NCI, within the National Institutes of Health (NIH), Public Health Service, Department of Health and Human Services, is the world’s largest sponsor of clinical trials in cancer treatment research. NCI spends about 20 percent of its research budget on clinical trials. Using its clinical trials network that includes cooperative groups, NCI funds therapeutic research that includes evaluating the safety and efficacy of investigational drugs in large multicenter clinical trials. NCI also sponsors therapeutic drug development through the submission of investigational new drug (IND) applications to FDA. FDA is responsible for ensuring the safety of the public in matters related to clinical research with investigational drugs. FDA regulations define the terms under which clinical research may proceed. Through the INDs, FDA reviews the experimental rationale for conducting clinical drug trials, including results of animal toxicology studies, manufacturing data, purity and stability information, and an initial plan for clinical investigation. The responsibility for monitoring the trials rests with the sponsor. Unexplained weight loss and physical deterioration of the body (cachexia) commonly accompany advanced cancer. Moreover, cachexia is associated with decreased survival. For example, data have shown that in patients with lung cancer, weight loss is associated with a 50-percent reduction in survival time. Joseph Gold, M.D., director of the Syracuse Cancer Research Institute in New York, proposed a theory to explain why cachexia commonly accompanies advanced cancer. After extensive research, Dr. Gold proposed the use of hydrazine sulfate, a chemical that interrupts the abnormal sugar metabolism associated with weight loss, to arrest and reverse cancer cachexia. In 1973, Dr. Gold reported on results of animal tests indicating that hydrazine sulfate inhibited the growth of various rodent tumors and enhanced the antitumor action of some chemotherapeutic drugs. In 1975, Dr. Gold reported the results of hydrazine sulfate’s use in cancer patients. Using reports from physicians whose advanced cancer patients were taking hydrazine sulfate, Dr. Gold noted several cases of tumor regression and subjective improvement in cancer patients treated with hydrazine sulfate. Additionally, Russian investigators have claimed some successes with hydrazine sulfate for more than 20 years. Although early clinical studies conducted in the United States found mixed results, later studies evaluating hydrazine sulfate as an anticachexia agent suggested that the drug benefited some cancer patients. In the 1980s, studies at the Harbor-University of California Los Angeles (UCLA) Medical Center indicated that adding hydrazine sulfate to a standard chemotherapy regimen improved the nutritional status and survival time of some cancer patients. Of particular interest was a randomized clinical trial—involving 65 patients with advanced, inoperable non-small-cell lung cancer—that compared chemotherapy and hydrazine sulfate with chemotherapy and placebo. Data from the study suggested that hydrazine sulfate may benefit some cancer patients. While overall survival differences between the two treatment groups were not significant, researchers found that hydrazine sulfate improved survival in a subset of study patients who began the trial in better overall condition. Given the inconclusiveness of the study, UCLA investigators believed that further trials of hydrazine sulfate were warranted to determine its effectiveness in improving survival. NCI sponsored three clinical trials that were designed to assess the effect of hydrazine sulfate on survival, weight gain, and quality of life. Two trials in patients with advanced lung cancer assessed the efficacy of hydrazine sulfate as an adjunct to chemotherapy. One of these trials, in patients with advanced lung cancer, was conducted by the Cancer and Leukemia Group B (CALGB) and led by a principal investigator at the Scripps Clinic and Research Foundation in San Diego, California. The other trial in advanced lung cancer patients, was conducted by the North Central Cancer Treatment Group (NCCTG) and led by a principal investigator at the Mayo Clinic in Rochester, Minnesota. The third trial assessed the efficacy of hydrazine sulfate as the sole medical intervention in patients with advanced colon cancer. This trial was also conducted by NCCTG and led by the same principal investigator at the Mayo Clinic. Figure 1 shows highlights of activities surrounding NCCTG’s and CALGB’s clinical trials of hydrazine sulfate. The NCI-sponsored clinical trials did not find the survival advantage observed in the earlier UCLA study. Results from the three clinical trials were published in June 1994. The data showed that hydrazine sulfate therapy does not result in any significant benefit. Specifically, in two trials involving over 500 patients with inoperable non-small-cell lung cancer, the addition of hydrazine sulfate to a standard chemotherapy regimen resulted in somewhat worse quality of life, no effect on weight gain or loss, and a suggestion of decreased survival when compared with placebo. In the trial evaluating the use of hydrazine sulfate as the sole therapeutic intervention in 127 patients with metastatic colon cancer, survival time for patients receiving hydrazine sulfate was decreased compared with patients given placebo. Criticisms regarding the design of the three clinical trials arose in the media. Proponents of hydrazine sulfate therapy alleged that NCI compromised the trials by permitting study patients to ingest agents that they believe are incompatible with hydrazine sulfate. Some proponents believed that the concurrent use of tranquilizers, barbiturates, or alcohol with hydrazine sulfate would nullify the therapeutic effect of hydrazine sulfate and cause toxicity in patients. They based their beliefs on Russian and unpublished animal studies as well as some pharmacological data that they said suggested that hydrazine sulfate interacts with tranquilizing agents (particularly tranquilizing agents classified as benzodiazepines), barbiturates, and alcohol. NCI rejected concerns that the concurrent use of hydrazine sulfate with tranquilizers, barbiturates, or alcohol would nullify the therapeutic effect of hydrazine sulfate. NCI concluded that there was no objective evidence or published studies of humans addressing interactions between hydrazine sulfate and these alleged incompatible agents to support the concerns. NCI concluded that, at most, Russian animal data suggested that large doses of alcohol or barbiturate medications consumed with hydrazine sulfate can increase the total overall toxicity. NCI also concluded that unpublished animal data did not support the hypothesis that the short-term use of tranquilizing agents with hydrazine sulfate would increase toxicity or prevent clinical benefit. These conclusions were based on the assessment of NCI scientists in consultation with CALGB and NCCTG researchers. In addition, NCI officials told us that because the UCLA study did not specifically prohibit patients from taking barbiturates and tranquilizers or consuming alcohol, the NCI-sponsored confirmatory trials did not have to be any different in that regard. Nevertheless, in response to the issue of incompatibility, NCCTG investigators (at the Mayo Clinic) prohibited patients from taking barbiturates or consuming alcohol. Furthermore, patients were prohibited from taking tranquilizing agents, except for antiemetic purposes. The NCCTG principal investigator told us that he felt it would have been unethical to perform either of the Mayo clinical trials without allowing the use of antiemetic drugs, including drugs otherwise considered to be tranquilizers, by patients experiencing nausea or vomiting. CALGB investigators, however, decided that it was more important to replicate the UCLA trial than attempt to address concerns of incompatibility by prohibiting the use of tranquilizers, barbiturates, and alcohol. Because the NCI-sponsored trials were designed to confirm the improved survival observed in the UCLA trial, CALGB investigators believed they should use essentially similar methods to those used in the earlier UCLA trial. Published reports of the three trials did not disclose the extent of tranquilizer use among study patients. In examining research records, however, we found that patients in all three NCI-sponsored clinical trials of hydrazine sulfate were prescribed tranquilizers under varying conditions. In the NCCTG and CALGB clinical trials in non-small-cell lung cancer, virtually all patients received a variety of antiemetic drugs, particularly tranquilizing agents, for the short-term relief of chemotherapy-induced vomiting. Our review of over 50 percent of CALGB’s standard research forms revealed that patients with advanced lung cancer routinely received benzodiazepine and phenothiazine tranquilizing agents to relieve the nausea and vomiting associated with chemotherapy. Although CALGB investigators decided not to collect data on concurrent medications on their standardized research forms, some research associates voluntarily provided information on antiemetic usage. Data on the use of antiemetic medications for about half of the patients in our review were recorded on the research forms. Our analysis of research forms listing antiemetic medications revealed that 88 percent of the patients received benzodiazepine and 71 percent received phenothiazine tranquilizing agents. Generally, it appeared that most patients were prescribed tranquilizing medications for short-term emetic relief. In several instances, however, patients were prescribed tranquilizing agents on an “as needed” continual basis. We also found one instance where a patient was prescribed a barbiturate. At our request, NCCTG and CALGB research associates reviewed research forms, medical records, or both for patients enrolled in their lung cancer trials to collect data on the concurrent use of antiemetic and barbiturate medications. Table 1 shows the number of patients receiving hydrazine sulfate and various antiemetic medications. Investigators said it was necessary to prescribe antiemetic medications, including tranquilizing agents, to patients in all three clinical trials. In the two clinical trials involving patients with advanced lung cancer, patients received chemotherapy in addition to hydrazine sulfate or placebo. Because the chemotherapeutic regimen used to treat advanced lung cancer induces severe nausea and vomiting in almost all patients, NCCTG and CALGB investigators did not deem it feasible or ethical to administer chemotherapy without the concurrent use of antiemetic drugs. During the time when NCCTG and CALGB were conducting their trials, the most effective antiemetic regimens available involved the use of tranquilizing agents.