FDA Consumer special report
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Moviegoers in the '30s and '40s were regularly treated to the high drama of a dying patient whose only hope lay in an experimental drug--usually called a "serum"--that had to be flown through a raging storm, at night, to the patient's bedside. In the Hollywood scenario, the "serum" always arrived in the nick of time, the patient was saved, the brave young doctor was acclaimed a hero with a brilliant future, and the world got a miraculous new weapon in the battle against death and disease.
And, in fact, thousands of people receive investigational products, not only in carefully controlled clinical trials, but also in innovative programs aimed at giving them all the medical help possible.
Using investigational agents in a sort of last-ditch effort to help desperately ill and dying patients is not new to medicine. FDA has permitted the emergency use of unapproved, investigational products for many years. Under the general rubric "compassionate use," the agency has permitted sponsors of investigational agents to provide them to doctors not involved in controlled clinical trials for use in individual patients who might be helped by the treatment.
In 1987, FDA changed its regulations on investigational new drugs (INDs) to specifically authorize treatment use of such agents. The term "Treatment IND" highlights the fact that an investigational agent is being administered not primarily to gain information about its safety and effectiveness, as in a controlled study, but to treat certain seriously ill patients.
The change in terminology is emblematic of a shift in the way FDA, the Congress, the pharmaceutical industry, health professionals, and health activists view the role of drug development and drug regulation in this country. All agree that a major goal of drug regulation must be to speed the journey from laboratory to bedside of important new drugs for devastating illnesses.
The shift involves more than just wider treatment use of unapproved agents. It also encompasses steps to accelerate FDA's process for reviewing applications to bring new drug and biological products to the market. Without compromising the approval requirements for safety and effectiveness of new drugs and biologics, FDA has taken numerous steps to shorten the time devoted to pre-approval drug testing. This streamlining of the process is geared to eliminating unnecessary, duplicative studies, and expediting the review of innovative agents for the most serious or life-threatening conditions.
Through published guidelines and meetings with sponsors, FDA reviewers help drug developers plan studies designed to generate the information FDA needs to make decisions about approvability. In addition, under a new congressional mandate, the agency will be able to collect user fees from product developers and manufacturers to cover the costs of expediting the review of prescription drug applications. (See "User Fees to Fund Faster Reviews.")
The first class of drugs to generate interest in treatment use outside formal clinical trials consisted of beta-blocking agents used in certain forms of heart disease. During the mid-1970s, many thousands of patients were treated with beta blockers for advanced, life-threatening heart and lung conditions for which no effective alternative treatment existed. In one instance, more than 600 cardiologists treated some 20,000 patients with the anti-arrhythmic drug amiodarone before it was approved for marketing as Cordarone in late 1985.
By far the most celebrated use of a Treatment IND involved expanding the availability before approval of zidovudine, commonly known as AZT, to people with AIDS. Initial (phase 1) testing of the drug in 33 patients with AIDS, carried out between July and December of 1985, yielded encouraging results. Phase 2 trials to assess the drug's safety and effectiveness began in February 1986. About 300 people with AIDS at several centers around the country were randomly selected to receive either AZT or a placebo.
These studies were abruptly halted in September 1986 when it was discovered that 19 patients receiving placebo had died, while only one death had occurred among those receiving AZT. Within a week of receiving this information, FDA authorized a treatment protocol for AZT. As a result, more than 4,000 AIDS patients were treated with AZT before its approval as the first anti-AIDS drug under the brand name Retrovir in March 1987.
Building on that and other experience with treatment protocols, FDA developed and issued in May 1987 regulations codifying the circumstances under which Treatment INDs can be granted. While the purpose is to make promising investigational drugs available as early as possible to patients with serious or immediately life-threatening diseases, the Treatment IND regulations also ensure that, despite possibly extensive treatment use of an investigational agent, carefully controlled trials will go forward to demonstrate the drug's safety and effectiveness.
The regulations reiterate the requirement that, as with all clinical use of investigational drugs, informed patient consent must be obtained, and the product cannot be promoted or otherwise commercialized. FDA also requires that a product administered under a Treatment IND must be under (or have completed) active clinical investigation, and its sponsor must be pursuing marketing approval with "due diligence."
It's critically important to complete definitive clinical trials, because once an investigational product appears in early studies to offer an important therapeutic advance and becomes available for treatment use, "you may never get another crack at it," says Robert Temple, M.D., director of FDA's Office of Drug Evaluation I. "If a study looks favorable--seems to show an effect on survival, for instance--physicians are very reluctant to redo the study. They want the active drug for their patients."
Ethical concerns make it difficult for physicians to withhold a promising investigational drug that might forestall severe disability or death. But if the study that showed promise was not well-designed--if, for example, there was no control group--what looked like favorable results may prove to be an illusion. "So it's very important to do a good study early--right at the beginning before impressions form that might turn out to be wrong," Temple says.
He points out that the early clinical trial showing AZT to be effective in AIDS patients was a placebo-controlled study, the results of which were dramatic and unequivocal. On the other hand, in the case of ganciclovir, an anti-viral drug used to treat an eye infection in AIDS patients, the path to treatment use and ultimate approval was quite different. Early suggestions of ganciclovir's effectiveness led to wide use before controlled clinical trials ever started.
Ganciclovir was approved in 1989 on the basis of a historical comparison with other treatments. But, Temple maintains, approval of ganciclovir was almost certainly delayed for years by the lack of appropriate, controlled clinical investigation.
FDA has indicated, for purposes of Treatment INDs, what constitutes serious or immediately life-threatening illness, what scientific information about the drug's safety and potential usefulness must be in hand, and how physicians can obtain investigational drugs for treatment use.
As of August 1994, 29 agents had been granted Treatment IND status. The conditions for which they have been used include AIDS and its complications, control of infection in kidney transplant patients, severe obsessive-compulsive disorder, Alzheimer's disease, severe Parkinson's disease, various advanced cancers, and respiratory distress syndrome in premature infants. At press time, 24 of these drugs had been approved by FDA and are on the market.
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An older, more targeted treatment-use initiative is aimed at making investigational cancer drugs available to patients who are not participating in controlled clinical trials. Since the mid-1970s, FDA has reviewed drugs for limited distribution by the National Cancer Institute (one of the National Institutes of Health) to provide promising new anti-cancer drugs and drug combinations to cancer patients for whom established therapy is ineffective.
Another mechanism to permit wider availability of experimental agents is the "parallel track" policy developed by the U.S. Public Health Service in response to the AIDS epidemic. Under this policy, patients with AIDS whose condition prevents them from participating in controlled clinical trials can receive investigational drugs shown in preliminary studies to be potentially useful. At press time, one drug (D4T) had been made available under the parallel track mechanism. D4T was approved for marketing in mid-1994.
Less dramatic, perhaps, than rushing investigational drugs to the desperately ill, but almost certainly of more long-range benefit to society, are measures to streamline FDA's review and approval process and expand the agency's resources for this task. Although not the stuff of which gripping movies are made, these efforts can mean earlier arrival of important new drugs in hospital and community pharmacies for the benefit of everyone who needs them.
One change FDA has adopted in recent years to speed drug review is categorizing new drugs as either standard or priority. Standard drugs are those that offer only minor improvement (or none) over drugs already on the market. Priority drugs, on the other hand--which may in fact be a new dosage form of, or new use for, an existing drug--are believed to represent potential major advances in health care. Distinguishing the two categories of drugs permits speedier review even before a new drug application is submitted.
FDA and sponsors of priority drugs may meet at the earliest stages of clinical testing to plan studies that will help develop the information necessary for a final decision on a product's approvability. Then, when a marketing application is submitted, FDA can mobilize available personnel and other resources needed to review the often large amounts of technical information contained in a priority new drug application.
In another effort to speed the review of marketing applications, the review process is becoming increasingly computerized. New drug applications that commonly run to thousands of pages are now arriving from sponsors in a form suitable for computer processing. This makes review and communication with the sponsor more efficient, saving time for both FDA and the firm.
A highly specialized mechanism for speeding the approval of drugs or biologics that promise significant benefit over existing therapy for serious or life-threatening illnesses--so-called accelerated approval--incorporates several novel elements aimed at making sure that rapid review and approval is balanced by safeguards to protect both the public health and the integrity of the regulatory process itself.
Accelerated review, established by 1991 regulations, can be used in two very special circumstances: when approval is based on evidence of the product's effect on a "surrogate endpoint," and when FDA determines that safe use of a product depends on restricting its distribution or use.
A "surrogate endpoint" is a laboratory finding or physical sign that may not, in itself, be a direct measurement of how a patient feels, functions or survives, but nevertheless is considered likely to predict therapeutic benefit. For example, high blood pressure and elevated serum cholesterol are risk factors for heart and blood vessel disease. Drugs that control blood pressure or cholesterol can reasonably be expected to help control or prevent direct signs of disease, such as angina, congestive heart failure after a heart attack, paralysis following a stroke, and sudden death. Once a drug has been shown effective as measured against such a surrogate endpoint, FDA can grant marketing approval.
As a condition of approval, however, FDA can require the sponsor to carry out post-marketing studies to confirm that the drug does in fact produce a clinical benefit, such as increased survival time. And if further research or experience shows that a product that received accelerated approval cannot safely remain on the market, FDA can order its prompt withdrawal.
As a further safeguard, distribution of accelerated-approval drugs can be limited to institutions that have the capability to use them safely and to physicians with specialized training or experience. The agency can also require that specific medical procedures, such as blood tests, be carried out if they are deemed essential for safe and effective use of the product.
In the summer of 1994, some health professionals and consumers active in the fight against AIDS began expressing concern that drugs in accelerated approval and expanded access programs (including parallel track and Treatment IND protocols) may be made available with insufficient details about side effects and effectiveness.
FDA convened its Antiviral Drugs Advisory Committee on Sept. 12-13, 1994, as part of a continuing dialogue about expanded access to new HIV drugs.
Based in part on public testimony and committee recommendations, FDA's anti-viral drug division is expected to issue a guidance document for sponsors of AIDS drugs applying for expanded access or accelerated approval status.
The agency has reaffirmed its commitment to these ways to make new drugs available for people with serious and life-threatening diseases. Working with its advisory committees and other outside experts, FDA will continue to consider improvements to these processes, and implement them where appropriate.
It is clearly too soon to know whether efforts to make drugs and biologics more rapidly and widely available to the desperately ill are contributing to genuine advances in health care. But many thousands of patients who might otherwise be beyond hope are now able to seek help from investigational agents, and all of us stand to gain from a more efficient, more responsive system by which to bring important new agents to market.
Ken Flieger is a writer in Washington, D.C.
"FDA Finds New Ways to Speed Treatment to Patients" originally appeared in the October 1993 FDA Consumer and was substantially revised for the FDA Consumer Special Report on New Drug Development in the United States (January 1995).