DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ONCOLOGIC DRUGS ADVISORY COMMITTEE OPEN SESSION
Thursday, June 7, 2001
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
GUESTS AND GUEST SPEAKERS (Non-Voting)
Steven D. Averbuch, M.D.
Carl F. Dixon
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
C O N T E N T S
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
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
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,
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
7 DR. NERENSTONE: I am Stacy Nerenstone,
8 Medical Oncology, Hartford Hospital.
9 DR. TEMPLETON-SOMERS: Karen Somers,
10 Executive Secretary to the committee, FDA.
11 DR. GEORGE: Stephen George, Duke
13 DR. SLEDGE: George Sledge, Indiana
15 DR. REDMAN: Bruce Redman, University of
17 DR. PRZEPIORKA: Donna Przepiorka, Cell
18 and Gene Therapy, Baylor College of Medicine,
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
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
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
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
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
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
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.
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
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
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
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
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
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
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
23 1. The approved therapies are not
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
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
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
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
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
7 When looking at single patient
8 compassionate use, several areas of concern stand
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
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
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
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.
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.
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.
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
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.
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
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.
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
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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
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.
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
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
17 So, these were the problems addressed in
18 the Astra/Zeneca expanded access experience.
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.
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
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
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
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
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
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
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.
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.
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.
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
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.
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.
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
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.
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
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
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.
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
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
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.
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
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.
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
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
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.
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
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.
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.
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
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
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
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.
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.
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.
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
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
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
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
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
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 clinicaltrials.gov, 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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
16 DR. WILLIAMS: George, that was with
17 progression, going off study if you did not
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?
11 DR. CARPENTER: No.
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
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
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.
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
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
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
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
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
10 DR. SLEDGE: How about if the leukemia was
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
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
17 DR. PRZEPIORKA: Yes.
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
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
18 DR. NERENSTONE: But they do, the FDA
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.
17 DR. NERENSTONE: Do we need to go to E?
18 DR. WILLIAMS: No.
19 DR. NERENSTONE: You get the general
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
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
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
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 - - -