Access for Therapeutic Purposes

The FDA press release that accompanied the final regulations in January 1963 addressed for the first time the issue of access to investigational drugs for therapeutic purposes. In an analysis of objections that had been raised to the regulations in draft form, the press release noted, "The proposed regulations were said to deny extremely important new drugs not yet approved for general distribution to patients who might need them urgently as a lifesaving measure."

The FDA's response set the tone for the next two decades. The press release explained, "The increased flexibility in the regulations will allow the sponsor of a new drug investigation to add new investigators after the program is started. There is no bar in the regulations to giving the necessary instructions to, and obtaining the necessary commitments from, a new investigator by telephone in case this is needed to save a life."

Growing Confusion

From 1962 until the beginning of the 1980s, access to investigational drugs was an informal process governed primarily by telephone. The FDA had no written policies. If a physician determined that a severely ill patient had no recourse other than an experimental drug, the physician called the FDA and requested access to that drug. Medical officers in the agency evaluated each situation separately and either approved or denied the request. The criteria were simple. Approval required four basic elements: a manufacturer willing to supply the drug, a physician willing to prescribe it, a patient willing to give informed consent, and some basis for believing that the treatment was not an outright fraud or poison.

The flexibility of this system enabled many very sick patients to receive drugs with a minimum of delay and paperwork. But there were also drawbacks to the informal approach. First, the system only worked for patients whose physicians knew what drugs were under investigation; patients treated by physicians outside the mainstream of academic medicine were less likely to have access to experimental therapies. Second, some ineffective or even toxic drugs, such as DMSO (dimethyl sulfoxide), attained widespread distribution among patients whose original illnesses did not justify extreme measures. Finally, the lack of written policies spawned a confusing array of terms and concepts that still cloud discussions and interfere with efforts to develop a more uniform approach to the access problem.

In the 1960s, FDA medical officers permitted access to investigational drugs under several mechanisms: orphan drug INDs, individual investigator INDs, and compassionate use INDs. The orphan drug concept actually predated the 1962 amendments and remains in use today. It refers to drugs developed to treat rare or unusual conditions. The "permanent" orphan drug IND was conceived to provide access to drugs that would never meet licensure requirements because there were simply too few patients to collect adequate data. (In 1983, Congress passed the Orphan Drug Act to provide certain tax and other financial incentives to the sponsors of therapies for rare diseases.)

The individual investigator IND enabled physicians to obtain experimental drugs for therapeutic purposes when it was not possible to enroll their patients in existing clinical trials. By the end of the 1960s, this concept had been incorporated into the compassionate use IND, which also covered the provision of experimental drugs to patients during FDA review of a new drug application, or NDA (the document submitted by a sponsor after the completion of clinical trials to request permission for marketing).

Two more expanded access concepts arose during the 1970s. Sponsors of controlled trials were permitted to develop concurrent open-label safety studies (also called open enrollment or open protocol). Through these studies, which continue today, thousands of patients received access to experimental drugs at various stages of investigation. Although the FDA requires sponsors of these studies to collect safety data, many observers of FDA policy believe that the primary purpose of the open-label studies is to provide therapy to patients. In 1976, the FDA also accepted the concept of the Group C cancer drug IND, which provides increased access to certain investigational cancer drugs distributed by the National Cancer Institute.

It is important to remember that all of these concepts evolved in the absence of any written policy. Over the years, several groups in Congress and the FDA attempted to develop a more rational approach to the use of investigational drugs for therapeutic purposes, but changes in administration and other political events intervened. Meanwhile, the drug development and approval process itself grew increasingly formal. By 1980, it took an average of 10 years for a new drug to progress from the laboratory to the medicine chest.

Improving Response Capabilities

Recognizing that FDA would be called upon to respond rapidly to the new challenges posed by AIDS, then commissioner Frank E. Young made a number of administrative and organizational changes at the agency. First, he assigned all AIDS treatments a special 1-AA designation, giving them top review priority. This meant that the FDA intended to act on all AIDS-related NDAs within 180 days of their submission. A new division of antiviral drug products was created within FDA's Center for Biologics Evaluation and Research to expedite the review and evaluation of potential AIDS therapies. In addition, FDA established the AIDS Coordination Staff to integrate the agency's various AIDS-related activities and to interact with other agencies and outside groups interested in AIDS drug development.

Expedited Development

Perhaps the most fundamental change, however, involved the clinical trials process itself. In October 1988, Dr. Young announced immediate implementation of a formal plan to reduce the time required for human testing of drugs for life-threatening and severely debilitating diseases, such as AIDS, Parkinson's disease, and certain aggressive cancers. The primary effect of the new "expedited development" process is to eliminate phase 3 clinical trials for drugs shown to improve survival or prevent irreversible morbidity. By planning the critical phase 2 studies well, the development and review process might be shortened by two to three years.

Expedited development follows a pattern established by the development of zidovudine. In February 1986, after a promising phase 1 trial at the National Cancer Institute and Duke University, researchers started a phase 2 study of zidovudine at 12 medical centers across the United States (the placebo-controlled randomized trial involved patients with AIDS or advanced AIDS-related complex [ARC]). The phase 2 study was stopped in September of that year, when an independent data safety monitoring board found a dramatic difference in outcomes between the 145 patients receiving zidovudine and the 137 patients receiving placebos (19 patients in the placebo arm of the trial had died, compared with only a single death in the zidovudine group). Burroughs Wellcome, the manufacturer, submitted a new drug application for zidovudine in December 1986. The FDA approved the NDA without a phase 3 clinical trial on March 20, 1987. At the time, officials explained that one reason for the rapid approval of zidovudine was that FDA scientists had had an opportunity to work closely with the drug's sponsor from the very beginning of the development process.

Current procedures for expedited development specify that the FDA will meet with drug sponsors to help devise efficient animal and human studies—studies that answer vital questions about safety and efficacy in the least amount of time possible. The FDA also monitors the progress of clinical trials and, if necessary, helps the sponsor develop appropriate postmarketing studies to provide additional information about risks, benefits, optimal uses, and dosages. The FDA approval process for drugs in the expedited pathway takes into consideration the severity of the disease being treated and the availability of alternative therapies, as well as the statutory criteria for approval.

Treatment Investigational New Drugs

The treatment IND first emerged as part of a long-term effort to incorporate the concept of expanded access into the IND regulations.

In June 1983, the FDA issued proposed regulations that included a very broad interpretation of the use of investigational drugs for therapeutic purposes: at any time during the investigational process, the FDA could approve a treatment protocol for any patient with a serious disease (the definition of ''serious" was left to the discretion of the patient and physician). The proposed interpretation would have incorporated virtually all of the older versions of expanded access, including the compassionate use IND and the orphan drug IND.

Some critics believe that when the final IND regulations emerged in 1987, the definition of treatment IND was much narrower. The treatment IND mechanism allows patients suffering from serious or life-threatening conditions for which there is no satisfactory alternative therapy to obtain a promising experimental drug. Clinical evidence must be available to show that the drug is relatively safe and that it "may be effective." In addition, controlled clinical trials must be completed or ongoing and the sponsor must be pursuing marketing with "due diligence." Others at the FDA argue that the only real difference between the 1983 and 1987 versions of the regulations was that the 1987 announcement received a great deal of publicity, which reminded the public that the treatment IND was an available mechanism.

A government scientist reports that, as of March 12, 1990, the FDA had approved 18 treatment INDs for conditions ranging from AIDS to respiratory distress syndrome in infants. Almost 20,000 patients had obtained access to drugs not yet approved for marketing. Nevertheless, persons with AIDS and their advocates say that the treatment IND has fallen far short of their expectations. They suggest that the FDA's interpretation and implementation of "may be effective" have been too rigorous—too close to the standard used for final approval of a drug. With one exception, they say, treatment INDs have simply bridged the gap between the end of clinical trials and full FDA approval. They have not increased access to drugs at earlier stages of development or helped patients who were ineligible for conventional clinical trials.

Another criticism of the treatment IND regulations has been that they increased, rather than decreased, confusion about the parameters of expanded access. People inside and outside the government had hoped that the regulations would furnish a framework for all of the different approaches to providing experimental drugs to desperately ill patients. Instead, the regulations defined one particularly narrow approach and left other options open. Early dissatisfaction with the treatment IND led to calls for a more flexible solution to the access problem.

Parallel Track

For almost a year after the release of the new IND regulations, patient advocates, community physicians, and government scientists exchanged ideas about other possible ways to expand access to experimental drugs. Finally, at a meeting in San Francisco in June 1989, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, presented the concept of the "parallel track" protocol. The parallel track would make selected drugs available to HIV-infected patients who could not participate in conventional clinical trials and who had no therapeutic alternatives, without disrupting the progress of controlled clinical trials. Parallel track protocols could be approved for promising investigational drugs when the evidence for effectiveness was less than that required for a treatment IND.

Several months later, an FDA Advisory Committee meeting convened by the FDA and a subgroup convened by the National AIDS Program Office began efforts to define the structure of the parallel track system. After a lengthy review process, they decided that parallel track protocols could be implemented within the framework of existing regulations. In December 1989, they submitted a proposed policy statement explaining the basic outlines of the parallel track to the Office of the Secretary of Health and Human Services. Drugs would be considered for the new track only if manufacturers could provide the following:

1.

information showing promising evidence of efficacy based on an assessment of all available laboratory and clinical data, as well as sufficient information to recommend an appropriate starting dose and preliminary pharmacokinetic and dose-response data;

2.

evidence that the investigational drug is reasonably safe, taking into consideration the intended use and the prospective patient population;

3.

a description of the intended patient population;

4.

evidence that the defined patient population lacks satisfactory alternative therapies;

5.

assurance that the manufacturer is willing and able to produce sufficient quantities of the drug for both controlled clinical trials and the parallel track;

6.

a statement of the status of existing controlled clinical trial protocols (drugs will be considered for parallel track only after protocols for phase 2 controlled clinical trials have been approved by the FDA; also, patient enrollment in phase 2 controlled trials must start before or concurrently with the release of drugs for parallel track);

7.

an assessment of the impact that the parallel track study may have on patient enrollment in controlled clinical trials and a proposed plan for monitoring progress of the controlled trials; and

8.

information describing the educational efforts that will be undertaken by the manufacturer or the sponsor to ensure that participating physicians and potential recipients have sufficient knowledge of the potential risks and benefits of the investigational agent.

Evidence for safety and efficacy might come in part from expanded phase 1 trials. As noted earlier, phase 1 trials for drugs for AIDS and other life-threatening diseases often involve persons with the disease instead of healthy volunteers. The expedited development process and the potential increase in the number of people who might get very early access to an experimental drug for therapeutic purposes have placed pressure on investigators to get as much information as possible from phase 1 trials. For example, the authors of the proposed policy statement on the parallel track indicate that expanded phase 1 trials should provide some information about potential interactions between an investigational drug and other drugs commonly used in the patient population. Other physicians suggest that expanded phase 1 trials should compare different doses of an experimental drug, primarily to avoid problems similar to those that arose with zidovudine. (Two years after the FDA approved zidovudine, a randomized trial carried out by the ACTG revealed that patients taking 600 milligrams per day of the drug did as well as patients taking the recommended dose of 1.2 grams per day. If this had been known sooner, some patients might have avoided adverse reactions, and many more would have been spared unnecessary expense.)

The proposed policy statement on parallel track also outlines eligibility requirements for patients. First, patients must have clinically significant HIV-related illness or be at imminent health risk as a result of HIV-related immunodeficiency. Second, patients must be unable to participate in related controlled clinical trials, either because they do not meet entry criteria (for example, laboratory test results are not within specified limits), because they are too sick, or because participation would create undue hardship (the nature of possible hardships, such as travel time to a research center, must be described in the parallel track protocol). Finally, physicians who wish to enroll a patient in the parallel track must provide evidence that existing FDA-approved therapies for the condition are contraindicated for that patient, that the patient cannot tolerate them, or that they are no longer effective.

Close monitoring of the parallel track will be essential to ensure that serious adverse effects (or, conversely, unexpected benefits) are recognized at the earliest possible moment. According to the proposed policy statement, sponsors will be required to establish a data and safety monitoring board (DSMB) with responsibility for overseeing the parallel track protocol and for comparing information gathered from the parallel track with information gathered from related clinical trials. The recent experience with ddI, described at the beginning of this chapter, underscores the importance of reviewing all available materials. Although data collection in the parallel track will be minimal compared with data collection in controlled trials, the DSMB should have a sufficient basis for comparison. If necessary, the DSMB or its equivalent may recommend to the FDA, to the sponsor, or to the NIAID AIDS Research Advisory Committee that the parallel track protocol—and possibly related clinical trials—be terminated.

In conventional clinical trials, educational materials and informed consent documents that describe the potential risks and benefits associated with an experimental drug must be approved by an institutional review board (IRB) at each participating institution. The PHS working group, however, determined that such an arrangement might be impractical for parallel track protocols, in part because many community physicians who wished to participate in the parallel track would not have access to IRBs. In addition, the time required to provide sufficient information to hundreds of IRBs around the country would defeat the main purpose of the parallel track—rapid dissemination of investigational drugs to desperately ill patients.

To overcome this problem, the working group has proposed a national human subjects protection review panel to provide continuing ethical oversight of all parallel track protocols. The panel would have a diverse membership, including persons with AIDS, physicians, government scientists, and others. It would be responsible for establishing the types of information that must be given to patients and for approving all informed consent procedures.