The Coronary Drug Project (CDP): Birth of a Groundbreaking Clinical Trial
Early 1960s recommendations of the National Advisory Heart Council included undertaking both a diet-heart feasibility trial and a trial of secondary prevention of heart attack from cholesterol lowering with drugs, the Coronary Drug Project. A member of the Council, Robert Wilkins of Boston, was charged with a committee to explore the feasibility of the CDP and William Zukel of the Heart Institute was appointed his staff assistant.1 The committee resolved that the time was right to test the hypothesis of cholesterol-lowering with drugs and that it should be undertaken right away before an untreated control series would become medically, legally, or ethically impossible (Zukel 1983).
The Heart Institute then appointed a Policy Board which, in turn, engaged a group of consultants to draft a protocol with the idea that they would also participate as initial investigators in the study.2 Within two years a protocol was prepared and approved by the Advisory Heart Council and funds for the start-up year were approved by the Appropriations Committee of Congress.
But suddenly, in fiscal year 1965, when the study was ready to go, the Bureau of the Budget, which had not been consulted about the project beforehand, withheld the funds. This unleashed frantic activity between Dr. Knutti at the Heart Institute and Dr. Shannon, NIH Director, the Surgeon General’s office, and Congress, to which the Bureau of the Budget responded by seeking an independent opinion about the scientific merit of the trial from the President’s Office of Science and Technology, headed by chemist Donald F. Hornig. That office raised scientific questions and the Bureau again held up the appropriation. [Note: Hornig, formerly member of the Los Alamos Project, was the last man to leave the 100-foot tower on which the first, experimental atomic bomb was mounted just prior to the detonation.]
Senator Lister Hill then went to bat for the project and called for hearings where supportive and convincing testimony was heard from surgeon Champ Lyons, preventionist Jerry Stamler, and other notables. At last, the funds were released and the study got under way.
An Aspirin Trial was added to the research plan mid-trial, but fairly early in the course, two drugs, thyroxin and estrogen, were stopped because of toxic effects. Only niacin was shown, after long years of follow-up, to reduce coronary risk. On the other hand, many generic problems of clinical trials were exposed and some resolved by the trial team in CDP, including working relationships within the new NIH contract mechanisms established for trials.
Generic problems of trials emerge in CDP
Of major complexity in CDP was, and still is for such trials, that most NIH grants are made for 5 years and renewal arrives at a moment when trial results are barely forthcoming and often inadequate for decisions in a competitive review of the grant. A further problem is achieving adequate peer review in mid-trial without jeopardizing the result by premature disclosure.
Zukel’s comfort with the new NIH contract mechanism he had helped set up for major clinical trials contrasts with the chillness of the investigators; their attitude became apparent in CDP deliberations. NIH felt it provided better monitoring and accountability than under the grant mechanism, as well as more accurate and timely information on expenditures. With contracts it also held stronger authority to terminate a trial. Investigators, on the other hand, felt oppressed by a lumbering and unresponsive bureaucracy and sometimes worse, were persecuted by ambitious young project officers who equated administrative support with scientific authority and direction.
Zukel provides a didactic opinion on this issue, with his rose-colored viewpoint from the “best of worlds”: “The contract mechanism will not transform a poorly-designed trial into a well-designed trial. [But] experienced investigators with a common scientific goal and the recognition of the individual contributions that can be made by their collaborating colleagues can establish the necessary discipline to carry out a quality clinical trial regardless of whether funded by grants, contracts, or other sources of funds” (ibid.295).
He goes on to opine: “A clear message from this [CDP] experience is that a long-term clinical trial needs full advance scientific and administrative discussion and an understanding of the resources required to bring it to its completion. Continuing scientific and administrative commitment are also essential to assure that the needed resources are provided over the course of the trial. Experience gained in this long-term clinical trail [CDP] involving 53 clinics, coordinating center, central laboratory, ECG reading center, and drug procurement distribution center has provided a basic model for the new generation of clinical trials that have since been undertaken by the NHLBI” (ibid. 296). The key word, “control” never appears, but NIH policy was set with CDP.
In another essay, Zukel and NIH colleagues delicately expose some of the internal problems at NIH in setting up the seminal Coronary Drug Project (Zukel et al.1983). For example, though the director of the Heart Institute had enforced effective coordination within the institute itself, the director of NIH refused to allocate additional positions to establish an adequate staff for the new undertaking. Since the failure to apportion new positions would require reassignments from other epidemiological and biometrics research programs at the institute, it was decided to appoint just a small nucleus of institute staff to work with the external CDP operational units. Zukel, as Associate Director for Epidemiology and Biometry, was given responsibility to accomplish this minimalized administration of the CDP. Though he sat as a non-voting member of the CDP Policy Board, he participated in all Steering Committee meetings as a senior NIH representative as well as on all CDP subcommittees. He also was able to assign young Public Health Service Medical Liaison officers to the trial throughout the period, as they became available through the draft for the Viet Nam war. And he gave those individuals increasing experience and influence by making them rapporteurs of the Steering Committee and Policy Board of the trial.
Philosophical differences between the National Heart Institute staff and the Institute’s Advisory Heart Council are also subtly indicated in Zukel’s comments: “Although individual Council members have different levels of enthusiasm for additional clinical trials, often considered to compete against basic research projects for limited funds, they [the trials] have been [kept] in place from the evidence that such cooperative clinical trials can be accomplished efficiently and that a special body of expertise has grown in this type of research.” (ibid., 351)
Zukel and the Institute continued to implement control of the growing Epidemiological Behemoth by increasing the review requirements for investigator-initiated clinical trials, and finally, by the early 1980s, when his articles were written, he was able to confidently say, “When major research questions of potentially national significance become identified as warranting Institute sponsorship of a clinical trial, the contract mechanism and seeking open invitations for proposals on a competitive basis is now accepted policy” (ibid. 352) (3)
Fait accompli. (Henry Blackburn)
Footnotes
- Members of the CDP planning group appointed by the National Heart Institute: Robert Wilkins, Boston University; Jacob Bearman, University of Minnesota; Louis Lasagna, Johns Hopkins; William MacFate Smith, USPHS Hospital, San Francisco; Francis Wood, University of Pennsylvania; and William Zukel of NHI ex-officio.
- CDP Planning Group to draft the protocol and form the first clinics: Jerry Stamler, Chicago Board of Health, chairman; Ken Berge, Mayo Clinic; Maurice Best, Louisville; Nicholas Galucci, USPHS Staten Island; Jesse Marmosten, University of California, and support staff from NIH, Jerry Cornfield, Eleanor Darby, Christian Climt, Joseph Schacter, John Turner, and Bill Zukel.
- Examples of major 1970s-80s National Heart Institute-sponsored trials to follow CDP were the Aspirin Myocardial Infarction Study, Hypertension Detection and Follow-Up Program, http://www.epi.umn.edu/cvdepi/study.asp?id=61 Multiple Risk Factor Intervention Trial, Coronary Primary Prevention Trial, Coronary Artery Surgery Study, and the Beta Blocker Heart Attack Trial.
References
Zukel, W. 1983. The evolution and funding of the Coronary Drug Project Journal of Controlled Clinical Trials 4: 281-312.
Zukel, W.J., M. Halperin, L. Freidman, and E. N. K. Darby 1983. Role of the National Institutes of Health. Journal of Controlled Clinical Trials 4:345-354.