G. INVESTIGATIONAL DRUGS USED IN THE PERSIAN GULF WAR
Under the Food, Drug, and Cosmetics Act, all vaccines and medical products must be proven safe and effective by the Food and Drug Administration (FDA) in order to be sold and distributed in the United States. This law also applies to medical products used by the Department of Defense, even if given to U.S. troops who are stationed in other countries.
FDA also regulates medical products that are proven safe and effective for some uses or with specific doses, but not for other uses or other doses. If the product is only sold at certain doses and not others, its use at the non-approved dose would be considered investigational. If the product is legally available for sale at the same dosage, physicians can legally prescribe it; however, manufacturers can not advertise it for that purpose. Such “off label” use is also considered investigational. So, for example, a drug may be proven safe and effective to treat one kind of cancer, but be considered investigational to treat a different disease.
Under current law, an unapproved vaccine or investigational use of a drug could only be administered by the DOD under an Investigational New Drug (IND) procedure. (Note 43) Under an IND, any individual who is given the investigational product must give informed consent, i.e., must be told of the potential risks and benefits of the product, orally and in writing, and choose freely whether or not to participate. In addition, the IND requires that the medical product be distributed under carefully controlled conditions where safety and effectiveness can be evaluated.
When the Department of Defense began preparations for Desert Shield and Desert Storm in 1990, officials were extremely concerned that Iraq would use chemical and biological weapons against the United States. Despite years of study and billions of dollars, the DOD lacked drugs and vaccines that were proven safe and effective to safeguard against anticipated chemical nerve agents and biological toxins. Therefore, DOD officials wanted to use a medication (pyridostigmine bromide) and vaccine (botulinum toxoid) that they believed might protect against chemical nerve agents and botulism. Because the safety and effectiveness of pyridostigmine bromide and botulinum toxoid had not been proven for their intended use, these products were considered investigational drugs.
Pyridostigmine bromide is a chemical which enhances the effectiveness of two drugs, atropine and 2-PAM, which are proven effective for the treatment of nerve agent poisoning. (Note 44) Pyridostigmine is also a nerve agent itself. Nerve agents exert their biological effects by binding to, and inhibiting, the enzyme acetylcholinesterase (AChE) which normally shuts off the neurotransmitter, acetylcholine (ACh). When levels of ACh increase, nerve impulses and organ activity increase. When nerve and organ stimulation are excessive, death can result.
There are two major categories of nerve agents, carbamates and organophosphate (OP) compounds. (Note 45) German scientists developed many of the OP compounds for warfare agents and pesticides in the 1930’s and 1940’s. Examples of warfare agents include tabun, sarin, soman, and VX. Many organophosphates permanently inhibit AChE. This permanent effect, which can only be reversed when new enzymes are synthesized, makes OP warfare agents extremely lethal.
Pyridostigmine bromide is a carbamate, rather than an OP compound. (Note 46) Although it is a nerve agent, pyridostigmine has a reversible effect which can protect the AChE from permanently binding to OP compounds. When appropriate doses are selected, pyridostigmine theoretically should not cause nerve agent poisoning and should help protect against some lethal chemical warfare.
Efficacy. Pyridostigmine only works when taken in combination with other drugs and only if taken before exposure to nerve gas. (Note 47) Two antidotes to nerve agents, atropine and pyridine-2-aldoxime methochloride (2-PAM), are reportedly enhanced if pyridostigmine has already been given. Atropine and 2-PAM were included in the nerve agent antidote kits (Mark I) which were issued to U.S. troops in the Persian Gulf.
In research studies, animals given pyridostigmine, atropine, and 2-PAM were more likely to survive exposure to one chemical nerve agent, soman, than those given only atropine and 2-PAM. However, pyridostigmine is unable to enter and protect the brain, so that animals exposed to soman can still suffer from convulsions despite the pyridostigmine pretreatment. (Note 48) To protect against brain damage from ongoing seizure activity, valium may also be required following exposure to a warfare nerve agent. Similarly, pyridostigmine may offer little protection against the damage caused by nerve agents in the spinal cord. (Note 49)
Safety. Pyridostigmine bromide is approved by the FDA for treating myasthenia gravis, a neurological disease characterized by extreme weakness. This disease occurs when individuals develop antibodies that prevent ACh from causing muscle impulses at the neuromuscular junction. Therefore, treatment with relative high doses of pyridostigmine increases ACh to levels that are able to overcome the “block” created by the antibodies. An analogy might be that of a fishing pond. The two ways to increase the number of fish caught are to increase the number of fishing poles or to increase the number of fish in the pond.
FDA and DOD officials claimed they were confident of the safety of pyridostigmine as an antidote enhancer for chemical warfare protection because it would be used at a much lower dose (Note 50) in combat than normally used for treating patients with myasthenia gravis. However, normal patients and those with myasthenia gravis may not respond similarly to the same dose of pyridostigmine bromide. Whereas the dosage of pyridostigmine bromide for patients with myasthenia gravis may reach 120 mg every three hours, (Note 51) the dose for U.S. troops was only 30 mg every 8 hours. A good analogy is the use of insulin for diabetes mellitus; very high doses of insulin are sometimes necessary to treat diabetics, but similar doses could be fatal for non-diabetic individuals.
Some scientists also question whether pyridostigmine is completely safe even for treating patients with myasthenia gravis. The proportion of patients with myasthenia gravis that recover after surgical treatment (thymectomy) has decreased since pyridostigmine therapy was introduced several decades ago. (Note 52) Experts speculate that whereas the problems caused by myasthenia gravis can be corrected by surgery, pyridostigmine may cause immune damage to the neuromuscular junction that cannot be corrected by surgery. Since the symptoms of pyridostigmine damage would be similar to the symptoms of myasthenia gravis, any damage from the pyridostigmine would be extremely difficult if not impossible to diagnose.
In addition to its use for myasthenia gravis, pyridostigmine bromide has been approved by FDA for use with surgical patients; it is administered after surgery to reverse the effect of anesthesia, which are neuromuscular blocking agents. The dose is relatively small (15 mg) and not repeated. This treatment does not provide relevant information about the safety of repeated use of pyridostigmine by healthy individuals, since the dosage is small and the patients have received neuromuscular blocking agents.
The bromide that is included in pyridostigmine bromide pills is known to sometimes cause problems referred to as “bromide intoxication” when used for the treatment of myasthenia gravis. (Note 53)(Note 54), (Note 55)
FDA has not approved pyridostigmine bromide for repeated use in healthy individuals as an antidote enhancer or for any other reason. Since it would be unethical to expose individuals to potentially lethal chemical weapons in order to evaluate the efficacy of pyridostigmine, this use has only been studied on animals. The product is therefore an investigational drug when used as an antidote enhancer for treating nerve gas poisoning.
Botulinum toxoid is an unapproved vaccine that is used to protect laboratory workers and others who are likely to be exposed to botulism. Botulism is caused by at least one of seven neurotoxins produced by the bacteria Clostridium botulinum. When home-canning of food was common, food poisoning was the most common cause of botulism in the United States; the bacteria in the food produces a toxin which is eaten. Today, the most common form of botulism occurs in infants, since the bacteria that produces the toxin can thrive in a baby’s intestinal tract.
A botulism vaccine that is intended to protect against five of seven neurotoxins (called A,B,C,D,E) is produced by the Michigan Department of Health. This is called pentavalent toxoid. This vaccine is not a licensed product and must be distributed as an Investigational New Drug (IND).
Efficacy. Desert Shield began on August 8, 1990. Since the air war did not begin until January 16, 1991, and the ground war took place from February 24-27, 1991, the Pentagon had several months to review the possible use of investigational drugs and vaccines. In December 1990, the FDA advised the Department of Defense that it would be unable to test the botulism vaccine for efficacy, presumably because of limited time before the onset of the war. The FDA agreed to test the vaccine for safety, but these tests were not completed until late January 1991. At a meeting of the Informed Consent Waiver Review Group (ICWRG) on December 31, 1990, a representative of FDA’s Center for Biologics Evaluation and Research discussed the vaccine, explaining that the existing supply was nearly 20 years old and consisted of three lots, stored under continuous refrigeration. (Note 56) Given the age of these vaccines, there were concerns about their safety.
The recommended schedule for immunization with the pentavalent vaccine includes a series of three initial injections at 0, 2, and 12 weeks, followed by a booster 12 months after the first injection. According to the Centers for Disease Control’s Center for Infectious Diseases, subjects given the vaccine did not have detectable antitoxin titers after the first two shots in the initial series, which means that they were unlikely to be protected at week 2. (Note 57) If for any reason only two immunizations can be given, at least 4 to 8 weeks should elapse between injections if most individuals are to be protected against the disease. (Note 58)
Safety. The Michigan Department of Health reported that 4.2 percent of patients reported a sore arm or other local reactions to the initial series of three shots, and 12.1 percent had local reactions to the booster shots. (Note 59) Almost 3 percent had systemic reactions, such as general malaise, after either the initial three shots or the booster shots. Because of the relatively large percentage of adverse reactions, new lots of the vaccine were manufactured in 1971. However, there is no evidence that the newer lots produced fewer adverse reactions than the older lots.
In her review of the DOD’s application for use of botulinum toxoid in the Persian Gulf, an FDA reviewer pointed out that in 1973, the Centers for Disease Control had considered terminating the distribution of the vaccine because of the relatively large number of individuals who had negative reactions to it. (Note 60) The FDA reviewer also pointed out that “there are no efficacy data in humans” and that the dose for humans was an estimate based on results from guinea pigs. In addition, potency testing had suggested that the vaccine would not be effective against two of the five botulism toxins.
According to the Michigan Department of Health, the effects of the botulism vaccine on pregnant women had not been studied prior to its use in the Persian Gulf War.
Anthrax vaccine is an FDA-approved vaccine that is considered safe and effective for individuals whose skin may come in contact with animal products such as hides, hair, or bones likely to contain the anthrax infection. It is also recommended for veterinarians and others who are likely to touch infected animals. (Note 61) However, the vaccine’s effectiveness against inhaled anthrax is unknown. Unfortunately, when anthrax is used as a biological weapon, it is likely to be aerosolized and thus inhaled. Therefore, the efficacy of the vaccine against biological warfare is unknown.
It appears that there is only one relevant animal study which showed that anthrax vaccine apparently provided additional protection against relapse in monkeys exposed to inhalation anthrax and treated with antibiotics. (Note 62) Although the results of this study suggest the vaccine might protect against anthrax that has been sprayed, it is not sufficient to prove that anthrax vaccine is safe and effective as used in the Persian Gulf. The vaccine should therefore be considered investigational when used as a protection against biological warfare.
The anthrax vaccine is given as three injections 2 weeks apart, followed by three additional injections given 6, 12, and 18 months after the initial injection. If immunity is to be maintained, subsequent booster injections of anthrax vaccine are recommended at 1-year intervals. (Note 63) According to the Interagency Task Force on Persian Gulf War Illnesses, one dose provides some immunity in 85 percent of those individuals vaccinated. (Note 64)
According to the Michigan Department of Public Health which manufactures anthrax vaccine, it is not known whether anthrax vaccine is safe for pregnant women or their offspring.
Findings & Conclusions
A. FOR AT LEAST 50 YEARS, DOD HAS KNOWINGLY EXPOSED MILITARY PERSONNEL TO POTENTIALLY DANGEROUS SUBSTANCES, OFTEN IN SECRET.
The U.S. General Accounting Office issued a report on September 28, 1994, which stated that between 1940 and 1974, DOD and other national security agencies studied hundreds of thousands of human subjects in tests and experiments involving hazardous substances. (Note 65) GAO stated that some tests and experiments were conducted in secret. Medical research involving the testing of nerve agents, nerve agent antidotes, psychochemicals, and irritants was often classified. Additionally, some work conducted for DOD by contractors still remains classified today. For example, the Central Intelligence Agency (CIA) has not released the names of 15 of the approximately 80 organizations that conducted experiments under the MKULTRA program, which gave psychochemical drugs to an undetermined number of people without their knowledge or consent. According to the GAO report, the CIA has not released this information because the organizations do not want to be identified. (Note 66)
WORLD WAR II VETERANS
As recently as 1993, the Institute of Medicine of the National Academy of Sciences reported that an atmosphere of secrecy still existed regarding World War II testing of mustard gas and lewisite. (Note 67) Although many documents pertaining to the World War II testing programs were declassified shortly after World War II ended, others remain “restricted” even today. In addition to the classified or restricted documents, World War II veterans who participated in the research were sworn to secrecy. These classified documents and promises of secrecy have impeded medical care for thousands of veterans during half of the last century. For example, Rudolph R. Mills participated in gas chamber experiments as an 18-year-old in 1945, one year after he joined the U.S. Navy. (Note 68) He was sworn to secrecy and did not learn until 46 years later that approximately 4,000 servicemen were human subjects in mustard gas experiments conducted from 1942 through 1945 by the Chemical Warfare Service. Although his health began to deteriorate even before his discharge from the Navy in 1946, he did not learn that mustard gas might be responsible for his physical problems until more than 40 years later. At a May 6, 1994, hearing of the Senate Committee on Veterans’ Affairs, entitled “Is Military Research Hazardous to Veterans’ Health? Lessons from World War II, the Persian Gulf War, and Today,” Mr. Mills testified, “I had on an experimental mask and the Navy was trying to determine if people wearing these masks could communicate with each other. I was enticed to sing over the intercom….No one ever told me that the mask became less effective against the gas with each use….We were sworn to secrecy….At the age of 43 I underwent a long series of radiation treatments and later surgery to remove part of my voice box and larynx….It didn’t occur to me that my exposure to mustard gas was responsible for my physical problems until June 1991, when I read an article in my hometown newspaper.” (Note 69) John T. Harrison participated in Navy chemical tests in 1943 to get an extra week pass. He was also sworn to secrecy. According to written testimony submitted to the Senate Committee on Veterans’ Affairs by Mr. Harrison, “[I] was never warned or told anything about the dangers of what [I] volunteered for….told never to reveal what [I] did or where [I] was; if anyone asked [I] was to say [I] was on rowing maneuvers.” (Note 70) At the time of his discharge from the military, he could not even describe his exposures to a Navy doctor who was trying to determine the cause of his severe respiratory illnesses. Although Mr. Harrison has suffered from recurrent breathing problems and has greatly diminished pulmonary function, he has never received any compensation for his illness. According to the VA and DOD, his medical and services records have been lost, making it difficult to prove that his disability is service-connected.
COLD WAR VETERANS
During the years immediately following World War II, military personnel were intentionally exposed to radiation during the testing of atomic bombs and during radioactive releases. While it is unclear how many of these servicemembers were intentionally exposed to what were known to be harmful levels of radiation, there is clear evidence that in some cases military personnel were ordered to locate themselves in areas of high radioactive fallout. They were given no choice in the matter, and they were not told of the potential risks of those exposures. Similarly, military personnel were intentionally given hallucinogenic drugs to determine the effects of those drugs on humans. The servicemembers were not told that they would be given experimental drugs, they had no choice of whether or not to take them, and even after the unusual effects of the drugs were obvious to researchers, the unwitting human subjects were given no information about the known effects of the drugs. Even if the DOD did not know about the potential long-term effects of the drugs, that would not justify their failure to provide information to thousands of servicemembers about the known short-term effects of the drugs.
PERSIAN GULF WAR VETERANS
Persian Gulf veterans were also given investigational vaccines and ordered not to tell anyone. In a Committee survey of 150 individuals who served in the military during the Persian Gulf War (see Appendix), many of those surveyed indicated they were ordered, under threat of Article 15 or court martial, to discuss their vaccinations with no one, not even with medical professionals needing the information to treat adverse reactions from the vaccine. Similarly, 86 percent of the military personnel who told the Committee that they were ordered to take pyridostigmine bromide reported that they received no information on what they were taking or the drug’s potential risks. According to a DOD study published in the Journal of the American Medical Association, commanding officers and medical personnel were also inadequately informed about the investigational drugs; as a result, they were ill-prepared to recognize or treat military personnel who experienced side effects. (Note 71)
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