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FDA Action Handbook




"The desire to take medicine is perhaps the greatest
feature that distinguishes man from animals."

-- Sir William Osler

Had private industry refrained from bilking and duping a credulous American public, there would never have been an FDA. Following a 26-year effort to protect the public from dubious, narcotic, poisonous and ineffective patent medicines, and in the wake of Upton Sinclair's expose of filthy meat-packing factories in The Jungle, Congress passed the Pure Food & Drugs Act of 1906. This established the Bureau of Chemistry (later to become the FDA) in the Department of Agriculture. The law forbade manufacturers from making unsubstantiated claims on medicine labels. Such claims were still permitted in advertising, however, due to a 1912 amendment written by lobbyists for Parke, Davis & Co., a large pharmaceutical.

The hogs, sheep and cattle of America were protected from worthless serums and drugs by Congress in 1913. The human citizenry, however, had to wait 25 years for similar protection.

In 1927 Congress created the Food, Drug and Insecticide Administration to regulate the 1906 Act; it was renamed the Food & Drug Administration (FDA) in 1937. With the advent of the New Deal in 1933, Roosevelt staffers drafted legislation to strengthen the FDA and protect the public from unsafe, ineffective drugs. Drug industry interests kept the legislation bottled up in committee for 5 years, however, and gutted it of it's efficacy requirements. (MH)

"Elixir of Sulfanilamide"

As with later reforms, it took a major disaster and a public outcry to bring about reforms. In 1937, as "Elixir of Sulfanilamide," containing a sulfa "wonder drug" mixed with a solvent closely akin to radiator antifreeze, caused 108 deaths. This provided the impetus, at last, for legal requirements that safety be proven before new drugs could be marketed. The comprehensive Food, Drug and Cosmetic Act of 1938 is still the basic law governing the FDA. Drugs marketed before 1938 could remain on the market without proof of safety. (MH)


The next 25 years were, according to pharmaceutical company economists, the "Golden Age" of drugs. New drug introductions reached a peak of 559 in 1949. Such figures are often deceptive, however, since most "new" drugs are anologues of existing ones or combinations thereof. Clinical trials were relatively inexpensive, and FDA review averaged but 7 months. In 1953, the FDA was incorporated into the Department of Health, Education and Welfare (HEW), predecessor to today's Department of Health & Human Services (HHS). Many pharmaceuticals took advantage of a trusting public to sell largely ineffective and sometimes dangerous substances. The unregulated use of antibiotics in throat lozenges and syrups resulted in bacteria becoming resistant to useful drugs and provoked sometimes-fatal allergic reactions.

Calls that proof of efficacy be legally required received an inhospitable reception in the pro-business climate of the Eisenhower administration. In 4 years of Senate hearings (1959-62), Tennessee Senator Estes Kefauver waged a lonely battle trying to expose drug industry stock manipulation, advertising fraud, collusion with the FDA and deception of the public. In April 1961, Senator Kefauver submitted the original draft of his bill to strengthen the FDA. Over the next 15 months, under pressure from the drug industry lobby, a Senate committee effectively crippled the bill. (MH/SS)


It took the birth overseas of thousands of limbless babies and the efforts of a single FDA official, Dr. Frances Kelsey, to turn the tide. Thalidomide was never marketed in the US, although it was tested on Americans. It was unreleased by the FDA because Dr. Kelsey had questions about its safety. Thalidomide, a sleeping pill, was enormously effective. However, when taken by pregnant women, it caused grotesque birth defects. When news and photographs of the deformed European infants reached the USA, the outcry was deafening, proving once again the equation: white babies plus pain equals "universal outcry." Representatives and Senators, until then quietly and obsequiously caving in to the drug lobby, began jumping on the drug-regulation bandwagon. After all, 1962 was an election year. The irony here is that thalidomide was an effective drug that was unsafe, but the legislation passed in its wake actually had a far greater impact on drugs that were safe but ineffective. (SS)

In March, 1962, President Kennedy, in a nationwide address, endorsed the Kefauver Amendments, and asked Americans to discard all unmarked pills in their medicine cabinets. Thalidomide was prohibited and Dr. Kelsey was lionized in the press. The Kefauver amendments were passed by a unanimous Senate in August 1962 (78-0). But neither the pre-Kefauver FDA hierarchy (Dr. Kelsey excepted), nor the majority of Congress, nor the pharmaceutical industry had shown much concern for public safety before the media blitz. On October 10, 1962, 26 years to the day of our planned ACT UP HHS Rally, Public Law 87-781, "The Drug Amendments of 1962," was signed into law by President Kennedy. (MH/SS)

The Kefauver Amendment

The Kefauver amendment is significant for AIDS activists for basically one reason: it requires that the FDA ensure drug manufacturers prove efficacy before a drug is put on the market. Efficacy must be shown for the specific use for which the manufacturer wants to market the drug. Before 1962, only proof of safety was required. In other words, manufacturers have got to prove a drug does what they say it does. This has resulted in the current three-phase structure of the FDA's approval process. The three phases were not mandated by the amendments, but were the FDA's decision on how to implement them.

Section 102 (c) of Kefauver amends Section 505 (d) of the Federal Food, Drug and Cosmetic Act to read:

"(5) ... [If] there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended or suggested in the proposed labeling thereof ... he [the Secretary of HHS] shall issue an order refusing to approve the application.
...The term 'substantial evidence' means evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved....

The drug industry lost an enormous amount with the passage of Kefauver. When previously they needed only to prove a drug safe before releasing it to market, now they were required to endure the time and expense of proving the drug actually did what they advertised it would do. Since 1962, the number of drugs annually approved in the USA has dropped considerably, from upwards of 350 in the 1950's to a low of 83 in 1969.

The current turf-conscious, restrictive attitude of the FDA is the bureaucratic descendant of the originally well-founded FDA distrust of unscrupulous drug companies which conducted hurried, badly designed trials and rushed shabby data to the FDA to gain New Drug Application (NDA) approval before rival companies could develop similar products. (SS)


Incest and Competition

Drug companies, depending on their size, may have two different responses to a rewriting of the regulations. The larger companies, which can afford the long and expensive process of the 3-phase trials, will usually oppose anything which will allow smaller, less solvent companies to get a foot in the door of the approval process. It is not uncommon for a small company which has done the initial research on a new drug to find it cannot afford the long approval process, and choose to sell the rights to its research to a larger company. HEM, developers of Ampligen, an expensive drug requiring 80 steps to produce, sold out to DuPont for just this reason. In August 1988, DuPont, having poured an unprecedented amount of money per patient into its Ampligen trials, decided, after a secret audit of incomplete preliminary trial data, that it had made a mistake: there wasn't lots of quick money to be made on Ampligen. DuPont is cutting its losses and withdrawing its sponsorship of the drug.

Also, the FDA, like any Federal regulatory agency, is staffed by many people who either have, or intend to one day work, in the industry they regulate. This revolving door network assures the drug manufacturers that they will have an insider's knowledge of what the FDA is going to look for in approving a New Drug Application (NDA).

Remember, the FDA does not test drugs. All drug testing is done by drug companies, by the National Institutes of Health (NIH) and other Federal institutions, by private foundations and by hospital and university-affiliated physicians (the NIH is currently conducting 40% of AIDS drug trials). The FDA then examines the results to decide whether the experiments have sufficiently proven safety and efficacy.

Obviously the drug companies are going to want to know what kinds of studies the FDA values most highly and takes most seriously. For instance, if the FDA only considers double-blind placebo studies to prove efficacy, a drug company is not going to waste years and money doing some other kind of study. Therefore, if your company has someone who has worked at the FDA and knows exactly what they look for, you've got an important edge in designing studies more likely to get through the FDA approval process. Consequently, changing FDA regulations upsets not only the bureaucrats, but the big business-as-usual boys as well.

Nevertheless, even with all the sleeping around that goes on, it still remains a love/hate relationship between the FDA and drug companies. When a drug intended for life threatening illnesses must repeatedly undergo Phase 1 trials because the FDA doesn't like the way the protocol was designed, lives are lost. Furthermore, Imreg claiming it has not sought Treatment IND status for their drug (Imreg-1) because the FDA hasn't explained to them how to do it, is symptomatic of petulant antagonisms that also cost lives. The FDA must provide maximum coordination and guidance for drug companies on Investigational New Drugs (INDs) intended for persons with life-threatening diseases. (SS)

The Orphan Drug Act

The Orphan Drug Act was signed on January 4, 1983 to encourage the development and manufacture of drugs that treat diseases which affect so few people that the cost of developing the drug far outweighs the potential profits. Sponsored by Congressman Henry Waxman (D-CA) and Senator Orrin Hatch (R-UT), the bill was drafted after lengthy negotiations with the Department of Health and Human Services, the FDA and the Pharmaceutical Manufacturers' Association (PMA) to fashion "a marketplace oriented solution" to the problem of orphan drugs. Congress established, as part of the HHS, an Orphan Products Board, run by the Assistant Secretary of Health with representatives from the FDA, NIH, CDC and other agencies.

The Orphan Drug Board's mission is to identify potential orphan drugs and entice drug companies into making them. As the pentamidine story (see below) demonstrates, many are reluctant to accept such drugs, but the rewards can be profitable. Originally the act covered drugs needed by under 200,000 people, but in 1984 it was amended to cover products which might be used by more people, but would still fail to recover costs from US sales. US sales.

The FDA may relax test criteria, such as determining long-term side effects, and diminish the size of the clinical trials group for orphan drugs, since so few people may end up receiving them. This is supposed to help put the drug on a high-priority "fast track." The Orphan Drug Board provided $4 million a year in seed money to support grants supporting sponsors' clinical research of orphan drugs. The FDA is supposed to assist the sponsor in designing the protocol. The drug company may claim up to 75% of the cost of clinical studies as a tax credit. Most important of all, the company is granted an exclusive patent or monopoly on marketing the drug for up to 7 years.

A severe deficiency in the act is the lack of freedom-of-information guarantees protecting the public, which has granted Orphan Drug monopolies, from unscrupulous, price-gouging manufacturers. The legislation needs to be amended to force companies receiving Orphan Drug licenses to open their books and justify their costs. It is ironic indeed that what originated in efforts to keep the situation "market oriented" ended up in distinctly uncompetitive, state-sanctioned monopolies. The public has a right to know Burroughs-Wellcome's investment in AZT and the amount of the tax credit it received. The same applies to LyphoMed and IV-pentamidine.

Several other important AIDS drugs have had orphan drug status: dextran sulfate (Ueno Fine Pharmaceuticals), ampligen (HEM/DuPont) and DHPG (Syntex). Frank Young has stated publicly that he believes applying the principles of exclusivity and tax incentives from an orphan drug and applying them to all drugs could focus research and speed drug development. Some AIDS activists lack the untempered faith in the free market held by the FDA Commissioner and have asked the FDA to require that companies profiting from orphan drug monopolies open their books. Frank Young responds the FDA is "above economics"! (RS/JE)




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



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