A Must Read On Actions and Concerns of the FDA

Date: Sat, 19 Feb 2000 05:52:29 -0600

"If a murderer kills you, it’s homicide," says an ad paid for by opponents of the Food & Drug Administration. "If a drunk driver kills you, it’s manslaughter. If the FDA kills you, it’s just being cautious." Another critic of the Administration describes commissioner David Kessler as the FDA’s answer to J. Edgar Hoover. Newt Gingrich says the agency is "the leading job killer in America" and that Kessler, the bespectacled bureaucrat appointed by George Bush, is "a thug and a bully."

With Republicans in Washington on the rampage over regulatory excess, the Food & Drug Administration may be the most reviled symbol of big government. Joining the Washington Legal Foundation, which created the ads that branded FDA a killer, are other stalwarts of conservatism such as The Cato Institute, Citizens for a Sound Economy, the American Heritage Foundation and the Progress and Freedom Foundation. Their charges include over-caution, capriciousness, and the pursuit of costly vendettas against those who speak out against its bureaucratic bullying.

"The fact is that the problem with health care in America is the FDA," asserts Daniel Popeo, chairman of the Washington Legal Foundation. "To the FDA it’s all just a numbers game; to the rest of America it’s life and death."

Interestingly, however, the giant pharmaceutical companies, medical device manufacturers and biotech entrepreneurs who are among the alleged victims of the FDA’s over-caution have been more muted in joining the chorus of criticism. Cynics may suggest that these companies fear FDA retaliation, in the form of even greater delays in the approval process, or even that big companies enjoy the status quo, which makes life much more difficult for upstart competitors, but the reality is that most members of the business community recognize the benefits that the FDA has wrought as well as its excesses.

And most believe that the most important FDA reforms would be cultural, rather than legislative.

Typical is Alan Magazine, president of the Health Industry Manufacturers’ Association, whose members - the makers of medical devices - have been the most critical of problems with the FDA: "It’s in the best interests of the American public and of patients and of our industry to have a strong, reliable FDA," he says. "The hallmark of real reform is to look carefully at the institution you’re dealing with and articulate a mission, a direction, a responsibility. That kind of analysis doesn’t lend itself to sound bites. When we talk about reform, we’ve got to be responsible, and we’ve got to put patients first."

Even so, there are some powerful voices pushing for reform, led by Gingrich and a handful of House Republicans and supported by Washington revitalized conservative think tanks, who have been supplying the ammunition for the political attacks and in the case of the Washington Legal Foundation taking the case to the public via a multimedia advertising campaign.

The most strident complaints have been those regarding delays in getting life-saving medications to market. Critics claim that:

• more than 20,000 people died between 1985 and 1987 waiting for streptokinase, the first drug that could be intravenously administered to reopen the blocked coronary arteries of heart attack victims;

• 7,000 people die every year because the FDA has not approved the Ambu CardioPump, a CPR device widely available in other industrialized nations;

• and between 1988 and 1992, about 3,500 kidney cancer patients died waiting for Interleukin-2, which was available in several European countries.

On this issues, conservatives have recruited some unlikely allies, including AIDS activist James Driscoll, vice president of Direct Action Treatment Access of San Francisco. "Delays in approving heart drugs, cancer drugs, AIDS drugs and life-saving devices have contributed to tens of thousands of deaths," Driscoll claims. "Drugs for rare diseases remain mere concepts because the FDA makes their development prohibitively expensive. Even major breakthroughs can be delayed for years by FDA red tape.

"Congress has tolerated FDA delay because its dangers are difficult to quantify. Patients usually don’t know about the unapproved drug or device that could save their lives. Few people grasp the complexities of drug development. Few politicians bother to evaluate carefully either the FDA’s priorities or the human cost of regulatory delays."

Another focus of FDA critics is the impact of these delays on the viability of U.S. companies. The lengthy trial and review process the agency requires ads considerably to the cost of drugs in this country, they say (though exact numbers are hard to come by) and some FDA rules - specifically one that prevents U.S. companies whose products have not yet been approved from exporting those products - are driving device manufacturers and pharmaceutical companies overseas.

"Delays in clearance are crippling companies, and it seems like reviewers have reached a new level of irrelevant detail in their questions," says Norman Estrin, president of Estrin Consulting Group, which helps companies in their dealings with the agency. "Inconsistencies among reviewers are another continuing problem. FDA’s premarket submission procedures have become so complex, confusing and time consuming that U.S. manufacturers are becoming less competitive worldwide."

Equally troubling to FDA watchers is the agency’s open hostility to business, reflected in Kessler’s increased emphasis on enforcement activities, and the zeal with which is pursues companies that challenge its authority. (Several sources contacted for this story declined to be interviewed for fear that the FDA might retaliate by delaying new drug approvals.) Some of these fears appear well-founded.

In 1989, for example, Edwin Cohen, president of Barr Laboratories, testified before a Congressional subcommittee that the FDA was guilty of "retroactive decision making, shifting standards, procedural and substantive leaks, favoritism by reviewers, high-handed and arrogant treatment." Shortly thereafter, FDA inspectors visited Barr’s facilities (the company had been under investigation as part of the generic drug scandal of the late-’80s) and the company was found to have committed numerous inspection violations.

Says Herbert Burkholz, author of the 1994 book The FDA Follies, which recounts that incident: "In matters of compliance, the FDA is supreme. If the agency says that the floor of your plant is dirty, then you’d better grab a mop and broom, even if you know that it’s pristine clean, because no court in the country will take your side."

Another company that challenged the FDA’s capriciousness, with more success, is RS Medical, which manufactures muscle stimulators. After it made minor modifications to its products, the FDA attempted to rescind its approval. RS Medical took the matter to court and the FDA agreed to let it continue marketing the products while its new application was reviewed. So RS Medical submitted its application for the revised products - twice. One application was made in its own name; another, identical application was made in the name of a consulting firm.

The consulting firm’s application, made one month after RS Medical's, was approved within four months, with the agency finding that the products were substantially similar to others already on the market. The FDA did not rule on RS Medical’s application for a full year, and then found that its devices were not substantially similar to products already on the market. RS Medical again went to court, where a judge found "glaring evidence of arbitrary action" at the FDA and issued an injunction.

Finally, there have been on-going questions regarding the FDA’s regulation of what companies may and may not claim for their products.This debate has focused in several areas: the dividing line, if any, between promotional information and educational information; the alleged dangers of direct-to-consumer advertising of prescription drugs; and the ability to promote new, unapproved uses for drugs that have already been found safe and effective for a specific condition.

There is nothing especially new about the current criticisms of the FDA, except perhaps their vehemence. Many pharmaceutical companies and some conservatives have suggested over the years that delays in approving products drive up drug development prices and that consumers suffer because they are denied access to life-saving devices available overseas. The charges predated the arrival of Dr. Kessler, but there can be little doubt that his activist agenda - food labeling regulations, the attack on breast implants, and the threat that tobacco might be reclassified as a drug - has put the agency in the crosshairs of the conservative movement.

Most observers trace the FDA’s current culture back to the thalidomide tragedy of the early-’60s. Thalidomide, a sedative that caused thousands of birth defects in Europe, was kept off the market in the U.S. by the FDA, but the European experience spurred Congress to pass the Kefauver-Harris Amendments to the Food Drug & Cosmetics Act, requiring that the FDA test drugs for efficacy as well as safety.

"Even then, FDA was just a massive bureaucracy," says one corporate public relations professional. "There’s this huge mythology surrounding Dr. Frances Kelsey [who held up thalidomide’s approval with safety questions] but the reality is that the delays in approving thalidomide had more to do with inefficiency than with sharp scientific analysis. And that’s the kind of approach FDA has celebrated ever since. Everybody wants to be known as the next Dr. Kelsey. No one wants to be known as the quickest in getting a new product to market."

"Congress blamed the FDA for mistaken approvals, and the agency made preventing new thalidomides its top priority," says AIDS activist Driscoll, less diplomatically. "Through scare tactics and deception, the FDA sold the public on this priority. To prevent a minor threat to public health, the FDA created a major health tragedy: needless deaths and suffering caused by delaying useful medicine."

In 1976, after the Dalkon Shield debacle, Congress passed the Medical Device Amendments, extending the same broad approval requirements to medical devices. The Safe Medical Devices Act of 1992, passed after problems involving defective heart valves and silicone breast implants, expanded the earlier efforts. This historical perspective is important, says Wayne Pines, a former director of consumer education at the FDA and now executive vp at Washington public affairs firm APCO Associates, because it provides a clue as to the culture at FDA: "There is a feeling at FDA that in the past they were underfunded and overworked and companies would try to slip things past them. There were, obviously, episodes in which companies submitted false or incomplete data or just flat-out lied to the FDA, and that has made the agency suspicious of business as a whole."

Current proposals for FDA reform range from the moderate to the extreme, from "semiprivitazation" of the drug approval process to allowing drugs on to market without any independent safety review.

The Health Industry Manufacturers Association has been working on a plan that would channel some reviews through private, government- certified labs. The Progress & Freedom Foundation, meanwhile, would prefer to replace the FDA with an agency that would put industry executives in charge of the approval process. And the Competitive Enterprise Institute suggests the FDA’s power to decide what comes to market should be diluted, to become one of certification.

"The agency’s safety and efficacy standards would remain as they are," explains CEI general counsel Sam Kazman. "However, rather than being banned outright drugs and devices that didn’t meet FDA standards would be available under professional supervision (still by prescription), with a clear warning of their unapproved status."

A hint of what the Republican majority has in mind came in a speech by House speaker Newt Gingrich to the Biotechnology Industry Organization in May. He called for streamlining of the clinical trial process by making the system "scientifically-driven not lawyer-driven, not bureaucrat-driven." He said the recent decision not to approve funds for the construction of a new FDA campus was an indication that significant changes were pending. "That was... designed to send a signal that we were really serious about creating a much thinner, smaller FDA and going to a much different market-oriented information- age model of regulation."

The FDA, meanwhile, has been mounting a spirited defense of its record. It has responded to specific criticisms - such as those concerning unapproved medical devices and drugs - by pointing out that in each case there are unanswered questions as to whether the new products offer any significant advantages over products already on the market, and in some cases there are serious safety concerns. Moreover, the agency says, many of the problems its critics have cited have already been addressed within the agency.

Between 1970 and 1989, the FDA approval process took between two and three years, says deputy commissioner William Schultz. In those years, he acknowledges, FDA typically took one or two years longer than the fastest European countries to bring a new drug to market. But he does not believe that patients were denied life-saving drugs.

"The reason is that years ago the agency adopted a fast track for breakthrough drugs, drugs that treat diseases for which there is no other treatment, or that have significant advantages over the drugs already on the market," says Schultz. As an example, he points to AZT, the Burroughs-Welcome drug for the treatment of AIDS, which was reviewed and approved in three and a half months. "Today, AIDS and cancer drugs for which adequate data are presented are typically reviewed and approved in a year or less, sometimes much less."

That point is supported by Pines, who says that most of the clients with whom he works have no complaints about the speed with which FDA reviews medically important products, although he says the agency still fails to recognize the equal importance of speeding up reviews of what he calls commercially important products, new treatments in which companies have invested significant research and development dollars.

Moreover, in 1992 Congress passed the bipartisan Prescription Drug User Fee Act, which was supported by the pharmaceutical industry and requires drug companies to pay application fees that the FDA uses to hire additional reviewers. Under that legislation, the FDA committed to review 90% of drug applications within 12 months, and 90% of all medically important drugs within six months by the year 1997. Schultz claims the agency is "well on its way to meeting these commitments."

"The user fee program is changing the culture at the agency," Schultz says. "Drug review deadlines, though ambitious, are realistic, and reviewers are beginning to get the resources they need. As a result, the U.S. drug review process will, by 1997, be as fast as that of any country in the world, and this will be accomplished without diminishing the public health protections the FDA has traditionally maintained."

Consumer advocates appear conflicted, despite the outspoken criticisms of some patient advocates like James Dricsoll. But while many have been critical of the FDA and expressed concern about delays in bringing life- saving products to market, they fear that relaxing safety requirements or allowing the industry to police itself would lead to a proliferation of hazardous products. Says Sidney Wolfe of Public Citizen Health Research Group: "Any attempt to weaken the regulatory safety net will meet with a significant amount of opposition."

That opposition may come from the corporate sector too. To a large extent, the strident tone of some of the think tank criticisms of FDA has backfired, forcing industry to come to the agency’s defense and making genuine reform less likely. "I think that in general a lot of the FDA reform debate has been ignorant and emotional and has failed to get at the heart of what really needs to be done," says APCO’s Wayne Pines. "That ignorance plays directly into the hands of the opponents of reform."

"FDA must maintain high safety standards," says Steve Berchem, spokesman for the Pharmaceutical Research & Manufacturers Association. "We are not suggesting that the FDA should lower its efficacy standards but what we are saying is that there are ways to speed up reviews. FDA’s objective should be the same as ours: to get prescription drugs to the American public as quickly as possible."

Carl Feldbaum, president of the Biotechnology Industry Organization agrees. His members, he says, are not interested in lowering efficacy standards. "We don’t want to be seen as Philistines. Our industry thinks that the FDA needs to be a credible and independent agency in which the public has a great deal of confidence."

Steve Grossman, a senior vice president in the Washington office of Hill & Knowlton and a veteran of the Department of Health & Human Services, says that business support of the FDA owes itself to a variety of impulses. There is a reluctance to criticize an agency that has considerable power to slow the progress of products to market, and there is a recognition that while the status quo is far from ideal, it is at least a system most major pharmaceutical companies have mastered.

"The most important thing, as far as business is concerned, is predictability," Grossman says. "I think the pharmaceutical industry is torn between wanting a much quicker, easier approval process and recognizing that the current system is one they have mastered. Philosophically, I suspect, many business executives would like to see modest or perhaps even dramatic reform at the FDA, but most business executives are pragmatists."

Ultimately, both Pines and Grossman predict, the only legislation that will pass will be consensus legislation, and the FDA itself will have to be a part of that consensus. "This is a very powerful agency, and it has a great deal of credibility with the public, and it is going to be very difficult to impose a solution without the FDA’s participation in the process," Pines says.

Typical of the more moderate approach is the process by which biotechnology companies, regulators and Congressional oversight bodies are seeking to streamline the approval process for new biotech products.

At recent hearings on the subject Nancy Kassebaum (R-Kan.), chairwoman of the Senate Labor and Human Relations Committee, did not make any of the highly-charged criticisms of the FDA that have been lodged by some of her colleagues, but rather focused her comments on cultural changes. Kassebaum’s committee is expected to frame much more moderate reform proposals than those suggested by some House members, especially since Kassebaum has a long-standing collaborative relationship with ranking committee Democrat Ted Kennedy.

The most compelling testimony the committee heard came from former FDA commissioner Charles Edwards, now with the Scripps Research Institute. Edwards urged the committee to keep the FDA "strong, and give it the resources to do its job," but not to permit the agency to "stray beyond its core duties."Addressing the agency’s anti-business culture, Edwards suggested it was "a reflection of the guy at the top. If the attitude at the top is that industry is the enemy, then that goes down through the ranks.

"FDA’s paternalistic tendency in recent years is more than bad policy. It is also bad management, because it diverts limited resources from key tasks such as drug and device approvals. We could accelerate the drug approval process by eliminating the long-standing requirement that new drugs be proven safe and effective before they are marketed, but we would be treating a symptom - the slow review process - rather than the real problem, which is poor management."

Similarly, at a recent Commerce Oversight and Investigations subcommittee hearing, there was evidence of an emerging consensus. Chairman Joe Barton (R-Tex.) opined that the FDA should rule on whether the product is "safe, pure and packaged safely" but not about efficacy, which would be corrected by the market; Amgen president Gordon Binder suggested several improvements in the approval process - including the use of private reviewers - while stressing that the company supported the retention of current safety and efficacy standards; and the FDA’s William Schultz made it clear that he felt the FDA had made significant progress, but he acknowledged merit in many of the industry’s criticisms.

One possibility suggested by Barton was a series of field hearings at the FDA’s headquarters in Rockville, Md., to review the management improvements the agency is implementing, including "quality circles, peer review, computerization and reducing the layers of bureaucracy."

Pines suggests four basic areas in which those who want realistic reforms should be focusing their attention.

First, he says, FDA does not accord the same attention to drugs that are commercially important rather than medically important, and it needs to recognize the investment such drugs represent and the value of encouraging such investment.

Second, the FDA needs to review the amount of proof it requires before approving a particular drug and decide which tests are unnecessary and which can be speeded up, and then to give some structure to the process so that it is more predictable and less dependent on the whims of individual reviewers. Third, the FDA needs to introduce a more user-friendly appeals process and to make it clear to companies that they will not be penalized for pursuing appeals against the agency’s findings.

And fourth, the agency should make itself more accessible to business, making its own experts available to companies when they are designing clinical trials and offering advice on the process as well as evaluation at its conclusion.

"These are all areas in which consensus can be reached and none of them are areas that require legislation," Pines points out. "The fundamental issues facing FDA are not legislative issues, they are administrative issues."

As for the role of Kessler, portrayed by the FDA’s critics as a Satanic figure depriving the American public of much-needed medication, most observers agree that his position at the top of the agency is secure. Hill & Knowlton’s Steve Grossman goes even further, suggesting that however unpalatable the prospect may be, Kessler may be the only one who can accomplish the kind of cultural changes the agency’s critics would like to see.

"If you are going to make real cultural change at the FDA, you need buy in from the staff there, who have a tremendous sense of mission, and that means they have to believe the person leading the change is one of them," Grossman says. "The fact is that David Kessler has the support and loyalty of the people at FDA. He has established his credibility by being tough on enforcement, by demonstrating his commitment to the agency’s mission. He may be uniquely capable of bringing about the kinds of changes that are needed."

Having said that, Pines and others concede that the debate in Congress may be necessary to stimulate the kind of administrative and cultural changes that are necessary. Legislation, in other words, is less important as an end in itself than as a wake-up call to the agency, a reminder that it is under close scrutiny and needs to adapt to a changing environment.