have only treated a few patients, I have

17 no evidence of activity, what is the compelling

18 reason that we should use this agent in this

19 situation as opposed to the latter.

20 DR. WILLIAMS: It is a different question,

21 though. It is not whether you have compelling

22 reasons, you and FDA, you have come to work for us,

23 and you would say no if someone wanted to. When

24 should we say no, if there is no activity, should

25 we say no in Phase II, or should we say yes?


131 1 DR. NERENSTONE: Dr. Redman.

2 DR. REDMAN: I think if the FDA is willing

3 to approve a drug on Phase II data from 40

4 patients, I think the FDA should say fine, but if

5 you are not willing to approve the drug, I would

6 ask the medical members here how many agents that

7 have gone through Phase II trials or to Phase III

8 trials, have shown increased efficacy over and

9 above that in a Phase II trial?

10 I think it has always been the exact

11 opposite. It has always been in Phase III trials

12 where the efficacy has either maybe been

13 equivalent, but more likely has been less. So, I

14 think, again, even if we have an ASCO abstract from

15 the Phase II trial that suggests that there is a 25

16 percent response rate of an agent, that that still

17 does not require it to be given out on a

18 compassionate, single patient, however you want to

19 define it, unless the FDA is willing to say, gee,

20 based on that information, we will approve the

21 drug, we recommend approval of the drug.

22 DR. NERENSTONE: I see this as a little

23 bit more of a gray area, and I could see where

24 patient pressure and physician pressure could be

25 brought to bear after several, either one or


132 1 several encouraging Phase II studies are released.

2 I agree, the likelihood that this patient

3 is going to benefit is indeed quite small, and I

4 think no matter what, that you still have to have

5 performance status criteria, and you probably have

6 to have end organ criteria, because treating

7 someone again with a bilirubin of 12 in a new drug

8 is very likely to be toxic, especially if we

9 haven't had a lot of experience with it, and you

10 can set up those end organ targets as to what would

11 be appropriate, but I think that later in Phase II,

12 when you actually have some published data, I would

13 make the argument that I could see at least the

14 potential of releasing that.

15 My feeling would be that you would try and

16 do it in open access because as soon as that kind

17 of data becomes available, especially for something

18 like small-cell lung cancer, it is not going to be

19 one or two patients who are interested in it, it is

20 going to be many patients who are interested in it.

21 Mr. Erwin.

22 MR. ERWIN: I just wanted to add one

23 further perspective on that comment about

24 indications of effectiveness. The reality is that

25 a lot of times, particularly biotech companies,


133 1 don't even go to Phase II unless they have some

2 indication of efficacy in Phase I.

3 I know that that doesn't fit the

4 traditional and official criteria for Phase I, but

5 they use non-validated surrogates to get some

6 indication of efficacy before making that decision

7 to go forward. So, the Phase I, Phase II, Phase

8 III distinction in many respects is even less clear

9 when it is now possible for a Phase II trial to be

10 designed for and designated as pivotal.

11 I think, again, my opinion comes back to

12 the individuals involved, the patient, the

13 physician, and particularly a clinical trial's

14 experienced physician making a decision about

15 possible benefit.

16 DR. NERENSTONE: Dr. Spiegel.

17 DR. SPIEGEL: I would ask if Grant could

18 clarify the position the FDA is in. If we are

19 really talking about a drug that is in Phase II, I

20 would pose that nobody knows during that period

21 where you are.

22 If a company comes to the agency at an end

23 of Phase II meeting and lays out all of the single

24 study or all of multiple Phase II's, and then the

25 agency could say it has knowledge of a level of


134 1 activity, but if you are called about a drug by an

2 investigator, by a patient, who knows of one

3 anecdote that looked great, or I think the last

4 comment is very good, even if Phase I had a proof

5 of concept aspect to it and some biological

6 principle was confirmed in Phase I, into and end of

7 Phase II, you don't know what the true response

8 rate is.

9 So, I think you should be comfortable

10 saying we don't know where we are if someone

11 requests it during Phase II.

12 DR. NERENSTONE: Dr. Temple.

13 DR. TEMPLE: I guess I want to press you,

14 Stacy, on the practicalities here. What I heard

15 you suggesting is that until people are ready to

16 provide quite wide access, treatment IND or its

17 equivalent, then, it doesn't make much sense to

18 have individuals do it, but there are some

19 practical considerations.

20 Companies are not always ready to provide

21 wide access, but they like to use the, I don't

22 know, pressure-releasing ability of a few

23 individuals getting the drug in the situation where

24 conceivably, if asked, we might allow a treatment

25 protocol, but nobody has actually asked for one.


135 1 That raises all the questions of

2 unfairness and capriciousness and people being in

3 the know and all that. Do you have any further

4 thoughts? What you were suggesting I think was,

5 well, once you know enough to have anybody on these

6 things, you probably know enough to have a lot of

7 people on these things, but what about the

8 practicalities, should we be saying no until you

9 are ready to do it for everybody, it is not really

10 fair or equitable to do it for a couple of people?

11 What are your thoughts about that?

12 DR. NERENSTONE: I think I was hoping in

13 the best of all situations, and I am very sensitive

14 to the fact that especially the smaller companies

15 are not going to have geared up and are not going

16 to be able to provide wide access, in the best of

17 all situations, especially with a lot of patients

18 with a disease like lung cancer, I just see this as

19 opening the flood gates, and you have to be

20 prepared for the flood gates to be opened.

21 Do I think we should absolutely prohibit

22 single patient treatment in later Phase II, if they

23 can't do that, no, I am not going to take that hard

24 a stance.

25 DR. TEMPLE: Would you want it to be done


136 1 in some way that was fair even if limited? There

2 have been lotteries, for example, where a company

3 wasn't willing to do it for a million people.

4 DR. NERENSTONE: Absolutely, I think that

5 is exactly right. Then, you have to be prepared

6 for the flood gates to be opened, because I think

7 they will be, and I am not saying that that is

8 necessarily a good thing. I don't see it as a good

9 thing, but I think that is bowing to the realities.

10 Dr. Albain.

11 DR. ALBAIN: You actually just stated what

12 I was going to state, Stacy, that I we are in some

13 of these situations right now with some of the new

14 molecules and that the pivotal trials have

15 completed, and we don't have all the answers,

16 however, there have been abstracts presented in

17 national meetings, and the companies have come

18 forward with lotteries with expanded access

19 programs, and I think that is the place to refer

20 our patients to rather than going through the

21 cumbersome process of a single use situation.

22 Although we weren't asked specifically to

23 address that, that is why I said earlier that

24 having a rapid consensus nationally on how to mount

25 these trials, how to help some of these smaller


137 1 companies do these through perhaps a central

2 mechanism when they cannot mount them individually

3 would be very useful right now.

4 DR. NERENSTONE: Dr. Blayney.

5 DR. BLAYNEY: I think I would support the

6 business of single patient exemptions, and I think

7 you ought to build that into your drug development

8 process. At the end of Phase I meetings, one of

9 the questions you might ask the sponsor is if this

10 really looks good, how do you propose a fair and

11 equal expanded access and at what point would you

12 feel comfortable doing that.

13 Some sponsors may have limited production

14 facilities, and that needs to be known in advance,

15 and I think it would give the agency, as well as

16 the sponsor, as well as the physicians and patients

17 who want access to these programs a better idea of

18 what the ground rules are going in.

19 I think also, if I may say, there may be

20 some compelling biologic reasons that may emerge

21 that you may want to give expanded access if there

22 are peculiar molecular targets that either are

23 known in advance or known beforehand with

24 individual patients whose tumors demonstrate

25 potential susceptibility to these molecular


138 1 targets, you may want to build that into your

2 thinking, as well.

3 DR. WILLIAMS: Could I clarify the

4 rationale that several of you have expressed? I

5 very clearly understood during Phase I, it was a

6 patient safety issue, you didn't have the data on

7 patient safety, but in Phase II, we do have the

8 data on safety, and you are entering your patients

9 with the hope of seeing a response rate or

10 whatever, and now perhaps you have other patients

11 that don't fit on that.

12 A company comes to you and says we are

13 early in Phase II, but we have a patient here that

14 doesn't fit, we would like to treat him by special

15 exception use, and your rationale for not giving

16 that patient an investigation agent, if they want

17 to, if the company wants to, is what?

18 DR. NERENSTONE: I think in early Phase

19 II, it is still a toxicity issue. You know, very

20 few patients have been treated on that, and so it

21 still could be much worse than placebo. So, the

22 idea of, well, doing no harm, I think is still an

23 issue here with early Phase II.

24 Dr. George.

25 DR. GEORGE: Actually, my comment is


139 1 related to that, and Dr. Williams' comment some,

2 and that is just to remind people that the

3 notorious unreliability of Phase I data, even with

4 respect to toxicity, these are very small studies

5 done with very restrictive eligibility criteria for

6 safety reasons, and then at the later stages, those

7 criteria change and just from a statistical point

8 of view, these studies are known to be very

9 reliable.

10 I have certainly been involved with a

11 number of Phase II and even Phase III studies where

12 we had to radically change dose and schedule

13 because of unexpected things.

14 So, you can't say that just because the

15 Phase I test is over, we know the toxicity, so

16 everything is okay about that, now, all we are

17 concerned about is efficacy.

18 DR. NERENSTONE: Dr. Linden.

19 DR. LINDEN: One argument I heard a little

20 while ago was that because Phase I--I am going back

21 to the Phase I question--because Phase I trials

22 have scientific objectives only, not treatment

23 objectives, under the scenario, treatment IND

24 requests should be denied, but Phase II or Phase

25 II/III trials also only have scientific objectives,


140 1 not treatment objectives.

2 So, there is a little bit of slippery

3 ground there in this group as to whether treatment

4 INDs should be permitted at all.

5 That is my comment.

6 DR. NERENSTONE: I think most people would

7 say that Phase II studies where you are looking for

8 disease response is a surrogate endpoint for

9 patient benefit. You are perhaps right in that

10 that is an abstract concept that we have not yet

11 proven, but certainly the expectation is that tumor

12 response, which is what we are measuring, is going

13 to be correlated with symptom relief and more.

14 So, I think that most of us who do

15 clinical trials would say that Phase II and Phase

16 III studies really do have patient benefit as a

17 goal of the treatment.

18 DR. NERENSTONE: Dr. Przepiorka.

19 DR. PRZEPIORKA: I just wanted to address

20 two issues regarding the Phase II studies, and that

21 is if we go back to the terminology treatment IND,

22 if we are really going to treat the patient, then,

23 we really do need to know not only safety, but

24 efficacy, there is no question about that.

25 I just want to broaden something that Dr


141 1 Nerenstone said about having performance status

2 requirements for those sorts of treatment INDs and

3 that even when we pick up the journal and read

4 about a new drug that has come out, we have to read

5 the Method section to see who was the patient

6 population that was studied.

7 When we sit down with the patient, we have

8 to tell them the results based on whether or not

9 they fit those eligibility criteria, so I would

10 even suggest that for a treatment IND, the patient

11 has to actually fulfill the eligibility criteria

12 for the study from which the activity was shown.

13 Anything else is going to be a new study,

14 and as was pointed out, even in Phase I studies,

15 and Phase II studies, eligibility criteria have had

16 to be changed because of that, and if you come to

17 the single patient exemption question, you know, it

18 would be valuable data to find out whether or not

19 the safety of that drug in such a patient would be

20 of value, but it has to be done in a controlled

21 setting. That means another study. It has to be

22 done with more than one patient.

23 DR. NERENSTONE: So, Donna, you are making

24 the safety argument that even Phase II data may not

25 be reliable enough to translate into a patient


142 1 treatment.

2 DR. PRZEPIORKA: If the Phase II study is

3 completed, and we know the activity, we know the

4 safety, and we know the patient population, then, I

5 would say yes, that would be somebody who you would

6 give a treatment IND to while you are waiting for

7 Phase III or other progress and development, but if

8 you are still within the Phase II and you don't

9 have the results yet, then, no, there is no

10 indications to treat someone with that drug.

11 DR. NERENSTONE: Dr. Kelsen.

12 DR. KELSEN: I agree, the issues for Phase

13 I, first of all, all studies have scientific aims,

14 they have primary objectives and secondary

15 objectives. Most Phase I's or at least many Phase

16 I's, the secondary objective is to look the

17 therapeutic efficacy, but it is not the primary

18 objective, it is the secondary objective.

19 The primary objective of Phase II and III

20 is an efficacy objective. It is not a scientific

21 reason you are not treating people on Phase I for

22 the single patient use, it is really just safety.

23 You just don't know the right dosing schedule, and

24 you put the patient at risk.

25 DR. NERENSTONE: Dr. Averbuch.


143 1 DR. AVERBUCH: Mostly to respond to Dr.

2 Blayney's comments, and I think to echo some of the

3 last speaker's comments about it is only going to

4 be at the end of Phase II where we begin to have a

5 level of confidence about benefit-risk, and it will

6 depend on the drug, on the patient population, on

7 the trial design, but I think it is only at that

8 point by which you can begin to make judgments

9 about expanded access and whatever setting you

10 provide.

11 The other point I want to make, I think I

12 want to throw out a very extreme caution about

13 trying to have different rules for these

14 molecularly targeted, defined agents. I mean those

15 are still hypotheses, and I think we still are

16 bound by the principles of good clinical trials to

17 either satisfy or refute those hypotheses based on

18 clinical outcomes.

19 I mean the hypothesis existed that

20 specific antiarrhythmics would lead to improved

21 mortality in cardiovascular disease, and we know

22 the outcome of some of those trials. So, I think

23 we have to be very cautious about changing the

24 rules for those molecularly defined agents.

25 DR. NERENSTONE: Dr. Temple.


144 1 DR. TEMPLE: I just want to observe that

2 what you are all saying is entirely consistent with

3 the rules of treatment IND. There has to be

4 reasonable evidence of effectiveness, obviously not

5 quite enough to get the drug marketed, but

6 something less than that, but still some, and there

7 is actually a slightly different expectation when

8 the disease being treated is fatal, which I guess

9 is the case here, and the rules suggest that it

10 will be very unusual to do that until the end of

11 Phase II or thereabouts where you have some

12 evidence, so what you are saying is quite

13 consistent with the current definitions.

14 DR. WILLIAMS: But not necessarily the

15 same as what has been done in, say, single patient

16 use.

17 DR. TEMPLE: Well, no, that is right. I

18 thought what Dr. Nerenstone said earlier is that

19 one should think of single patient uses that aren't

20 to learn something, but to provide access as

21 roughly similar to being ready to allow for almost

22 everybody. That is what I heard before, which is

23 an interesting formulation.

24 DR. NERENSTONE: Ms. Delaney.

25 MS. DELANEY: I would just like to say


145 1 something as a practical matter from the experience

2 that we have in our office, that while the focus of

3 our discussion is clearly advice to FDA and how we

4 should handle single patient INDs, our practical

5 roll up the sleeve experience with this is that

6 companies usually start by saying yes to single

7 patient INDs, and their entire, let's call it

8 compassionate use until we change it, the

9 compassionate use plan is unanticipated.

10 It is sort of like tumbleweed and it

11 starts to roll, and then panic sets in, and many

12 times also I think these are always good people

13 caught in a bad situation, but nobody wants to say

14 no to the patient, and so oftentimes companies will

15 refer patients even today inappropriately to us,

16 knowing that the answer is no, but we have to turn

17 them right back to the company and say this is a

18 decision of the company.

19 My request is that sponsors anticipate

20 this ahead of time. Think ahead what will the

21 triggers be to when they might consider a treatment

22 IND, when will they consider an expanded access

23 protocol, under what circumstances will you allow

24 single patient INDs, and not get the patients and

25 family members caught up in the phone calls back


146 1 and forth to FDA saying no, it is not our job, it's

2 the company's job. It is really very distressing

3 for people who are, for the most part, at the end

4 stage of their life.

5 DR. NERENSTONE: Dr. Santana.

6 DR. SANTANA: One of the problems I have

7 with this whole discussion is--and I think it was

8 presented by one of the patient representatives

9 earlier in a letter--was that we are really talking

10 without having much data in front of us and we are

11 trying to make these rules, if that is what the FDA

12 wants us to advise them on, on how to put patients

13 in these categories to allow this or not to happen

14 without really knowing what the real world is all

15 about.

16 It was triggered by Donna's comment in the

17 sense that for a patient to get one of these drugs

18 under the mantra that it is non-research, but it is

19 still investigational blah-blah-blah, that they

20 have to meet some eligibility requirements that are

21 very similar to the patients that otherwise would

22 go on the Phase II study, but the reality is that I

23 bet you that a lot of these requests are because

24 patients do not meet the eligibility requirements

25 as stated in the protocol or for many other


147 1 reasons, that they may not have access, they live a

2 long distance, so we are dealing with a whole

3 heterogeneous set of reasons of what initiates the

4 process to request a practitioner or a patient or a

5 family to request these products, and now we are

6 setting a brand-new set of rules that, in essence,

7 will impede that process, if that is the goal of

8 the process.

9 So, one of the questions that I have--it

10 sounds like a little bit of a circular

11 argument--but one of the questions I have for the

12 FDA is when people request this, why are they

13 requesting it, what are the reasons, is it because

14 they are not meeting the eligibility criteria for

15 studies or because it is their last chance hope,

16 and they want to get a hand on anything, or is it

17 because they don't have access to the trial. I

18 mean what are the real reasons?

19 DR. WILLIAMS: I think all of those and

20 more, and we may not even be supplied with it in

21 that way.

22 DR. SANTANA: If that is true, then, we

23 have got to be very, very careful that we don't set

24 a set of rules to allow these special exemptions to

25 be approved.


148 1 DR. WILLIAMS: Actually, you have not been

2 asked to allow them. We are mostly interested in

3 when we would say no, because we do have that

4 responsibility, and clearly we do say no sometimes,

5 not that often, but we are interested in your

6 comments about not necessarily would you in various

7 circumstances, but what is the basis for why you

8 would say no, and I think it was pretty clear about

9 Phase I, the reason behind it.

10 DR. SANTANA: Yes, for safety, I think

11 that is very true.

12 DR. WILLIAMS: I would worry too much

13 about we are not going to take these and set rigid

14 rules based on a majority vote. That is why we are

15 not even having voting, but we would like to

16 understand your reasons and get your input, because

17 we have to make these decisions on basically a

18 daily basis, and we would like to have some input

19 from the committee.

20 DR. NERENSTONE: Dr. Przepiorka, would you

21 like to respond to Dr. Santana?

22 DR. PRZEPIORKA: Yes. I would actually

23 not disagree totally with he said. I think there

24 does have to be a mechanism available for patients

25 who do not fit eligibility criteria and therefore


149 1 would not be considered, quote, unquote,

2 "treatment," that is responding to the standard

3 regimen and the eligibility criteria that was used

4 to demonstrate activity.

5 This is where I think safety protocols in

6 the expanded access setting have to be set up

7 early, because most of the patients who will be

8 treated, will be treated outside the eligibility

9 criteria, and it is really important to get some of

10 that information available.

11 I also want to address one comment that

12 Dr. Williams said earlier, which was that he

13 doesn't believe that some of the things that we

14 were discussing earlier today were actually within

15 the purview of the FDA, and one of the things that

16 I am really concerned about is there is probably a

17 lot of data from expanded access protocols and

18 safety data, and information that we could possibly

19 draw some conclusions about who should or should

20 not be treated under these circumstances.

21 It is unfortunate that it is largely

22 probably all on archaic medium, so we can't really

23 access it very well, but I would hope that the FDA

24 would have a plan to actually get that formalized

25 in the future, so that we could use that data to


150 1 make more reasonable conclusions.

2 DR. NERENSTONE: Dr. Linden.

3 DR. LINDEN: The discussion so far has

4 focused on the risk-benefit ratio and the toxicity

5 factor and the activity-benefit ratio, and we have

6 heard a lot today about the problematic use of the

7 word "compassion," and yet it is my understanding

8 that compassion is yet another element that needs

9 to be figured, that does need or may not need

10 depending on where you stand, to be figured into

11 this pot of elements that need to be taken into

12 account.

13 If that is so, if there is an element of

14 compassion in this mechanism, then, number one, I

15 would suggest that we not throw that term out of

16 our lexicon, but that that needs to be wed in some

17 way to these other factors because it is a

18 significant factor.

19 DR. PAZDUR: Just to answer this question,

20 and Dr. Santana's question, when we looked at this

21 issue, the vast majority of reasons why people are

22 looking to go onto the single patient is because of

23 too many therapies. Basically, they are third,

24 fourth, fifth, sixth line therapies, and they are

25 looking for a treatment option here.


151 1 To answer Donna's question, one of the big

2 problems that we have is just the uncontrolled

3 nature of many of these expanded access, which

4 makes really scientific conclusions very difficult

5 to make. I assume she is referring to toxicity

6 considerations in this aspect.

7 Because of the uncontrolled nature here

8 and also the reporting many times of the

9 information, it is difficult to make a really

10 scientific conclusion.

11 DR. SANTANA: I hate to be simplistic, but

12 if the majority of the patients fit in this

13 category, then, maybe the clinical study should

14 have a strata of patients that defines that

15 subgroup. That may not be used in terms of the

16 analysis of the approval process, but certainly

17 would offer the clinical investigation to go

18 forward.

19 If that is a big part of the pie, I hate

20 to be simplistic, there may be a solution to that.

21 DR. NERENSTONE: Dr. Temple.

22 DR. TEMPLE: I just want to totally agree

23 with that. There is no reason why the primary

24 efficacy analysis couldn't be done in the subset of

25 people who do have good performance status while


152 1 you maintain the other groups. I mean they are

2 already in the institution, it should be little

3 burden to include them, and you will get

4 information on what the drug is like in those, and

5 that is really an excellent idea.

6 DR. NERENSTONE: Dr. Spiegel.

7 DR. SPIEGEL: I wanted to respond to some

8 of the comments that particularly the FDA members

9 have contributed today, although I would resist Dr.

10 Temple's provocative question should the FDA demand

11 justice, I think we have enough trouble writing

12 guidances and rules for things that are better

13 understood than that. But I think it would be very

14 appropriate for the FDA either at the end of Phase

15 II, although usually we have a very limited time to

16 talk about other issues about how we are developing

17 the drug, but either in the context of that meeting

18 or when the first request comes in and an important

19 senator or somebody else has requested it, I think

20 it is appropriate for the FDA to ask us what are we

21 going to do with the next request.

22 The other thing I would say is the FDA is

23 a wonderful source of good and bad experience to

24 share with sponsors. You can't divulge proprietary

25 information about other companies' products, but if


153 1 you have seen a very good ECAP program run, there

2 is no reason why you couldn't challenge either a

3 Big Pharma company that may have done things pretty

4 well, but could do them better or might have done

5 things lousy, or small companies that are here for

6 the first time, to say have you considered, instead

7 of an individual patient exemption, doing an

8 expanded access for 20 patients and see what

9 happens, or if you want to treat 200 patients, why

10 don't you do it under these types of mechanisms

11 that might help us all learn more about it.

12 So, I would encourage the agency to feel

13 that it has the authority to have these discussions

14 with big or small companies, although I don't want

15 any rules.

16 DR. NERENSTONE: Dr. Carpenter.

17 DR. CARPENTER: I think I wanted to

18 comment on compassion. It may be under-rated, but

19 I think a number of the physicians in the field

20 also feel a certain amount of compassion toward

21 this group of patients, but feel very much on the

22 spot when they get requests in people whose organ

23 performance is bad or performance is bad where you

24 wouldn't give more standard treatment because there

25 is almost no real chance of benefit, then being


154 1 asked to give an experimental drug with a lot less

2 knowledge and a lot more uncertainty to the same

3 person.

4 So, the idea of some very general

5 guidelines about organ performance and performance

6 status, to give a person a realistic idea about the

7 chance of improving on anything, much less the

8 experimental drug, could well be part of the

9 process at some point, and I don't know whether the

10 FDA would want to say that for certain people this

11 could be done, but really don't feel it's in usual

12 guidelines of good practice. There is that person,

13 and there are some who simply exhausted the usual

14 things, does have good organ function and

15 performance, for whom a promising new drug that is

16 not yet widely available might be a very reasonable

17 option. It is getting some balance in that, that I

18 think that we are chasing issues.

19 DR. NERENSTONE: Mr. Erwin.

20 MR. ERWIN: I think these last few

21 comments have been extremely good, and one in

22 particular regarding inclusion of nontraditional

23 patient groups in clinical trials, all of those

24 patients for which people legitimately express

25 concern about safety will ultimately be treated


155 1 once the drug is approved for marketing.

2 The more insight that can be gained into

3 those populations early, the better, I would say,

4 and it gets back to the whole question of what

5 quality information do we have in this discussion,

6 how many patients, if any, have ever actually

7 received a survival benefit from individual access

8 to a Phase II, Phase I, Phase III drug, how many

9 patients, if any, have ever actually been harmed by

10 that access, how does that compare to what happens

11 after marketing approval is granted.

12 You know, there is a lot of information

13 that is probably out there that we haven't compiled

14 into a systematic way to help in these sorts of

15 debates, and it keeps coming up over and over

16 again, you know, access to god quality information,

17 a retrospective analysis that could be very helpful

18 through some mechanism.

19 DR. NERENSTONE: I suspect that that data

20 does not currently exist, nor is it retrievable on

21 the basis of discussions with FDA with single

22 patient exemptions as it now operates.

23 DR. PAZDUR: Plus many of these trials are

24 single arm, so it is going to be hard to determine

25 any survival benefit from any single-arm study.


156 1 DR. TAYLOR: Right, and the reason we are

2 doing the trials, and the reason that they have

3 strict criteria is to try to get good data and to

4 get good scientific answers, and I guess I am going

5 to show my age, but many years ago there weren't

6 the restrictions on treatment that there currently

7 are when we put people on investigational trials,

8 and what we have learned were those patients who

9 had had multiple treatments didn't respond. In

10 fact, the statistic I was taught was that after

11 each treatment, your chance of responding drops by

12 20 percent.

13 So, we have done that before. I am not

14 opposed to it. I have a lot less problem giving

15 Phase II agents out in this individual basis, but I

16 think that to criticize our trials, the reason they

17 have been developed that way was to try to give a

18 fair answer about a particular drug or a particular

19 treatment, so that a patient would know it.

20 I don't also agree that I would

21 necessarily, if that drug were on the market, give

22 it to a patient, because I think part of compassion

23 is to tell them when they are wasting their time

24 and their money.

25 If you have had four treatments for


157 1 non-small-cell carcinoma of the lung, you are

2 wasting your time and your money to do another one,

3 and if you can say that there is a benefit to

4 society because I am going to be on a Phase I trial

5 or there is a benefit in some other way, that's

6 fine, but I am not sure it is compassionate when I

7 have people coming back and forth for blood counts

8 and CT's and spending that time for something that

9 I have pretty good evidence it is not going to work

10 because they have had four prior treatments.

11 DR. NERENSTONE: Dr. Linden.

12 DR. LINDEN: Hypothetically, what if a

13 study were commenced today to look at outcome

14 measures for patients who are granted treatment

15 INDs, and a second study on expanded access, and

16 what if it were learned that the outcomes are

17 virtually, unilaterally poor for both kinds of

18 studies, and there is anecdotal evidence and more

19 than anecdotal evidence, as Dr. Taylor just

20 suggested, that people do rather poorly on

21 treatment INDs because they come to them so late,

22 because they have received so much pretreatment, et

23 cetera?

24 If we are talking about safety, that is

25 one matter, but if we are talking about activity


158 1 and efficacy, if there is no efficacy, is that a

2 basis for--and I am speaking in late Phase II

3 trials, for drugs that are in late Phase II

4 trials--is that a basis for eliminating this

5 mechanism? I am just asking this as question to

6 try to help us focus on what our justifications or

7 criteria are.

8 DR. NERENSTONE: I guess you are asking if

9 we already know that the response rate is zero, do

10 we as physicians, who are trained ostensibly as

11 scientists, have the right to refuse treatment to a

12 patient, and I would say yes. I would say I don't

13 like including the word "compassion," because I

14 don't think that that is appropriate for us to be

15 talking about.

16 I think the compassion that we show our

17 patients is at the individual level. I think we

18 have to set guidelines, and oncology likes to think

19 itself as being a part of evidence-based medicine,

20 and just as physicians have too long given

21 antibiotics for patients who walk in the door with

22 a viral infection and said, oh, the patient wants

23 it, and therefore they should get it, I think it is

24 asking us to throw out all of our medical training

25 to say we should be giving patients, and as I said,


159 1 it is not placebo, it is worse than placebo,

2 because these are toxic medications, but even if it

3 weren't toxic, should we be giving them medications

4 that we know don't work because the patients are

5 demanding it.

6 I would say no, as a licensed physician,

7 that is irresponsible and unethical because I know

8 from a science-based point of view that it is not

9 going to work. So, I would say yes, we have a

10 responsibility to tell patients no, that you should

11 not be getting this drug.

12 DR. TEMPLE: Some of the suggestions that

13 we might learn more from this experience are I

14 think unlikely to be fruitful because they are

15 uniformly uncontrolled in a population that is

16 typically not terribly well defined, so that

17 getting survival data, I think is going to be very

18 difficult.

19 This sort of violates Grant's law, but I

20 just want to throw out one thought that hasn't come

21 up much, which is the possibility that some forms

22 of expanded access could actually be done in the

23 form of large, simple trials--that was on Grant's

24 slide--especially if the likelihood of benefit is

25 modest, that is, you are talking about people who


160 1 have failed multiple therapies, then, you really

2 have to wonder what you are going to accomplish.

3 There is no requirement that treatment

4 INDs and their like not provide useful data, it is

5 just works out that way. So, there is the

6 possibility of actually randomizing. There is at

7 least one AIDS trial that randomized between two

8 doses. There are very few similar examples, but

9 that is another possibility, that the right form

10 for wider access to take in people might be one

11 that actually provides information of a somewhat

12 different kind from what we are used to, not

13 focusing so much on tumor size and things like

14 that, but on things like survival outcomes, which

15 would need large numbers and might support wider

16 access, and might actually be economically feasible

17 for companies, as well.

18 It is worth throwing into the mix although

19 it doesn't get to Grant's main problem, which is

20 single patient.

21 DR. NERENSTONE: Grant, do you want us to

22 go back to the questions?

23 DR. WILLIAMS: Let's see, how many more do

24 we have? Fifteen minutes.

25 DR. NERENSTONE: We are still on A. There


161 1 is no standard therapy. How about Phase III

2 trials? The drug is already in Phase III trials.

3 Should the patient be able to have a single patient

4 exemption? Have we beaten that to death? I think

5 the general consensus is that would be okay.

6 DR. REDMAN: I disagree for the record.

7 DR. NERENSTONE: B. Available treatment

8 shows a marginal survival benefit. Non-metastatic

9 lung cancer, 1 to 2-month median survival, produces

10 moderate toxicity. Should they be able to

11 get--Phase I, we have sort of talked about, Phase

12 II or Phase III? I don't think it is really a big

13 different discussion actually than we have already

14 had.

15 DR. WILLIAMS: It is because we are no

16 longer talking about whether they have used all

17 available therapies. Here, we are saying available

18 therapy has 1 to 2 month survival benefit. What

19 would you have to see in a drug to allow you to

20 substitute it for that, or does it even play into

21 your consideration?

22 DR. NERENSTONE: Dr. Albain.

23 DR. ALBAIN: I guess I would ask you,

24 Grant, at least we have numerous in untreated

25 metastatic non-small-cell trials that have shown an


162 1 improved survival benefit, not just measured in

2 median, but we are talking about significant 1- and

3 2-year survival benefit, and quality of life

4 benefit versus best supportive care.

5 These trials have been conducted in

6 Canada, the United States, and Europe, so that I

7 would personally have a problem making a broad

8 statement that one could allow someone to go off

9 onto experimental therapy when you had standard

10 therapies that not only improve survival, but

11 improve quality of life, and that is where the

12 education of the patient comes back in, and the

13 public, on what can be achieved in this disease.

14 DR. WILLIAMS: That is this agent is

15 nontoxic, it seems to be relatively nontoxic, let's

16 say, and has a response rate. Would you allow it

17 or not?

18 DR. ALBAIN: Right now I thought we were

19 talking about Phase I.

20 DR. NERENSTONE: No, we are moving to end

21 of Phase II.

22 DR. WILLIAMS: Where would you draw the

23 line, what amount of efficacy or proven efficacy or

24 toxicity of this drug, in what setting would you

25 allow it, or would you never allow it?


163 1 DR. ALBAIN: I think I would work very

2 hard first to educate the patient and the family

3 about what we can achieve with standard therapy in

4 this scenario where not only do we know that we

5 have an improved statistical survival benefit, but

6 we have quality of life data over and over now that

7 is compelling, that it is better with treatment.

8 DR. NERENSTONE: Dr. Taylor.

9 DR. TAYLOR: I would disagree a little

10 bit. I would say that in this setting, I would not

11 be opposed to giving them a Phase II agent because

12 I don't have a curative treatment, and it is a very

13 small group of patients that gain that benefit. I

14 don't disagree that because there is something

15 standard available, that that shouldn't be brought

16 up to them as one way of doing it, but I have no

17 problem with giving Phase II agents to patients

18 with non-small-cell lung cancer.

19 DR. NERENSTONE: But remember off study.

20 Dr. Sledge.

21 DR. SLEDGE: This actually is an area

22 where we have a little data, actually from your

23 group, Kathy, in breast cancer, where there was

24 several years ago a randomized trial in breast

25 cancer between novel Phase II agents--


164 1 DR. ALBAIN: It was not my group, it was

2 the CALGB.

3 DR. SLEDGE: --CALGB--between novel Phase

4 II agents and standard therapy.

5 That trial was done with very strict

6 criteria, which is if you progressed after a couple

7 of cycles of therapy on the nonstandard regimen,

8 you went to the standard regimen, but there was

9 identical survival between the two groups.

10 It is hard for me to imagine that if you

11 had it under that sort of carefully controlled sort

12 of setting, that it would be a danger. The real

13 danger, of course, comes up due to the fact that

14 most of these settings are not carefully

15 controlled.

16 DR. WILLIAMS: George, that was with

17 progression, going off study if you did not

18 respond?

19 DR. SLEDGE: Correct. My recollection of

20 the trial was if you got two cycles, six weeks, 10

21 weeks of therapy, and had evidence of progressive

22 disease, you immediately crossed over to the

23 standard therapy.

24 There was identical survival between the

25 two arms.


165 1 DR. WILLIAMS: How large was the trial, do

2 you know?

3 DR. SLEDGE: It was actually a set of

4 rotating Phase II trials compared to a standard

5 arm. It was a fairly large database.

6 DR. ALBAIN: I was not disagreeing, Sarah,

7 with offering this end of Phase II investigational

8 drug, but my concern would be if that was a broad

9 policy, that some patients would not derive the

10 benefit of quality survival for 1 to 2 years with

11 extensive small-cell, and to go back to Dr.

12 Sledge's point, we don't have that data from that

13 breast trial available in extensive non-small-cell

14 lung cancer now that we have therapies that can

15 improve quality of life in the standard setting,

16 although one could argue the breast standard agents

17 did do that, so it's a good point.

18 But I think it is education. I would be

19 very nervous about letting a message get out that

20 this is an appropriate setting when we have worked

21 so hard to educate the lay community about what we

22 can achieve for lung cancer survivorship.

23 DR. NERENSTONE: I think that is a very

24 important point because I think all of these

25 scenarios are when the FDA is approached with this


166 1 problem. That is not to say this is something that

2 we advocate as treatment at all, and I think that

3 is a very important tenet, to make sure everybody

4 understands, because this is going to be

5 disseminated widely and this is for the patient who

6 has decided after a lot of counseling with their

7 private physician why this is probably not a great

8 idea and insists on it anyway.

9 DR. NERENSTONE: Dr. Carpenter, did you

10 want to add anything?


12 DR. NERENSTONE: Dr. Blayney.

13 DR. BLAYNEY: I would be reluctant to

14 advise the FDA to allow a single patient exemption

15 at the end of a Phase II, I think in this setting,

16 because I think it may jeopardize further drug

17 development both because of accrual to clinical

18 trials and it may uncover some toxicity that would

19 take some time to explain and impede the timely

20 development of a potentially rational and useful

21 therapy.

22 DR. NERENSTONE: If we can go on then to

23 the third scenario. Standard therapy provides a

24 substantial prolongation of median survival. That

25 is a patient with advanced ovarian cancer, 1 to 2


167 1 year median survival benefit, but is generally not

2 curative.

3 I would be happy to start this

4 conversation. I would find it very difficult to

5 approve someone who is not going to take standard

6 treatment, which in general is not

7 life-threatening, does not have prolonged severe

8 permanent side effects, and instead, wants to use a

9 single patient exemption for a drug that is in

10 Phase II where we have no idea of its activity and

11 its survival benefit or even duration of median

12 response benefit as a single agent.

13 So, I would be hard pressed to think that

14 this is a good idea.

15 MR. ERWIN: I agree with you this time.

16 [Laughter.]

17 DR. ALBAIN: Stacy, what do you say if it

18 is in Phase III, though, what is your reply?

19 DR. NERENSTONE: Single agent treatment is

20 not a standard in the United States, and I would be

21 hard pressed to think that a single agent is going

22 to be better or even the same as our current

23 upfront treatments.

24 So, usually, when you are talking about

25 Phase III, it is in combination with something else


168 1 by the time it gets to Phase III, so as a single

2 agent, I don't see the scenario where that would be

3 appropriate.

4 DR. WILLIAMS: So, you would like to see

5 results from the randomized trial showing a similar

6 sort of outcome.

7 DR. ALBAIN: The reason I jumped to that,

8 as we all know, the new agents, the small molecules

9 are going from Stage 1, quasi-Phase II, and

10 oftentimes not a true Phase II trial, into Phase

11 III, leapfrogging, so that I don't know that we

12 want to give the message that we are all saying

13 that Phase III trials, if it is out there, that we

14 could go ahead and justify, so I wouldn't in this

15 situation.

16 DR. KELSEN: It does get a little muddier

17 when you have a study--I will disagree with you on

18 that--when we have a Phase III or a Phase II trial,

19 we have an experimental drug plus conventional

20 therapy in some of these settings, so what they are

21 saying is, oh, well, I have this small molecule,

22 monoclonal antibody, and it is being used in

23 combination with proven, approved, approved for

24 that indication chemotherapy, but I don't fit

25 entrance criteria into the study, and I would like


169 1 to get that drug. That makes it a harder decision.

2 The easier decision for me is the patient

3 perfectly fits criteria for the trial, but says I

4 don't want to be randomized to that arm. As soon

5 as you do that, then, it would be very hard to do

6 Phase III trials.

7 DR. NERENSTONE: I think, though, that

8 that is the problem. When you start allowing that

9 drug to be given out as the adjunct, you will

10 completely shut down your clinical trials, and

11 again, these are molecules not without very high

12 cost, some toxicity, and you are going to get into

13 the same problem you had with the bone marrow

14 transplant situation, which is everybody got it, no

15 one went on to study, and you never knew what the

16 real answer was to your question.

17 DR. KELSEN: I agree with you. I am just

18 saying it's an even trickier situation.

19 DR. NERENSTONE: Dr. Przepiorka.

20 DR. PRZEPIORKA: Just to underscore that,

21 I think if you are writing rules for yourself, one

22 rule to say no is patient is eligible for a study.

23 Then, they should not be under treatment IND.

24 DR. NERENSTONE: Dr. Linden.

25 DR. LINDEN: And that is precisely part of


170 1 the regs, that is written in stone. If the person

2 is eligible for a trial, they are not eligible for

3 treatment IND or expanded access.

4 DR. WILLIAMS: It may or may not say that

5 for treatment IND, but it doesn't even cover

6 expanded access. I mean some of these practices,

7 there really aren't regs for at this time.

8 DR. LINDEN: Well, treatment IND.

9 DR. WILLIAMS: Right.

10 DR. TEMPLE: Actually, it says that we can

11 stop a trial that is interfering with the

12 randomized trials. It doesn't actually say that

13 they can't both coexist. Maybe it could, but it

14 doesn't.

15 DR. BLAYNEY: I think, Grant, you also

16 raised the issue if the drug is nontoxic or very

17 close to being nontoxic, I think the response to

18 that is we don't, if it's nontoxic, it is likely

19 that the pivotal trial or the licensing trial will

20 move along and accrue very quickly, and you can, by

21 granting a single patient exemption, you can

22 perhaps impede that, and you don't want to impede

23 the completion of the pivotal trial, so I think you

24 also have an easy answer even if the drug has zero

25 toxicity.


171 1 DR. NERENSTONE: Moving on to the next

2 question, then. The standard therapy provides a

3 substantial rate of cure. The example is a patient

4 with acute leukemia who does not want to receive

5 chemotherapy that is associated with a 40 percent

6 rate of cure with substantial acute toxicity, but

7 that produces few lasting toxic effects.

8 Would some of our leukemia doctors like to

9 comment?

10 DR. SLEDGE: How about if the leukemia was

11 CML?

12 [Laughter.]

13 DR. WILLIAMS: George, you have been

14 wanting to say something.

15 DR. SLEDGE: What I am asking is the

16 obvious question. I mean we have a drug that

17 basically was approved on a Phase I and early Phase

18 II trial basis. We have a disease where we have a

19 proven long-term cure rate with albeit a very toxic

20 therapy. The ethical considerations must have

21 entered into your approval process.

22 DR. WILLIAMS: It wasn't approved for

23 initial therapy.

24 DR. SLEDGE: But you know darn well what

25 it is going to be used for.


172 1 DR. NERENSTONE: Other comments from the

2 committee?

3 DR. WILLIAMS: George is unhappy we didn't

4 bring it to the committee.

5 DR. BLAYNEY: What I said three minutes

6 ago applied to that, and that is approved for

7 principle. If it is a relatively nontoxic drug,

8 the trial was done very quickly, and you didn't

9 need this individual, a single agent exemption, and

10 fortunately, the company was responsive and had an

11 expanded access program in place, so that is

12 exactly what is approved for principle, that is why

13 you don't need the single patient exemption for

14 such a home run, a nontoxic home run.

15 DR. NERENSTONE: Dr. Przepiorka.

16 DR. PRZEPIORKA: I think perhaps a more

17 germane example would be the alternative drug for a

18 treatment IND is one that has no cure rate, but a

19 lot less toxicity and perhaps can just keep things

20 under control for an extended period of time.

21 I think there you have to start weighing

22 the risk and the benefit if the patient really and

23 truly says no, I don't want toxic therapy, period,

24 which patients can do especially elderly patients.

25 Then, the question is what do we benefit from the


173 1 investigational drug, and if the investigational

2 drug has shown efficacy or rather has not shown any

3 safety problems and does keep things under control

4 for a period of time, then, this may be something

5 that we are going towards palliative care.

6 So, it may be appropriate for a treatment

7 IND for a palliative care setting, but if this is

8 another drug that doesn't have a good cure rate,

9 and we are really not too sure whether it has any

10 efficacy at all, then, I would say no, there is no

11 reason to give something to the patient that

12 doesn't harm him, but we really don't know if it is

13 going to help him either.

14 DR. NERENSTONE: So, you are saying there

15 has to be some clue of efficacy even in this

16 situation.


18 DR. SPIEGEL: I am just curious on that

19 last comment, what you are accepting as evidence of

20 efficacy. At the end of Phase II, we have

21 activity. We sometimes call it efficacy, but we

22 usually think only at the end of Phase III, where

23 you have compared it to a standard therapy and

24 showed long-term benefit of some type, it could be

25 quality of life benefit, not just survival.


174 1 But at the end of Phase II, you know you

2 have activity unless you have CML with Philadelphia

3 chromosome disappearing, you usually don't really

4 have that much confidence that whatever you saw as

5 a response is sustainable and better than standard

6 therapy.

7 DR. PRZEPIORKA: That is a very good

8 question, and I would actually like to turf that to

9 Dr. Taylor. If you have a patient, an elderly

10 patient with leukemia who really doesn't want to

11 undergo toxic therapy, how much activity would you

12 look for to give him something palliative?

13 DR. TAYLOR: I don't know that I think I

14 have to give him some anti-cancer treatment to

15 palliate him, and I think you have to decide that

16 with the patient whether it is going to be

17 palliation with symptom management, pain control,

18 nausea control, or whether you are truly going to

19 try to palliate in terms of lowering white counts

20 and lowering the complications of that disease. I

21 think palliation can be done either way, and it is

22 going to be dependent upon that patient and what

23 their goals are. I think they have to determine

24 their own goals, and some of them choose, their

25 goals are just to be comfortable, and others want


175 1 to try some less than aggressive treatment.

2 In that setting, I don't know that I have

3 to have great response for efficacy data if I have

4 good toxicity profile and which I am not going to

5 aggravate my palliation.

6 DR. NERENSTONE: I guess the question is,

7 if you don't need any efficacy data, and it is a

8 drug that hasn't been studied in the leukemia, but

9 it has very low toxicity, is it reasonable to have

10 that patient call up and say I want that drug, and

11 essentially tell you what to give them, because it

12 is not toxic?

13 DR. TAYLOR: Well, I guess the practical

14 part says I rarely have that happen, that when

15 someone has chosen that they don't want to be

16 aggressive, I don't have them asking for new

17 agents.

18 DR. NERENSTONE: But they do, the FDA

19 does.

20 DR. TAYLOR: But is it in the setting

21 where they have really chosen to not be aggressive?

22 DR. WILLIAMS: This specific question was

23 set up. We have a few examples where people have

24 very good curative treatment, we are not talking

25 that person who really doesn't have good option,


176 1 really do have curative treatment, they don't want

2 it. They want investigational drug, and we have

3 felt that going along with that was not in the

4 patient's best interest, and there has been

5 autonomy issues.

6 DR. TAYLOR: I agree with you on the

7 autonomy, but I guess what I was hearing is I have

8 an elderly patient, I am sorry, I don't like the

9 response to acute leukemia treatment in elderly

10 patients, they don't do well, so that is a little

11 bit different.

12 DR. WILLIAMS: But that is a different

13 value judgment, a little farther on down the line

14 toward the lung cancer, I would say, or even before

15 that. The answer to this is probably pretty

16 obvious, even what you said with ovarian cancer, I

17 mean this is even higher level of benefit that

18 someone might be deciding they don't want, because

19 they want this new treatment.

20 DR. NERENSTONE: What I would say is that

21 somebody who has a treatable pneumonia, but they

22 want echinacea, and they want you to prescribe it,

23 and I would say no, I am a doctor, I prescribe

24 antibiotics, that is the appropriate treatment.

25 You can't get echinacea from me.


177 1 DR. TAYLOR: Right, and if this is a young

2 person who has no reason for avoiding his acute

3 leukemia treatment, then, I agree, I would not want

4 to go with any.

5 DR. NERENSTONE: Dr. Blayney.

6 DR. BLAYNEY: There are plenty of other

7 nonexperimental alternatives for that person,

8 prednisone, or whatever fits into their value

9 system, but I was also going to go the CML one step

10 further, that if hidrea was the experimental agent,

11 it is nontoxic, it is largely palliative, I think

12 that is a reasonable palliative maneuver.

13 But anyway, to your specific example,

14 there are plenty of non-IND requiring agents to

15 mistreat acute leukemia.

16 [Laughter.]

17 DR. NERENSTONE: Do we need to go to E?


19 DR. NERENSTONE: You get the general

20 sentiment.

21 Question 2. As noted above, the FDA

22 strongly endorses participation in clinical trials.

23 Patients should first consider entering a clinical

24 trial before pursuing treatment under a single

25 patient IND. If a patient is eligible and able to


178 1 receive Drug X as part of a clinical trial, but is

2 unwilling to do so, should that patient be allowed

3 to receive Drug X under a single patient IND?

4 Again, we have answered that. No is the

5 sentiment I think of the committee.

6 Mr. Erwin?

7 MR. ERWIN: I definitely agree the answer

8 should be no, but as a separate topic, I think

9 there needs to be consideration of how and when to

10 use crossover provisions in clinical trials. I

11 think that that can definitely accelerate accrual

12 and for the right agents and the right clinical

13 trial design. It doesn't have to interfere with

14 getting efficacy data.

15 DR. NERENSTONE: Question 3. If FDA has

16 sufficient evidence to conclude that a drug is

17 ineffective for treatment of a particular cancer,

18 discuss under what circumstances, if any, single

19 patient treatment use should be permitted.

20 You know how I feel about this, though. I

21 will open it up to the committee.

22 DR. TAYLOR: I agree, it should not be

23 used.

24 DR. NERENSTONE: Any other comments?

25 Do you feel that you have gotten what you


179 1 need?

2 DR. WILLIAMS: Yes, very much. Let me

3 just ask one question. There was a lot of

4 discussion about whether we should have a consensus

5 conference, who should be involved, et cetera. I

6 would just like to hear a little discussion about

7 where should we go in trying to move forward the

8 discussions about the justice of how to do these

9 programs.

10 We have talked about when you shouldn't,

11 when FDA should say no, but is there maybe a

12 different level for the industry and the community

13 when should it be provided, and how should it be

14 provided.

15 What do you think about how we should go

16 forward, who should be involved?

17 DR. NERENSTONE: Dr. Albain.

18 DR. ALBAIN: Grant, I just want to make

19 clear that we have been saying a lot of no's for

20 the single patient query to you, but I don't think

21 we have been saying no's to proper design of

22 expanded access programs or treatment IND programs,

23 that the companies can start planning very early in

24 their process of drug development as we are into

25 this exciting era of small molecules.


180 1 I think the time is ripe to have dialogue

2 about that issue at a national level.

3 MR. DIXON: I think, by and large, the

4 advocacy community would very much welcome a

5 consensus conference on this. The community itself

6 does not speak with one voice, and even more reason

7 why a consensus conference would be beneficial for

8 all of us.

9 DR. PAZDUR: We had entertained, and we

10 will be talking to people from the NCI, ASCO,

11 advocacy in general, and industry, PhRMA, to bring

12 this together, because we really think that this

13 needs further really voicing and looking at where

14 we would go with this whole topic.

15 DR. NERENSTONE: If there are no further

16 comments, thank you, everybody, for that discussion

17 and we will re-adjourn at 1 o'clock. This is a

18 closed session only, so it is just the committee

19 members and FDA.

20 Thank you.

21 [Whereupon, at 12:10 p.m., the Open

22 Session adjourned.]

23 - - -