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Jane E. Henney, M.D. - Cancer Research Foundation

"This text contains Dr. Henney's prepared remarks. It should be used with the understanding that some material may have been added or deleted during actual delivery."

Remarks by:
Jane E. Henney, M.D.
Commissioner of Food and Drugs
U.S. Food and Drug Administration
for

Cancer Research Foundation of America
Colorectal Cancer: Clinical Trials and Treatment Options

Washington D.C.

March 17, 2000

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Good evening. I am very pleased to take part in this conference. I would like to talk briefly about the availability of drugs and drug combinations for treating colorectal cancer, and the challenge we face collectively regarding the conduct of clinical trials that will need to be undertaken to find answers for this disease.

First let me say that I strongly support your efforts to bring public attention to the very serious health problem presented by colorectal cancer. The threat of this disease--which can be prevented or treated very successfully if discovered early--is in large measure due to the lack of awareness the public has on screening and prevention.

The diagnosis of any type of cancer just a few short years ago was mentioned only in whispered tones, if at all. Treatment options were few. Diagnoses were not discussed and dealing with the silence was a killer. Still, colorectal cancer has had nowhere near the attention of certain other cancers. But that is beginning to change. People are starting to pay more attention, with increased educational campaigns, the recent death of Charles Schultz--the creator of Peanuts, and the well-publicized battle against colorectal cancer by Jay Monahan, Katie Couric's husband. We have to remember that in order to deal with the disease one must confront the silence and fear first.

I applaud Katie Couric's conviction, bravery and continued commitment to bring this matter to the attention of the world. She is doing enormous good in getting people to talk about this illness and...to realize the importance of being tested on a regular basis. I think we all recognize the challenge of getting people to think about this disease, and then to have them actually phone their doctors and ask to be screened...and if diagnosed, to see what treatment options are available.

Clearly, our emphasis should be on screening and prevention--this is critical to reducing the suffering and death caused by colorectal cancer. While we have useful screening tools--sigmoidoscopy, colonoscopy, "virtual colonoscopy," and tests for occult blood in stool, these are only useful when put into practice. Increasing the awareness to this disease is the responsibility of all of us in the healthcare delivery system.

What are the treatment options once the cancer has developed?

5-fluorouracil, or "5-FU" has, of course, been around since the 1950's. Many chemotherapeutic agents alone and in combination were then studied with no standard second line treatment once a patient relapsed. CPT-11 (irinotecan) received accelerated approval in 1996 as a treatment for patients with colorectal cancer whose disease had progressed in spite of treatment with 5-FU-based therapy. Prior to this there was no standard second-line treatment available for this refractory disease.

Another product approved by FDA last December was Celebrex, for treatment of polyps in familial adenomatous polyp syndrome--a precancerous lesion. Celebrex is the first chemotherapeutic agent approved for this syndrome, and an important advance in preventing progression of this cancer.

As for treatment prospects on the horizon...as you may know, the FDA Oncology Drugs Advisory Committee met yesterday to consider two new drug therapies for colorectal cancer.

The first therapy presented to the Advisory Committee was CPT-11 in combination with 5-FU/LV (5-fluorouracil and leucovorin). As I mentioned, CPT-11 has already been approved for those cases where 5-FU has failed. Now, approval is being sought for these three drugs in combination as a first line treatment.

The second is Oxaliplatin in combination with 5-FU/LV as a first line treatment for colorectal cancer. This treatment combination is currently approved in France.

The advisory committee unanimously recommended approval of CPT-11 plus 5-FU/LV as first line therapy for metastatic colorectal cancer. The committee unanimously recommended DISAPPROVAL of oxaliplatin plus 5-FU for metastatic colorectal cancer.

Dr Richard Pazdur, Director of the Division of Oncology Drugs, at FDA's Center for Drug Evaluation and Research, will be presenting data tomorrow afternoon on these two therapies.

We are encouraging industry to develop drugs that will move the field forward, and improve the options for treatment of this very serious disease and fortunately, in the past few years, more have shown interest. For drugs under consideration, we have consistently asked, "What will be the clinical benefit in the first line setting?"

In addition, we have made a concerted effort to move new drugs through the approval process as efficiently as possible. In the case of CPT-11, we used the "accelerated approval process," meaning that approval was granted on the basis of a surrogate endpoint such as response rate, with the understanding that survival studies would be done after the drug was approved. Most colorectal cancer drugs--in fact, most treatments for all cancers--are put on the accelerated approval track.

We have shortened the approval time for cancer therapies by expanding this use of the accelerated approval mechanism. FDA approved a number of therapies under this mechanism in FY 1999. We also expanded access to investigational drugs to ensure that cancer patients in the U.S. have access to potentially beneficial treatments approved by recognized foreign regulatory authorities, but not approved in this country.

Eight drugs were approved this past year for the treatment or diagnosis of cancer, including epirubicin (Ellence) for treating early stage breast cancer; temozolomide (Temodar), for the treatment of adult patients with a relapsed anaplastic astrocytoma; and a new indication for Taxotere as a drug for non-small cell lung cancer that is refractory to cisplatin-based chemotherapy. Also significant was the approval of denileukin diftitox (Ontak), a new biologic treatment of patients with advanced or recurrent cutaneous t-cell lymphoma. In addition, we approved a drug/device combination product using aminolevulinic acid HCl (Levulan Kerstick) for the treatment of certain precancerous skin lesions.

Looking at all drugs evaluated...In 1999, FDA took actions on 185 New Drug Applications, 77 of which were approvals. The median approval time was 11.9 months, a one-percent decrease in median approval time compared with FY 1998. 49 of these new drug applications were approved in 12 months or less. Of the 77 approvals, 27 were for new molecular entities--drugs that are structurally different from those already on the market. The median approval time for new molecular entities was 9 months, a 25% decrease compared with FY 1998. Of the 27 new molecular entities, 19 were drugs given a priority review, because these products offered a significant improvement over currently marketed drugs.

In FY 99 the Center for Biologics Evaluation and Research approved one vaccine and seven therapeutics. Among the approvals were etanercept (Enbrel), a genetically-engineered protein indicated for reducing the signs and symptoms of moderate-to-severe active rheumatoid arthritis; LYMErix, a Lyme disease vaccine (Recombinant OspA) for active immunization against Lyme disease in individuals 15-70 years of age; and a new indication for Antihemophilic Factor/von Willebrand Factor Complex (Human), marketed as Humate-P. This product is now approved to treat severe or hard-to-treat cases of von Willebrand's disease.

All of these advances came about in a scientifically and methodologically sound fashion and required the willingness of patients to participate in clinical trials.

From a patient's standpoint, often the primary purpose of participating in a clinical trial is to get access to an important new treatment that is not commercially available. Patients faced with life-threatening illnesses are willing to accept significant risk in taking an unproven drug if they think it will make a difference in their condition--or let them live a little longer. Patients clearly volunteer for altruisic reasons as well, reasoning that if a treatment does not benefit them directly, others will benefit from the knowledge gained.

Particularly when a perceived blockbuster drug is developed and made available to clinical trial participants, patients will stand in line to get into a trial. For instance, when Taxol, for ovarian cancer, and Herceptin, for breast cancer--were developed, patients were clamoring to enter the clinical trials.

Clinical trials have both paybacks and drawbacks for physician investigators as well. Being involved with discovery and development of new therapies is exciting as we all want something even better for our patients than most of today's treatments offer.

But participation in a clinical trial means spending the extra time and dealing with the necessary but tedious detail of proper clinical trial conduct.

Unless the drug or treatment is thought to be highly likely to offer additional benefit to traditional therapy, a physician may not think it is worth the patient's--nor his or her--extra effort to participate in the clinical trial. We know that the attitude of a physician can have a great deal of influence on his or her patient's desire or willingness to pursue a clinical trial. If the physician seems negative about the clinical trial option, the patient may be less inclined to pursue the option. If the physician is too enthusiastic or optimistic, patients may receive a false impression about the promise or the benefits in participating.

Another issue that can be a barrier to a patient's entry into a trial is that the patient may be precluded from participating by the specific study's eligibility criteria (clinical parameters, for example, or the fact that they cannot be on any other study drugs).

With respect to this challenge, the FDA is committed to a careful rethinking of this matter. Current eligibility requirements often result in an artificially defined population being studied. We believe a reassessment of the eligibility criteria, so that the clinical trial populations will better reflect the population that will actually be taking the drug, should be considered. It is only when we are able to accomplish this that we will have a high degree of confidence that effects are real, and the side effects have been reasonably characterized.

Even though we know that many patients with life threatening diseases tend to be extremely well educated about their diseases, potential therapies and ongoing research...learning about new developments from their doctors, books, the media, the Internet...a concerted effort is being made to make sure individuals are generally aware of the wide range of clinical trials in which they may be eligible to participate.

Several years ago, when I was at the National Cancer Institute, we started a computerized database, PDQ, to assist physicians and patients in their search for information about a particular disease and possible protocols available. These early efforts have now been greatly enhanced with the development of the clinical trials database by the National Institutes of Health. We at the FDA have felt privileged to work in this collaborative effort to increase knowledge of and enrollment in clinical trials. The database is available on the Internet at and is housed and maintained at the National Library of Medicine.

ClinicalTrials is being developed as a result of a critical portion of the 1997 FDA Modernization Act that required the Department of Health and Human Services, through the NIH, to establish a registry of clinical trials for both federal and privately funded trials of experimental drugs for serious and life-threatening diseases and conditions. The database includes a description of the purpose of each experimental drug, eligibility criteria for participants in clinical trials, location of trial sites, and points of contact for those who want to enroll in a clinical study. Also included will be information pertaining to the results of the trial--with consent of the sponsor--such as potential toxicities associated with use of the experimental drug.

Right now the database contains over 4000 clinical studies sponsored primarily by NIH. In the next year it will be expanded to include additional studies from other federal agencies and the pharmaceutical industry.

The site contains a great deal of background explanation about the clinical trial process, health care information from the National Library of Medicine, and links to other sites such as "healthfinder," a consumer health and human services information website. The database can be browsed by disease or condition, or by sponsor, to identify the kinds of research for which clinical trial subjects are needed. It also provides a wealth of information for patients on protection of volunteers, such as informed consent, data monitoring committees, FDA inspections and institutional review boards--IRBs.

The National Library of Medicine also has a list of current and past clinical trial participants who are available to discuss their experiences in locating and participating in a medical study. [List is available by calling 301-496-6308.]

While there are significant challenges to increasing participation in clinical trials, the ClinicalTrials database is a step in the right direction and will be a critical resource for both patients and physicians seeking treatment options beyond the traditional therapies available. This is particularly important for the development of cancer therapies, including treatments for colorectal carcinoma, for which new options are being studied. I encourage your using-and encouraging others to use-this important tool.

Tremendous progress has been made in increasing the number of treatments available for many types of cancer. Survival times are improving, and in many cases prognoses are good for patients dealing with cancers that would have been fatal just a few years ago. FDA is encouraging industry to target research and development toward therapies that will offer benefits beyond those of drugs previously approved. Proposed new cancer treatments are being reviewed in an accelerated fashion, making new treatments available to those who need it, as efficiently as possible. FDA, and others involved in health care and patient advocacy, are increasing educational efforts to inform consumers about the importance of prevention and screening, treatment options that are available for those who have cancer, and opportunities to participate in clinical trials.

With increased awareness by the public of the importance of prevention and early detection of colorectal cancer, the promise of expanded treatment options, and the potential benefits obtained from clinical trial participation--both for individuals and the patient population as a whole-we can reduce the suffering and death caused by this deadly, but largely preventable, disease.

I look forward to working with you and many of the organizations you represent as we address this challenge.

Thank you for the opportunity to be here tonight and for the work you do.