Promising Therapies for Seriously Ill and Dying Patients

 

Statement of

Richard Padzur, M.D.
Director
Division of Oncology Drug Products
Food and Drug Administration
Department of Health and Human Services

before

the House Committee on Government Reform

June 7, 2000

INTRODUCTION

Mr. Chairman, Members of the Committee, I am Richard Pazdur, M.D., Director, Division of Oncology Drug Products (the Division), Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA or the Agency). The Division's mission is to ensure that new cancer drugs are as safe and effective as possible and to facilitate access to promising therapies for seriously ill and dying patients when no other treatment is available. Prior to coming to FDA approximately nine months ago, I was associated with the M.D. Anderson Cancer Center in Houston, Texas, for eleven years where I was involved in patient care, cancer research, medical education, and administration.

Because of my prior experience with patient, academic, and scientific communities, I am acutely aware of the impact FDA's processes and decisions have on the public we serve. Under the Federal Food, Drug, and Cosmetic (FD&C) Act and related statutes, the Government has a vitally important role in helping to ensure that the medical products upon which patients and their health care practitioners rely are both safe and effective. These safeguards are particularly important for our most vulnerable citizens, those who are seriously ill.

Having treated and worked with cancer patients and their families for the past 20 years, I have seen the face of desperation frequently. When the effective treatment options have been exhausted, some cancer patients contact FDA asking for help in getting access to an unapproved product that is being investigated.

We understand that cancer patients and their family members are often unfamiliar with FDA's legal and regulatory responsibilities, and often are unaware that FDA cannot lawfully compel a company to supply an individual patient with an investigational drug outside of clinical trials. To more thoughtfully work with the concerns of cancer patients and their families, FDA hired staff in 1994 who are available to answer their questions and listen to their concerns. I will describe the functions of this office in greater detail later in my testimony, however, I want to emphasize that FDA staff spends time with these callers explaining, to the extent that our confidentiality restrictions allow, how and why we make our decisions.

I am pleased to share with you what our Agency is doing to accelerate the development of new treatments for cancer, to provide access to unapproved treatments, and to meet the needs of cancer patients and their families. First, however, I would like to address the specific issues raised in your letter of invitation to FDA, to the extent that information is available and public.

Mr. Chairman, you have requested that as part of our testimony, we discuss clinical trials in complementary or alternative therapies for cancer that FDA has under investigational new drug (IND) application status, information on the types and numbers of calls the Agency receives regarding these therapies, information we provide to the public about these treatments and about complementary and alternative medicine (CAM), an explanation of the process that a family goes through in being able to access a clinical trial for an alternative cancer therapy and the reasoning why a less toxic, safer therapy cannot be tried prior to a therapy that has known serious adverse events, and last but not least, the role of freedom of choice in medicine.

CLINICAL TRIALS IN COMPLEMENTARY OR ALTERNATIVE MEDICINE

When it comes to clinical research, there are good studies, and then there are the rest. FDA is interested in good studies and good data independent of the type of therapy being tested. We do not categorize therapies but rather seek good clinical data from whatever intervention is being tested. Our primary obligations are those vested in us by Congress in the FD&C Act, namely to help ensure that marketed medical products are properly labeled, safe, and effective, and that the procedures in studies conducted on unapproved products are designed to protect the vulnerable -- particularly patients with life-threatening diseases and serious illnesses. To FDA, it does not matter whether the product or treatment is labeled alternative or complementary, or mainstream or conventional. We are indifferent as to the source and nature of any potential therapy as long as consistent good manufacturing standards and good laboratory and clinical practice are used.

Before gaining FDA marketing approval, new drugs, biologics, and medical devices must be proven safe and effective by controlled clinical trials. Under the FD&C Act, FDA must rely on evidence from adequate and well-controlled studies. The persons who participate in those clinical trials need to be adequately protected and fully informed of the risks and possible benefits of their participation. Patients want to make informed choices about medical treatments, whether conventional or alternative or complementary. This is possible only when there is adequate data to provide the information upon which informed consent can be made.

CAM is a broad term referring to treatments that are either unapproved or not widely accepted in this country. Treatments range from botanicals and animal extracts to biofeedback to visualization techniques, chiropractic, homeopathy, massage therapy, acupuncture, and prayer. As we have emphasized, FDA relies on evidence, and is required to do so under the FD&C Act, from adequate and well-controlled studies as its basis for approval, not on theories of healing, animal studies or strongly held beliefs. Complementary and alternative treatments are as readily studied in well-controlled trials as are conventional treatments and some are being studied under National Institutes of Health (NIH) grants and other funding sources. FDA is eager to see formal controlled studies of CAM and has advised potential sponsors of such studies on study design and conduct.

Examples of products used in complementary and alternative medical practice that are being or have been evaluated for the treatment of cancer either in the United States (U.S.) or abroad, under an IND, include the following: Green Tea extract(s) for cancer; Shark cartilage extract for advanced lung and other cancers; ozone therapy for transfusion-related diseases; Antineoplastons for cancer; Dietary Arginine Supplements for cancer; Vitamin D for cancer; and, Zinc Supplementation in Head and Neck cancer patients.

In addition, we are developing a guidance on the study and development of botanical products that facilitates their entry into clinical trials and will describe how to develop appropriate specifications for these complex products.

FDA works with NIH's National Center for CAM as well as the Division of Cancer Treatment, Diagnosis, National Cancer Institute (NCI) in the pursuit of evaluating unproven treatments for cancer. FDA is involved with these agencies in clarifying existing regulations and policies and participating in ongoing meetings regarding issues of mutual interest.

ACCESS TO A CLINICAL TRIAL FOR ANY CANCER THERAPY

The access process starts with a drug sponsor, a pharmaceutical company or a research scientist at a university or at NIH, seeking to develop a new drug it hopes will find a useful and/or profitable place in the market. Before clinical testing begins, researchers analyze the drug's main physical and chemical properties in the laboratory and study its pharmacologic and toxic effects in laboratory animals (pre-clinical studies). If the laboratory and animal study results show promise, the sponsor can apply to FDA to begin testing in people.

Once FDA has reviewed the sponsor's plan and allowed it to proceed, and a local Institutional Review Board (IRB) (a panel of scientists and non-scientists that oversees clinical research) approves the protocol for clinical trials, experienced clinical investigators give the drug to a small number of cancer patients who have no other available therapy. These Phase I studies assess the most common acute adverse effects and examine the amount of drug that patients can take safely without unacceptable side effects. Initial clinical studies also begin to clarify what happens to a drug in the human body, how it is changed (metabolized), how much of it (or a metabolite) gets into the blood and various organs, how long it stays in the body, and how the body gets rid of the drug and its effects.

If Phase I studies do not reveal major problems, such as unacceptable toxicity, the next step is to conduct a clinical study in which the drug is given to patients who have medical conditions that may benefit from the drug; for potential cancer drugs, often several different types of cancers are explored (Phase II studies). Researchers then assess whether the drug has a favorable effect on the condition.

Testing experimental drugs in people inevitably presents ethical questions. For example, is it ethical to give patients a placebo when effective treatment is available? Not all authorities agree on the answer. The generally accepted practice in the U.S., and one increasingly being adopted abroad, is that well and fully informed patients can consent to take part in a controlled-randomized-blinded clinical trial, even when effective therapy exists, as long as they are not denied therapy that could alter survival or prevent irreversible injury. They can voluntarily agree to accept temporary discomfort and other potential risks in order to help evaluate a new treatment. In any trial in which a possible effect on survival is being assessed, it is important to monitor results as they emerge. That way, if a major effect is seen, positive or negative, the trial can be stopped.

In some cases, a new treatment can be compared with established treatment, as long as the effectiveness of the latter can readily be distinguished from placebo and the study is large enough to detect any important difference. It is also possible to evaluate new drugs in this situation in "add-on" studies. In this kind of trial, all participants receive standard therapy approved for treating the disease, but those in the treatment group also get the investigational drug. The control group gets either no added treatment or placebo. Any difference in results between the treatment and control groups can be attributed to the investigational drug.

We recommend that anyone interested in participating in a clinical trial discuss the idea with his or her physician. Doctors are generally aware of investigational drugs that might be of benefit to their patients and of clinical trials involving these drugs. Detailed information can be obtained from a variety of sources, including drug sponsors, FDA (if the information is public), and NIH. Clinical trials are carried out at major medical research centers such as teaching hospitals, at NIH, and even in doctors' offices. Although they often involve hospitalized patients, many clinical trials can be conducted on an outpatient basis, with participants more or less going about their normal activities. The center or institution where a study is to be carried out often runs newspaper ads recruiting potential participants for clinical studies that tell readers where to call or write for further information.

These and other aspects and implications of taking part in a clinical trial must be fully explained in advance by the people conducting the trial, and patients must agree to the conditions before they can participate. The hope of personally benefiting from a new drug, or the desire to take part in research that might one day benefit millions, is what makes people volunteer for clinical trials. It should not prevent them, however, from finding out all they can about being a part of the process.

EXPANDING ACCESS TO INVESTIGATIONAL NEW PRODUCTS

The ideal mechanism for a patient to receive a promising but unproven drug is as a participant in a controlled clinical trial. Such trials provide appropriate patient protections and potential benefits (for example, IRB review, informed consent, free product or treatment, and FDA review of pre-clinical data and the protocols for the clinical trials) and maximize the gathering of useful information about the product, potentially benefiting the entire patient population. It is not always possible, however, for all patients who might benefit from the drug to enroll in controlled clinical trials.

In this situation, FDA believes that it is possible, and appropriate, to help make certain promising, but not yet proven, products available to patients with serious and life-threatening illnesses. This should be done in a way that does not pose an unreasonable risk to the patient and does not prevent the collection of the information needed to support the effectiveness and safety of the drug.

While the phrase "compassionate use" is commonly used to describe some of the ways of making unapproved products available, there is no FDA regulation or policy defining a "compassionate use." Compassion, however, should be, and is, an element of all our activities. Section 402 of the Food and Drug Modernization Act of 1997 (FDAMA) has codified certain FDA regulations and practices regarding expanded patient access to experimental drugs and devices. FDAMA addresses three expanded access procedures with respect to: 1) emergency situations; 2) individual patient access to investigational products intended for serious diseases; and 3) treatment IND applications and treatment investigational device exemptions (IDE). The Agency continues to review current regulations and practices in light of FDAMA.

There are a number of mechanisms FDA has used to provide access to promising investigational therapies, including: treatment INDs; treatment protocols; single patient INDs; emergency INDs; open label protocols; continued availability of investigational devices; protocol or special exceptions; open label extensions; parallel track; emergency use of unapproved medical devices; and treatment IDE.

In the drug development process, FDA's primary point of contact is with the sponsor of the product. At times, FDA communicates with a patient's physician, who is seeking permission to use an investigational therapy on an individual patient, for example, when an individual patient is seeking access to an investigational therapy for personal use, and who may or may not be eligible for enrollment in a clinical trial.

The commercial or other sponsor (e.g. NIH) of the investigational drug must decide whether it is willing to make the product available for individual use by the patient. Assuming it is, and such access cannot be provided through an existing protocol, FDA may be asked to consider a physician-sponsored individual patient IND. If the sponsor of the already ongoing study (the "owner" of the drug or biologic) is not willing to make the product available, the single patient study cannot proceed, even if the Agency has no objections to the treatment. In considering such cases, the Agency is bound by strict rules of confidentiality governing the types of information it can disclose to a physician about the sponsor's product and development data.

One may ask why FDA is involved in this process at all. That is, why should not the physician and patient decide on the appropriateness of treatment. We believe that the independent scientific consideration provided by the Agency is critical and is an essential component of patient protection, when one is considering drugs about which relatively little is often known. In the typical single patient IND situation, especially those involving emergency IND requests, the patient's physician generally has only very limited information about the investigational therapy being requested.

The Agency's primary responsibility in deciding whether to allow a single patient IND to proceed is to determine whether use of the therapy in the particular patient involved would be reasonable or safe. In oncology, with respect to patients for whom no curative treatments exist, our practice has been to permit almost anything that is reasonably safe without regard to efficacy or potential efficacy. There may be several INDs for the same product with each sponsor working confidentially and in ignorance of what others are doing and of their results. FDA is often the only party that has all of the information.

Can an unapproved therapy believed to be less toxic be tried prior to a curative therapy that has known serious adverse events?

Indirectly harmful products are those that do not themselves cause injury, but may lead people to delay or reject proven remedies, possibly worsening their condition. For example, if cancer patients reject curative drug therapies in favor of unproven therapies and the unproven therapies turn out not to work, their disease may advance beyond the point where proven curative therapies can help.

There have been two well publicized cases where FDA refused to permit patients to receive an unproven cancer therapy prior to receiving the standard of care that was likely to cure the disease because, there was NO evidence of clinical data to suggest a benefit from the investigational product requested. More importantly, the standard of care for these two diseases was and is considered "CURATIVE THERAPY," a rare opportunity in cancer treatment. Prior to use of the curative therapy in these situations, death was the most certain outcome for patients with these diseases. It is now highly likely that patients can expect long term survival. In over 700 cases where curative treatments were not available and patients requested use of this same unproven therapy, FDA permitted such patients to go ahead with the treatment.

Researchers are constantly striving to improve on past accomplishments with the goal of finding new and better treatments with minimum side effects. For example, in childhood leukemia, progress was made in improving the cure rate and decreasing the toxicity by substituting one drug at a time in multi-drug combinations. Initial treatments for protecting or treating children with leukemia in the brain were considered too toxic, but worth the risk due to the high cure rate. With careful observation and no compromise in the cure rate, the toxic therapies were replaced with less toxic therapies as newer drugs became available. Now, the cure rate for some types of childhood leukemia are greater than 90 percent with excellent follow up and development.

As long as a curative treatment for a disease is available, FDA cannot permit the use of an unproven product, and risk patients forgoing proven treatments for that which is unknown.

The Office of Special Health Issues (OSHIs)

FDA is mindful of the frustrations that patients with life-threatening illnesses and their families experience when trying to obtain information about potentially helpful therapies, especially when there is no standard therapy. In addition to offices within FDA's Center for Biologics Evaluation and Research (CBER) and CDER that routinely provide assistance and information to consumers, the Agency created OSHI to provide information and to work with cancer patients and their advocates on cancer-related issues. Most activity in OSHI is on behalf of patients with life threatening diseases, most often cancer and AIDS.

Usually, callers want information about treatments currently being researched. For example, a kidney cancer patient called recently asking for access to an unapproved biologic therapy. He was not eligible for the clinical trial and asked if FDA could please get the drug for him or make the company give it to him. After explaining that FDA cannot compel a company to supply a product, an FDA staff member, trained to work with cancer patients, spent many hours on the phone with this patient over the course of a week, explaining sources of information regarding kidney cancer clinical trials and helping him to understand options he might pursue in lieu of the trial he was not eligible to enter under the company's protocol.

Although we cannot disclose proprietary information about products under development, we are able to talk with patients about any treatment that appears in public access data bases, such as the NCI's Physician Data Query database at http://cancertrials.nci.nih.gov or through the NCI's telephone service at 1-800-4-CANCER. This database contains close to 1800 cancer trials; pharmaceutical company trials represent only 10 percent of that database. Additional information is available through the National Library of Medicine's clinicaltrials.gov website.

Section 113 of FDAMA requires drug companies to list trials of therapies for serious or life-threatening diseases in a public access database once the trial sponsor begins to investigate the effectiveness of that therapy. Our staff is working actively with the National Library of Medicine and the pharmaceutical industry to include more clinical trials into the clinicaltrials.gov database.

Our goals in serving patients with life-threatening diseases and their family members are straightforward:

1) Promptness (returning patients' and family members' calls within 24 hours);

2) Accessibility (listening to the caller's concerns and giving him or her as much time as he or she needs);

3) Education (about the drug approval process and his or her options); and

4) Assistance (providing additional information to the patient or family member that may be helpful, e.g. other sources of information).

The nature of the calls vary greatly. Sometimes they are simple calls in search of information on clinical trials. Often, the calls are more complex, such as distraught patients or family members seeking access to a drug that has not been approved.

These calls, by their nature, are very difficult ones. OSHI has a trained staff dedicated to providing as much assistance as possible to patients and family members in extremely difficult situations. It is our responsibility to remain reasonable and sympathetic, even in the face of the frustration and anger that may be present. The staff explains the steps to follow in requesting access to unapproved products. Patients and family members are encouraged to call back as often as needed to get their questions answered or express their point of view. OSHI receives approximately 1000 inquiries (phone and e-mail) from patients and family members annually requesting access to unapproved products.

OSHI also works within the Agency to assist with patient and consumer requests to become more involved with the drug approval process. There is a web page that is updated regularly with information on AIDS and cancer issues. Specifically, there is information on clinical trials, product approvals, meetings, and other matters of interest to this constituency.

Also, we are discussing with sponsors ways to educate patients about the clinical trial process. We know that recruitment of patients into cancer clinical trials is often the rate-limiting factor in cancer drug development. Less than three percent of adult cancer patients participate in clinical trials, in large part because cancer patients do not know about clinical trials for which they may be eligible, or fear being part of a study.

The Cancer Liaison Program within OSHI also serves as an access point for the organized cancer patient advocacy community. Many cancer patient advocacy organizations, in addition to providing valuable information to cancer patients, are focused on monitoring the development of State and Federal policies governing a variety of cancer issues, such as health insurance or research or, in the case of the Agency, the drug development rules and regulations.

FDA's Cancer Liaison staff actively participates in discussions of FDA policies that affect the regulation and review of cancer therapies. Consequently, informing the advocacy community about FDA policy matters and making certain that meetings are convened between representatives of cancer patient advocacy organizations and FDA specialists is one of our major responsibilities. We maintain a 300-member mailing list that is used to notify the cancer community about FDA advisory committee meetings, open public hearings or seminars on cancer research or policy. As promptly as possible, we notify the cancer community about FDA's approval of a new cancer drug, biologic or device.

In furtherance of the Agency's goal of educating cancer survivors and advocates about FDA and the drug review and approval process, FDA's Division of Oncology Drug Products, in partnership with OSHI's Cancer Liaison Program, designed a pilot Visiting Oncology Patient Advocates Program.

Visiting advocates attend a one-week scientific seminar with FDA staff, followed by two to four training sessions in the Division of Oncology Drug Products. Participants receive one-on-one orientation from FDA scientists and attend division drug review meetings. At the completion of the program, each visiting advocate will write a "reaction paper" about the program, and will, we hope, through speeches, workshops and articles, educate their cancer constituency about the experience.

REINVENTING THE REGULATION OF CANCER DRUGS AND FDAMA

For the past four years the Agency has been working under the "Reinventing the Regulation of Cancer Drugs," initiative, which included: 1) Expediting approval of cancer therapies; 2) Encouraging new uses of marketed products in cancer treatment; 3) Expanding access to investigational cancer therapies that have been approved in other countries; and 4) Including cancer patients on our Oncologic Drug Advisory Committee that reviews cancer therapies.

In addition, FDAMA codified many of FDA's initiatives and existing programs intended to expedite drug development and expand access to unapproved therapies. FDAMA also created powerful new incentives for the development of treatments for children.

Expediting Development, Review, and Approval for New Products

FDA has implemented mechanisms designed to increase access to new drugs, biologics, and medical devices by expediting their development, review and approval. All of these programs have been instrumental in shortening the time to marketing approval for cancer drugs and biologics. FDA programs include:

• Expedited development under Title 21, Code of Federal Regulations (CFR) Part 312, Subpart E expedites the development, evaluation, and marketing of new therapies intended to treat persons with life-threatening and severely debilitating illnesses. Since the effective date of the Subpart E regulations, there have been 48 new drug applications (NDA) approved that had been identified for expedited drug development under Subpart E while in the IND stage. Of these NDAs, nine were for cancer, and 39 were for indications other than cancer, including several for conditions that occur in patients with cancer.
• Priority Review to speed the review of NDAs, biologics license applications (BLAs), and effectiveness supplements that could have important therapeutic impacts. A priority designation is intended to direct overall attention and resources to the evaluation of applications for products that have the potential for providing significant therapeutic advances. FDA's goal is to review a priority NDA within six months rather than the standard review time of ten months. Since 1996, five biologics and 31 drugs (20 NDAs and 11 supplements) for cancer therapies have received priority review and approval.
• Fast Track section 112 of FDAMA, amends the FD&C Act to consolidate the various provisions intended to facilitate the investigational development and approval of drugs and biologics that provide significant advances in the treatment of serious diseases. This codified FDA's accelerated approval regulations, 21 CFR Part 314, Subpart H and 21 CFR Part 601, Subpart E, unified provisions for consideration of serious and life-threatening diseases, established the provision for "rolling" review of marketing applications and thus consolidated FDA's approach to expedited drug development and approval. To provide clear information to industry regarding participation in the fast track process, we issued a guidance document on this provision in September 1998.

It is important to note that FDAMA did not alter FDA's effectiveness standard, except by giving explicit authority to the Agency to rely on a single, adequate and well-controlled study with confirmatory evidence, in particular cases, as support for approval. Even for drugs intended for serious and fatal illnesses, there must be substantial evidence that the drug will have the effect it purports to have. The law recognizes, however, that the magnitude of the effect that needs to be demonstrated might vary depending on the urgency and clinical need. It therefore permits FDA to approve drugs for serious or life-threatening illness that provide meaningful benefit compared to existing treatments where there is a demonstrated effect on a surrogate endpoint that is reasonably likely to predict a real clinical benefit but where a real clinical benefit has not yet been clearly shown. A surrogate endpoint is a laboratory effect or other clinical measurement that does not itself directly measure clinical benefit but is thought to predict clinical benefit. The effect on clinical benefit is then ascertained in postmarketing clinical trials (Phase IV studies).

FDA's goal is to improve significantly patient access to promising cancer treatments without compromising patient safety or the requirement that drugs be proven safe and effective before they are sold. Importantly, FDA regulations emphasize safeguards for the protection of human subjects, including the requirement for informed consent, IRB review, conduct and review of animal studies prior to human testing, IND safety reports and updates, and adverse drug reaction reports.

Encouraging New Uses of Marketed Products in Cancer Treatment

In the spirit of section 403 of FDAMA, FDA will continue its efforts to encourage sponsors to submit supplemental applications for new uses for their products. In December 1998, we published Guidance for Industry, "FDA Approval of New Cancer Treatment Uses for Marketed Drug and Biological Products." The guidance is for sponsors planning to file applications for new uses of marketed drug and biological products for the treatment of cancer. This guidance discusses the quality and quantity of data that may be adequate to add a new use to the prescribing information for a product used in the treatment of cancer. It also describes specific steps FDA is taking to encourage the updating of labeling for products used in cancer treatment.

Product labeling is intended to provide full prescribing information for a product and should include all clinical indications for which adequate data are available to establish the product's safety and effectiveness. Many newer uses of anticancer products are common in clinical practice, but are not listed in product labeling, despite the fact that they appear to be supported by published data from clinical studies.

1. Community Outreach

As part of its continuing effort to be aware of, and stimulate applications for new uses of marketed drugs, FDA efforts have included community outreach. FDA has surveyed private, academic, and professional groups involved in cancer research and treatment for their views regarding appropriate uses of products in cancer treatment not described in current product labeling. Where appropriate, FDA has met with commercial sponsors of marketed products and has encouraged the submission of supplemental marketing applications.

As specified in FDAMA, FDA will continue its outreach efforts to survey major groups in the cancer research and treatment community, including professional societies, cancer patient and research advocacy organizations, other government agencies, and other interested groups and individuals, for their views regarding new cancer treatment indications that should be examined for possible inclusion in labeling for currently marketed products. These groups and individuals will be asked to identify published and unpublished studies that may support a supplemental application.

Specifically, they will be asked to collaborate with FDA to encourage sponsors: 1) to prepare supplemental applications in cases where definitive studies have been completed or 2) to conduct further research that may be needed to provide support for a supplemental application that is suggested by preliminary research findings. The Agency will contact the commercial sponsor(s) of a promising product and encourage the sponsor(s) to evaluate the available data and, if the data appear adequate, to submit a supplemental marketing application.

2. Support Sponsors in Application Development

In some cases, commercial sponsors of a product may be unable or unwilling to accommodate an FDA request to evaluate the data regarding a currently unlabeled indication for a product used in cancer treatment or to consider filing a supplemental marketing application. In such cases, FDA may pursue other avenues, depending on specific circumstances and in accordance with applicable laws and regulations.

For example, FDA may provide public notification of the Agency's interest in receiving a supplemental application for review. FDA may request a summation and analysis of the data from staff of other governmental agencies (e.g., staff of the NCI), for review by FDA. If necessary, FDA may directly approach study investigators and request study data for summary and analysis by Agency staff.

3. Continue to Prioritize Certain Supplemental Application Reviews

Supplemental applications will continue to be assigned a review priority based on the importance of the new use of the product, if, based on preliminary review of the application, it appears that the new product use may represent a significant improvement (compared to other marketed products) in the treatment, diagnosis, or prevention of a disease. The fact that a product is already marketed for another indication does not affect FDA's determination of whether a new supplemental application will receive priority review.

4. Designate Key Persons

Consistent with section 403(c) of FDAMA, CDER and CBER have designated key persons who will: 1) encourage the prompt review of supplemental applications for approved products; and 2) work with sponsors to facilitate the development and submission of data to support supplemental applications.

Expanding Access to Investigational Cancer Therapies That Have Been Approved in Other Countries

The third goal of the reinventing government initiative was to utilize current mechanisms for expanded access of investigational agents to ensure that cancer patients in the U.S. have access to potentially beneficial treatments that have been approved by recognized foreign regulatory authorities, but not yet marketed in the U.S.

In 1996, FDA sent a letter to the regulatory authorities of 24 countries requesting a list of all cancer or cancer-related therapies approved in their country over the last ten years. Detailed responses were received from 15 countries. In 1996, forty-four drug products not marketed in the U.S. but marketed in one or more of these countries were identified. In 1998, the Agency completed its evaluation of the drugs identified as having been approved in foreign countries. Some of them were later approved in the U.S.; some are under review. The Agency concluded, however, that there do not appear to be significant differences in the spectrum of drug products available for the treatment of cancer in the U.S. and in foreign countries. There are no products that appear to potentially provide a significant benefit in cancer treatment that cannot be accessed by U.S. patients, either in the marketplace or through an established IND mechanism.

Including Cancer Patients on FDA's Oncology Drug Advisory Committee

The fourth goal of the reinventing initiative was to include cancer patients in the review process by ensuring that all FDA cancer-therapy advisory committee meetings include an ad hoc member with personal experience with the illness for which a product is being considered. Since 1996, all meetings of the Oncologic Drugs Advisory Committee have included a patient representative in discussions of products under review. These representatives have been full voting members of the panel. The Division continues to work with OSHI's Cancer Liaison Staff to assure full inclusion of patient representatives in all advisory committee proceedings.

PEDIATRIC ONCOLOGY DRUGS

The development of pediatric oncology agents merits special consideration. Compared to adult malignancies, pediatric cancers afflict smaller numbers of patients, clearly a problem in developing treatments. On the other hand, and unlike most adult cancer patients, the majority of pediatric patients already receive their cancer therapy as participants in clinical research protocols. That is, participation in oncology trials has become the "standard of care" in pediatric oncology.

Children with cancer are usually treated at specialized centers by pediatric oncologists who are members of national pediatric cooperative study groups. One of the highest priorities of these groups is to develop improved novel therapies, and early access to new agents is an important component of achieving this goal. There should be great benefits from FDA, industry, and academic cooperation.

Ensuring that there is adequate pediatric use information for drugs and biologics has long been a high priority for the Agency. The pediatric exclusivity provision of section 111 of FDAMA has provided a powerful development incentive, an important complement to the Agency's final rule issued in November 1998, requiring pediatric testing for drugs. We are pleased that there has been an enthusiastic response from industry to the incentives offered by this provision. In June 1998, FDA issued written guidance "Qualifying for Pediatric Exclusivity Under Section 505A of the FD&C Act to communicate to industry the Agency's plans for implementation of the pediatric program, and updated this document in October 1999 to provide additional information to industry. FDA is also in the process of issuing a guidance pertaining to pediatric oncology drugs specifically.

To encourage the development of treatments for pediatric cancers, FDA expects to make written requests to sponsors of new drugs that may qualify a product for pediatric exclusivity under FDAMA. In general, these requests will ask for early (Phase I) studies to assess pediatric tolerability and, if the drug is tolerated, will request Phase II studies to follow potentially responsive tumors in specific populations. If approval is based on surrogate endpoints or smaller safety numbers, further studies would usually be needed after approval.

To expedite this initiative, FDA has posted on its website a "Sample of a Written Request for a Pediatric Oncology Drug Product Plan." FDA has suggested that sponsors discuss a pediatric development plan with a pediatric cooperative study group, utilizing the group's expertise and resources to optimize study design and patient accrual and to determine which cancers should be studied. Sponsors are encouraged to generate proposals for written requests from the Agency (the trigger for the FDAMA exclusivity provision) working with pediatric cooperative groups to refine the proposals prior to submission to the Division of Oncology Drug Products.

CONCLUSION

Mr. Chairman, we are often asked the question: where should we, as a matter of public policy, draw the balance between public health protection and personal autonomy? We think Congress has drawn that balance correctly in the FD&C Act. This law was designed to protect the public health, and it has done a good job of assuring safe and efficient development of drugs and protection against marketing of unsafe or ineffective drugs. Recent changes in law, together with FDA program changes, have also made the application review process very rapid; new, properly developed drugs are marketed in the U.S. as rapidly, or more rapidly, than in any other country in the world.

Even as they provide high standards and protection of patients, the laws and regulations are flexible and allow desperately ill patients accessto promising unproven treatments, while preserving the system of well-controlled clinical trials that provides the information necessary to determine the safety and effectiveness of proposed new products. Protection of public health and compassion and respect for individuals, can, and do, co-exist.

Thank you for the opportunity to testify. I will be happy to answer any questions the Committee might have.