> page three

FDA Action Handbook





As noted before, there are three ways in which a PWA or seropositive person can obtain access to a drug fro HIV-infections. This section will review these 3 ways in order: the normal testing procedure of three phases leading to approval and marketing; extraordinary release of promising drugs under Treatment IND and Compassionate Use IND protocols; and underground and foreign treatment sources.

The Standard Drug Approval Process:
Clinical Trials: Phase I, II and III

Before clinical (human) trials may begin, the drug company must submit results from test tube and animal studies; these are called pre-clinical trials. If the FDA doesn't disapprove the Investigational New Drug (IND) application within 30 days, clinical trials may begin.

PHASE 1: Toxicity and Dosage. These trials seek to establish a safe dose range for the drug, to gather information on how it is absorbed and distributed within tissue, how it is excreted and how long a dose acts on the body. These trials are usually completed within a year and involve under a hundred research subjects. About 70% of all INDs (Investigational New Drugs) are successful in this phase of trials.

PHASE 2: Safety and Efficacy. These trials are designed to precisely assess the drug's effectiveness and to detect major adverse reactions (side effects). These trials range from 100 to 1,000 subjects and last 2-3 years. Approximately 33% of all INDs are successful in this phase of trials.

PHASE 3: Efficacy. These trials involve up to several thousand human subjects to confirm earlier findings of effectiveness and detect side effects that may occur only rarely or after a long period of treatment. Phase 3 trials can take several years. From 25-30% of all INDs complete this trial successfully.

NDAs (New Drug Applications): Upon completion of Phase 3, if successful, the drug sponsor presents the data, in hundreds of volumes and thousands of pages, as a New Drug Application (NDA), to the FDA. Review and approval takes 2 to 3 years from the conclusion of clinical trials. Only 20% of drugs fro which IND's were submitted are eventually approved. This The Wall Street Journal, in its crusading editorials for regulatory relief, conveniently neglected to mention, making the difference between 33% making it through Phase 2 and 25% through phase 3 seem less consequential. the point is that one quarter to one third of drugs which make it through Phase 3 do not get approved.

The only known exception to this is AZT, which was reviewed and approved in only 3 1/2 months. The manufacturer, Burroughs-Wellcome, had worked closely with the FDA throughout its clinical trials.

Obviously, the 8 to 10 year testing and approval process most new drugs undergo is hopelessly long for a PWA, PWARC or HIV-infected person (or anyone living with a life-threatening illness) to wait for a promising new drug. The FDA has assured AIDS activists that it will attempt to rule on NDA's for AIDS drugs within 180 days of receipt. During the coming 6 months, over 12,040 people will die of AIDS and bureaucratic indifference. Delays of such length are, therefore blatantly unacceptable.

Protocols, IRB's and Informed Consent

Protocols: Every clinical trial, in any phase, has a detailed plan called a protocol that names a trial's drug or drugs, gives a theoretical background and states its objectives. A protocol details a trial's design, its procedures, and how data are to be collected and managed. It specifies the trial drug's dosage levels, treatment durations and methods of administration. It lists the trial's inclusion and exclusion criteria; that is, who may be enrolled, their disease and symptoms, and traits which may exclude them; it often indicates subjects' age, sex, and in a disease like AIDS, a range of blood values. The FDA must approve a clinical trial's protocol before the trial can begin.

Institutional Review Boards (IRB's): Every institution that conducts or supports biomedical or behavioral research involving human subjects must have an IRB that initially approves proposed research and periodically reviews it. Its concerns are primarily ethical; its purpose is to protect the rights of human research subjects. Before it can approve a trial, the IRB must determine that a subject's risks in that trial are reasonable in relation to anticipated benefits and to the knowledge that the trial will produce, and that trial-related risks have been minimized. IRB's for AIDS drug trials have been inadequately sensitive to the needs of PWA's and seropositives; for example, they have sanctioned trials in which subjects had to discontinue all outside treatments while possibly receiving nothing but an inert placebo; such trials are injurious to participants' health.

Informed Consent: An IRB must determine that the information a subject receives in the written and oral informed consent form complies with Federal guidelines. Trial investigators are answerable to the IRB; IRB's are answerable to the FDA. The FDA requires that IRB's approve all advertising aimed at recruiting study volunteers, and to review, modify and approve the terms of any financial remuneration for volunteers. Thus the FDA is the ultimate guarantor of the health rights of drug trials subjects; a role it has abdicated in, for example, tolerating the prohibition of AIDS drug trial subjects from continuing on PCP prophylaxis while in antiviral or immunomodulator trials. (JE)


The FDA currently has 2 basic programs in which people with HIV infection and AIDS can gain access to experimental treatments outside of the normal clinical trials process: Treatment IND (Investigational New Drug) and Compassionate Use IND.

Treatment IND

The FDA has for some time allowed drugs still in the investigational stages to be used by persons with illnesses for which there was no other treatment. Before May 1987, there were no formal regulations for these programs, and people seeking drugs were pretty much at the mercy of bureaucratic whim.

In May 1987 Treatment IND (Investigational New Drug) was formalized in Federal regulations. Treatment IND is a shortcut to drug access for patients with serious or life-threatening illnesses. The drug company must apply for Treatment IND status for their drug and must be actively pursuing drug approval for that drug in order to qualify. Treatment IND may only be grated to drugs completing Phase 2 or currently in Phase 3 trials.

If Treatment IND status is granted, the drug will be available through physicians to patients who meet certain criteria. The drug companies hate Treatment IND because they have to make the drug available to patients they really would rather have in their clinical trials. Activists dislike Treatment IND because the standard is vague, has been interpreted narrowly, and because the FDA may let the drug company charge for the drug. This has not yet been done, however, because in order to charge for Treatment IND, the company must open its books and justify the cost, something pharmaceuticals, with their usually massive markups, are rarely eager to do.

Any medical costs incurred with the taking of a drug as yet officially unapproved by the FDA will not be covered by insurance or Medicaid. this includes not only the cost of the drug itself, but any lab tests necessary to gauge its effectiveness or toxicity, any hospitalization due to an adverse response, any lab time necessary for administering the drug -- IV's, aerosolizer, etc. This is deleterious to the health of people with HIV, most notably in the case of aerosolized pentamidine. Though the treatment is the most effective preventive against PCP, it is unapproved, so neither insurance nor Medicaid will pay the cost of doctors' time, nebulizers, etc. The result is PWA's who can't pay for prophylaxis and show up in the emergency room with PCP.

To make Treatment IND drugs available to more than a handful of people, a) the FDA must have the power to compel drug companies to apply for it; b) laws must require Medicaid and private insurance to pay for experimental treatment; c) FDA must interpret all HIV-infection as life threatening. Until the FDA has these powers, it can induce companies to apply for Treatment IND by a) revealing the names of drugs they would consider favorably (letting the AIDS communities apply pressure on the companies); b) telling the companies that a disease for which the makers are as ambiguous as AIDS (T4 counts, p24 antigenemia), the quickest way to get approval is to have lots of data on effectiveness, such as they would gather from putting the drugs through the Treatment IND process. (MM/JE)

Compassionate Use IND

This IND has changed greatly in the past year; a lot of what was previously Compassionate Use IND in now covered under the Treatment IND regulations. Basically, as it exists now, Compassionate Use IND applies in 2 circumstances:

1) Small Market for a Drug

Manufacturers are rarely willing to spend the money to get a drug for a rare disease tested and approved even if the drug is the usual therapy for the disease. So some drugs are available on a permanent compassionate basis to patients with a rare disease. This was the case with pentamidine for PCP before AIDS came along and in the early stages of the crisis.

2) Experimental Drugs Under Investigation

Most experimental AIDS drugs fall under this category: drugs which are at some stage of the drug development process and which may be useful against a disease. This IND works on a case-by-case basis; doctors must fill out a detailed application to get the drug, and the FDA looks at the individual patient's condition in deciding whether to dispense the drug or not. Significantly, if the drug company does not want the drug released, then it will not be out on Compassionate Use. consequently, due to the case-by-case nature of this IND, it can take weeks for the FDA to give word on any individual application.

An example of this dangerous delay is provided by Fluconazole, an experimental drug used to treat blood fungus associated with AIDS. While waiting the weeks to hear from the FDA on their Compassionate Use IND for Fluconazole (if they are lucky enough to have a doctor willing and knowledgeable enough to do their paperwork), their only option is Amphotericin B, the approved therapy, which has deadly side effects; thus FDA ensures that such patients suffer both from deadly blood fungus and from deadly drug side effects. (MM)


Lack of money is a great obstacle to getting any sort of IND drug. For people who have insurance or Medicaid, they can't get coverage for the drug cost associated with taking the drug, including blood and other lab tests, hospitalization and drug administration. In many cases, then, people can't take a drug that would save their lives because no one will foot the bill. (MM)




Back to beginning of FDA Handbook > > >

Introduction: WHY THE FDA?

The Federal Health Bureaucracy

___Who's Involved with AIDS
___The NIH and AIDS
___AIDS & the FDA
___FDA: Who Does What
A Brief History of the FDA

___Elixir of Sulfanilamide
___The "Golden Age" of Pharmaceuticals
___The Kefauver Amendment
The FDA and Drug Companies:
___Incest and Competition
___The Orphan Drug Act

The Standard Drug Approval Process:
___Clinical Trials: Phase I, II and III
___Protocols, IRB's and Informed Consent
Extraordinary Release:
___Treatment IND
___Compassionate Use IND
___Post-Marketing Surveillance and De-Regulation:
___Combined Phases II-III and a new Phase IV?
The Underground Market

Pentamidine Wars
Trimetrexate: Treatment IND Hoax
Imreg-1: Treatment IND Omission
DHPG: Bad Oversight Delays Sight-Saving Drug
IVIG: A Pernicious Placebo
Exclusion of Women, People of Color, Poor People,
___People in Rural Areas, IV Drug Users, Hemophiliacs,
___Prisoners & Children from Drug Trials
FDA & Discrimination in Drug Trials
The Rights of Drug Trials Subjects:
___Drug Trials are Health Care Too
ATR: AIDS Treatment Registries, Local & National

Federal Drug Law Timeline

Federal AIDS Bureaucracies
AIDS Drug Development Flowchart



use back button on browser to return