terms it—namely, research to answer basic questions about pharmacokinetics and safety through initial trials in the first few human beings after laboratory and animal work has been completed.

It is a matter of some importance that these two sets of purposes be made very clear, both in the protocol and (particularly) in the consent form, since the effects of the two aspects of the study are likely to be very different for the subjects. In the second branch of their experiment, it was intended to give a relatively small dose of MTHHF "labeled" with a small amount of radioactivity. This amount would be too small to be expected to have any effect on patient-subjects' tumors. The size of the dosage probably explains why the consent form would put these words into a prospective subject's mouth: "I understand ... that the amount of drug used solely for the pharmacology studies... will be free of toxic effects."37

Any subject who understood the term "pharmacology studies" to be synonymous with the experiment itself-an understandable, indeed predictable, mistake, given the way the consent form is written-would have gotten the misleading impression that the study as a whole, to the extent it was not treatment, would be "free of toxic effects." Yet, the other branch of the study design was actually a search for "the highest dose which does not cause the following toxicities," which had been reported from studies on dogs and monkeys:38

severe hemolytic anemia, ... congestive heart failure, life-threatening arrhythmias, ... severe diarrhea requiring hospitalization for fluid replacement, coma, seizures, nerve paralysis, progressive mental deterioration or weakness.

The standard to be used was that

...

if three patients develop any of the above toxicities at a similar dose level during Phase 1 evaluation, the dose will be considered to be above the maximum tolerated dose.39

The amount of the drug that would produce those effects in humans was unknown; by step-wise increments (or decrements, if the initial guess on tolerable dosage was too high) the researchers intended to find the point where these (or other) toxic side effects would begin.

One would expect such possible consequences to be

37 The consent form is contained in the Summary Report of the NIH Site Visit Team, supra note 57.

38 Id., Protocol DT 78-31, paragraph 3.14: Animal Toxicology. 39Id., Protocol DT 78–31, Appendix A, Maximum Tolerated Dose.

spelled out clearly in the consent form. They were not mentioned. Of course, under the HHS rules in effect at the time the protocol was approved, it was also (and still is) permissible to use a "short form" written consent that indicates that "the basic elements of informed consent have been presented orally to the subject." But in that case, "written summaries of what is to be said to the patient are to be approved by the Board." The rules required that the form be signed not only by the subject but also "by an auditor witness to the oral presentation and to the subject's signature. A copy of the approved summary, annotated to show any additions, is to be signed by the persons officially obtaining the consent and by the auditor witness."40 No such summaries were prepared for, or approved by the IRB (nor do any such forms and procedures appear to have employed in the MTHHF study actually performed 1980), which violated not only the HHS regulations but M.D. Anderson Hospital's own general assurance.41

The failure of the consent form to describe the risks of the experiment is more grave because of another, perhaps central, deficiency in the form: it gives the impression that the cancer patient is being asked to consent to treatment, with perhaps some small added studies ("free of toxic effects") on the side. The form does not make clear that MTHHF had never before been administered to humans and therefore that its possible efficacy was wholly unknown. The language of the consent form, as approved by the IRB, is instead replete with references to "therapy" and "my treatment." Indeed, after formal language naming the physician and the "treatment," the body of the consent form be

40 Section 46.110 of the 1974 regulations required documentation of the "actual procedure utilized in obtaining legally effective informed consent and the basis for Institutional Review Board determinations that the procedures are adequate and appropriate." The documentation of consent was permitted to take one of two forms in biomedical research. When the "short form" written consent procedures was utilized, the document must indicate "that the basic elements of informed consent have been presented orally to the subject or his legally authorized representative." Sample copies of the consent form and of the summaries as approved by the Board must be retained in its records.

More typically, a subject is provided with "a written document embodying all of the basic elements of informed consent. This may be read to the subject or to his legally authorized representative, but in any event he or his legally authorized representative must be given adequate opportunity to read it." The regulation required that the document be signed by the subject or his legally authorized representative, and that "Sample copies of the consent form as approved by the Board be retained in its records."

41 Report of FDA's Inspection Report, supra note 58, Exhibit #2.

gins with the assertion: "I am about to receive a form of chemotherapy recommended by my physician. He has explained the potential benefits and hazards of this treatment to me."42

Although the NCI site visitors' report did note that the consent procedures in this case failed to conform to the HHS regulations and the hospital's general assurance, most of the attention (and subsequent sanctions) were based upon the principal investigator's having acted on the (incorrect) assumption that in the two years since the IRB approved the protocol, appropriate clearance had been obtained from the FDA and NCI to administer the drug to humans. There was no apparent concern that the deficiencies revealed in the MTHHF consent form might be widespread or that the IRB should have mechanisms to assure that all additional certifications are in place prior to giving its final approval for a research project.43 Nor did the site visitors find noteworthy the fact that at least two IRB members had disagreed as to whether the research would be "therapeutic" for the subjects and, moreover, had advised that additional information be provided in the consent forms.44

The response of both NIH and the administrators at M.D. Anderson was to direct strong criticism and sanctions against the principal investigator. NIH terminated all work under the contract in question, except for two studies "of high programmatic priority" for which a new principal investigator was named, and the government sought reimbursement of funds used to support the unauthorized clinical studies.45 The hospital, in addition, formally censured the principal investigator and barred him from further participation in studies involving human subjects. He was also relieved of all responsibilities as principal investigator or co-principal investigator on federal contracts or grants. (Both of the latter sanctions are of indefinite duration but

42 Consent form in Summary Report of NIH Site Visit Team, supra note 57.

43 The principal investigator had also failed to obtain approval from the hospital's Radioactive Drug Research Committee, which was required for use of radioactive "labels" which facilitate study of the subjects' metabolism of the drug.

44 Summary Report of NIH Site Visit Team, supra note 57, Reviews of Protocol DT 78-31 by Alexander Y.M. Wang, Ph.D. (81878) and W.W. Sutow, M.D. (August 2, 1978).

45 Memorandum from Director, NCI to Acting Director, NIH (August 6, 1981) forwarding Recommendations Regarding Ti Li Loo, Ph.D. and the M.D. Anderson Hospital and Tumor Institute, University of Texas System Cancer Center and attached Site Visit Report.

are subject to periodic review.)46

A joint NIH/NCI panel that reviewed the site visit report added two additional sanctions: that the investigator's infraction be brought to the attention of the appropriate NIH advisory council should he submit a grant or contract proposal during the next two year period and that he not be asked to serve on any NIH advisory committees or as a site visitor during that same period.47

The Director of OPRR reported to the Commission that his office engaged in additional correspondence and telephone calls with M.D. Anderson, following the formal imposition of sanctions by NIH, in an effort to improve the hospital's overall review procedures. The only recommendations directed at the institution and formally endorsed by the Acting Director of NIH, however, were that its procedures for handling investigational new drugs be improved with respect to documentation, record keeping and distribution from the pharmacy and that "documents be developed by the University which describe the policies and procedures for the clinical research utilizing investigational drugs, which will ensure compliance in the future with the NCI policy and HHS regulations for the protection of human subjects with follow-up visits by NCI and the Office of Protection for Research Risk [sic]."'48

Throughout, officials at NIH remained unaware of the routine FDA inspection of M.D. Anderson that had taken place on March 20, 1981,49 despite the assurances given to the President's Commission that NIH has developed good communication with FDA and that "when FDA inspectors find any practice which may constitute noncompliance with 45 CFR 46, the HEW regulations, OPRR is immediately notified."50 Perhaps OPRR was not notified of the clear deficiencies reported by the FDA inspectors because, although the reviewers noted a failure to conduct annual review of individual protocols (instead, the IRB reviewed and reapproved the "parent project" which might contain any number of individual protocols), the FDA classified the re

46 Id. 47Id.

48 Id. The sanctions recommended by NCI were approved by the NIH Acting Director on August 11, 1981. (See concurrence signature on p.4 of the memorandum.)

49 Testimony of Charles MacKay, Deputy Director, OPRR, at 14th meeting of the President's Commission (Nov. 14, 1981) at 323. 50 Testimony of the Director, OPRR at the 2nd meeting of the President's Commission (May 16, 1980) at 82. See also, letter from Dr. Charles R. McCarthy to Morris B. Abram (May 7, 1980) at 4.

sults of its inspection as "No Action [is] Indicated."51 The failure of the IRB to review each protocol, however, violates regulations governing research supported by HHS as well as FDA's own regulations governing research with investigational new drugs. Moreover, while the FDA investigation showed that, in the case of the drug reviewed, the IRB had required modifications in the consent form, the important changes recommended by the two IRB members with primary review responsibilities in that case were not in fact incorporated in the revised form as approved. 52 Finally, the form (also for a Phase 1 drug study) is less than clear and candid about the likelihood (or lack thereof) of therapeutic benefit to subjects and contains "boilerplate" language that certain information has been provided, rather than a full description of the information itself. In the absence of any summary of the risks, the consent form and the IRB review process described in the FDA inspection documents appear not to meet the HHS regulations and the hospital's general assurance, just as was true in the IRB's handling of the 1978 MTHHF protocol.

It appears, therefore, that neither the FDA nor the NIH has developed inspection procedures that are sensitive to significant factors; moreover, communication between FDA and NIH regarding their site visits is far from adequate. An additional problem is whether "Phase 1" tests of new cancer drugs can be considered "therapeutic" and, if so, whether they should still be classified as "Phase 1."

51 FDA Inspection Report, supra note 58, at 1.

52 Id. See, Exhibits la-d, 4c, and 4d.