[U.S. Food and Drug Administration]

APRIL 22, 1998

STATEMENT BY

MICHAEL A. FRIEDMAN, M.D.

LEAD DEPUTY COMMISSIONER

FOOD AND DRUG ADMINISTRATION

DEPARTMENT OF HEALTH AND HUMAN SERVICES



BEFORE THE

COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT

U.S. HOUSE OF REPRESENTATIVES

APRIL 22, 1998



INTRODUCTION

Mr. Chairman, Members of the Committee, I am Michael A. Friedman, M.D., Lead Deputy Commissioner for the Food and Drug Administration (FDA or the Agency). I am pleased to be here today to discuss the various programs for providing access to promising therapies for seriously ill and dying patients. Our commitment to these programs is longstanding and unequivocal. While most of our attention today will focus on drugs and biologics, my written statement also covers medical devices to provide the Committee information on the full scope of FDA's activities and of H.R. 746, "The Access to Medical Treatment Act."

Under the Federal Food, Drug, and Cosmetic (FDC) 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 desperately ill. We believe the existing programs under which patients can obtain access to experimental therapies, and those under which we expedite approval of such therapies, establish the appropriate framework for achieving our mutual goal of providing patients with serious and life-threatening diseases the earliest reasonable access to promising therapies. These programs were codified in the recently enacted "Food and Drug Administration Modernization Act of 1997" (FDAMA). Of course, we recognize the value of even more effective access programs, and as we proceed with implementation of FDAMA, we will focus particularly on ways to improve the effectiveness of these processes.

Finally, as I discuss below, we have significant concerns with H.R. 746, "The Access to Medical Treatment Act." This legislation would lower the standard for safety, thus putting patients at unnecessary risk. We also believe this legislation would have at least three unintended consequences. First, by allowing access to unapproved therapies outside of the investigational new drug, biologic, and device processes, the bill would reduce, or eliminate, the critical process of scientific data collection necessary to establish the safety and effectiveness of a product. Second, assurance of appropriate informed consent and human subject protection would be diminished. Third, the bill would make it very difficult to protect consumers against health fraud.

I. THE STATUTORY AND REGULATORY FRAMEWORK

FDA's primary mission for over 90 years has been to promote and protect the public health, as directed by the FDC and Public Health Service Acts. These statutes were enacted and amended, in part, in response to devastating public health tragedies resulting from the sale to, and use by, an unsuspecting public of unsafe and ineffective products sold as medicines and medical devices. The FDC Act requires that new drugs be shown to be safe and effective before being marketed in this country.

The requirement that a person wishing to sell to the public a product to prevent, cure or mitigate illness or injury must first prove that such product is safe, and actually does what the vendor claims it does, is the single most important consumer protection provision of these statutes. It is this statutory provision that affords consumers the most effective protection against untested and unproven products. Sadly, such products most often are promoted to desperate victims of illness and injury.

A new drug or biologic (referred to in this statement as "drug") may not be distributed in interstate commerce (except for clinical studies) until a sponsor, usually the drug manufacturer, has submitted and FDA has approved a New Drug Application (NDA) or a Biologics License Application (BLA) for the product. For approval, an NDA or BLA must contain sufficient scientific evidence demonstrating the safety and effectiveness of the drug for its intended uses.

The evidence of safety and effectiveness usually is obtained through the conduct of controlled clinical trials. The disciplined, systematic, scientific conduct of such trials is the most effective and efficient means of getting the data which will let the patient/consumer and his or her health care practitioner know how to use the new product so that it will have the most beneficial effect.

A. INVESTIGATIONAL NEW DRUG APPLICATION PROCESS

To obtain approval for a new drug, the first step a sponsor usually must take is to test the drug in animals for toxicity. The sponsor then takes that animal testing data, along with additional information about the drug's composition and manufacturing, and develops a plan for testing the drug in humans. The testing plan generally is referred to as the protocol. The sponsor submits these data, along with its study plan, the qualifications of the investigators who will conduct the clinical studies, and assurances of informed consent and protection of the rights and safety of the human subjects, to FDA in the form of an Investigational New Drug application (IND).

FDA reviews the IND for assurance that the proposed studies, generally referred to as clinical trials, do not suggest that human subjects might be exposed to unreasonable risk of harm. FDA also verifies that there are adequate assurances of informed consent and human subject protection. At that point, the first of three phases of study in humans can begin. Phase 1 studies primarily focus on the safety studies of the drug in humans. Phase 1 studies carefully assess how to safely administer and dose the drug with an emphasis on evaluation of the toxic manifestations of the therapy, how the body distributes and degrades the drug, and how side effects relate to dose. Phase 1 studies typically include fewer than 100 healthy volunteers or patients.

The next step, called Phase 2 studies, are clinical studies to evaluate the effectiveness of the drug for a particular indication and to determine common short-term side effects. Phase 2 studies typically involve a few hundred patients. Importantly, it is estimated that 80 percent of all drugs tested are abandoned by their sponsors after either Phase 1 or 2.

Once Phase 2 studies are successfully completed, the drug's sponsor has learned much about the drug's safety and effectiveness. At this point Phase 3 studies, involving up to several thousand patients, may be conducted. These studies can examine additional uses, obtain further safety data including long-term experience, and consider additional population subsets, dose response, etc. FDA strongly encourages sponsors to work closely with the Agency in planning definitive Phase 3 clinical trials so as to help assure that the trials are designed to have the greatest likelihood of producing results sufficient to permit product marketing.

Once Phase 3 trials are completed, the sponsor submits the results to FDA in the form of an NDA. FDA's medical officers, chemists, statisticians, and pharmacologists review the application to determine if the sponsor's data in fact show that the drug is both safe and effective. The manufacturing facility is evaluated to confirm that the product can be produced consistently with high quality. Of note, it is common to allow participants in Phase 2 and 3 studies to continue on a therapy if it seems to be providing benefit. This practice provides longer term safety information at an early stage in this process.

At present, there are literally thousands of clinical trials ongoing, involving hundreds of thousands of patients. There are over 13,000 active drug and biologic INDs filed with the Agency, with as many as 50,000 patients enrolled under a single IND. It is estimated that well over 100,000 patients are enrolled per year in NIH sponsored treatment clinical trials alone. In addition, there are hundreds of clinical trials assessing approved drugs for new, unapproved uses that are conducted under the auspices of local Institutional Review Boards.

Results of controlled clinical trials are the basis of evidence-based medicine. They allow physicians and patients to utilize therapies with a clear understanding of their benefits and risks and, in some cases, a basis for strong public health recommendations for treatments. Clinical trials also have saved us from disastrous public health consequences as illustrated below.

For example, when AZT was the only approved AIDS treatment, ddC was made available under treatment-IND for the several years while clinical trials were underway. These trials were to assess whether ddC was superior to AZT or if it was effective for patients intolerant of AZT. Although the product could cause permanent, sometimes severe nerve damage, there was great demand for early access to the product. It was even manufactured by sources other than the company (probably by amateur chemists) and this "bath-tub" ddC was made available through buyers clubs when the demand exceeded the sponsor's supply. FDA acted with the sponsor, the buyers clubs, patient advocates, and investigators to make more of the drug available and get the illicit, poorly manufactured product off the market.

What did the ddC clinical trials show? In a head-to-head comparison versus AZT as initial therapy, an independent data safety monitoring board stopped the trial early because the death rate in the ddC group was at least twice higher than in the AZT group. For patients intolerant to AZT, a clinical trial compared switching to ddC versus ddI. In this study the trend was that ddC had superior survival to ddI. Later studies showed that ddC in combination with AZT had superior survival to AZT alone. Each of these studies involved hundreds of patients and was essential to determining where ddC improved survival and where it did not. Although some of the early access uses were later found to be poor choices, it was considered reasonable at the time to provide the drug while the question was still being answered. The important point is that patients are only well served by early access when the controlled clinical trials proceed in parallel with early access.

A second example that illustrates the need to conduct trials is Clarithromycin for treatment of atypical mycobacterial infections (Mycobacterium-avium-intracellulare complex or MAC). This infection, related to tuberculosis, is an infection of patients with damaged immune systems and is one of the fatal complications of HIV infection and AIDS. In cultures of the MAC organism, clarithromycin is one of the most active drugs against the organism. Before clinical trials were completed, it was used widely in high doses to treat MAC. Such doses have the best effect on reducing the severity of the infection. In this case, the early access trials randomized patients to high and low doses as did the controlled clinical trials. Both trials demonstrated an increase in the death rate in the high dose group, even though there was better control of MAC.

This was a totally unexpected, counter-intuitive result. A third trial was done which showed the same higher death rate in the high dose group. Had the product simply been used off-label (it had other approved uses) clinicians using MAC control as their rationale for treatment with high doses might not have recognized the fatal toxicity of chronic high doses of the drug. At the lower dose this drug was life-extending.

At the same time, it cannot be disputed that as science and technology have advanced, proving that a product is safe and effective can require considerable effort, time, and money. This makes our system of drug development particularly susceptible to market forces. Most new therapies today reach the market because a private commercial entity was willing to invest in the development and testing process necessary to bring a product to the market.

I want to stress that it does not matter to FDA whether a product is characterized as "mainstream" or "alternative"; it does not matter whether the product was synthesized in a state-of-the-art laboratory or was found in the Brazilian rain forest. What does matter is that a product is manufactured consistently and with high quality; studied scientifically in properly controlled clinical trials, so that we can know whether it is safe and works for a specific purpose; and that the persons who participate in clinical trials are adequately protected and fully informed of the risks and possible benefits of their participation. The Agency frequently works with sponsors and investigators, whether in large organizations or as individuals, to facilitate the development of new products. The amount and kind of information that is required for any new product is commensurate with the risks involved and the complexity of the issues that the particular product presents.

There are many examples of products used in complementary and alternative medical practice that are being evaluated either in the United States or abroad, under an IND, including the following:

St. John's Wort (Hypericum) for depression;

Ginkgo biloba for cognitive impairment/cerebrovascular insufficiency vascular indications;

Chinese Herbal product mixture for postmenopausal hot flashes;

Chinese Herbal preparation (topical) for plantar warts;

Chinese Herbal preparation for HIV-associated chronic synositis;

Saw Palmeto for benign prostatic hypertrophy;

Green Tea extract(s) for cancer;

Shark cartilage extract for advanced lung and other cancers;

Ozone therapy for transfusion-related diseases;

Melatonin for chronobiology and reproductive indications;

Antineoplastons for cancer;

Dietary Arginine Supplements for cancer;

Vitamin D for cancer; and,

Zinc Supplementation in Head and Neck cancer patients.

B. EXPEDITING APPROVALS AND EXPANDING ACCESS TO INVESTIGATIONAL PRODUCTS

Let me emphasize that FDA is committed to providing early access to promising, but unproven, medical treatments for seriously ill patients who might otherwise have no hope. The Agency for many years has worked to provide patients broad access to unapproved therapies. For example, Nifedipine, first approved in 1981 under the brand name Procardia, was the first calcium channel blocker. Prior to approval, tens of thousands (20,000 to 30,000) of patients had access to the drug in open protocols. In recent years, FDA has reexamined the product approval and review processes to identify ways to improve access to promising therapeutic agents, without compromising the thoroughness and scientific integrity of their development or of the review of such products, or the protection afforded to human subjects. Importantly, we also are addressing ways to improve public awareness of these processes.

Our efforts are aimed at two main areas: 1) to speed the approval process of important new drugs, biologics, and medical devices, including expedited review, priority review, and accelerated approval; and 2) to expand the availability of promising, but unapproved, products to seriously ill patients. FDA has developed regulations and issued guidance documents that explain when a breakthrough product can be approved before clinical research is completed (accelerated approval). These documents also describe how and when promising, but unapproved, therapies can be made available to patients while controlled trials are still in progress (e.g., treatment IND and parallel track). These efforts reflect an evolving institutional philosophy supportive of more thoughtful risk-taking in the pursuit of safe and effective products with describable benefits and toxicities for patients with serious and life-threatening diseases that are not well-treated by available therapies.

We still believe that the best means of providing access to useful medical treatments for all Americans is to continue to shorten the review and approval times and to continue to work with industry to shorten development times for drugs, biologics, and medical devices. Today, we are approving drugs in time periods that are as fast, or faster, than any country in the world with a comparable system of human subject protection. We are doing so while maintaining our longstanding standards for safety and effectiveness.

In addition to our overall efforts, we have implemented a number of specific initiatives targeted at products for serious and life-threatening diseases. These include the expedited review procedures (21 CFR Part 312, Subpart E), the accelerated approval process for certain drugs and biologics (21 CFR Part 314, Subpart H and 21 CFR Part 601, Subpart E), and our commitment to early and frequent meetings with product sponsors, among other efforts. All of these efforts have contributed substantially to shortening the time for many important products to get to market.

Despite this important progress in speeding therapies to market, FDA recognizes that, for a person with a serious or life- threatening disease, who lacks a satisfactory therapy, a promising but not yet fully evaluated product may represent the best available choice. FDA wants such patients to have early access to promising medical interventions. FDA has worked hard to balance two compelling factors: the need for the disciplined study necessary to identify treatments that may improve patients' health; and, the desire of seriously ill persons, with no effective options available, to have the earliest access to unapproved products that could be the best therapy for them. The specific programs FDA has put in place to expedite the approval of promising investigational drugs and medical devices and to make them available to the very ill as early in the development process as possible without unduly jeopardizing their safety, are described in detail in the Appendix.

Importantly, these issues were considered extensively during Congressional action in 1996 and 1997 on FDA reform and modernization legislation. Congress affirmed the approach the Agency has taken by codifying in FDAMA the expanded access and expedited approval programs developed by the Agency. Congress specifically included the safeguards the Agency had incorporated into those programs. As guided by FDAMA, FDA currently is reviewing its processes to optimize the Agency's ability to assist and expedite development of, and access to, important new products for serious and life-threatening illnesses.

C. ROLE OF SPONSORS, INVESTIGATORS AND PATIENTS IN IND PROCESS

It should be noted that in the drug development process, FDA's primary point of contact is with the sponsor of the product, or sometimes with a patient's physician, who is seeking permission to use an investigational therapy on an individual patient. This is true even in the case of an individual patient who is seeking access to an investigational therapy for herself, and may or may not be eligible for enrollment in a clinical trial. The sponsor of the investigation must decide whether it is willing to make the product available to the patient. Assuming it is, and such access cannot be provided through an existing protocol, FDA may be called upon to consider the patient's physician as the sponsor for a study involving the patient. If the sponsor of the already ongoing study is not willing to make the product available, it is impossible for the single patient study to proceed even though 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.

We understand that there have been instances where sponsors who did not want to provide access to an experimental product under a single patient IND told the patient or requesting physician that FDA had refused the request, when we had not. We also are aware of situations where patients or physicians have sought access to a particular investigational product without knowing all of the relevant information that needs to be considered in deciding whether use of the product would be appropriate for a particular patient. Our ability to fully disclose such information to the patient, her physician, or, for example, a member of Congress who inquires on her behalf, is dependent largely on the sponsor's willingness to disclose confidential commercial information.

One may ask why FDA is involved in this process at all. We believe that we play a crucial role and one that provides a unique and vital service to the patient, the physician and the American public. In the typical single patient IND situation, especially those involving emergency IND requests, the patient's physician may have only very limited information about the investigational therapy being requested. The Agency's primary role 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. In making that determination the Agency considers a variety of factors, including: the patient's diagnosis; the evidence of potential benefit and toxicity from clinical situations; the availability of therapies that are likely to be curative or highly beneficial; the sufficiency of information on dosage and toxicities; and whether the patient is being provided timely, complete and useful information as part of the informed consent process. We are mindful, as well, that the clinical trial process -- which is vital to understanding the clinical utility of a product, and which is therefore vital to all patients with the disease -- not be impacted negatively by the availability of the product outside the clinical trials.

Although, for the most part, the Agency does not keep records of denials of single patient or emergency IND requests received orally, an informal survey of the drug and biologic divisions suggests that such denials are rare. In the case of an emergency, it is common for FDA to give a physician permission over the telephone to begin treatment and to allow the paperwork to be completed later.

D. THE OFFICE OF SPECIAL HEALTH ISSUES

Given the frustrations that patients and their families experience in being one step removed from what may be life or death decisions involving the availability of potentially helpful therapies, the Agency created the Office of Special Health Issues (OSHI). The center piece of the activity in OSHI is the patient with a life threatening disease, most often cancer and AIDS. Most callers want information about treatments currently being researched. Although we are constrained by statutory and regulatory requirements from disclosing 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 National Cancer Institute's PDQ data base which contains more than 1500 cancer clinical trials.

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);

    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 which has not been approved.

These calls, by their nature, are very difficult ones. OSHI has a trained empathetic staff dedicated to providing as much assistance as possible to patients and family members undergoing extremely difficult times. It is our responsibility to remain rational and reasonable and most of all compassionate. 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 calls 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 which is updated regularly with information on AIDS and cancer issues. Specifically, there is information on patients and clinical trials, product approvals, meetings, and other articles of interest to this constituency. This web page receives approximately 27,000 hits per month.

* * * * *

Sometimes, there are persons who refuse to participate in the statutory scheme. This puts patients at risk of using unproven products and also denies to all patients the knowledge of therapies that actually may work. Our challenge today is to find ways to speed remedies to patients, without sacrificing the protections established in the law. Collectively, we need to address how to promote research on possibly effective remedies where market incentives may not work.

We have faced, and met, many challenges in keeping pace with unprecedented medical and scientific breakthroughs and the evolving and increasing expectations regarding access to medical products and meaningful health information. An individual with a life-threatening and chronic illness for which there is no adequate remedy has a compelling case. As compelling as an individual case is, however, the cost of providing individual access cannot be to sacrifice the system that ultimately establishes whether therapies are safe and effective. It is essential to preserve the system of controlled clinical trials that provides the information necessary to make the final determination on the safety and effectiveness of unapproved products. The two concepts, the protection of public health and compassion and respect for individuals, can, and must, coexist.

II. CURRENT ACTIVITIES REGARDING "ALTERNATIVE" AND "COMPLEMENTARY" PRODUCTS

FDA has undertaken a number of initiatives to address some of the new and varied challenges posed by alternative and complementary products. I would like to share some examples with you today.

A. FDA COLLABORATION WITH THE NIH OFFICE OF ALTERNATIVE MEDICINE

Since establishment of the Office of Alternative Medicine (OAM) at the National Institutes of Health (NIH) in 1992, FDA has worked closely with this new office. In addition to collaborating with OAM in the organization of a series of conferences, FDA also has provided assistance to OAM and to others interested in examining alternative or complementary products. FDA has been involved in clarifying existing regulations and policies, and in the design and conduct of research studies.

FDA and OAM have held ongoing meetings to discuss issues of mutual interest. At these meetings, Government and non-Government participants discussed current policies and cost implications of reimbursement for alternative medicine and medical management. The discussions touched upon how one can make the determination that a particular modality is safe and effective. There also has been consistent representation of FDA at the meetings of OAM's advisory panel since 1992, and at the meetings of the Alternative Medicine Program Advisory Council.

B. BOTANICALS

There is increasing public interest in botanicals. Botanicals include herbal products made from leaves, as well as products made from roots, stems, seeds, pollen or any other part of a plant. Many of these products are marketed legally as dietary supplements. Botanical products used as "articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals" would be considered "drugs", under the FDC Act.

NIH has filed several INDs for botanical products being studied under NIH grants, as indicated above. The announcement of the filing of these IND's raised the public's awareness of the issues involved in the medicinal use of unpurified forms of botanicals.

Botanical products pose some issues that are unique to this class of product, including the problem of lot-to-lot consistency. These unpurified products, which may be either from a single plant source or from a combination of different plant substances, often are thought to work through mechanisms or "active principles" which are either unknown or undefined. For these reasons, the exact chemical nature of these products may not be known, as it is with small molecular weight drugs. In addition, issues of strength, potency, shelf-life, dosing and toxicity monitoring need to be addressed.

Currently, FDA is developing a guidance document on botanicals used as "drugs." This document will address certain types of information to meet statutory requirements for an IND for a botanical. On another track, the Agency is considering requests to accept foreign marketing data for products that might be best suited for sale as over-the-counter products. This mechanism could allow the American public much quicker access to many types of products, including botanicals, currently marketed abroad.

Many workshops have been held over the past several years to examine the use of botanicals for treatment of health conditions. For example, FDA and NIH collaborated on a conference held in late 1994. This conference, the Symposium on Botanicals: A Role in U.S. Health Care?, attended by more than 450 participants, brought together representatives of United States and foreign herbal, food, and pharmaceutical industries, their trade organizations, researchers and practitioners of herbal medicine, academia, and regulatory and other Government agencies.

The conference identified and addressed issues concerning the use and development of botanical products in the United States. Participants discussed such questions as: 1) What are botanicals and how are they currently used? 2) How could we know that botanicals work? 3) How can we know that these products are safe? 4) How can we ensure that botanical preparations will be of good quality? 5) How do regulations affect the marketplace and impact the cost of health care? Reports of this conference have been published. There was consensus regarding the need for improved quality control, including proper plant classification and nomenclature, and control of growth, harvest conditions, and other parameters important for lot-to-lot product consistency. If a product varies greatly, as can occur with botanicals, it is critical to obtain lot-to-lot product consistency. Without this, it is difficult to determine if the product is causing the change in a patient's condition, or the change is related to some other factor. The conference concluded that safety of these products is difficult to evaluate with certainty in the absence of quality control standards for the product and effective monitoring for adverse effects associated with product use.

C. ACUPUNCTURE

In 1994, FDA and NIH identified the need to examine the regulatory status of acupuncture needles. Acupuncture needles were still considered investigational in the United States and, as a result, had to be labeled as investigational and could not be advertised or promoted. On March 29, 1996, after reviewing the data on acupuncture needles, the Agency reclassified the needle from a Class III medical device (a category in which clinical studies are required to establish safety and effectiveness) to a Class II medical device (a less restrictive category for which regulatory controls, in this case, focused on matters such as sterility and needle breakage). This change effectively removed the needle from the "investigational" category, established some minimum standards for manufacturing and labeling and confirmed their safety.

III. PROTECTING THE PUBLIC HEALTH: FDA'S CONCERNS ABOUT H.R. 746

Our primary concern with "The Access to Medical Treatment Act" (AMTA), H.R. 746, is that it would weaken the protections of the FDC Act. Specifically, it would limit FDA's ability to help assure reasonable safety, effectiveness, informed consent, and scientific data collection. In assessing the impact H.R. 746 would have on the Agency and, more importantly, on the consumer, we must begin with an understanding that the consumer protection afforded by the FDC Act is grounded in the ability of the Agency to make science-based health and safety decisions about the medical products offered in the United States. In turn, these science-based health and safety decisions are a cornerstone of the informed consent process on which patients rely in deciding what types of medical treatment to pursue. We know from experience what happens to consumers left to fend for themselves in a health marketplace.

FDA's original law, the Pure Food and Drug Act of 1906, was passed by Congress as a result of unhygienic conditions in Chicago's meat-packing plants. The law, however, did little to control the use of dangerous and fraudulent drugs and devices. It took a catastrophic incident to propel further action. In 1937, more than 90 people in 15 States, almost all of them children, died as a result of taking a liquid dosage form of the drug sulfanilamide. This new liquid formulation, Elixir Sulfanilamide, contained diethylene glycol (used commonly as antifreeze) and was marketed without benefit of any toxicity testing. At the time, the law did not require safety studies on new drugs. The Elixir of Sulfanilamide scandal followed closely on the heels of another tragedy. In the 1930's, another drug, dinitrophenol, widely used for weight reduction, resulted in deaths, as well as hundreds of cases of blindness, agranulocytosis (a potentially fatal blood disorder), and other serious adverse reactions.

These incidents hastened the enactment of the FDC Act in 1938, which considerably expanded consumer protection by requiring safety testing of new drugs prior to approval for marketing. In short, in 1938, Congress told companies that they had to test their drugs for safety and submit an application to FDA before a drug could be legally marketed. Under this law, FDA had the necessary authority to keep products such as thalidomide off the market for use during pregnancy to reduce nausea (which caused phocomelia, a severe limb deformity in exposed fetuses). Consequently, the American public was spared enormous suffering. Of note, thalidomide is now under investigation, under multiple INDs, for a variety of other indications for populations that may benefit. The authority to regulate biologics and the responsibility for protecting the public against communicable diseases are contained in the Public Health Service (PHS) Act. The regulation of biological products was administered by NIH until 1972 when the regulation of biologics was transferred to FDA.

In 1962, Congress set in place the second cornerstone for our public health and consumer protection efforts. Congress stated that before a company could legally market its drug to patients, the company had to test the drug and show that it was both safe and effective. Effectiveness had to be shown through adequate and well-controlled trials, including clinical trials, which represented the scientific standard for evidence in 1962, and still does today. In 1976 and 1990, Congress again amended the law to establish a regulatory scheme designed to help ensure that medical devices also would be safe and effective. Also, a major amendment to the PHS Act, the National Childhood Vaccine Injury Act of 1986, extended FDA's authority by authorizing FDA to recall biologics.

Finally, as recently as November of last year, Congress again amended the FDC Act and related statutes through enactment of the "Food and Drug Administration Modernization Act of 1997." This legislation was the culmination of over 2 years of hearings, oversight and other legislative activity assessing the Agency's performance and reviewing its statutory mandate. Congress specifically rejected the arguments of those who urged that the fundamental requirements of the statute -- that drugs and devices be found to be safe and effective before they can be marketed -- be lowered or eliminated in order to open the marketplace. Moreover, as noted above, the expanded access and expedited approval processes already being used by the Agency were codified.

These laws were designed to protect the public health, and they have done a good job. At the same time, the laws are flexible and allow desperately ill patients access to unproven treatments and drugs. While FDA shares with the sponsors of H.R. 746 interest in expanding the options for medical treatment for the American public, we must take care to do so in a way that does not lower existing public health protections.

Patients want to make informed choices about medical treatments, whether conventional or alternative and complementary. While H.R. 746 addresses access to unproven products, the bill, as written, does not adequately address the need for accurate information on the safety and effectiveness of such unproven products.

A. PROTECTING THE PUBLIC FROM UNSAFE PRODUCTS

Unlike current law, H.R. 746 does not require a company to test a drug or device before selling it to humans. There will be no teratogenicity tests, which give information about the potential toxicity of drug products, like that of thalidomide, so that teratogenic drugs will not be given to pregnant women; there will be no tests to determine whether the drug causes cancer in animals; there will be no acute toxicity tests, of the kind that keep many drugs out of human studies altogether; there will be no tests to determine whether the drug causes acute damage to the liver or kidneys; and there will be no assessment of chronic animal toxicity prior to chronic exposure of humans.

There is also no requirement to study drugs carefully in humans prior to widespread use in treatment. A very significant percentage of all drugs tested in humans are dropped from further development because of unacceptable toxicity. This toxicity is not apparent initially, but often is discovered during early clinical testing.

Medical history is replete with examples of useless and sometimes even dangerous products and procedures that were used based on anecdotal information, not evidence, and were thought for years by many clinicians to be effective. For example, in the 1940's and 1950's, it was common clinical practice to administer pure oxygen to premature infants. It took over a decade to discover that the treatment was causing blindness. By that time, approximately 10,000 babies had been made blind. If clinical trials and systematic data collection and analysis had occurred early in the use of this oxygen treatment, these babies may have been spared their eyesight. After the effectiveness standard was established in 1962, FDA worked with the National Academy of Sciences National Research Council to review the effectiveness of drugs marketed for various claims in the United States before that effectiveness standard was established. Of the 3,443 drugs on the market, 1,124 were pulled from the market because they were not effective for their intended use.

Under current law, the burden is on the sponsor of a product to prove that the product is safe and effective. In essence, this legislation would shift that burden to the Government. Under this bill, a product would be assumed safe unless the Government could show that it "poses an unreasonable and significant risk of danger." In addition, it appears that such a showing would need to be made on a product-by-product basis. This would make it enormously difficult and resource intensive, and in many cases might require laboratory and research capabilities that do not exist, to regulate the marketplace effectively.

In addition, we are concerned about products that are labeled "natural" or from an herbal source that may be assumed to be safe under H.R. 746, but could pose serious risks. For example, FDA published a proposed rule last year to reduce the risks with dietary supplement products containing ephedrine alkaloids by, among other things, limiting the amount of ephedrine alkaloids in such products and requiring labeling to give adequate warning and information to consumers. (62 Federal Register 30678) The proposal also articulates FDA's policy that products marketed as alternatives to illicit street drugs are drugs, not dietary supplements.

The ephedrine alkaloids in dietary supplements usually are derived from one of several species of herbs of the genus Ephedra, sometimes called Ma huang or Chinese Ephedra. Ephedrine alkaloids are amphetamine-like compounds with potentially powerful stimulant effects on the nervous system and heart. Since 1994, the Agency has received and investigated more than 800 reports of adverse events associated with the use of dietary supplement products which contained, or were suspected of containing, ephedrine alkaloids. Reported adverse events range from episodes of high blood pressure, irregularities in heart rate, insomnia, nervousness, tremors and headaches, to seizures, heart attacks, strokes, and death. Most events occurred in young to middle aged, otherwise healthy adults, using the products for weight control and increased energy.

The proposed rule was developed based on FDA's review of its adverse event reports, the scientific literature, and public comments reviewed by the Agency, including comments generated by an October 1995 advisory working group public meeting and an August 1996 public meeting of FDA's Food Advisory Committee. These experts suggested a number of steps the Agency might take to reduce injuries associated with use of dietary supplements containing ephedrine alkaloids. If implemented, the proposed rule will reduce the risk of adverse events for consumers who use these products.

H.R. 746 attempts to address some of these concerns by requiring that patients be informed of "any reasonably foreseeable" side effects. The difficulty is that there will be no way to know about potential side effects without systematic testing, data collection, and evaluation. In effect, patients will not have the information necessary on which to make informed consent.

Moreover, H.R. 746 effectively removes any requirements for reporting adverse events for treatments or products that are used to treat serious medical conditions. The bill only requires practitioners to report medical treatments that are a "danger" to the patient. The bill's definition of "danger" only includes negative reactions that are "more serious than reactions experienced with routinely used medical treatments for the same medical condition or conditions." Even well-studied drugs, biologics, and devices that are "routinely used" to treat patients can, in themselves, cause significant adverse effects in some patients. For example, many conventional drugs "routinely used" to treat cancer patients can have serious or life-threatening effects. Without the comprehensive collection of data on adverse events, there will be no way of knowing whether a product is safe, or for that matter, dangerous.

B. KNOWING WHETHER PRODUCTS WORK AS INTENDED

We are concerned that H.R. 746 would significantly diminish incentives for practitioners and manufacturers to gather data on whether products are effective for their intended use. Based on substantial scientific experience, it is critical to obtain data on specific uses of products and to analyze those data so that we can know if a product will work as intended. Encainide and flecainide are two drugs that unfortunately illustrate this point quite dramatically. These drugs were approved by FDA only for the treatment of serious, potentially fatal, abnormal heart rhythms or rhythms that were severely symptomatic. The labeling for the drugs specifically warned that effectiveness and safety were not established for people with recent heart attacks. These drugs appeared to be safe and effective anti-arrhythmia drugs, and therefore, many physicians prescribed them for recovering heart attack victims with mild, non-symptomatic rhythm abnormalities, hoping to lower their risk of sudden death (which is increased in people with mild heart rhythm abnormalities). This practice came to an abrupt halt when a large clinical trial sponsored by the NIH found that these drugs, while effectively suppressing the abnormal rhythm, were actually killing heart attack victims, not helping them. Encainide and flecainide increased the sudden death rate in recovering heart attack patients by two and one-half fold.

We are concerned that under this bill limited data would be collected on the effectiveness of any treatment and ineffective, or even unsafe, treatments could become widely used. While the bill requires that OAM be informed of beneficial medical treatments and the Secretary of Health and Human Services be informed of dangerous medical treatments, there is no requirement for systematic data gathering or testing. The bill is silent on the extent of data gathering and analysis a practitioner must perform in order to inform OAM. Systematic data collection must be conducted in order to obtain a clear understanding of the range of benefits a patient may gain from a treatment or combination of treatments.

We do not believe that the bill's labeling and advertising restrictions are adequate to assure patients will not be misled into accepting unsafe and/or ineffective treatments. From FDA's experience, advertising, as discussed in H.R. 746, is not necessary to achieve wide use of a medical treatment. We know that widespread use of medical products or treatments by health care practitioners is not dependent on "advertising" claims, but can occur simply through professional meetings, seminars, conventions, articles, and word-of-mouth communications. Information technology, such as the Internet, have increased the speed and volume of such informal communication many fold. Moreover, FDA has found that often seemingly independent seminars, conventions, and press conferences have, in fact, been sponsored by the companies whose medical products were discussed at the meetings.

Further, by allowing for the informal marketing of treatments without any evaluation, this bill actually creates a disincentive to testing. In fact, under the definition of "seller," H.R. 746 specifically excludes the health care practitioner who receives payment for a treatment. Allowing wide dissemination of a treatment and subsequent widespread use combined with little accountability or liability, significantly reduces the incentive for manufacturers and health care practitioners to conduct studies of safety and effectiveness.

C. INFORMED CONSENT

Let us now turn to the informed consent provisions in the bill. It is well accepted that informed consent exists only if the patient is given information about the risks and benefits of a treatment before making a decision. Under current law, a patient is not considered to have given informed consent unless the patient has been advised, in writing, among other things, of the reasonably foreseeable risks or discomforts to the patient; a description of the potential benefits that might be expected, either to the patient or to others; a disclosure of appropriate alternative procedures or courses of treatment that might be advantageous to the patient; and an explanation of who will pay for the patient's care if the patient is harmed by the experimental treatment. Furthermore, FDA's informed consent regulations are intended to work in concert with Institutional Review Board oversight.

While H.R. 746 attempts to include these provisions, one must question whether informed consent can truly be achieved without consistent collection and analysis of data. Under H.R. 746, a patient will have little or no information upon which to base a decision, because no preliminary work on possible risks and benefits will have been required.

Informed consent is a particularly important matter for the acutely ill as well as for those suffering from a chronic illness. H.R. 746 does not preclude practitioners from either unknowingly or intentionally misleading patients with little or inadequate information. This increases the chance that patients will be subjected to unorthodox testing of new medical treatments without adequate protections or information.

D. REMOVAL OF DANGEROUS PRODUCTS

We also are concerned that under this bill the only authority the Secretary has when she does learn of a dangerous therapy is to publicize the fact. Now, when a product is determined to be unreasonably dangerous, we can remove the product from the market. This legislation raises serious questions about FDA's authority to remove dangerous and/or fraudulent products from the market. Rather, the Federal Government would have to expend significant resources to engage in an ongoing educational campaign about the dangers of the treatment so that health care practitioners and their patients will not make the same harmful mistake over and over again. This brings us back full circle to the years before the 1938 FDC Act, when FDA could do little to protect the public from dangerous and/or fraudulent drugs and had no authority to require the submission of reliable information before a drug could be legally marketed.

IV. CONCLUSION

We have learned a lot about expanded access and expedited product approval from the various programs we have implemented to provide access to unapproved products. We have learned that uncontrolled expanded access cannot co-exist with the need to pursue controlled clinical trials, which provide the information necessary to serve the interests of everyone. The best interest of the patient, of all patients, is not only to provide access, but also to complement it with the collection of information necessary to lead to a demonstration of safety and effectiveness. We also have learned that it is possible to make promising products available before approval in ways that protect the patients, gather valuable information, and permit the timely completion of the clinical trials. Patients, physicians, sponsors, and FDA all want the same thing -- safe and effective products to treat patients with serious and life-threatening diseases. We believe that the role FDA has played in expanding and expediting access has permitted, and will continue to permit, the most critically ill patients to have access to the most promising products.

There is always more that remains to be done. There may be more FDA could do to make physicians aware that there are mechanisms through which they may be able to treat patients with promising experimental products. FDA also must explore mechanisms to make physicians and patients more aware of potentially beneficial products that are available currently under expanded access. Equally, we must explore mechanisms to communicate to physicians and patients how much accurate information is known and how much is unknown about a particular experimental drug. There must be processes to evaluate and disseminate data rapidly on new products, both unapproved and approved, in a manner that is credible to patients and useful to physicians.

It seems that there also are questions to be addressed that go beyond the scope of FDA's authority or particular expertise. There are questions about how to create the market incentives that may be necessary if existing, unpatentable products are going to be tested. The Congress looked at that question in addressing the need for private investment in the development of products to treat so-called orphan diseases, those which affect populations that are too small to attract standard commercial investment. There are questions about how to encourage sponsors and manufacturers to be willing more frequently to provide expanded access. There also are questions about how we as a country spend our scarce public health research dollars, and whether more of those dollars should be spent understanding the safety and effectiveness of alternative and complementary treatments. We certainly would be willing to work with the Committee in examining such questions.

Fundamentally, you ask 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 FDC Act.

FDA shares the Committee's concern about making promising new treatments available to the public in a timely manner. To that end, we have tried to be responsive and compassionate to individual patient requests for products for which the necessary studies have not been completed. Our core mission remains to help ensure that there is adequate scientific evidence that new treatments are safe and effective as the public deserves and the law requires.

Thank you for the opportunity to testify.

APPENDIX

I. EXPEDITING DEVELOPMENT, REVIEW AND APPROVAL OF NEW PRODUCTS

FDA has implemented mechanisms designed to increase access to new drugs, biologics, and medical devices by expediting their development, review and approval. FDA has three such programs for human drugs and biologics: expedited review, priority review and accelerated approval. Section 112 of FDAMA amends the FDC Act providing explicit authority for FDA to approve a drug based on surrogate endpoints, i.e., accelerated approval.

A. Expedited Review

FDA assists companies to expedite the development, evaluation, and marketing of new therapies intended to treat persons with life-threatening and severely debilitating illnesses under procedures contained in 21 CFR Part 312, Subpart E. Recognizing that such drugs are often approved with a smaller safety data base than drugs with less significant clinical benefits, FDA is prepared to assist sponsors in designing definitive clinical trials to evaluate safety and effectiveness at the earliest possible stage point in the drug development.

Subpart E emphasizes that while the statutory standards for safety and effectiveness apply to all drugs, the many kinds of drugs and range of uses compel flexibility in applying the standards. In general, patients and physicians are willing to accept increased risks from products that treat life-threatening or severely debilitating diseases. If a beneficial effect is demonstrated, approval may be warranted without the additional data and usage information developed during Phase 3 studies. In these instances, additional data, long-term effects, and differences in response among subsets of the population, may be obtained after approval. In the meantime, patients with life-threatening diseases are afforded direct access to the drug.

Since the effective date of the Subpart E regulations, there have been 43 new drug applications (NDA) approved that had been designated under Subpart E while in the investigational new drug application (IND) stage. Of these NDAs, 27 were for cancer and AIDS, and 16 were for indications other than cancer and AIDS, including several for conditions that occur in patients with cancer or AIDS. It should be noted that almost all cancer and AIDS therapies are handled under expedited review in accordance with the Subpart E procedures, even if the sponsor has not requested the designation.

B. Priority Review

To further assist in speeding the review of NDAs, BLAs and effectiveness supplements, FDA has implemented a review priority classification. Upon initial receipt, applications are classified as either priority or standard based on the estimate of therapeutic preventive or diagnostic value. A priority designation is intended to direct overall attention and resources to the evaluation of applications for such products that have the potential for providing significant preventive, diagnostic, or therapeutic advances, particularly for patients with serious or life-threatening illnesses. Such a classification will determine an overall approach to setting review priorities.

C. Accelerated Approval

In December 1992, FDA published final regulations outlining a new procedure for accelerated approval of certain new drugs or biological products based on the product's effect on an objective surrogate endpoint that is reasonably likely to predict effectiveness of the product. (21 CFR Part 314, Subpart H and 21 CFR Part 601, Subpart E). In addition, FDAMA provides explicit authority for FDA to approve a drug based on surrogate endpoints. A surrogate endpoint is a laboratory effect or other clinical measurement that does not itself directly measure clinical benefit but is thought to correspond to clinical outcome. Approval can be based on such an endpoint if it is scientifically reasonable to believe that an effect on the surrogate will correlate to a clinical benefit. For example, lowering blood pressure or cholesterol in patients with cardiovascular disease is desirable only if lower blood pressure and/or lower cholesterol are correlated with decreased rates of stroke, heart attack, or other clinical events, not because a low blood pressure reading or lower cholesterol is good in and of itself. Well-established surrogate endpoints have been the basis of approval of many drugs in the past. Under accelerated approval, less well established surrogates also can be the basis of approval if they are reasonably likely to predict benefit.

The accelerated approval regulations apply to products used in the treatment of serious or life-threatening illnesses that appear to provide meaningful therapeutic benefits over existing treatments. When approval is based on substantial evidence of an effect on a surrogate endpoint, the sponsor may be required to conduct additional adequate and well-controlled studies that are necessary to verify that the effect on the surrogate marker represents improved clinical outcome. Often, the postmarketing studies will be underway at the time of approval. The procedures also allow for a streamlined withdrawal process if, for example, the postmarketing studies do not verify the drug's anticipated clinical benefit, or if there is other evidence that the drug product is not shown to be safe and effective.

Because effects on surrogate markers usually can be demonstrated with studies that are much smaller and much shorter than studies using endpoints like survival, these efforts have allowed drugs for serious and life-threatening diseases to be marketed much sooner than normally would be the case. There is always the risk that the effect on the surrogate, despite its reasonableness, will not reflect an ultimate clinical benefit, but in these urgent cases, that risk appears acceptable. Since its inception, there have been 17 drugs and biologic products that have received accelerated approval under this procedure.

Importantly, FDA regulations also emphasize several safeguards for the protection of human subjects, including the requirement for informed consent, Institutional Review Board (IRB) review, conduct and review of animal studies prior to human testing, IND safety reports and updates, and adverse drug reaction reports.

II. EXPANDED ACCESS TO, AND ACCELERATED APPROVAL OF, CANCER THERAPIES

In March 1996, building on FDA's accelerated approval program, President Clinton and Vice-President Gore announced a new FDA initiative to improve patient access to promising new cancer therapies. Under this initiative FDA is taking four steps to speed the approval of promising therapies for treating cancer. These include:

FDA undertook these initiatives after careful consideration of suggestions and advice offered by cancer patients and their advocates, pharmaceutical industry representatives, and physicians and researchers about how to speed access to cancer therapies. FDA's goal is to improve significantly patient access to promising cancer treatments without compromising patient safety or the requirement that marketed drugs be proven safe and effective before they are sold.

III. EXPANDING ACCESS TO INVESTIGATIONAL 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 a range of patient protections and benefits (for example, IB. review, informed consent, free product or treatment, and FDA review of pre-clinical data) and maximize the gathering of useful information about the product thereby benefitting the entire patient population. It is not always possible, however, for all such patients to enroll in controlled clinical trials. In this situation, FDA believes that it is possible, and appropriate, to help make certain promising, but unproven, products available to patients with serious and life-threatening illnesses. This should be done in a way that poses neither an unreasonable risk to the patient nor an unreasonable risk of losing valuable information about the effect 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. FDAMA has codified certain FDA regulations and practices regarding expanded patient access to experimental drugs and devices. The new legislation 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 investigational new drug applications and treatment investigational device exemptions. The Agency is in the process of reviewing current regulations and practices to assure coordination with FDAMA. There are a number of mechanisms FDA has used to provide access to promising investigational therapies. These mechanisms fall under a variety of terms, including: treatment INDs; treatment protocols; single patient INDs; emergency INDs; open label protocols; protocol exemptions; continued availability of investigational devices; special exceptions; open label extensions; parallel track; emergency use of unapproved medical devices; and treatment Investigational Device Exemptions (IDE).

A. Treatment INDs or Treatment Protocols

As noted, the most useful mechanism for access to unapproved drug or biologics therapies is for patients to be enrolled in a controlled clinical trial under an IND which may benefit patients' health as well as contribute to the data necessary to determine whether the drug or biologic is sufficiently safe and effective to merit final marketing approval. Some patients who might benefit from access to an investigational new drug, however, might not be enrolled in a controlled clinical trial. If there is sufficient evidence available to provide a reasonable basis for concluding that the drug or biologic may be safe and effective for patients with a serious or immediately life-threatening disease, one mechanism through which patients can have access to the drug or biologic prior to approval is a treatment protocol or treatment IND.

The most explicit expanded access mechanism in the regulations is the treatment IND or treatment protocol. The final rule on treatment protocols or treatment INDs was issued in 1987 and is found at 21 CFR Section 312.34. These regulations were codified in FDAMA. This mechanism is intended explicitly to facilitate the availability of promising new drugs and biologics to desperately ill patients as early as possible in the development process before general marketing begins.

Although a primary purpose of a treatment IND is to allow treatment, this mechanism also is intended to obtain additional data on the drug's safety and effectiveness under certain criteria: the drug must be for a serious or immediately life-threatening disease; the available data must provide a reasonable basis for concluding that the drug or biologic may be effective for its intended use; there must be no comparable treatment alternative; the controlled clinical trials of the drug or biologic must be completed or underway; and the sponsor must actively be pursuing marketing approval.

Since the treatment IND procedures were developed, FDA has designated 40 drug or biologic investigational products for such early availability, and 36 of the products have proceeded to marketing approval or licensure under NDAs or product license applications (PLAs). Of the products approved, 11 have been for cancer, 11 for AIDS or AIDS-related conditions, and the remainder for a wide variety of other severely debilitating and life-threatening diseases, including obsessive compulsive disorder, severe Parkinson's Disease, multiple sclerosis, respiratory distress syndrome in infants, Gaucher's disease, diabetes, amyotrophic lateral sclerosis or ALS (Lou Gehrig's disease), and others.

B. Single Patient/Compassionate INDs

As early as 1968, an FDA mechanism, informally known as a "compassionate use" study, provided patients who were not participating in the controlled clinical trials access to investigational drugs. The "compassionate use" study could be conducted either under a separate or existing IND. Such studies were not formal controlled trials, but they permitted use of an investigational drug under a protocol for an individual patient or patients, or for an early exploration of a novel idea. As noted previously, FDAMA addresses expanded access to unapproved therapies in emergency situations and in the case of individual patients who seek access to investigational products intended for serious diseases. An FDA working group is reviewing existing regulations and practice to assure coordination with FDAMA. Currently, the mechanisms used to provide expanded access include: single patient/single use IND, an emergency use IND, an open label protocol, or an open label extension. The term emergency IND refers to single patient uses for which there is not enough time for the treating doctor to file the required IND paperwork before administering the investigational product. In such cases, FDA can authorize the use of the product over the phone.

Under current practice, single patient/single use (non-emergency) and emergency INDs often are allowed to proceed when a physician determines that a particular unapproved therapy might be of benefit to a particular patient under his or her care for whom other options do not exist. For a treating physician to administer an unapproved product to a patient, the following conditions are necessary: a) the patient must be informed about the relevant circumstances about the drug and consent to take the product; b) the physician must be properly licensed and she/he must agree to administer the product and be responsible for monitoring and reporting data on the patient's use of the product to the sponsor; c) the IB. must approve the proposed single investigation (note that in emergency situations, the physician may notify the IB. promptly but after treating the patient); and d) the manufacturer/sponsor must be willing to provide the product without charge (unless the sponsor has applied for and FDA has allowed charges for cost recovery). Each of these conditions is critical to maintaining the dual goals of providing the patient with a promising product, and protecting the patient from potentially unsafe or ineffective products. There is a minimal amount of paperwork required to process a request for a single patient or emergency use IND.

Emergency INDs are treated as matters of medical urgency and are intended to be handled expeditiously by FDA. In the vast majority of emergency INDs, FDA renders a decision on such requests within a few hours. There are some rare exceptions when the particular therapy is completely unknown and may require additional information. These usually are approved within 48 hours.

For certain unapproved products, FDA has set up internal procedures to facilitate single patient IND requests. One example of this is the process for single patient IND requests for thalidomide. Physicians are put in touch with a consumer safety officer within the relevant reviewing division; the consumer safety officer helps the physician understand the IND process to facilitate completion of the IND application. Some of the information required includes the name of the drug supplier, the patient's disease history and prior therapies, a detailed protocol of treatment, the patient's informed consent, and the investigator's qualifications.

C. Open Label Protocol

Patients may be able to gain access to an unapproved product through what is termed an open label protocol. An open label protocol allows patients to receive the drug while some safety information is collected, but these patients have no control group. In effect, these are similar to single patient INDs, but multiple individuals can be processed through one general request by the drug sponsor. When many patients are in need of an unapproved therapy and the above-mentioned conditions pertain [e.g., a physician judges that a particular unapproved therapy might be of benefit to a particular patient for whom other options do not exist; there is sufficient evidence of safety and effectiveness to support the use of the investigational product; and the sponsor of the unapproved new drug or biologic has agreed to provide the drug free of charge (unless the sponsor has applied for, and FDA has allowed charges for cost recovery)] the drug or biologic may be available through the open label protocol.

Many thousands of patients have received unapproved therapies by this means. For example, there have been several large open label protocols for anti-retroviral drugs (e.g., anti-HIV drugs) which have involved tens of thousands of patients.

Open label extensions provided another mechanism for gaining access to unapproved products. These extensions enable those patients who received a therapeutic response during a controlled clinical trial under an IND that has ended to continue the investigational drug treatment.

There are a number of situations in which a patient who wants access to an unapproved drug is unable to receive the drug. In many cases a sponsor is unwilling to provide the product. Patients sometimes are confused by this situation and misinterpret a company's unwillingness to provide the product as an FDA action. Much less frequently, the cause may be FDA's concern about the risk to patients because of the nature of the product. Generally, if a physician makes the request and a sponsor agrees to provide the product, FDA does not object to the study proceeding.

At times, there may be relatively little evidence supporting the usefulness of the drug for the particular indication, but its use may be considered appropriate because there is no alternative for the particular condition. Physicians may always contact FDA to propose such a use for a specific patient when they believe circumstances warrant. Of course, the company still has to make the product available before a patient can gain access.

D. Protocol Exception/Exemptions

In cases where a patient cannot be enrolled in a protocol because of some factor that makes the patient ineligible to participate in the study, research sponsors or investigators often can make a protocol exception to enroll a patient without including the data on that patient in the report of the results from the controlled study participants. This mechanism is sometimes referred to as a special exception.

E. Parallel Track

Another mechanism, parallel track, is an FDA policy that was formally announced in the Federal Register in 1992 (53 Federal Register 13250, April 15, 1992). This policy allows promising investigational drugs for AIDS and other HIV-related diseases to be made more widely available under "parallel track" protocols while the controlled clinical trials are carried out. The purpose of the parallel track mechanism is to permit access to unapproved drugs for people with AIDS and HIV who are not able to take standard therapy, or for whom standard therapy is no longer effective, and who are not able to participate in an ongoing controlled clinical trials. Included in this mechanism is the possibility of having a National Institutional Review Board to review the ethical access to these products.

There has been one large parallel track program since the policy was implemented that included 12,000 patients. Other anti-HIV drugs have been made available by the open protocol mechanism, as noted above. Given the accelerated rate of approval for many drugs for people with AIDS and HIV and the availability of open label studies, it has not been necessary to use this process in recent years.

IV. ACCESS TO MEDICAL DEVICES

Although the Committee has asked that we concentrate on access to drugs and biologics, we feel that a complete picture requires an overview of other FDA mechanisms to permit access to promising investigational products. Similar procedures for access exist in the Center for Devices and Radiological Health (CDRH) which allow access to investigational devices. Under the CDRH "Continued Availability of Investigational Devices" policy, FDA has worked with sponsors and investigators to facilitate treatment use of promising or important investigational devices once the core clinical investigation of new devices has been completed. The policy allows additional subjects to be enrolled in the IDE protocol while the marketing application is being prepared by the sponsors and reviewed by FDA. This policy has allowed the collection of additional safety and effectiveness information while providing continued access to promising new devices. FDAMA has codified FDA's practice with respect to expanded access to investigational devices.

A. Treatment Investigational Device Exemption

To formalize an access process for important medical devices and to more clearly define procedures and criteria for treatment use, FDA published a final rule on September 18, 1997, effective January 16, 1998, to allow for treatment use of investigational devices. The regulation is patterned after the drug treatment IND regulations with modifications to account for the differences in the IDE process. FDA anticipates that this regulation will facilitate the availability of promising new devices to patients as early in the device development process as practicable while safeguarding against the proliferation of fraudulent products. This regulation also will ensure the integrity and validity of controlled clinical trials.

B. Emergency Use of Unapproved Medical Devices

In 1985, FDA published a guidance document to address those cases in which an emergency need for an unapproved device had been identified, but the device was to be used in a manner not approved under the IDE; the physician or institution was not approved under the IDE; or no IDE existed. The guidance provides criteria to establish whether an emergency exists. These include instances when: 1) the patient is in a life-threatening condition that needs immediate treatment; 2) no generally acceptable alternative for treating the patient is available; and 3) the need to use the device is immediate because there is no time to use existing procedures to get FDA approval for the use. The physician is expected to determine whether the criteria have been met. The guidance also describes patient protections in these circumstances including informed consent; institutional clearance; the IB. chairperson's concurrence; an independent assessment from another physician; and, authorization from the sponsor if an IDE exists.

C. IDE Protocol Deviations

In addition to the above mechanisms, for diagnostic and therapeutic devices for which there is no satisfactory commercially available alternative and the patient does not meet the clinical protocol requirements, FDA has approved requests to modify the existing protocol to treat single patients who do not meet the initial protocol requirements. In these cases FDA required the requester to submit a justification for such use and to follow certain patient protection measures.

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