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DRUG TEST LOOPHOLES
More On The Inadequate Testing Of Drugs

By Meryl Nass, MD

One question that I believe needs a legal resolution is the difference between "research" and "unlicensed use in the absence of research" of investigational products.

FDA generally approves an investigational new drug application (IND) to permit drug developers to perform human studies of the drug. The intention is to gain evidence of safety and efficacy for eventual licensure.

Yet INDs have been employed by the Defense Department to permit routine use of untested drugs, without any intention of putting the drug through the rigorous experimental process required for licensure.

Scores of vaccines and other products have been developed at USAMRIID (the Army's center for biological defense research) for instance, and received INDs, but human clinical trials required to support a license application were never performed. Some of these drugs and vaccines have been given to USAMRIID staff and to special operations troops for many years, although recipients were not always offered informed consent. [CDC 1960s anthrax vaccine trial data, obtained by the author via FOIA.]

Some were given to troops in the Gulf War. Although a waiver of informed consent was issued by FDA for use of only two unlicensed products in the Gulf theater, recent reports revealed that at least eight such products were used. The medical, legal and ethical repercussions of the use of the other six products have not been publicly discussed.

Normally one is obliged to collect extensive data using active surveillance when testing experimental drugs, but in the USAMRIID case, data collection has generally been passive. In other words, if someone reports a problem, a record is kept. But recipients of experimental products are not required to report symptoms on a regular schedule, whether or not they feel their symptoms, if any, merit attention. So the adverse event profiles for these drugs remain undefined. To my
mind, this represents unlicensed use, without adequate preliminary testing, and without collecting the data that could be used to evaluate a drug's safety.

In the Gulf War, not only were no records kept of adverse events: there are almost no records of who received these experimental products. According to the Presidential Advisory Committee on Gulf War Veterans' Illnesses, this use did not comply with the record-keeping or surveillance requirements issued by FDA when it granted the waiver. Besides the ability to save effort and expense on formal clinical trials, another advantage may accrue to the user of IND, as opposed to licensed, products. IND products have no expiration date! Therefore, the use of 1970-vintage botulinum toxoid vaccine in Gulf War forces, after twenty years of storage, was perfectly legal. This has been viewed as a big money-saver for the Defense Department, since it alleviates the need to rotate stock, and manufacture new lots of vaccine.

The Defense Department appears to have an ad hoc agreement with FDA that such products can be used, as long as they pass one test for potency prior to use. [Documents to show this were provided in my testimony to the House Armed Services Committee, Military Personnel Subcommittee, September 1999.] To my mind, this is a regulatory loophole which allows
DoD to avoid meeting current good manufacturing practices, the standard for commercial drug approval and use.

A potential disadvantage to DoD when using INDs is the need for informed consent. The waiver of informed consent given by FDA to DoD for use of experimental products in the Gulf War was the first "official" time the Nuremberg Code was abrogated in the US. It received a lot of attention as a result.

Because of a) the possible relationship of Gulf War Syndrome to use of experimental products, b) the ethical issues regarding the informed consent waiver and lack of record-keeping, and c) mismanagement of the experimental use of Tick-Borne Encephalitis vaccine in the mid-1990s Bosnia theater (which repeated the problems with data collection first identified in the Gulf War, according to the Presidential Advisory Committeeís Special Report), it was unlikely that another blanket waiver of informed consent by FDA would be forthcoming.

That is likely to have been one impetus to finally license products for chemical or biological warfare (CBW) protection, some of which have remained in IND status for decades.

Obtaining a new drug license from FDA became cheaper and easier in 1997, when the number of clinical trials required for licensure was reduced from two to only one. But because human efficacy and safety data must be obtained for a license, some products for CBW use could never be licensed. Smallpox vaccine, for example, could not be tested for efficacy: smallpox was completely eradicated in 1977.

Acambis, a small company, was given the US government contract to supply a total of 209 million doses of smallpox vaccine last fall. Tommy Thompson got it at a good price.

Dr. Anthony Fauci was quoted in the October 27, 2001 New York Times as saying he thought that surrogate markers, and tests in monkeys, would be used to license the new smallpox vaccine.

Think about that. The contract has been signed, and the vaccine is on its way. But the surrogate markers and the monkeys have yet to complete testing. In fact, it is unclear from the article whether the vaccine is even in its final form.

Here we have a vaccine that has yet to prove itself safe and effective, but it appears it is being manufactured anyway, at a cost of $850 million. Some vaccine is supposed to be available within the year.

Extensive discussion took place in the media last fall regarding smallpox vaccinations for all Americans. Several deaths, and cases of neurologic damage, were expected for every million injections of the old smallpox live viral vaccine. The number of injuries was expected to be much higher in the many Americans who have immune systems damaged by infection, chronic disease or medical therapy. How the newer vaccine will compare to the old is anybody's guess.

Mandatory vaccination, if any cases of smallpox do occur, remains a real possibility.

By not requiring human efficacy testing, the bar for approval is lowered. Until very recently, there existed no animal model for smallpox, but now a monkey model has been found. Let's hope it is a good one, and can provide information relevant to humans. What do you think the likelihood is that the vaccine could fail testing, with so much riding on its rapid availability? What a blow that would be to HHS prestige!

FDA is an agency of the Department of Health and Human Services. Even if the final smallpox vaccine product was found to be unsafe and/or ineffective (or neither, because the needed testing was never performed) do you think FDA will refuse it a license?

My bet is that it would get a license, but the label would have a lot of warnings and disclaimers, buried way down in the fine print. FDA has discovered that the burden of protecting the public health can be shifted from the agency, and onto the backs of doctors and patients, by using "creative" labeling.

RECOMMENDED READING

Pollack A. Rush for new drugs raises questions about testing. NY Times,
October 27, 2001.

Presidential Advisory Committee on Gulf War Veterans' Illnesses --
Special Report

Documents demonstrating the DoD policy to hold IND products in storage
without expiration dates

Military Use of Drugs Not Yet Approved by the FDA for CW/BW Defense:
Lessons from the Gulf War, Richard A. Rettig, MR-1018/9-OSD, 1999 (RAND)

Ernest T. Takefuji, M.D., MPH, and Philip K. Russell, M.D., from

Military Immunizations: Past, Present And Future Prospects, Infectious
Disease Clinics of North America, March 1990, Page 156.

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