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Availability of Investigational Drugs for Compassionate Use

Statement of

Robert J. Temple, M.D.
Associate Director for Center for Drug Evaluation and Research
Food and Drug Administration


the House Committee on Government Reform

June 20, 2001


Mr. Chairman, Members of the Committee, I am Robert Temple, M.D., Associate Director for Medical Policy, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA or the Agency). Also with me today is Ms. Patricia Delaney from FDA's Office of Special Health Issues (OSHI), Cancer Liaison Program.


FDA would like to thank the Chairman for drawing attention to the important issue of the availability of investigational drugs for what is commonly referred to as compassionate use. First, let me say that while the phrase "compassionate use" is commonly used to describe some of the ways of making unapproved products available to patients, there is no FDA regulation or policy defining a "compassionate use." Compassion, an intent to help, should be, and is, an element of all drug investigation activities. In general, we describe these uses of drugs as "treatment uses," because their intent is to provide treatment of patients, not primarily to evaluate the safety and effectiveness of the drugs, the primary and usual purpose of studies under an Investigational New Drug Application (IND). FDA refers to compassionate use requests for individual patients as a "single patient IND" study, wider use would usually take place under a "treatment IND" or "treatment protocol" under an existing commercial IND.

We are very much 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 marketed medical products upon which patients and their health care practitioners rely are shown to be both safe and effective. Just as important, we have critical responsibilities in helping to ensure that the use of investigational drugs is carried out safely, and that the limitations of current information on the drug is conveyed to the patient. We are particularly aware that even before a drug is approved for marketing, there may be enough information to support varying degrees of treatment use for people with serious illness when there is no effective treatment available. In various ways, FDA has attempted to make it possible for investigational drugs to be available in these situations, but availability must bear a relation to how much information we have. The safeguards provided by FDA's activities are particularly important for our most vulnerable citizens, those who are seriously ill.

We understand that patients and their family members are often unfamiliar with FDA's legal and regulatory responsibilities. Often they are unaware that FDA cannot compel a company to supply an individual patient with an investigational drug outside of its planned clinical trials. The manufacturer or sponsor makes the final decision to provide an experimental drug or therapy to a patient. The sponsor may consider many factors, including the amount of information available about the drug, the amount of drug available, and how best to use its resources to optimize development of the drug for marketing. This maximizes the availability of the drug to patients who can benefit from it. In some cases, the sponsor is unwilling to provide the product outside of clinical trials, especially relatively early in drug development. Patients are sometimes confused or angered by this situation and misinterpret the company's unwillingness to provide the product as an FDA action.

FDA may not allow treatment uses because of safety concerns. Generally, however, if a physician makes a request for treatment use of an experimental drug, in a patient for whom no effective therapy exists, and there is an ongoing study of the drug and a sponsor agrees to provide the product, FDA does not object to the treatment use.

There have been cases in which treatment use has been considered appropriate, despite relatively little evidence supporting the usefulness of the drug for the particular indication. Generally, when there was no effective alternative drug or treatment for the particular condition and there was sufficient information about safety, treatment use be justified. Physicians may always contact FDA to propose such a use for a specific patient when they believe circumstances warrant this use.

It is apparent that many manufacturers of promising drugs do not have standard operating procedures in place for handling requests for single patient INDs, especially when the promise of the drug is just becoming appreciated. This has created confusion and, in some cases, led to perceptions of an unfair system, in which some people can gain access to therapies while others, who appear similarly situated, cannot. The patients seeking these drugs are frequently cancer patients who have exhausted standard treatment. They, and their relatives, are often desperately seeking a last chance to prolong their lives. Any impediment to obtaining the drugs would be most unwelcome. Actual or perceived unfairness would seem intolerable.


FDA is generally satisfied with how the current system of access to INDs and single patient INDs is working, but there are problems and some inherent limitations of the system. We realize that the experience of some individuals has not been satisfactory and has seemed unfair and there is a public perception of a very convoluted system to gain access to these drugs.

Let me bring you up to date on some recent FDA activities that have addressed issues of access to experimental drugs and single patient INDs.

At the December 13 and 14, 2000, and the June 7, 2001, Oncologic Drugs Advisory Committee (ODAC) meetings, FDA solicited advice from the committee on when it is appropriate for FDA to allow investigational drugs to be used for treatment of individual cancer patients. An important additional objective of the meeting was to educate the public, physicians, and ODAC on the issues surrounding access to investigational cancer drugs for single patient treatment use.

The individual presentations and discussions at the meeting were wide-ranging, very thoughtful and, it is fair to say, somewhat surprising. These were patients or relatives of patients who spoke feelingly of their difficulties and frustrations in seeking potentially useful treatment for cancers that had not responded to other therapy. A number of patient groups spoke with equal feeling on the need to develop treatment rationally, to defer treatment use until adequate information supports it (and only then to make it available) and to correct the widespread misimpression that there are magic bullets available for treatment of refractory malignancies. They also emphasized the need for widely available information about drugs under study and those drugs for which more widespread availability was appropriate and available. It was clear that the overall situation was one of great complexity, but these groups did not believe that wide use of toxic drugs without known benefit was a service to seriously ill patients.


Commercial sponsors are not always willing to supply drug for treatment uses. A number of industry concerns about the use of experimental drugs were discussed at the June 7, 2001, ODAC meeting.

(1) There may be a limited drug supply early in drug development. The batches prepared for early drug studies are usually small; making larger amounts available is expensive and not considered reasonable until there begins to be evidence that the drug is of value.
(2) There may be competition between expanded access programs and the regulatory programs that will lead to drug approval. Competition can be either for patients entering trials or for internal company resources. The process of individualized packing and shipping of drugs for single patient use on an emergent basis can be very disruptive to departments that are organized to pack and ship drugs in a scheduled manner for clinical trials. There is significant concern that availability of all investigational drugs outside a formal protocol will decrease participation in the formal study. In fact, FDA rules allow open studies to be put on hold if they are interfering with the conduct of clinical trials
(3)The use of an investigational drug in less controlled setting, in patients with very advanced disease could lead to adverse reactions that might raise difficult to resolve but spurious safety concerns about the drug.
(4)Industry seems to learn little about a drug from single patient use. FDA expects very low response rates in patients who have received multiple previous therapies and a low rate in such patients would not damage the drug's chance for approval.

At the conclusion of the meeting, it was obvious that this issue deserved further discussion and exchange of views. FDA has suggested that a consensus development meeting be convened in the near future, involving industry, academia, patient advocacy groups and regulators to discuss these issues. FDA and the National Cancer Institute could play an important role in organizing and facilitating the conference. We will be glad to provide the committee with the written statements offered at the ODAC meeting and a transcript of the June 7, 2001, discussions.


We would like to clarify FDA's role in making INDs available for treatment uses. First, to put the subject into context, I would like to briefly address the public health system of getting unapproved drugs to patients.

Clinical Trials

FDA's primary obligations are those vested in us by Congress in the FD&C Act and the Public Health Service Act, that ensure that marketed medical products are, safe, effective, properly labeled and that experimental drug studies are designed to protect the patient volunteers.

Before being approved by FDA for marketing, new drugs and biological products must be proven effective in controlled clinical trials and shown to be safe. FDA is directed, under the FD&C Act, to rely on evidence of effectiveness based upon adequate and well-controlled studies. The persons who participate in any trials under an IND must be fully informed of the risks and possible benefits of their participation and studies must be designed to adequately protect the patients from harm. Patients must be informed about alternative medical treatments, whether approved or investigational. This is possible only when there is adequate pre-clinical data from animal studies or from other sources to provide the information upon which informed consent can be based.

Access to a Clinical Trial

The access process starts with a drug sponsor, a pharmaceutical company or a research scientist at a university or at the National Institutes of Health (NIH), seeking to develop a new drug. 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 must submit an IND to FDA for review before beginning a trial in people.

After a study passes FDA review 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 patients. These Phase I studies are designed to assess the most common acute adverse effects and examine the amount of drug that patients can take safely without unacceptable side effects. It is unusual in this setting to see important patient benefits. Initial clinical studies are also designed to better understand 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, Phase II studies are conducted to determine the effectiveness of the drug in patients who have the medical condition that is intended to be affected by the drug. Researchers then assess whether the drug has a favorable effect, for example, in cancer patients by seeing whether the tumor size is reduced.

In some cases the Phase II studies reveal results so impressive that these studies alone are the basis for approval, generally for treatment of refractory disease. This is often done under FDA's accelerated approval rule (similar to the fast-track provision under FDA's Modernization Act of 1997 [FDAMA]) which allows FDA to approve drugs on the basis of a surrogate endpoint (effect on a measurement such as a tumor size likely to lead to a real patient improvement) on condition that post-marketing studies demonstrate a tangible patient benefit. In most cases, if Phase II studies show desirable responses, Phase III studies are conducted. Those are concurrently controlled studies in which two therapies are compared. These usually are 1) a comparison of standard treatment alone, or 2) a comparison of the new treatment alone with an older treatment to show that the new treatment is not worse than the older treatment or is its superior.

It is generally believed that it would be in everyone's interest if more patients participated in trials of new cancer treatments. 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), a new website www.clinicaltrials.gov , 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.

The full implications of taking part in a clinical trial must be fully explained to potential patient subjects 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. These hopes and desires should not prevent them, however, from finding out all they can about being a part of the process. Many seemingly promising agents prove not to be helpful or too toxic to use and, especially in early trials, major benefits are clearly the exception.

Protocol Exception/Exemptions

In cases where a patient cannot be enrolled in an existing 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 treat such a patient. The data from that patient would not be part of the report of the original study. Usually such special exceptions arise in the same institutions that are conducting the original study, where investigators are familiar with the drug.

Access to Investigational New Products

The ideal way 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 possible, however, for all patients who might benefit from the drug to enroll in controlled clinical trials.

FDA believes that it is appropriate to make certain promising, but not yet approved, products available to patients with serious and life-threatening illnesses who lack alternative treatment. This should be done in a way that does not interfere with recruitment to the clinical trials needed to support the effectiveness and safety of the drug. It should also be done fairly. A major goal of the treatment IND proposed in 1982, and made final in 1987, was to make unapproved but promising drugs with appropriate evidence of effectiveness widely available prior to marketing. In the past such drugs often had been available but only at selected sites.

Single Patient INDs

The paperwork reporting responsibilities a sponsor must submit for a single patient IND or single patient use under an existing IND is modest. If a patient is treated under an existing IND, the sponsor must collect and report adverse reactions and include such events in its annual reports. A single investigator wanting to treat a patient will refer to the commercial IND for most information and will have to provide additional information about the patient to be treated to obtain informed consent and local IRB approval. Exactly what to do is described in the oncology part of FDA's website and the Agency's role in the process.


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 and especially when potential toxicity is great. 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.

FDA has set up internal procedures to facilitate single patient IND requests. Physicians are put in touch with a Consumer Safety Officer (CSO) within the relevant reviewing division; the CSO helps the physician understand the IND process to facilitate completion of the IND application.


Section 402 of FDAMA 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 and is currently developing new regulations to codify current practices. FDAMA continues to emphasize for all those cases, including individual uses that the appropriateness of expanded access depends on available data, i.e., "sufficient evidence of safety and effectiveness to support the [proposed] use."

For the past four years, Agency efforts have 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) appointing cancer patients to our Oncologic Drug Advisory Committee, which reviews new cancer therapies.


An important means of providing access to new cancer therapy is the rapid development and approval of new agents. FDA has implemented mechanisms designed to increase access to new drugs and biologics 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.
  • Priority Review to speed the review of NDAs, biologics license applications (BLAs), and effectiveness supplements that could have important therapeutic impacts. 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. Perhaps the most important, yet under appreciated aspect of fast track is FDA's commitment to work closely with sponsors throughout the drug development process to agree on study designs and appropriate outcome measures, etc. This allows companies to plan and carry out the most rapid possible responsible development. FDA meets constantly with sponsors taking advantage of this opportunity.

FDA's overall goal is to improve significantly patient access to promising cancer treatments and treatments for other life-threatening illnesses without compromising patient safety. When we do this we seek optimal development and use pre-marketing access when this is safe and appropriate. Importantly, FDA regulations emphasize safeguards for the protection of human subjects, including the requirement for informed consent.


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 and CDER that routinely provide assistance and information to consumers, OSHI provides information and works 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. 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 databases.

In response to Section 113 of FDAMA, FDA has worked with NIH to develop a data bank of clinical trials of therapies for serious or life-threatening diseases. The data bank, www.clinicaltrials.gov, currently lists over 5000 trials sponsored by NIH, other Federal agencies, universities, and the pharmaceutical industry. We anticipate that many more industry trials will be included after the final guidance document is available.

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).


Even as they provide high standards and protection of patients, the laws and regulations are flexible and allow patients with no alternatives access to promising, but not yet unapproved 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, 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.