By Robert Oldham. Mr. Oldham is chairman of the South Carolina Biotechnology Association and CEO of Cancer Therapeutics Inc.
It is now known in every household that a vast and complex feat of science called the genome project holds great promise for the well-being of mankind. Less understood, even in Washington, is that if the framework regulating the development of new drug therapies isn't modernized soon, many people will fail to see the fruits of the genome project in their lifetimes.
Indeed, the regulatory avalanche the Clinton administration set in motion on Jan. 8 of this year threatens to smother this nascent field of discovery.
Dense Rulebook
Officially, the administration's handiwork appeared in the Federal Registry under Food and Drug Administration regulations as 21CFR, Part 1271. These "rules" on "current good tissue practices" would apply to all human cellular and tissue-based products. In addition to the 50 dense pages of federal regulations, the FDA published 43 pages of interpretations to make the regulations more understandable. All were to be written in "plain language" as directed by Bill Clinton on June 1, 1998.
These regulations are not in "plain language." If anything, they expand the complexity of taking an individual's own tissues and storing or activating them outside the body prior to reinjection into that individual. These "autologous" therapies have been largely developed without the heavy hand of FDA regulation.
The recent experience of one such next-generation drug perfectly illustrates the problem with the FDA's regulators.
Bristol-Myers Squibb has developed a very promising drug called UFT to treat patients with colon cancer. But the company's experience raises serious doubts about the standards the FDA is applying for the approval of drugs that have finished their clinical trials.
The Oncology Drug Advisory Committee is a panel of cancer experts who review clinical trials and the scientific basis for a drug's approval. It then gives recommendations to FDA staff with regard to a drug's safety and efficacy. The advisory committee unanimously recommended approval of UFT, which the FDA rejected. This caused considerable controversy in the professional cancer community.
One expert commented that the FDA should not be playing "Guess what I'm thinking." It was suggested that review problems of this sort would negatively impact the development of "molecules that are going to work in subsets of patients." Especially troubling to the cancer experts was the FDA's suggested standard that all new drugs should be tested against a placebo control group in cancer trials. Dr. Robert Comis, chairman of the Eastern Cooperative Oncology Group, said: "None of us would randomize our patients to. . . inactive drugs for the sake of pharmacology and an inane regulation."
Tough words, which reflect an increasing disconnection between the reality of developments in molecular biology and an FDA regulatory framework shaped for a past era. A major effort must be mounted now to rethink regulation for this promising new world of individualized therapies.
Consider the world of regulation as it now exists for any new drug attempting to find its way to patients. Only one of every 50,000 drugs initially screened actually becomes an approved medicine, yet it costs over $500 million to develop a single drug for commercial availability in the U.S. Given these figures, it isn't hard to understand why the cost of "one size fits all" drug development is so high.
Since so few candidate drugs actually make it through the pipeline, there are many expensive failures, the cost of which the biotechnology and pharmaceutical companies must absorb in the process of developing the much smaller number of successful drugs. It now takes about 10 years to bring a drug through testing to market, so it's no wonder that this expensive and risky process produces drugs with high price tags.
This problem will get worse as we attempt to exploit the benefits of modern biology, whose promise is becoming reality. In the early 1980s, when I was at the National Cancer Institute, I first proposed the concept of custom-tailored medicines for individual human beings. Today, numerous companies are pursuing vaccines built from the patient's own tumor cells, so-called autologous vaccines. Other companies are pursuing activated T lymphocytes as potential cancer fighters using lymphocytes (white blood cells) from the cancer patient's own blood, or from cells infiltrating the patient's own tumor.
The sequencing of the human genome has given us a vastly better understanding of individuality. It is clear from looking at differences in facial features, size and disposition that the human genome is indeed unique and that each of us has highly individualistic characteristics. Therefore, it is intuitively obvious that cancer is a disease of a highly individual nature. Since the cancer cell is nothing more than an aberration of our normal cells, the genetic program within the cancer cell must be different from patient to patient.
It is now recognized that many drugs that were made for everyone act differently in each of us. Companies are beginning to use individual genetic differences to try to tailor drugs for smaller and smaller groups of patients, right down to the individual human being. It is apparent to those of us active in individualized therapy that the field needs careful study, and that the FDA needs advice on how to develop systems that would bring individualized therapies through a regulatory maze in a timely and less expensive manner.
Over the past 20 years, the FDA has reinvented itself several times. There have been programs to speed up drug development, paperless applications, and user fees to help fund the FDA. Committees and commissions have looked at the FDA in an attempt to improve and modernize the regulatory processes for drug development. We're told that the point of it all is to speed drug development so the sick can get access to the best new medicines quicker, and at less cost.
Challenges Ahead
Has it worked? Not from the evidence. The timeline remains about a decade per drug and the cost has risen in excess of inflation -- $500 million a drug in 2001, up from $200 million a drug in 1980.
While the Bush administration has many challenges ahead, the cost of drug development and its impact on the quality of life and medical-care costs should rank near the top. We're now on the verge of realizing the scientific opportunities afforded by the genome project. Unfortunately, our regulatory book is many pages longer than the book of life. A country that could produce minds able to decipher the human genome can surely find minds able to crack the code at the FDA.
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