FDA Reform in Congress: FDA's Concerns

Perhaps the best case against major elements of the FDA reform legislation now being considered by Congress is the February 21, 1996 testimony of FDA Commissioner David A. Kessler, M.D., before the Senate Committee on Labor and Human Resources -- chaired by Senator Nancy Kassebaum, Republican, Kansas, who introduced S. 1477. It is impossible to meaningfully summarize this statement, which is 48 pages double spaced plus 19 pages of attachments. But we want to give our readers a sense of some of the concerns. (Note: Kessler's testimony addressed only S. 1477; H.R. 3199 had not been introduced yet.)

Dr. Kessler urged Congress to consider the progress in rapid drug reviews and other areas that has been made in the past several years. "If we are to achieve our shared goals of improving the Agency's ability to protect and promote the public health, we must base our work on FDA's current performance. Unfortunately, too many of our critics justify the call for 'reform' based on how the FDA did its job in the 1980s or earlier. They have missed the substantial progress that the dedicated doctors, nurses, engineers, chemists, microbiologists, biostatisticians, nutritionists and others at the FDA have achieved over the past several years. They would have us ignore the important lessons that we have learned about the kinds of change that will result in getting safe and effective drugs and devices to the market more quickly. Those who fail to recognize the Agency's performance and achievements threaten -- intentionally or not -- to undermine the real progress the Agency has made. Undermining progress in critical public health and consumer protection is not 'reform.'"

Dr. Kessler pointed out that according to a study by the General Accounting Office (GAO), the average time for approval of new drug applications was 33 months for applications submitted in 1987, but reduced to 19 months for those submitted in 1992. This, he noted, was largely due to user fees for prescription drug approvals -- a system created by Congress in 1992, with the approval of the pharmaceutical industry. Under this system, companies pay to have their applications processed by the FDA -- which uses the money to increase staff and other resources to get the applications handled more quickly. This system included performance goals for the FDA, which has already met the 1997 goal for reduced review time, three years ahead of schedule.

Kessler cited extensive comparisons between drug approval times in the U.S., the UK, Germany, and Japan -- making a strong case that the U.S. now has the fastest drug approvals of the four.

But Dr. Kessler was concerned about the requirement of S. 1477 that by July 1998 the FDA would review all drug approval applications within 180 days, and priority drugs within 120 days. "I do not believe that the Agency could meet the product review times set forth in S. 1477, with existing resources, without compromising existing public health protection...

"What does it take to review an application within four to six months? First, it takes an excellent application. With only four to six months there would be little opportunity to obtain clarifications or additional information from the sponsor. Although every application could be reviewed exactly as it is submitted, very few applications are so complete and accurately presented as to be approvable without further discussion with the sponsor. Second, it requires having the necessary review staff, including all the various disciplines, ready to work on the application the day it comes in the door. That means other work needs to be put on hold. Third, it means companies will need to be fully ready to manufacture the drug... Fourth, the shortened review times will compromise the effectiveness of advisory committees...

"Under the S. 1477 timeframes, the Agency also would be required to limit its involvement in the production and post-approval areas... In fiscal 1995, there were 251 product recalls."

"Shortening the review times also will adversely impact Agency programs that are NOT related to drugs or other product approval process, such as the safety of the blood supply, food safety and tampering, and mammography quality. Our efforts to protect the public from unsafe imported products -- whether it is botulism-contaminated mushrooms or hepatitis-contaminated human tissue, will have to be curtailed. It will also severely curtail our ability to respond appropriately to emerging public health threats, crises, or even to new areas where a little work would have a large payoff."

Kessler outlined many other concerns:

"There are several sections of the bill that would establish new and lower product approval standards. For example, Section 407 would establish a new process for approving new uses of existing drugs that would completely bypass the drug approval process. It would establish a procedure for recognizing new uses based on medical practice... This provision moves us away from the accepted scientific standard of evidence back toward evidence based solely on anecdotal experience..."

"We are also concerned that the bill would eliminate FDA's role in assuring that modifications made to a product do not adversely affect its safety and effectiveness. Under the bill, unless the manufacturer's own data show that safety and effectiveness were to diminish, FDA could not require data on the modified product (Sections 702 and 707). Yet we know that such modifications can carry initially unrecognized risk..."

"We are equally concerned that the bill would remove even the basic assurance that most new devices will be well made. Under Section 702 a company, even one with known manufacturing problems directly relevant to its new device, would have to be given marketing approval even though the Agency has evidence the firm is unable to produce a quality product..."

"There are a number of provisions throughout the bill which would allow companies to market products without FDA approval, if the Agency fails to meet review deadlines..."

"The bill's requirement for third party review is equally troubling... FDA's scientists and experts are charged with exercising independent and unbiased judgment. They comply with stringent financial disclosure and conflict of interest requirements designed to protect the decision-making process against bias. It is not clear whether, and how, this independence can be maintained with private sector review organizations...

"The substitution of judgment also extends to the manufacturing area. When a contractor has given a manufacturer good marks for its production process, FDA is prohibited from inspecting the plant for two years unless the Agency learns through other means that there is something seriously wrong at the plant."

Other concerns involve expanded access -- now available through FDA regulations, which would be legislated instead, beyond the FDA's control:

"Unfortunately, S. 1477 (Section 202) would permit drug and device companies to side-step completely FDA's approval process and go into the manufacture, promotion, and sales of a product for any serious disease or condition without FDA approval. Under S. 1477's provisions, expanded access protocols could be given for any product that diagnoses, monitors, or treats a serious disease or condition, so long as other therapy is not 'comparable or satisfactory.'

"In addition, S. 1477 would permit the manufacturer to widely promote the availability of the expanded-access protocol (Section 202). Unlike FDA's current system for cost recovery under a treatment IND, there is no requirement in the bill that adequate enrollment be obtained for clinical trials that are designed to determine the safety and effectiveness of the product, and that the manufacturer pursue marketing approval with due diligence. In short, the patient would have to pay full price for an experimental product, and the company would be under no obligation to ever find out its true value. Coupled with the provision for cost recovery, promotion of the availability of experimental treatments would create a climate where the unscrupulous could sell untested hope with scant risk of being found out and only weak sanctions if they were. The 1995 Health and Human Services Inspector General's review of commercialization of unapproved medical devices shows this is not just a theoretical risk but a predatory business practice hard to control even with today's stronger law."

Off Label Drug Information

Major controversy exists about whether pharmaceutical companies should be allowed to promote "off label" uses of approved drugs -- that is, uses which have not specifically been approved by the FDA. The FDA realizes that off label drug uses can be appropriate and beneficial. But at present, a pharmaceutical salesperson cannot give a physician a peer-reviewed journal article about an unapproved use of the company's product, unless the physician asks for it.

Kessler did not address this issue, but left it to William B. Schultz, Deputy Commissioner for Policy, to present the FDA's position to the Senate Committee on Labor and Human Resources, on February 22, 1996. Schultz described a number of cases where allowing companies to promote off label uses would have led to serious harm.

We have not seen a similarly detailed case in favor of changing the current law. Such a document is needed, because this issue requires a judgment call. The examples cited by Schultz must be balanced against the damage caused by poorly informed physicians who do not read the literature or who find it safer for their careers to avoid initiative, and provide poor treatment to patients when better treatment is possible.

Schultz also described major FDA initiatives to reverse certain problems at the FDA in the past, and make it much easier for companies to get new indications onto the label. He noted that many off label uses could be approved with no new clinical trials, if companies would just copy existing data and submit them to the FDA. And the FDA is now working with leading physicians to identify the most important off label uses, in order to work with companies to get them approved.

Comment

Our goal in reporting the controversy about Congressionally-mandated FDA reform has been to expose our readers to leading advocates of both sides, and to the complexity of the issue. Those who work seriously in this area will need to study and listen to differing views. So far the custom has been to hear one side, and demonize the other.

The remarkably articulate and compelling arguments on both sides are only a beginning to understanding in this area. On closer look, both leave much to be desired. Hutt addresses easy issues of the current legislation. Kessler addresses hard ones, but questions remain.

For example, it could be argued that a "climate where the unscrupulous could sell untested hope" might ultimately save many more lives than the climate we have. For excluding "untested hope" has also largely excluded all contributions except from big business -- shutting out small companies, which are often the most creative, but which have to sell out to the big ones. (It is no accident that the driving force behind the current FDA-reform legislation is the medical-device industry, largely consisting of entrepreneurial companies far smaller than the huge corporations of the pharmaceutical industry.)

And also largely excluded is every medical tradition on Earth except for one -- the one which has developed only in the last several decades but has used its money to dominate Western institutions, especially in the U.S. This dominant tradition is increasingly based on formal evidence -- perhaps a major advantage -- but also it is notably crude, inefficient, narrow, and cruel in its methods of gaining knowledge. A better public policy might be to open the door somewhat wider, trusting more in the judgment of patients and physicians, judgment which of course includes formal evidence when available, but also includes other evidence not formalized yet. Yes, quacks will use the opening; but nothing eliminates quackery faster than treatments that really work. And it is preposterous to think that the best way to find treatments that work is to eliminate all of the human race except for the narrowest elites from any real role in medical development.

The most central issue, we believe -- beyond anything Congress does this year -- is how to make medical research and drug development work better. We fear that neither side in the politically charged debate has a useful answer. For decades, an FDA controlled by Democrats in Congress piled rule upon rule in the name of public safety, oblivious both to financial costs, and to the human costs of research stagnation. Now Republicans control Congress, and industry believes its day is here, and wants its reward. Both ideologies are a disservice to the public.

Perhaps the best we can hope for immediately is what has already been happening so far -- no new law, but the FDA so afraid of one that it does more than seemed possible to improve itself from within.

We believe that the key bottleneck in medical research is the difficulty of obtaining the first credible data in human testing of a new idea or approach. Senator Kassebaum's office chose NOT to address this issue in S. 1477 -- probably because the most visible proposal for doing so (letting institutional review boards bypass the FDA and approve human trials) clearly has drawbacks. No one knows how to balance safety and progress at the edge of creativity and the unknown. Perhaps there is no systematic way.

The current debate has been productive in stimulating FDA reform. It could be equally valuable if it shakes official Washington out of its traditional ignorance and disinterest in the obstacles to medical progress, and the opportunities to do better.

For More Information

* Anyone can get current copies of this (and other) current Federal legislation through the World Wide Web, at address http://thomas.loc.gov/. Search for bill numbers s1477 and hr3199. There is no charge for using this service, which is provided by the Library of Congress.

* The text of the testimony by Dr. Kessler and Mr. Schultz is available from the FDA Office of AIDS and Special Health Issues, 301/443-0104, fax 301/443-4555. On the World Wide Web, Dr. Kessler's talk is at http://www.fda.gov/ola/nktest.html. Also note the FDA home page, http://www.fda.gov.

* The Log Cabin Republicans, a gay political organization, is supportive of both S. 1477 and H.R. 3199; their views are often close to those of Peter Hutt. They can be reached at 202/347-5306.

* Most AIDS organizations which have a position are opposed to both bills. One source of information on the opposition is the Patients' Coalition; call Derek Link 212/337-3502. This association of health groups has many concerns. Link sees the bills primarily as privatization -- allowing private companies to do inspection and other work now done by FDA staff.

* AIDS Action Council is working on this issue and is opposing both the bills. Press can contact Joe Zuniga 202/986-1300, x3042. Others can contact Scott Sanders at the American Foundation for AIDS Research, 202/331-8600.