Findings & Conclusions
B. DOD HAS REPEATEDLY FAILED TO COMPLY WITH REQUIRED ETHICAL STANDARDS WHEN USING HUMAN
SUBJECTS IN MILITARY RESEARCH DURING WAR OR THREAT OF WAR. The major principle of all research ethics involving human subjects, as described by the Nuremberg Code, the Declaration of Helsinki, and the “Common Rule” of the U.S. Government, states that the voluntary, competent, informed, and understanding consent of the subject is absolutely essential, whether during war or peace. (Note 72)
These standards are more than 50 years old. For example, the Nuremberg Code was based on testimony of two U.S. physicians, Drs. Leo Alexander and Andrew Ivy, who served as expert medical witnesses for the Nazi crime prosecutors. The code was not the outcome of an attempt to frame a new code of ethics, but rather a description of criteria said to be widely accepted by the medical profession at the time. (Note 73) Therefore, DOD research during the 1940’s was clearly conducted in an era when researchers were well aware of ethical codes regarding the use of human subjects.
The Department of Defense has violated these well-established ethical principles each time soldiers are required to participate in military research or take investigational drugs or vaccines or are not adequately informed about the risks of the experiments.
WORLD WAR II VETERANS
Many individuals were recruited for various military experiments of mustard gas and lewisite under the guise of testing clothing, without being warned beforehand that they would be exposed to dangerous chemicals. Additionally, young servicemembers frequently reported that they were enticed to volunteer for experiments by being promised extra leave time from duty.
For example, in 1944, Nathan Schnurman was a 17-year-old sailor who was recruited to test Navy summer clothing, in exchange for a 3-day pass. Instead, he participated in the testing of gas masks and clothing while he was locked in a gas chamber and exposed to mustard gas and lewisite. Mr. Schnurman believes that he was not really a volunteer since the research was misrepresented. Additionally, Mr. Schnurman stated in written testimony submitted to the Committee that “many were denied the 3-day pass, and many went to their graves without revealing this story.” (Note 74) Perhaps most outrageous, Mr. Schnurman was not allowed to leave the gas chamber when he became violently ill. Mr. Schnurman testified before the Committee on the Judiciary of the U.S. House of Representatives that, “During my sixth exposure in the chamber, I determined something was wrong. I called to the corpsman, via an intercom, and informed him of my condition, and what was happening and requested I be released from the chamber, now. The reply, was `No’ as they had not completed the experiment. I became very nauseous. Again, I requested to be released from the chamber. Again, permission was denied. Within seconds after the denial, I passed out in the chamber. What happened after that, I don’t know. I may only assume, when I was removed from the chamber, it was presumed I was already dead.” (Note 75)
John William Allen enlisted in the U.S. Navy in 1945 at the age of 17. Immediately after boot camp, he volunteered to test summer uniforms so he could go home before shipping out. His test clothing consisted of one pair of pants, undershorts, a gas mask, and a shirt that had been used in previous experiments and was therefore impregnated with toxic chemicals. According to Mr. Allen, the actual testing consisted of determining the amount of sulfur mustard that would cause illness (“man-break” test), not the testing of summer uniforms. He was exposed several times to sulfur mustard and was removed from further exposure on May 5, 1945, when he passed out in the gas chamber. A physical examination on May 14, 1945, revealed many wounds as the result of exposure to mustard gas.
Mr. Allen stated in written testimony submitted to the Committee, “The government has lied to us for 50 years over and over again. If I would have been shot on the front lines at least I would had it on my record and would have received medical treatment.” (Note 76)
PERSIAN GULF WAR VETERANS
Almost 50 years after World War II veterans were exposed to unethical research, the Department of Defense again failed to comply with the well- established ethical requirement that all soldiers and civilians make an informed choice of whether or not to use investigational medical treatment.
1. Military personnel were not given the opportunity to refuse investigational drugs.
When the Department of Defense began preparations for Desert Shield and Desert Storm in 1990, officials were extremely concerned about the need to protect U.S. troops against chemical and biological weapons that were believed to have been developed by Iraq. However, the DOD lacked drugs and vaccines that were proven safe and effective to safeguard against expected weapons, such as soman and botulism.
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, or used by U.S. troops. However, DOD officials were interested in using a botulinum toxoid, which is a vaccine to prevent botulism, that was not approved by FDA. They also wanted to use pyridostigmine bromide, a medication to protect U.S. troops against chemical nerve agents. Although approved by the FDA for treating patients with a neurological disorder called myasthenia gravis, pyridostigmine is not proven safe or effective for repeated use by healthy persons under any circumstances, and is normally unavailable in doses that would be likely to be safe for healthy individuals. (Note 77)
Under current law, the unapproved vaccine and the investigational use of pyridostigmine for healthy individuals could only be administered under an Investigational New Drug (IND) procedure. (Note 78) 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.
In August 1990, the DOD contacted FDA to review regulatory restrictions of DOD’s plan to use pyridostigmine and botulinum toxoid for U.S. troops in the Persian Gulf. The major focus of the meeting was informed consent. The DOD sought a waiver of requirements for informed consent for the use of pyridostigmine bromide and botulinum toxoid, arguing that these investigational products had well-established uses and were safe. They also claimed that there were no reasonable alternatives. According to minutes of the meeting, “FDA expressed some concern about liability and the need to comply with the regulations,” and FDA’s Deputy Director for Drug Review “pointed out the need to establish an appropriate investigational framework to collect observational data and evaluate the military medical products in question.” (Note 79)
In summary, DOD informed FDA that they did not want to abide by informed consent regulations, and FDA officials pointed out that pyridostigmine and botulinum toxoid were investigational and that there are laws regulating how they can be used. DOD claimed that “under the DOD directive the Secretary of Military Departments [could] dictate the use of unapproved FDA regulated products” in the Persian Gulf, but “DOD’s current position is that this not their primary choice at this time.” (Note 80)
The issue was debated by the two agencies for several months. Finally, at a meeting on December 31, 1990, an agreement was reached. According to minutes of that meeting, DOD officials agreed that the botulism vaccine would be administered by trained individuals with a health care background, and that information would be provided orally “at minimum, and in written form if feasible, to all personnel receiving the vaccine.” (Note 81) Officials from the DOD said that the feasibility of distributing an information sheet would depend on many factors, and would vary from location to location within the military theater of operation. DOD officials “reiterated that at least verbal [sic] information would be provided to each person receiving the vaccine.”
The FDA Informed Consent Waiver Review Group recommended that pregnant women be excluded from receiving the vaccine and that information about the vaccine be “posted at places where vaccine is administered.” However, DOD argued that pregnant women would be at greater risk from exposure to botulism toxins than to the vaccine, and FDA agreed that instead of excluding pregnant women, a statement would be added to the information sheet stating that, “If you are pregnant, it is not known if this vaccine will hurt the unborn baby, however, most vaccines do not.” (Note 82)
In their application for a waiver, DOD described the safeguards that would be in place regarding the distribution of the botulism vaccine. In addition to oral warnings regarding the vaccine, DOD promised that the soldiers would be observed for 30 minutes after receiving the vaccine, and if possible, they would also be checked again 48 hours later. In addition, DOD claimed that they would provide all three vaccine injections and stated that all three were necessary to provide protection.
FDA granted the waiver on a temporary basis, concurring that obtaining informed consent during wartime is not feasible in a specific military operation involving combat or the threat of combat. (Note 83) On January 8, 1991, Dr. David Kessler, FDA Commissioner, wrote to the Assistant Secretary of Defense for Health Affairs regarding the waiver for informed consent for pyridostigmine. In his letter, Dr. Kessler agreed that since there was “no available satisfactory alternative therapy” for protection against organophosphorus nerve gas, he would “concur with your assessment that informed consent is not feasible.” This agreement was apparently based on DOD officials’ promise to “provide and disseminate additional information to all military personnel concerning the risks and benefits of pyridostigmine.” (Note 84)
Although FDA agreed to waive informed consent for both the pyridostigmine bromide and the botulism vaccine, the Assistant Secretary of Defense for Health Affairs notified Dr. Kessler on March 15, 1992, that “Central Command” had decided that the vaccine would be administered on a voluntary basis. (Note 85) However, based on interviews with 150 Persian Gulf War veterans by Committee staff (Appendix), 88 percent of those who said they received a botulism vaccine were told they had no choice.
According to the DOD, all 696,562 U.S. troops in the Persian Gulf War were issued pyridostigmine bromide as a pretreatment for nerve agent poisoning, and officials estimate that approximately two-thirds took the drug for varying periods of time. Of 150 who were interviewed by Committee staff, 73 took pyridostigmine and 74 percent of them were told they could not refuse to take it. Approximately 8,000 individuals received botulinum toxoid in the Persian Gulf. Given the high proportion who have reported that they had no choice, it appears that hundreds of thousands of U.S. troops were ordered to take an investigational drug or vaccine without having the opportunity to refuse.
2. Military personnel were not informed about the risks of the investigational drugs.
Although DOD officials convinced FDA they need not offer choice, DOD had promised to provide extensive information about potential risks orally and in writing. In addition to being ordered to take an investigational product without informed consent, most Persian Gulf War military personnel surveyed claim they received no oral or written information about the drug or vaccine, despite the DOD promises to FDA to provide information about potential risks. These claims are supported by a survey conducted by the Department of Defense following the Persian Gulf War. Sixteen of 23 selected Persian Gulf War medical personnel surveyed by the DOD indicated that no information on the side effects of pyridostigmine bromide was provided to those who were ordered to take the drug. (Note 86) These medical personnel were responsible for 8,366 military personnel during the Persian Gulf War.
There are two kinds of risks associated with lack of information. One is a lack of trust. In the survey conducted by Committee staff, 14 of 73 (19 percent) Persian Gulf War veterans who had been ordered to take pyridostigmine bromide indicated that they did not take all the pyridostigmine bromide they were ordered to take, fearful that the drug was responsible for the symptoms they experienced (Appendix). Because no one would answer their questions about the safety and efficacy of the pyridostigmine bromide, they feared they were receiving a potentially harmful drug. Therefore, if pyridostigmine bromide had been crucial for surviving nerve agent exposure, an unknown number of individuals would have lacked protection because they had received inadequate information about the drug.
The other risk is that even if serious side effects were rare, they could have been treated if medical personnel were able to diagnose the problem. For example, Carol Picou, a nurse who was stationed in the Gulf for 5 months, had obvious side effects from the pyridostigmine starting on the third day that she took it. These side effects included incontinence, drooling, and blurry vision, among others. The side effects became worse 1 hour after she took each pill. One day, she did not take the pill as scheduled, and the side effects stopped; unfortunately, her commanding officer ordered her to continue taking the pills, and watched to make sure she swallowed them. She was ordered to take the pills for 15 days. She now has many permanent medical problems, including incontinence, muscle weakness, and memory loss, that might have been avoided had she been allowed to stop taking the pills. (Note 87)
Similarly, Lt. Col. Neil Tetzlaff had immediate side effects when he started taking pyridostigmine bromide on the plane ride over to Saudi Arabia. His nausea and vomiting became so severe that he needed emergency surgery to repair a hole in his stomach. When he became ill, the military doctor told him to continue to take the pills, because the doctor apparently did not know that nausea and vomiting were known side effects. According to Tetzlaff’s sworn testimony, the doctor acted as if the pyridostigmine was as safe as a cough drop. (Note 88)
CIVILIANS IN THE GULF WAR
Numerous civilians have reported to Committee staff that they also were given investigational drugs during the Persian Gulf War without informed consent. For example, civilians who worked for DOD contractors and news media personnel were apparently instructed to take the pyridostigmine bromide tablets. They usually were not told it was experimental or that the pyridostigmine bromide was being administered in a regime that was not proven efficacious or safe, and received no information on potential side effects of the drug.
For example, according to journalists who covered the Gulf War, some were given the pills by the U.S. military. Several of these journalists experienced serious medical problems similar to Persian Gulf War veterans. (Note 89) The Committee has also received letters from civilians who are suffering from “Gulf War syndrome” who report the widespread use of pyridostigmine by civilians working for DOD during the Gulf War.
OTHER STUDIES OF PYRIDOSTIGMINE
Following the Committee’s May 6, 1994, hearing, several individuals who were in the Air Force during the 1980’s contacted Committee staff to report they had also received pyridostigmine bromide without their consent. (Note 90) They indicated that they did not volunteer for any research study, were ordered to take the pyridostigmine pills as part of a research project, and were ordered to report any side effects to the flight surgeons. One individual estimated that several hundred individuals in his squadron participated in the pyridostigmine studies, and reported that the studies were conducted over a period of at least 2 years.
The descriptions of these studies are disturbing because, if accurate, they indicate that even during peacetime, the Air Force totally ignored the requirements of informed consent that are a central provision of the Nuremberg Code, the Declaration of Helsinki, and the “Common Rule” which had been in effect in at least some U.S. Government agencies at the time.
In addition to being unethical, these studies were reportedly unscientific; there were apparently no safeguards to ensure that the pilots took the pills or accurately reported the side effects. Many pilots who participated in these studies were on flight status; if they reported any side effects, they could lose their flight pay. (Note 91) Obviously, this provided an incentive for them not to report any side effects, since they did not want to lose their flight pay. Similarly, those who experienced side effects had an incentive to stop taking the drug without notifying the researchers conducting the study. Moreover, pilots who contacted the Committee staff reported that many of their friends and colleagues did not take any of the pills at all, and many of those who did take at least one pill stopped taking them when they experienced headaches and other side effects. Despite the pressure to obey orders, many of the pilots apparently believed that they should not trust the Pentagon regarding the safety of these experimental pills.
One member of the air crew who was given pyridostigmine as part of these studies, Craig Crane, notified the Committee that he now has memory loss, joint pain, sensitivity to chemicals, and other symptoms that are commonly associated with Gulf War syndrome, although he is only 32 years old and did not serve in the Gulf War. He has left the Air Force because of his disabilities. (Note 92)
Findings & Conclusions
C. DOD INCORRECTLY CLAIMS THAT SINCE THEIR GOAL WAS TREATMENT, THE USE OF INVESTIGATIONAL DRUGS IN THE PERSIAN GULF WAR WAS NOT RESEARCH.
Despite the fact that pyridostigmine was an investigational drug whose safety and effectiveness had not been proven to FDA, the DOD claims that its use in the Persian Gulf War was prevention and treatment, not research. For example, Dr. Edward Martin, Acting Principal Assistant Secretary of Defense for Health Affairs, stated at the Committee’s hearing on May 6, 1994, that “..investigational products were employed during the Persian Gulf War as prophylactic treatments against biological and chemical warfare agents. This was not research but direct prevention and treatment.” (Note 93) Additionally, John M. Bachkosky, Deputy Director, Office of the Director of Defense Research and Engineering, wrote to Sen. Rockefeller on May 19, 1994, that “[botulinum toxoid and pyridostigmine bromide] were used for direct prevention and treatment and were not employed as part of any research effort.” (Note 94)
In a letter to Sen. Rockefeller dated November 17, 1994, DOD continues to claim that its use of pyridostigmine was not research. John Deutch, Deputy Secretary of Defense, wrote that, “Although pyridostigmine and botulinum toxoid were classified as investigational drugs as required by FDA regulations, they were not used for experimental purposes in [Operation Desert Storm] and the military personnel who received these products were not experimental subjects.” (Note 95) Mr. Deutch added that, “The fact that these drugs were used for treatment purposes, not research purposes, was clearly understood by all parties involved and specifically approved by the courts in litigation challenging the governments [sic] actions.” Once again, it appears that the DOD confuses the goals of using these medical products with the process, which was clearly considered investigational by FDA.
Dr. Arthur Caplan, who at the time he testified was Director of the Center of Biomedical Ethics at the University of Minnesota, addressed that issue at the May 6 hearing. He explained that the fact that the goal is treatment and that DOD believed the benefits of the pills and vaccines would outweigh the risks “doesn’t transform the use of experimental, innovative, investigational agents into therapies. These agents were used, as we have heard, in large populations for purposes other than those for which they were originally designed in some cases, and circumstances under which they had never before been tried out in the desert. This seems to me to cinch the case that what took place fell into the category of experimental, innovative and investigational, and that makes them research.” (Note 96)
Since the end of the Persian Gulf War, DOD has repeatedly requested that the waiver of informed consent be made permanent, arguing that “to not finalize it provides an arguable defect under the Administrative Procedures Act and leaves both DOD and FDA open to greater liability.” (Note 97) To finalize the interim rule would grant unrestricted use of investigational drugs by military personnel, even though investigational status means that efficacy and safety have not been proven. FDA has not yet decided whether to concur with DOD’s request.
Continued on next page…
