asked the GAO to investigate the manner in Laz tablet was developed The found a shocking 2. and knowing failure by Feder Lencies to abide by ws.ve attitude about the use of people as the sub

Siazid was originally given to patients three times s. Doctors at the Communicable Disease Center, to administer the drug, began to have patients tablets all at once every day.

* erors next sought to develop a single 300-milligram =reventive programs. In order to experiment on het the doctors needed an FDA exemption for g or human beings. The FDA exemption was that the smaller 100-milligram tablet was already is increased, FDA regulations treat the larger rate approval.

he Communicable Disease Center-CDCcational use of a 300-milligram tablet. The formation would be required before experirid begin, including all available data defrom clinical studies and experience with was also required.

d information to the FDA. Instead, experimental program on a wide range of

ween 1964 and 1970.

sitional testing procedures into three phases.
main to determine human toxicity and other
logical trials on a limited number of patients
a. Finally, the vestigators may move to
up of pat
To evaluate the drug's

Contrary to those established procedures, CDC skipped the first two phases altogether and moved immediately to tests on groups of patients. FDA never knew what happened to the 6,000 people CDC was experimenting with-even though the agency is required by law to evaluate the results of all testing programs-because CDC never told the FDA anything about its results. This failure is all the more disturbing in view of the fact that on two occasions the FDA requested such information and the CDC promised to supply it.

The FDA's own records contain ample evidence that the agency was fully aware of the inadequacies of the data CDA had submitted. For example, an FDA chemist's evaluation dated December 28, 1970-more than 6 years after CDC had started investigational use of the 300-milligram tablet and more than a month after Bleck and Stuckey had died-contained the following evaluation:

Labeling-unsatisfactory.

Other ingredients-unsatisfactory.

Synthetics-unsatisfactory.

Raw materials controls-unsatisfactory.
Other ingredients-unsatisfactory.
Laboratory controls-unsatisfactory.
Control number-unsatisfactory.

Stability-unsatisfactory.

Even with this report, FDA had not moved either to obtain the missing information from CDC or to stop the investigational programs.

The FDA Division Director told GAO investigators that the FDA had been unable to give appropriate attention to the isoniazid application at the time of the CDC request for exemption in 1964 because of the heavy work load resulting from the 1962 drug amendments. No reason was given to explain why the FDA had still not collected the required information more than 6 years later.

FDA officials also stated to the GAO that the failure of CDC to submit the data amounted only to a "technical violation." Even if there had been reports to the FDA of hepatitis or jaundice in experimental programs, the FDA officials said they would not have been concerned because hepatitis and jaundice were well-known dangers even in small doses and could be expected to occur at least as frequently with the experimental larger tablet. Apparently, the greater the likelihood of danger, the less the FDA was concerned with protecting the public. Even the FDA's negligence is exceeded, however, by the CDC's disregard for the human subjects of its medical experiments. As noted, the CDC ignored its statutory obligations and disregarded the FDA's requests for information about its treatment programs. Had it reported on those treatment programs, it would have had to admit that, even before the Capitol Hill test, two patients treated with the 300-milligram tablet had died of hepatitis.

Perhaps most surprising, however, was the manner in which CDC conducted the Capitol Hill program. Many persons who were given the drug were told by CDC doctors there would be no side effects. One patient remembers a CDC official describing the drug with the phrase, "as safe as aspirin." Another patient described an orientation session at which a CDC doctor refused to answer questions about side effects, stating if he described them then "everyone might come down with them."

Attempts to monitor results were haphazard and inept to the extent they existed at all. CDC officials seem to have behaved as if they were unaware that they were dealing with a potentially dangerous drug.

Throughout the program, the rights of the patient were ignored. A patient who actually has tuberculosis may be willing to run certain risks of side effects from a drug which can help cure him. But a patient who merely has a positive reaction to a test which only establishes that he has 1 chance in 1,400 of actually having tuberculosis may well decide that the risks of using the same drug may be excessive. At the very least, a patient should know what risks he is running and be able to make this choice.

The FDA and the CDC have committed appalling mistakes in the use and the regulation of isoniazid. I am concerned that what we have discovered about isoniazid may be only the tip of a massive iceberg of bureaucratic neglect. I am therefore asking the GAO to undertake a comprehensive investigation of all drugs approved by the FDA for investigational use, with special attention to be given to drugs approved for such use in 1964 and 1965.

We urgently need to test and develop new drugs. At the same time, there is an equally pressing need to be sure that drugs used on human beings-especially

EXHIBIT 59

WASHINGTON, D.C.

Dr. ROBERT Q. MARSTON,
Director, National Institutes of Health,
Bethesda, Md.

DEAR DR. MARSTON: Your meager plan to shift DBS regulatory activities to FDA, and your inaccurate and incomplete response to the suggestion that the scientific work of DBS is not what it should be, indicate that you are willing, in fact desire, to take responsibility for the public health problems that result from reliance on the discredited CCA test for determination of influenza vaccine potency. This suggests that once again all of the relevant information has not reached your office.

The DBS inspector of two companies producing influenza vaccine recently reported in writing to the DBS director that the CCA test is not giving satisfactory results. Variance in multiple test results of a single lot of influenza vaccine exceeded 100%. The companies, according to the written reports of the investigator, are routinely excluding the highest set of results to give a better picture of the test's accuracy than actually exists. A recent meeting of company and DBS officials held in the DBS established that even with careful attention to the large number of variables in the test the results achieved by dif ferent operators varied far in excess of the claimed 15% error.

All of this practical experience supports the conclusions contained in the scientific literature that, in the words of Dr. Kilbourne, one of the members of the Benenson Committee, the CCA test is "archaic and unsatisfactory." That the people in your office who prepared your latest defense of science at DBS can see no contradiction between this statement about the CCA test and the assertion that the CCA test "appears to be a satisfactory procedure for estimating the content of the major influenza virus antigens in a vaccine" reveals a kind of myopia that explains much of the NIH inability to respond reasonably to questions about its scientific competence.

Other equally inaccurate assertions clutter the latest defense of DBS science. For some reason, the inclusion of the ship study concerned with influenza is quoted for exactly the opposite points made by the data and the author. The reference to the polio situation does not take into consideration the 1968 position of Dr. James Shannon that the polio decision was arrived at in too much secrecy; that in 1954, Sven Gard, of the Swedish vaccine control authority, warned the American officials that the formaldehyde system they were relying on could not be expected to kill live polio virus contained in the vaccine; or that from witnesses who were at the meeting-Dr. Workman objected to proceeding with the polio vaccine licensing. Nor does the NIH defense explain how test methods, which they had great faith in, could be effective in detecting live polio virus contamination when many lots were released to the public without testing. There are a number of other assertions, mis-statements, or over-sights contained in the "comments on" and "staff analysis of" the suggestions of scientific problems at DBS which I helped to raise. Hopefully, this is not a document that the NIH intends to rely on for scientific purposes.

I am curious to know the reason that one version of this document was presented to the Senate Appropriations Committee and another version was presented to the press. To me, this handling of the document supports the impression of its contents that it was not intended to be scientific. I sincerely hope that neither document represents the standard of science that is acceptable in the Director's office of the NIH.

Unfortunately, an exchange of letters between Dr. B. G. Young and the Director's office suggests otherwise. Specifically, Dr. Young wrote to you asking for the reasons that Dr. J. Anthony Morris was barred from speaking at a seminar conducted in the Department of Microbiology at the University of Maryland where Dr. Young is the chairman. The answer given, in both its substance and the authority it distortingly quotes, suggests that the quality of scientific thinking at NIH has slipped greatly since the days when NIH was one of the world's foremost research institutions.

Specifically, the response to Dr. Young's inquiry states that scientists are only allowed to raise controversial scientific issues within the "republic of science." It cites Alvin Weinberg in a way that suggests that he supports this idea. The letter also argues that the presentation of the views of "dissident scientists" outside the republic of science "is only likely to mislead and alarm an already underinformed and unsophisticated public *

Both of these ideas are directly counter to the growing belief of many individuals inside and outside of scientific circles that the general public must be more widely included in scientific debates.

No more effective and eloquent a spokesman of this point of view exists than the Alvin Weinberg whose name is used in your office's response to lend prestige to the opposite point of view. In his book, Reflections on Big Science, Dr. Weinberg makes two points relevant to the inaccurate impression given by the use of his name in a letter justifying the restriction of scientists to speak on "Science, Law and Public Policy." He says, "In the long run, how much our society is going to spend on basic science depends upon the extent to which nonscientists develop the intellectual power and taste to appreciate, if not discover, science." Restricting the presentation of a scientist like Dr. Morris because his audience in this case a group of microbiology graduate students and their professors is too "underinformed or unsophisticated" to understand and make judgments about what he has to say is surely not the way to develon the support for science that Dr. Weinberg sees as necessary. To use Dr. Weinberg's ideas as if they support such an action suggests not only that NIH does not feel public support is necessary but also has difficulty in understanding the point of the Weinberg argument.

Dr. Weinberg also says, "In this age of big money for big science, it is harder than in earlier days to find the scientists dedicated solely to the truth ***" I must say that my experience with the DBS and the NIH for the past two years suggests that an ever increasing consideration is given to other than scientific truth. Emphasis appears to be given to cost benefit analysis, risk-benefit ratio, personality consideration, and the expenditure of tremendous amounts of energy and money in an effort to support a position erroneously taken seem more important to the NIH leadership than arriving at scientific answers. You have a copy of the speech that Dr. Weinberg made at NIH. It makes a number of very important points about the nature of the scientific debate. Most importantly, it points out that the Republic of Science is a place where the credibility of scientists is tested. The Republic of Transscience is where policy debates to which some scientists might have some input takes place. The debates in the Republic of Transscience are public debates. In it is that kind of debate which is being conducted now about vaccine regulation.

I hope that this letter has helped to put into context the policy issues which I am attempting to draw to your attention. Most specifically, whatever you may think about the Weinberg arguments, you must take some steps to insure that the currently indefensible state of influenza vaccine potency testing by the CCA method be investigated and corrected. As I have always made clear, I would be more than happy to discuss these issues with you at any time. I have found useful, and enjoyed, by various conversations with other NIH officials with whom I have spent time discussing the DBS situation over the past month. I hope to hear from you about these points.

Sincerely yours,

JAMES C. TURNER.

EXHIBIT 60

DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE-PUBLIC HEALTH SERVICEBACTERIAL VACCINES AND BACTERIAL ANTIGENES

REVIEW OF EFFECTIVENESS

[Federal Register, Vol. 37, No. 51, Mar. 15, 1972]

In accordance with the delegation of authority (37 F.R. 4004-4005) authorizing the Director, National Institutes of Health to administer the provisions of the Federal Food. Drug and Cosmetic Act with respect to those human drugs that are biologicals subject to section 351 of the Public Health Service Act (42 U.S.C. 262), the Division of Biologics Standards is undertaking a review of the effectiveness of all licensed biologicals. The first categories of licensed products to be reviewed for this purpose will be those bacterial vaccines and bacterial antigens whose labels are required by 42 CFR 73.001 (r) to state "No U.S. standard of potency."

A licensed manufacturer of such bacterial vaccines or antigens who wishes to continue manufacturing and marketing such products shall advise the Division