United States General Accounting Office

GAO Report to the Chairman and Ranking

Minority Member, Human Resources and

Intergovernmental Relations

Subcommittee, House Committee on

Government Reform and Oversight

September 1995 CANCER DRUG

RESEARCH

Contrary to Allegation,

NIH Hydrazine Sulfate

Studies Were Not

Flawed

GAO/HEHS-95-141

GAO United States

General Accounting Office

Washington, D.C. 20548

Health, Education, and

Human Services Division

B-261063 

September 13, 1995

The Honorable Christopher Shays

Chairman

The Honorable Edolphus Towns

Ranking Minority Member

Human Resources and Intergovernmental

 Relations Subcommittee

Committee on Government Reform and Oversight

House of Representatives

Cancer takes almost 500,000 lives annually and is the second leading cause

of death in the United States. About 400,000 of the 1 million Americans

who will develop cancer this year, however, will be cured.1

 Despite

advances in treating cancer, some forms of cancer are often resistant to

current therapies and have a very poor outcome. Based on the findings of

an earlier study that suggested the drug hydrazine sulfate may improve

survival for some patients with advanced cancer, the National Cancer

Institute (NCI) sponsored three studies of hydrazine sulfate.

All three NCI-sponsored studies, however, failed to demonstrate any benefit

from hydrazine sulfate. The developer of hydrazine sulfate therapy alleged

in documents furnished to the Subcommittee that NCI compromised its

studies on hydrazine sulfate. He asserted that the NCI-sponsored clinical

trials2

 did not demonstrate any benefit for hydrazine sulfate because NCI’s

clinical investigators permitted the concurrent use of tranquilizers,

barbiturates, and alcohol. He and other proponents of hydrazine sulfate

therapy have interpreted animal studies and other data to suggest that

hydrazine sulfate is incompatible with these agents. This allegation was

echoed in the popular media.

This report responds to your request that we provide further information

about the NCI-sponsored clinical trials of hydrazine sulfate. It provides

background on the trials, including information on protocol design and

data management procedures. It also discusses how NCI and the trials’

investigators dealt with the issue of potential incompatibility with certain

agents, the extent to which patients may have received these agents, and

how this issue was reported.

1

Cured is defined as being free of any evidence of cancer for 5 years or more. These cured individuals

will have the same life expectancy as others of the same age and sex who have never had cancer.

2

Clinical drug trials involve testing a new drug in humans to determine whether it has therapeutic

benefit.

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To obtain information for this report, we reviewed NCI’s policy guidance

for conducting clinical trials of investigational agents. We also reviewed

agency memorandums pertaining to protocol development for the

hydrazine sulfate clinical trials and related correspondence. For each of

the hydrazine sulfate clinical trials, we visited the research facilities and

reviewed a sample of the research records documenting patient

medications, including concurrent antiemetic (antinauseant and

antivomiting) and barbiturate medications.3

 We discussed the conduct of

these trials with NCI officials and investigators, Food and Drug

Administration (FDA) officials, and proponents of hydrazine sulfate therapy

to obtain their perspectives on the issues involved. A more detailed

description of our scope and methodology is in appendix I.

Results in Brief In three large clinical trials, NCI found that hydrazine sulfate did not

prolong survival for cancer patients. Nevertheless, controversy and

confusion developed, in part, because some researchers have suggested

that hydrazine sulfate is incompatible with tranquilizers, barbiturates, and

alcohol. In testing hydrazine sulfate, NCI permitted study patients to use

tranquilizing agents, barbiturates, and alcohol in one NCI-sponsored clinical

trial. In the other two trials, NCI prohibited the use of barbiturates and

alcohol, but patients were permitted to use tranquilizing agents as

antiemetics to control nausea and vomiting. However, subsequent analyses

of the use of concurrent medications found no evidence to invalidate NCI’s

conclusion that hydrazine sulfate is ineffective.

Nonetheless, there were lapses in record-keeping and reporting in these

clinical trials. NCI did not require that complete and accurate research

records be kept during one clinical trial documenting the use of

tranquilizing agents, barbiturates, and alcohol by study patients. Also,

NCI-sponsored investigators did not analyze this issue until recently, and

the published results did not accurately describe the use of tranquilizing

agents during one of these clinical trials.

FDA may have contributed to the confusion surrounding these trials of

hydrazine sulfate with its more conservative position on how the drug

should be administered to some patients. While accepting NCI’s study

designs and therapy plans, FDA apparently had concerns over possible

incompatibility. About the same time these three trials were occurring, FDA

approved more than 70 applications permitting the compassionate use of

hydrazine sulfate. These approvals were accompanied by an FDA caution to

3

Information was not available for us to document possible alcohol use by study patients.

Page 2 GAO/HEHS-95-141 Hydrazine Sulfate
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physicians that their patients should avoid taking tranquilizers,

barbiturates, or alcohol while taking hydrazine sulfate. Other FDA

documents reflect this same concern.

Background 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,4 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.

Early Studies of Hydrazine

Sulfate Found Mixed and

Inconclusive Results

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.

4

Clinical cooperative groups are composed of multiple institutions and investigators who collaborate

to develop and implement treatment research in large numbers of patients. There are 11 cancer clinical

cooperative groups, and all involve highly organized collaborations among geographically dispersed

institutions with central data management offices and large statistical centers that support the

administrative requirements of the research and perform data collection and analysis.

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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.5

 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 cancer6

—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 Trials

Found Hydrazine Sulfate

Ineffective

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

5

The Russian studies, however, were not randomized or blind and have involved various types and

stages of cancer. Randomized clinical studies are the “gold standard” for evaluating medical

interventions. In a randomized study, each patient is randomly assigned to one of a number of

treatments in order to ensure unbiased comparison of outcomes. Random assignment is the best

method for ensuring that the patients in each group have equivalent prognoses. Because the groups

should not differ on variables related to cancer survival, their outcomes can be directly compared, and

any difference in survival can be attributed to the difference in treatment.

6

Non-small-cell lung cancer is commonly used as a catchall phrase to include all of the primary

malignant lung cancers except small cell and accounts for approximately 70 to 80 percent of lung

cancers. Almost all primary malignant cancers of the lung are one of four types: squamous cell

carcinoma (cancer originating in the glandular, skin, or linings of internal organs), adenocarcinoma,

large cell carcinoma, and small cell carcinoma.

Page 4 GAO/HEHS-95-141 Hydrazine Sulfate
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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.7

 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.

7

We are using the term principal investigator to describe the role of the scientific coordinator (protocol

chair) of a multicenter clinical trial. The principal investigator is responsible for developing and

monitoring the study as well as analyzing, reporting, and publishing its results.

Page 5 GAO/HEHS-95-141 Hydrazine Sulfate
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Figure 1: Time Line of the UCLA and NCI-Sponsored Clinical Trials of Hydrazine Sulfate

1 2 3 4 1 2 3 4 1 2 3 4 1 2 1 3 4 2 3 4 1 2 3 4 1 2 3 4 1 2 3 4

1987 1988 1989 1991 1992 1993 1994 1990

Spring 1987

UCLA presents preliminary study

results indicating small but intriguing

benefits of adding hydrazine sulfate to

chemotherapy regime

January 1990

UCLA publishes

study results

May 1988 – March 1989

CALGB develops protocol

for conducting study

February 1991

CALGB lung

trial ends

June 1994

Results

published

June 1994

Results

published

June 1994

Results

published

July 1989

CALGB lung

trial begins

October 1992

NCCTG lung

trial ends

November 1992

NCCTG colon

trial ends

October 1990

NCCTG colon

trial begins

January 1988

NCI asks CALGB to conduct

hydrazine sulfate clinical trial to

confirm UCLA results

May 1990

NCCTG lung

trial begins

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 1994.8

 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

8

Results of the three studies of hydrazine sulfate supported by NCI were published in the Journal of

Clinical Oncology, Vol. 12 (June 1994), pp. 1113-29. The articles were “Cisplatin, Vinblastine, and

Hydrazine Sulfate in Advanced, Non-Small-Cell Lung Cancer: A Randomized Placebo-Controlled,

Double-Blind Phase III Study of the Cancer and Leukemia Group B,” by Michael P. Kosty and others;

“Randomized Placebo-Controlled Evaluation of Hydrazine Sulfate in Patients With Advanced

Colorectal Cancer,” by Charles L. Loprinzi and others; and “Placebo-Controlled Trial of Hydrazine

Sulfate in Patients With Newly Diagnosed Non-Small-Cell Lung Cancer,” by Charles L. Loprinzi and

others.

Page 6 GAO/HEHS-95-141 Hydrazine Sulfate
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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.

Negative Trial Results

Contested

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.9

NCI Concluded

Concerns That

Hydrazine Sulfate Was

Incompatible With

Some Agents Were

Unfounded

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

9

Dr. Mikhail Gershanovich, one of Russia’s leading cancer specialists and a professor at the Petrov

Research Institute of Oncology, told us that he had no evidence of incompatibility between hydrazine

sulfate and tranquilizers. He confirmed, however, that his studies with hydrazine sulfate have

demonstrated an incompatibility with barbiturates and alcohol.

Page 7 GAO/HEHS-95-141 Hydrazine Sulfate
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consuming alcohol, the NCI-sponsored confirmatory trials did not have to

be any different in that regard.10

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.

NCI-Sponsored Trials

Included Some Use of

Tranquilizing Agents

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

10Initially, there was some confusion surrounding whether these alleged incompatible agents,

particularly tranquilizers, were permitted in the UCLA trial. Reports in the media were apparently

inaccurate in suggesting that the UCLA researchers did not allow patients to take tranquilizers. Some

of the confusion may have developed because in research documents describing protocols for other

trials of hydrazine sulfate, UCLA researchers previously expressed concerns over potential

incompatibility with hydrazine sulfate and alcohol, tranquilizers, and barbiturates. As noted on p. 10,

however, the principal researcher said he did not have such concerns in the more recent UCLA trial.

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88 percent of the patients received benzodiazepine and 71 percent

received phenothiazine tranquilizing agents.11,12 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.

Table 1: Number of Patients Receiving

Specific Antiemetic Medications Along

With Hydrazine Sulfate in the Lung

Cancer Clinical Trials Medication

CALGB

trial

(n=135)

NCCTG

trial

(n=116)

Benzodiazepines 119 43

Lorazepam 113 43

Other 6 0

Phenothiazines 108 43

Prochlorperazine 98 37

Other 10 6

Serotonin antagonists 0 91

Ondansetron 0 90

Other 0 1

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. Accordingly, many study patients in both clinical

11The primary benzodiazepine and phenothiazine drugs prescribed were lorazepam (Ativan) and

prochlorperazine (Compazine), respectively.

12Our results closely paralleled the results obtained in a comprehensive subsequent review done by

CALGB and presented in table 1.

Page 9 GAO/HEHS-95-141 Hydrazine Sulfate
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trials were prescribed phenothiazines and benzodiazepines.13 Although

patients in NCCTG’s colon cancer trial were not undergoing chemotherapy,

some patients with advanced colon cancer experience nausea and

vomiting associated with their disease. NCCTG and CALGB investigators told

us that they would not deny standard medical care to control nausea and

vomiting in patients who were dying from cancer.

Also, patients enrolled in the UCLA clinical trial reportedly received

tranquilizing agents while taking hydrazine sulfate. Medical records for 40

study patients treated at Harbor-UCLA Medical Center indicated that 22

patients received hydrazine sulfate and chemotherapy.14 In addition, these

patients received tranquilizing agents to control their

chemotherapy-induced vomiting. Specifically, patients who received

hydrazine sulfate also received a total of 16 doses of benzodiazepines and

20 doses of phenothiazines. Other possible uses of tranquilizing agents and

barbiturates outside of chemotherapy treatment as well as possible

alcohol use are not known.

Retrospective

Analyses Found No

Evidence of Adverse

Effects From the Use

of Allegedly

Incompatible Drugs

Analyses of data from NCI-sponsored clinical trials found no evidence of

adverse effects on survival associated with hydrazine sulfate and the use

of tranquilizing agents as antiemetics and barbiturates. Researchers at the

Mayo and Scripps clinics retrospectively analyzed clinical trial data in an

attempt to address the issue of incompatibility raised by hydrazine sulfate

proponents. Their analyses suggested that the concurrent use of hydrazine

sulfate with tranquilizing agents or barbiturates did not adversely affect

the survival of lung cancer patients enrolled in the hydrazine sulfate trials.

Also, their post-trial analyses did not change the conclusions originally

drawn from the clinical trials: There was no benefit for patients who

received hydrazine sulfate compared with those who received placebo.

Because patients who entered later in NCCTG’s lung cancer trial did not

receive benzodiazepine tranquilizing agents as antiemetics, NCCTG

investigators were able to retrospectively compare the clinical outcomes

of patients who received benzodiazepines with those of patients who did

13In the late 1980s, tranquilizing agents were used extensively in oncology to treat

chemotherapy-induced vomiting. In addition to sedation, phenothiazines and benzodiazepines have

some antinauseant and antiemetic effects. Furthermore, benzodiazepines were useful additions to

antiemetic regimens because they relieve anxiety about nausea or vomiting surrounding chemotherapy

treatment.

14Because data on concurrent medications were not collected on standard research forms, we asked

the principal investigator to review the medical records for study patients maintained at Harbor-UCLA

Medical Center. We did not attempt to verify these data.

Page 10 GAO/HEHS-95-141 Hydrazine Sulfate
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not.15 The data showed no statistically significant differences in survival

time between patients who received hydrazine sulfate and a

benzodiazepine tranquilizer as an antiemetic and patients who received

hydrazine sulfate and new non-benzodiazepine antiemetics. Furthermore,

analyses showed no statistically significant differences in terms of time to

disease progression for patients who received hydrazine sulfate and a

benzodiazepine tranquilizer compared with those who did not.

CALGB researchers also looked retrospectively at this incompatibility issue.

Beginning in January 1995, CALGB conducted a retrospective review of

primary medical records and documented the medications that were used

by patients enrolled in its clinical trial of hydrazine sulfate. On June 5,

1995, we received the results of CALGB’s examination of the effect of

benzodiazepines, barbiturates, or phenothiazines on patient survival. The

data showed no statistically significant differences in survival between

patients who received hydrazine sulfate and barbiturates or

benzodiazepines or phenothiazines and patients who received hydrazine

sulfate but none of these allegedly incompatible agents. Furthermore, the

data also showed no statistically significant differences in survival

between patients who received hydrazine sulfate and barbiturates or

benzodiazepines or phenothiazines and patients who received placebo and

any of these agents.

FDA Handled the

Issue of Possible

Incompatibility

Somewhat Differently

From NCI

FDA handled the issue of possible incompatibility differently in approving

the use of hydrazine sulfate by individual physicians than it did in

approving NCI’s sponsored clinical trials. FDA recommended that

NCI-sponsored investigators monitor study patients to detect possible

interactions between hydrazine sulfate and possible incompatible agents.

However, while NCI was conducting its clinical trials, FDA was cautioning

other physicians to avoid possible incompatible agents when

administering hydrazine sulfate.

In reviewing NCI’s IND applications to conduct clinical trials of hydrazine

sulfate, FDA raised safety concerns to NCI regarding hydrazine sulfate’s

interactions with other drugs, including tranquilizing agents. In his review

of NCI’s IND, the FDA medical officer stated, “The following drugs are

interdicted, due to known interactions: ethanol [alcohol], barbiturates, and

15Patients entered later in NCCTG’s clinical trial were treated with new antiemetic agents, primarily

ondansetron (Zofran). Ondansetron was the first of a whole new class of antiemetics—serotonin

receptor antagonists—to become widely available for the prevention of nausea and vomiting

associated with emetic chemotherapy. The development of serotonin receptor antagonists represented

a vast improvement in controlling vomiting. For example, ondansetron works well even against

chemotherapy regimens most notorious for causing severe vomiting in most people.

Page 11 GAO/HEHS-95-141 Hydrazine Sulfate
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tranquilizers.” This was followed by a recommendation that NCI outline all

precautions to be taken by study investigators “to fully explore the

neurotoxic potential of hydrazine.” NCI complied.

FDA took a more conservative view of the use of possible incompatible

agents with hydrazine sulfate under its compassionate use program.

Before completion of NCI’s sponsored clinical trials, FDA approved more

than 70 applications permitting the compassionate use of hydrazine

sulfate. Because of publicity given to hydrazine sulfate, FDA received many

requests from individual physicians for approval to use hydrazine sulfate

on a case-by-case “compassionate” basis on the chance that patients with

no other available effective therapy might benefit.16

A central nervous system depressant effect associated with hydrazine

sulfate consistently prompted FDA to caution patients regarding the use of

hydrazine sulfate with any potential sedative agent.17 In its approvals, FDA

staff requested that physicians caution their patients to avoid tranquilizers,

barbiturates, and alcohol while taking hydrazine sulfate. FDA officials told

us that the reason for this instruction was that these physicians were not

trained clinical investigators and, under the circumstances, would be less

likely to recognize adverse reactions from interactions between hydrazine

sulfate and possible incompatible agents.

NCI Did Not Ensure

Collection of Data on

the Use of Alleged

Incompatible Agents

NCI contributed to the subsequent controversy surrounding these trials by

not requiring better data collection and analysis of this issue. Although NCI

officials were aware of the concerns surrounding the use of allegedly

incompatible agents with hydrazine sulfate, they did not believe it was

necessary to maintain research records during its trial regarding

concurrent medications and possible alcohol use.18 NCI and CALGB

documents, however, stated that all data, including concurrent

medications taken by study patients, would be recorded on standardized

research forms.

16In the case of a serious disease, a drug that is not approved for marketing but is under clinical

investigation may be made available for a serious or immediately life-threatening disease in patients

for whom no comparable or satisfactory alternative drug or other therapy is available.

17FDA may also have been influenced by positions taken by other researchers in trials of hydrazine

sulfate. In earlier INDs submitted to FDA, a few researchers had developed study protocols or therapy

plans that said patients should not receive alcohol, barbiturates, or tranquilizers.

18As stated above, data on the actual antiemetics as well as any concurrent medications used by

patients in CALGB’s clinical trial were available from patients’ primary medical records.

Page 12 GAO/HEHS-95-141 Hydrazine Sulfate
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The Chairman of CALGB told us that the cooperative group decided before

starting the trial that they would not require such data to be recorded on

standardized research forms because the evaluation of concurrent

medications with hydrazine sulfate was not a study objective. Even after

the trial began, however, the CALGB principal investigator and an NCI official

assured proponents of hydrazine sulfate that CALGB would collect and

analyze data on antiemetic medications to determine the possible effects

of benzodiazepines and phenothiazines on patients taking hydrazine

sulfate. A statement submitted by NCI staff to media representatives

pointed to the purpose for this:

“[A]ll concurrent medications were well documented in the Cancer and Leukemia Group B

(CALGB) study (a routine component of clinical trials data collection) so that any differences

in study outcomes could be reviewed from the perspective of these potential

‘incompatibles’.”

Despite these assurances, CALGB did not uniformly collect data on the use

of concurrent medications, including tranquilizing agents and barbiturates,

and possible alcohol use. Furthermore, in a published article describing

the results of the clinical trial, CALGB investigators incorrectly reported that

data on the use of concurrent medications were recorded on standardized

research forms. CALGB investigators should have accurately reported their

data collection efforts. In addition, NCI should have ensured that CALGB

investigators prospectively collected data on concurrent medications and

alcohol use on research forms to permit investigators to analyze trial data

to determine the possible effects of these agents on patients taking

hydrazine sulfate.

CALGB’s Published

Trial Results Did Not

Accurately Describe

Tranquilizer Use

A paper presenting the final results of the CALGB clinical trial did not

clearly describe the use of tranquilizing agents by study patients. Authored

by the principal investigator for the trial, this scientific paper did not

accurately reflect the widespread use of tranquilizing agents in the CALGB

lung cancer trial.

In the published paper, the investigator wrote that “no patients received

barbiturates and virtually no patients received phenothiazine-type

tranquilizers, with the exception of prochlorperazine . . ., which was used

as a short-term antiemetic.” Data from the medical records, however,

showed that phenothiazines, including prochlorperazine, were prescribed

to 80 percent of study patients. In addition, over 88 percent of study

patients were prescribed benzodiazepines. Medical records also showed

Page 13 GAO/HEHS-95-141 Hydrazine Sulfate
B-261063 

that approximately 5 percent of study patients were treated with

barbiturates. The principal investigator told us that he used data submitted

by some research associates to form his “impressions” of concurrent

medication usage. Because CALGB did not routinely collect data on

concurrent medications, however, the data used to support his

impressions are not an accurate and complete reflection of information

contained in the medical records.

In a letter to us dated February 27, 1995, the Chairman of the CALGB

cooperative group said the principal investigator would prepare a letter to

the Journal of Clinical Oncology correcting his statement regarding study

patients’ use of barbiturates. The Chairman told us, however, that he

believed the description of tranquilizer use was accurate. He based his

assessment on, first, the fact that most medical records did not indicate

that phenothiazines were prescribed for long-term use as tranquilizers.

Second, the tranquilizing agents, phenothiazines and benzodiazepines,

were interchangeable in the investigator’s description of their use as

short-term antiemetics. Accordingly, he concluded that the principal

investigator was justified in stating that “virtually no patients received

phenothiazine-type tranquilizers.” We disagree with the Chairman in this

regard. We believe the investigator erred in not reporting the widespread

use of benzodiazepine tranquilizing agents.

In June 1995, the Journal of Clinical Oncology published a letter to the

editor from CALGB correcting and clarifying CALGB’s published results.19 The

letter corrected information on the use of barbiturates during CALGB’s

clinical trial. The letter also clarified that in addition to the use of a

phenothiazine tranquilizing agent as an antiemetic, many patients received

a benzodiazepine antiemetic.

Conclusions In three large, randomized, placebo-controlled clinical trials sponsored by

NCI, hydrazine sulfate was ineffective in extending the survival time for

certain cancer patients. The developer of hydrazine sulfate therapy has

suggested that the trials were compromised because investigators

permitted some study patients to take agents that are possibly

incompatible with hydrazine sulfate. We confirmed that all three trials

permitted some use of tranquilizing agents to varying degrees and one trial

permitted the use of barbiturates and alcohol. Specifically, many patients

received short-term dosages of tranquilizers for antiemetic purposes.

Retrospective analyses, however, found no evidence that the use of

19Vol. 13 (June 1995), pp. 1529-30.

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B-261063 

allegedly incompatible agents adversely affected NCI’s clinical trial results.

Although our work did not support the allegation that the studies were

flawed, NCI should have made sure that complete and accurate records

were kept during CALGB’s clinical trial regarding concurrent medications

and possible alcohol use. Furthermore, this issue should have been

analyzed on a more timely basis in the NCCTG and CALGB clinical trials, and

the published results of CALGB’s trial should have been accurate with

regard to tranquilizer use.

Agency Comments In commenting on a draft of this report, the Public Health Service agreed

with the report’s main conclusion that there is no evidence to support the

allegation that the three trials sponsored by NCI were flawed. In addition,

retrospective analyses suggested that the use of tranquilizers as antiemetic

agents, barbiturates, or alcohol by patients receiving hydrazine sulfate did

not produce greater toxicities or interfere with hydrazine sulfate’s alleged

benefits. (See app. II for a copy of the Public Health Service’s comments.)

The Public Health Service did not agree, however, that either NCI or the

clinical investigators were remiss for not ensuring that concurrent

medications were recorded on research forms. NCI and CALGB documents

provided that data on concurrent medications would be recorded on

research forms. As noted previously, NCI staff wrote to media

representatives that all concurrent medications were well documented as

a routine part of the trial’s data collection so that any differences in

outcomes could be analyzed in terms of the allegedly incompatible agents.

Although CALGB informed NCI that the use of concurrent medications would

be captured on the patient research forms in accordance with the research

plan, CALGB investigators did not uniformly record this information on the

forms as originally intended. Under the terms of the cooperative

agreement that provided funding for CALGB’s clinical trial, it was the

responsibility of CALGB to record such data. NCI officials told us that the

agency has specific expectations with respect to cooperative group

performance and it is the grantee’s responsibility to successfully

accomplish these. We believe, however, that NCI, as the funding agency,

has the oversight responsibility for ensuring that their expectations are

met. Furthermore, CALGB should have complied more completely with its

proposed plan for data recording.

The Public Health Service also does not believe that NCCTG and CALGB

clinical investigators should be criticized for not having analyzed data on

Page 15 GAO/HEHS-95-141 Hydrazine Sulfate
B-261063 

concurrent medications promptly. The issue of incompatibility was

consistently part of the public controversy surrounding the NCI-sponsored

clinical trials of hydrazine sulfate. Therefore, we believe that NCI was

remiss as were NCCTG and CALGB investigators for not settling the

controversy by promptly analyzing data on the impact of specific

medications on the effects of hydrazine sulfate.

The Public Health Service agreed that the initial published article

describing the findings of CALGB’s study was not accurate with respect to

the use of tranquilizing agents as antiemetics and barbiturates. NCI

criticized this lapse and ensured that a letter from the CALGB investigator

was published that provided more complete and accurate information.

The Public Health Service also provided technical comments which have

been incorporated where appropriate, in our report.

We are sending copies of this report to the Secretary of Health and Human

Services and the Director of NCI; the Commissioner of Food and Drugs;

and interested congressional committees. Copies will also be made

available to others upon request.

Please call me at (202) 512-7119 if you or your staff have any questions.

Other major contributors to this report include Barry D. Tice, Assistant

Director, (202) 512-4552, and Gloria E. Taylor.

Mark V. Nadel

Associate Director, National

 and Public Health Issues

Page 16 GAO/HEHS-95-141 Hydrazine Sulfate
Page 17 GAO/HEHS-95-141 Hydrazine Sulfate
Contents

Letter 1

Appendix I 

Scope and

Methodology

20

Appendix II 

Comments From the

Public Health Service

21

Table Table 1: Number of Patients Receiving Specific Antiemetic

Medications Along With Hydrazine Sulfate in the Lung Cancer

Clinical Trials

9

Figure Figure 1: Time Line of the UCLA and NCI-Sponsored Clinical

Trials of Hydrazine Sulfate

6

Abbreviations

CALGB Cancer and Leukemia Group B

FDA Food and Drug Administration

IND investigational new drug

NCCTG North Central Cancer Treatment Group

NCI National Cancer Institute

NIH National Institutes of Health

UCLA University of California Los Angeles

Page 18 GAO/HEHS-95-141 Hydrazine Sulfate
Page 19 GAO/HEHS-95-141 Hydrazine Sulfate
Appendix I 

Scope and Methodology

To obtain information for this report, we reviewed NCI’s policy guidance

for conducting clinical trials of investigational agents, agency

memorandums documenting protocol development for the hydrazine

sulfate clinical trials, and related correspondence. We also discussed the

conduct of these trials with NCI officials, cooperative group representatives

and investigators, FDA officials, officials in the Office of Research Integrity,

and proponents of hydrazine sulfate to obtain their perspectives on the

issues involved. We performed an extensive literature search on hydrazine

sulfate as well as topics related to cancer research, the conduct of clinical

trials, approaches to chemotherapy treatment, and drugs to control

chemotherapy-induced vomiting. In addition, we discussed the issue of

incompatibility with a leading Russian researcher and viewed several

hours of a taped interview with senior Russian oncologists. We also

discussed the interpretation of animal data with experts in pharmacology.

In our examination of the extent to which barbiturates and tranquilizers

were used during the clinical trials, we reviewed research records

maintained by the data management and statistical centers for each

cooperative group. For the CALGB clinical trial, we visited the cooperative

group’s Data Management Center located at Duke University. We

randomly selected research records for 137 of 291 study patients for

review. For the NCCTG clinical trial, we visited the Data Management

Center for the cooperative group at the Mayo Clinic. Before our arrival,

NCCTG research associates had compiled a list of antiemetic medications

administered to each study patient. We randomly selected 15 percent of

116 study patients’ research records to verify the accuracy of NCCTG’s data

collection efforts.

We conducted our work from July 1994 to April 1995 in accordance with

generally accepted government auditing standards.

Page 20 GAO/HEHS-95-141 Hydrazine Sulfate
Appendix II 

Comments From the Public Health Service

Page 21 GAO/HEHS-95-141 Hydrazine Sulfate
Appendix II 

Comments From the Public Health Service

Page 22 GAO/HEHS-95-141 Hydrazine Sulfate
Appendix II 

Comments From the Public Health Service

Page 23 GAO/HEHS-95-141 Hydrazine Sulfate
Appendix II 

Comments From the Public Health Service

(108998) Page 24 GAO/HEHS-95-141 Hydrazine Sulfate
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