Seven obstacles that “threaten to choke off the significant clinical research which is essential to our ultimate goal of the control of cancer” were described by Emil Freireich in the David A. Karnofsky Memorial Lectureship at the annual meeting of the American Society of Clinical Oncology.
“I think the time has come to change directions to swing the boat 90 degrees back toward the type of clinical research that is more observational, and I propose that such a change will keep us relentless on target to our goal of cancer control,” Freireich said.
Freireich, chief of developmental therapeutics at M.D. Anderson, is noted for willingness to challenge accepted practices and to question popular theory. The seven obstacles cited in his talk, “Who Took the ‘Clinical’ out of ‘Clinical Research’? Mouse vs. Man” and which led to the development of “Freireich’s Seven Laws” were:
- “Oppressive regulation” of the clinical investigator, primarily by the federal government, with the most serious problem being FDA’s regulation of drug development. “Another area of regulation that has become sufficiently oppressive so that the conduct of clinical research is threatened is informed consent.” Acknowledging the “wisdom and importance” of informed consent, Freireich said that “aggressive implementation of such regulations has resulted in an extraordinary mountain of bureaucratic excess, which has itself become a significant impediment to research.” Law No. 7 is a refutation of “the Regulator’s Creed-the general solution to a specific problem will soon become a specific problem requiring a general solution.” Drug review and informed consent procedures are designed to protect against the occasional abuse, he suggested. “It is a great human weakness to generalize from exceptions. As scientists, we know that the best solution to a specific problem is a specific solution. We should attempt to prescribe regulatory procedures which accomplish our objectives without interfering with research.”
- “A second major obstacle to clinical research is the current clamor for ‘primary health care’… The clinical scientist is viewed as a super specialist, completely isolated from the problems of illness and health care.” Freireich’s Law No. 6: “The best patient care, or patient service, is clinical research. If there is documented progress from the discovery of new treatment, then it should follow that the patients participating in such research are themselves the beneficiary of those new advances, in contrast to those patients not participating in clinical research.”
- Freireich said he was concerned about generalizations being applied to priorities in cancer research. In choosing priorities, he offers as a guide Law No. 5–instead of the admonition that the physician should as a first principle “do no harm, a particularly offensive admonition since that requires no action at all, “he suggests, “Do what can possibly be done, more important, do that which is necessary. We cannot turn our backs on any part of the cancer problem. We must investigate problems in the clinic as they present themselves. We are required to care for the elderly and the young, for acute leukemia and for lung cancer…. The clinical scientist must be in the vanguard of physicians, emphasizing the prospects for a
continuously improving outlook and for the achievements of clinical research.”
- Freireich attacked the use of concurrent controls and randomization. “When the physician’s judgment is that the benefit-risk favors the developmental therapy, then to ask the patient to consent to receiving therapy which in that physician’s judgment is inferior, would not be honest…. blind studies should be done rarely if ever.” Physicians who recommend new or developmental therapy should be convinced that the probability is greater for benefit than risk. “In the absence of that conviction, I don’t honestly believe that the physician should offer the patient the extra risk of developmental therapy.” He defended the use of historical controls. Freireich’s Law No. 4: The best therapeutic research gives the best results.
- Freireich described a “good is bad, bad is good” principle which invalidates results because concurrent randomized studies are not conducted. Referring to two clinical research projects-granulocyte replacement and reverse isolation procedures to diminish infectious complications, “we found that by objective criteria such as survival, frequency of complete remission, frequency of infections, the eventual outcome was substantially better than the historical control data.” Yet the academic judgment was that the research was bad, although it gave good results. Other classical clinical trials were conducted over the next 10 years, randomly allocating half their patients to the conventional treatment and the other half to the new. “In both instances, these studies unambiguously confirmed the positive results already published. They did, however, have a bad result-half of their patients had unfavorable results.” Law No. 3: “If we must experiment with patients to obtain medical information, then we had best do without that information. It cannot be necessary to have a bad result before we can be convinced of the good results.”
- Freireich referred to the problems of false-positive, false-negative findings. The classical approach uses the null hypothesis, in which the investigator hypothesizes that no difference exists and the test is made to reject that hypothesis. “This type of thinking emphasizes lack of willingness to make a falsely positive error.” But Freireich insisted that when there is a false-positive error, it is quickly found in subsequent studies, since others will be anxious to try the new therapy. However, a false-negative finding will rarely be disputed, since it is not likely confirming studies will be undertaken. “The investigator’s greatest fear should be a false negative result, and his efforts should be aimed at protecting against that risk.” Law No. 2: “Always be prepared for success, because failure creates few problems… If the clinical investigator is not optimistic in his choice of new treatments for his patients, who in the health care system will be? We have to offer this optimism to our patients so that they also feel that the drugs to which they are being exposed and the treatments which they are receiving do have prospects for dramatic changes in outcome for the better. There have been dramatic breakthroughs in the clinical investigations of cancer and virtually all of these have been initiated by optimistic individuals in sequential series of patients, making quantitative observations. A strategy which has been effective in the past and will be effective in the future.”
- Ethical aspects of clinical research-“commitments to our patients, our institutions, our community and even to the world of man”–led to Law No. 1–“The Clinical Investigator’s Creed: The primary beneficiary of clinical research is the patient participating in that research.” Justifying certain types of experimental plans because of commitments to future cancer patients or to science “is the first step on a slippery slope toward experimenting on people which ends in violating all of the other six Freireich Laws. The first consideration of a clinical investigator must always be the welfare of that person. Other considerations, while important, must always be secondary.”