On January 17, 1961, President Dwight D. Eisenhower, in his farewell address to the nation, coined the term “the military-industrial complex.” His purpose was to warn of the inefficiencies that could result from such a relationship, which would imperil the strength of our military and the safety of our nation. In an analogous fashion, today we have an “FDA–pharmaceutical industry complex.” This relationship imperils the effectiveness of our outstanding academic medical community and their partners in the pharmaceutical industry, hindering the development of innovative and highly effective treatments for the major diseases that threaten the health of our nation.
FDA’s Perspective
Since the enactment of the Kefauver-Harris Amendment to the Federal Food, Drug, and Cosmetic Act in 1962, the FDA has had a legal responsibility to ensure the safety and effectiveness of all new drug development in the country. In addition to its responsibility for protecting the public from drugs that were unsafe or ineffective, the agency acquired a new responsibility for ensuring that the processes of drug development were also safe and effective. The result was the investigational new drug (IND) application.
Over the next 49 years, the FDA requirements for awarding INDs have progressively escalated. The reason for this is clearly that any new drug that causes an unfavorable outcome—whatever it might be—would certainly be to the strong detriment of the FDA official who approved the IND. In contrast, if a new drug is highly effective and saves many lives, the FDA official reviewing and approving such an application would benefit not at all. Thus, the regulator is motivated to disapprove applications. But even better is the strategy of delay, ie, to require additional information that must be provided by the sponsor.
Pharma’s Perspective
On the pharmaceutical side, since the business goal is to develop treatments that can be marketed and produce profits for shareholders, industry executives clearly want to bring potential treatments to the marketplace as quickly as possible. Toward that end, and recognizing the important role of the FDA regulators, industry has acquired a mirror-image group of professional regulatory experts, many of whom have served in the FDA. These experts shepherd new treatments through the regulatory process to bring them to the market. Of course, this excessive regulation results in progressively escalating costs and progressively escalating delay in the time necessary to bring new treatments to patients who are in desperate need of them.
Recognizing this time factor and seeking to facilitate the process, the regulatory employees in the pharmaceutical industry design all of the studies in collaboration with the regulatory officials at the FDA. The consequence of all this is that the scientific and professional decisions are made by people who have the least expertise in the area of drug development and therapy. At the same time, the individuals with the greatest achievement, knowledge, resources, and capability to design, develop, and implement new therapies—the academic physician scientists—are excluded entirely from the process. When the regulatory officials in the pharmaceutical industry and those in the FDA reach an agreement that an IND should be issued, specific protocols are often presented to senior investigators as a fait accompli.
Intent vs Consequence
Thus, while the intent of the Kefauver-Harris Amendment was to provide safety for subjects participating in early clinical investigations of new treatments, its consequence has been to exclude the most talented and capable members of the scientific community from the drug development process.
Even worse is the fact that virtually no one benefits from the IND process as it is currently practiced. It greatly escalates the cost for industry and patients. It greatly escalates the cost for the FDA to conduct these regulatory activities. Those who are harmed the most, of course, are the patients, who suffer from delays in the development of potential cures for their illnesses.
Solutions
The solution is obvious. The IND process is an extremely useful concept that should be effective without increasing delay or cost. Over the past 49 years, clinical investigation of new drugs has become more sophisticated. The major academic institutions involved in cancer research and the network of comprehensive cancer centers are staffed with highly knowledgeable, highly effective, experienced physician scientists who should play the leadership role in the drug development process, advising both FDA and industry.
The other change since 1962 is the implementation of patient safety laws, which require institutional review boards (IRBs) for all protocols. In the comprehensive cancer centers, all proposals for novel procedures to be transferred from the laboratory to the clinic require formal protocols, which are formally reviewed within the departmental structure, approved by the head of the department, and reviewed by clinical research committees staffed by all the disciplines that support development of new drugs and therapies. Ultimately, such proposals must be reviewed and approved by the IRB to ensure that every effort is made to ensure patient safety for any new therapeutic approach.
That being the case, we are long past the point where the FDA–pharmaceutical industry complex needs to be decentralized. Authority for both designing and implementing new drug studies should be the responsibility of institutions that are regularly inspected to have the necessary regulatory processes in place, to ensure patient safety, and to establish objective methods of evaluating effectiveness. Transferring authority in this way would bring the academic physician scientist back into the business of developing new therapies, which will benefit all parties involved.
Finally, it is time to move away from outdated toxicology studies to guide new agent development, and move to more appropriate new techniques for the development of targeted therapy and personalized medicine. ■
Financial Disclosure: Dr. Freireich reported no potential conflicts of interest.
Dr. Freireich is Ruth Harriet Ainsworth Chair, Distinguished Teaching Professor, and Director, Special Medical Education Programs and Adult Leukemia Research Program, The University of Texas MD Anderson Cancer Center, Houston.
The views expressed herein are those of the author and not necessarily those of The ASCO Post.
References
1. Freireich EJ: Should terminally ill patients have the right to take drugs that pass phase I testing? Yes. BMJ 335:478 2007.
2. Freireich, EJ: The investigational new drug application—who benefits? Nature Clinical Practice Oncology 3:62-63, 2006.
