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Linda A. Suydam, D.P.A. - FDLI Conference

Keynote address



Linda A. Suydam, D.P.A.,

Senior Associate Commissioner,

Food and Drug Administration


FDLI Conference on

Advertising and Promotion in the New Millennium

September 13, 1999


Good morning.

The agenda for this event describes today's and tomorrow's program as an "exciting conference," and an exploration "of the world of off-label promotion" after the federal court in the District of Columbia found unconstitutional the statutory provisions in the Food and Drug Modernization Act and FDA's implementing regulations addressing the promotion of off-label uses of drugs and devices.

Normally, we who work for FDA are more than ready to cooperate in making the FDLI conferences exciting, but this time our contribution will have to be circumscribed. All I can say in regards to the District Court decision is that we find it disappointing -- we believe that FDAMA, as we call the Modernization Act, provided a good and workable framework for achieving important and much-needed public health gains in a particularly difficult and controversial area.

We are intensively studying the Court's ruling, but we disagree with it, and we have requested that the Solicitor General of the United States authorize an appeal. The Solicitor General has approved our request, and we are now working with the Department of Justice on the appeal, to be heard by the U.S. Court of Appeals for the District of Columbia. Since the matter is still to be further adjudicated, that's all I -- and my FDA colleagues participating in this conference -- can say about the recent ruling in the case of the Washington Legal Foundation.

Naturally, we respect the court's authority, and therefore we will limit any explanation of our disagreement with that decision to the papers we will file with the only appropriate forum for such a discussion, which is the Court of Appeals. I want to make this clear -- neither my FDA colleagues nor I can provide any further comment on the WLF case or any matter subject to the court's order.

On the same grounds, I see no point in speculating about the future of the relevant FDAMA provisions or of FDA's regulation on off-label promotion. Instead, I will try to accomplish two goals:

First, I want to briefly outline our Commissioner's policy regarding science and scientific evidence, and to discuss some of the reasons for the growing complexity and length of clinical trials.

And second, I'll try to explain FDA's experiences with -- and views about -- off-label uses and drug promotion that we've acquired in the past, and that continue to anchor our policies.

All of these topics, I believe, are germane to the theme of this conference, and -- I hope -- will help place your discussions in a broader and more all-inclusive context.

Let me preface my remarks by noting that FDA has always recognized -- and respected --the limits of its authority in regards to off-label prescribing. I'll return to this subject a little later, but right now I want to make the point that the legislative history of the Federal Food, Drug, and Cosmetic Act shows that Congress did not intend FDA to interfere with the practice of medicine, and FDA -- whose Commissioners typically have been medical doctors, and which has many MDs on its staff -- has never had such a goal.

As for the dissemination of medical information from all sources to health care professionals, our agency generally does not interfere with it. What FDA does care about, and care about deeply, is that off-label prescribing and promotion do not undermine the agency's obligation to protect the public health by pursuing scientific knowledge about the regulated products, and by advancing its dissemination in a truthful and non-misleading fashion.

Those of you who have followed the FDA's past attempts to take the guesswork out of off-label prescribing know that FDA's aim has been, and is, to replace anecdotal evidence with solid scientific data documenting the effects of new uses on patients, and then get that information on the drug labeling. We learned in the past -- and again last month -- that the incentives to encourage this process can be misunderstood or controversial, and we appreciate that on this aspect of the off-label issue, views can differ.

We do, however, firmly hold that scientific evidence is the essential bedrock of FDA's activities and mission. Science and the FDA are synonymous: to undermine FDA's ability to regulate on the basis of scientific facts would be to deprive the agency -- and 93 years of public health protection in this country -- of their relevance.

Our Commissioner, Dr. Jane Henney, feels so strongly about FDA's critical dependence on unbiased and state-of-the-art knowledge that, as one of her first and foremost goals, she has set out to raise the level of the agency's scientific expertise. Since all FDA's decisions, policies and standards are evidence-based, she wants our agency to have the resources and be able to acquire all relevant scientific information that bears on public health issues. She believes that this information must be applied to regulatory decisions, and provided, as needed, to consumers and the industries whose products we regulate. The alternative, as Dr. Henney has pointed out, would have serious consequences for FDA, the health care industry, as well as patients.

If FDA has to set standards on the basis of incomplete information, it could resort to compensating for the uncertainty by requiring more regulation. More regulation raises costs to the agency because of the need to review more data; it imposes additional financial burden on the sponsors, who have to generate the data; and ultimately it increases the price of the product for the consumer. Such chain of events could have a serious effect on America's ability to develop new technologies, undermine our economic progress, rob the public, and detract from the agency's credibility.

Dr. Henney is therefore determined to strengthen FDA's scientific potential -- to increase the agency's ability to anticipate and comprehend new technologies, detect and address their risks, and achieve greater understanding of disease mechanisms and their impact on humans.

Against this background, you will perhaps better understand our concern over any disincentives or objections to the conduct of clinical studies and the process of scientific fact-finding -- a process that has been the backbone of public health protection ever since the early years of this century when Dr. Harvey W. Wiley's "Poison Squad" of brave young men tested the safety of chemical preservatives in food, by eating it. To us at FDA -- and, I believe, to many in the industry -- it is obvious that it is the rigor of our standards and scientific evidence that accounts to a large degree for the enormous economic success of our pharmaceutical firms -- one of the most prosperous industrial sectors of this country -- as well the growing longevity and better health of our population.

As for the complexity of clinical trials, it is an unavoidable -- and, indeed, commendable -- consequence of the intensive search by the scientific community for ways of optimizing the drugs' effectiveness and safety. We're reaping the benefits of medical progress. In the last 15 years or so, the emphasis on pharmacological dose finding has been augmented by a new and growing interest in the evaluation of drugs in important subsets of the total population.

With tens of millions of baby boomers approaching their middle age, and with our seniors rapidly becoming the fastest-growing demographic category, it became obvious that the elderly should not be excluded from clinical trials, and that it is necessary to examine whether their subset responds to and metabolizes medications differently from the rest of the population. FDA addressed this issue in a guideline whose validity has been recognized by the International Harmonization Conference, which in 1993 accepted it for use also in Japan and the 15 countries of the European Union.

The same year, our agency issued similar guidelines that addressed the anomalous exclusion of women from many trials in coronary artery disease and major intervention studies.

In addition to these developments affecting the complexity of clinical trials, there has been in recent years a growing recognition of the importance of individual metabolic differences, and the fact that these could be induced not only by drug-drug reactions, but also smoking and diet. As a result, evaluation of these potentially dangerous interactions has become a critical -- if, perhaps, demanding -- part of the drug development process.

It is also well to remember that while these findings served to make studies lengthier, FDA was taking many steps to help bring new drugs to patients as fast as possible. In the early 1980s, FDA's new "treatment IND" and so-called "parallel track" programs gave thousands of seriously ill patients access to important investigational drugs as soon as there was a reasonable likelihood of benefit.

During the same period, a new mechanism called accelerated approval dramatically reduced the timeframe for marketing of new drugs for the treatment of life-threatening and chronic diseases. For the benefit of the manufacturers, FDA has issued and updated more than 30 drug class clinical guidelines, each describing in detail the study designs and expected data for particular therapeutic classes. More recently, our agency has developed also more broadly applicable documents such as guidelines on the format and content of new drug applications, and on developing dose-response information.

In addition, our reviewers have been meeting with sponsors, particularly when they need to design studies involving new molecular entities and major new uses of marketed drugs. Another helpful source of guidance to drug sponsors has been the frequent meetings of FDA's many advisory committees, whose discussions provide a continuing insight into FDA's views as well as wealth of scientific information. Last but far from least, FDA -- with the help of the drug industry's user fees -- in the past seven years has slashed its median drug review time by more than one one-half, to 12 months.

To cite just a few of the many indicators of the drug industry's robust health under these conditions, in 1997, the U.S. prescription drug market grew 15.3%, with each of the 72 top brands generating at least $500 million in sales, and 27 of them breaking the one billion dollar mark.

The need for adequate and well-controlled clinical studies of new drugs and devices is also evident from the long and largely familiar history of public health setbacks that did not end with the poisoned elixir of sulfanilamide that prompted the passage of the 1938 Federal Food, Drug and Cosmetic Act.

To mention just a few examples, after the world learned about the horror caused in Europe by the inadequately studied thalidomide, Congress passed in 1962 the Kefauver-Harris Drug Amendments that required evidence of effectiveness, and made adequate and well-controlled studies the only acceptable source of evidence. To implement the law, FDA examined the effectiveness of 3,443 prescription drugs already on the market, and found 1,124 of them -- almost one-third -- to be useless.

In 1976, a Senate committee reported that unregulated medical devices had caused 10,000 injuries -- 731 of which were fatal -- in the preceding 10 years. And in recent years, the importance of thorough clinical trials was again brought home during the desperate search for drugs to stem the AIDS epidemic. One example was ddC, the second therapy for AIDS, which was widely used under treatment IND -- as well as illegally produced and sold without restriction by so-called buyers's clubs -- as a hoped-for addition or alternative to AZT. The hopes were buried by trials showing that patients who took ddC as an initial therapy had a death rate at least twice as high as patients on AZT -- although later studies demonstrated that ddC in combination with AZT had superior survival to AZT alone.

Another example from that period that illustrates the vital importance of trials is the use of clarithromycin for treatment of atypical mycobacterial infections collectively known by the acronym MAC. MAC, which is related to tuberculosis, is one of the fatal complications of HIV infection and AIDS. Since clarithromycin, when used in cultures, was found to be one of the most effective drugs against MAC, it was prescribed for patients in high doses without waiting for the results of several clinical trials. The trials demonstrated the fallacy of that treatment. Contrary to the in-vitro experience, the use of high doses of clarithromycin resulted in high mortality -- while at a lower dose, the drug was life-extending.

The need for clinical studies and FDA review of their evidence is most convincingly documented by the many hazards associated with off-label prescribing -- a widespread practice to which physicians resort in the absence of dependable guidance on approved product labeling. As I have suggested a few minutes ago, at FDA we consider off-label prescribing to a certain extent to be appropriate, although we're also mindful of its risks.

Physicians prescribe off-label primarily in two situations: First, many drugs are approved for only one use, even if they belong to a class of drugs whose other members are approved for several indications. In these cases, physicians may assume that all members of the drug class will behave similarly, and prescribe them interchangeably. This assumption, however, may be very risky, because all members of a drug class do not behave identically. The second main reason for off-label prescribing is that many drugs are developed and marketed first for a narrow purpose -- either for the most seriously ill patients, or for the most important, though not most common, potential use.

This is both medically and economically rational practice: it makes sense to study the most needed use of the drug first; in addition, showing a benefit in less ill patients may be more difficult and costly, because it may require longer study and larger number of patients. Many oncologic drugs, for example, are first studied in treatment of refractory tumors, which makes the initial studies often small and relatively simple.

As a general policy, FDA has not opposed legitimate approvals for a narrow product use, even if it had a potentially greater use. This is because we recognize that larger studies can be carried out later, and the findings can be added to the drug labeling after FDA's review and approval of a supplemental submission. Unfortunately, it has been our experience in the past that even important drugs continued to lack the supplemental labeling while less-well documented reports helped promote unapproved uses, sometimes with tragic consequences. One example was the use of the drugs encainide and flecainide, which were approved by FDA only for life-threatening and symptomatic arrhythmias, with a labeled warning that their use in people with recent heart attack had not been studied.

In the late 1980s, physicians began to prescribe these two medicines to prevent increased mortality of heart attack victims who had a high level of ventricular premature complexes. This was an unstudied and unapproved use that was supported in some published peer-reviewed journal articles, but after its value began to be questioned, the National Institutes of Health subjected the treatment to clinical testing. The results showed that the death rate of patients receiving the two drugs was more than twice the rate of patients on placebo.

Another example involves the widespread off-label use of calcium channel blockers, or CCBs. These drugs are effective for patients suffering from angina or hypertension, but have no established role in patients who have had a heart attack but have no symptoms. These symptom-less patients, however, do benefit from another class of drugs, beta-blockers, which reduce mortality after heart attacks by up to 30 percent. In the absence of appropriate labeling, CCBs are widely used off-label in post-heart attack patients who do not benefit from them and in fact need beta-blockers -- and there are publications that can be interpreted as supporting this ineffective use. In many cases, use of CCBs actually prevents the use of beta blockers, because the two drugs generally should not be used together. The resulting failure to use beta blockers probably costs thousands of lives each year.

The third and last example I want to mention is the fentanyl patch, a product that was approved for use against chronic pain, but not for acute post-operative pain because of concern that it would cause respiratory depression. Prior to FDA's approval, however, a number of publications described the patch as safe and effective for post-operative pain, apparently not without effect. After the patch became available, we have received, and read in professional literature, reports of post-operative patients who were prescribed the patch off-label, and suffered life-threatening respiratory depression.

I have spent some time on this overview of FDA's experience with off-label prescribing not to criticize the practice, which -- as I have suggested -- FDA recognizes as potentially useful. Rather, I wanted to remind you that unstudied treatment can be worst than useless, and to help explain the agency's long-standing wariness about the dissemination of off-label information by the regulated industry. This is an extremely difficult issue because it occupies the highly sensitive area where our deep respect for the First Amendment meets our equally profound dedication to the protection of the public health. I am not suggesting that these are competing loyalties, because we have never intended to limit anyone's right to know.

Physicians always have had access to information about off-label uses through compendia, journal articles, textbooks, independent symposia, and professional meetings. They have access to data bases that provide information about unapproved uses. FDA has not attempted to regulate a physician's use of any of these types of independent off-label information, regardless how preliminary it may be. And FDA has not prohibited a manufacturer from providing a medical doctor with off-label information that he or she requested. Drug companies have been free to distribute independent reference texts even if they contain certain information about off-label uses of approved products, as long as the texts do not have a significant focus on an off-label use of a product manufactured by the firm that disseminates, or supports the dissemination, of the text.

Far from blocking the flow of reliable information, FDA's historic policy has been to encourage firms to submit scientific evidence about the new use in a supplemental application, with the aim of getting the approved data on the label, where they can do the most good. As has been the case with many other FDA procedures, the agency has taken steps to simplify and accelerate the process by which the sponsor can secure the review, approval and labeling of a new use.

Some off-label uses can be approved by the agency on the strength of a submission that includes mere compilation of existing literature. Others may require only limited data or data about the studies, such as protocols, data tapes, or verification of endpoints, all of which merely need to be copied and submitted to the agency. And FDA has stressed that the benefits of including reliable prescribing information in the product labeling go well beyond the company's ability to promote it to physicians.

Approved labeling helps to get the new use included in formularies. It ensures the patient's reimbursement from third party payors. It can be presented to regulatory authorities in other countries, thereby strengthening the sponsor's application for their approval abroad. And most important of all, it gives the medical community more complete, carefully reviewed information about the product.

In contrast, FDA believes that allowing off-label promotion would negate all of these advantages by sending a strong signal that the safety-and-effectiveness evidence is not necessary. This position predates FDAMA. The legislative history of the Kefauver-Harris Drug Amendments of 1962 reflects the congressional awareness that the ability to promote off-label uses would lessen the manufacturer's incentive to marshal the new evidence of effectiveness and submit it for supplemental labeling.

While debating that bill, a group of Senators, lead by Senator Estes Kefauver, argued that unless the effectiveness requirement was added to the definition of drugs, "the expectation would be that the initial claim would tend to be quite limited, which, of course, would expedite approval of the new drug application. Thereafter, 'the sky would be the limit,' and extreme claims of any kind could be made."

The Senators' concern, as we all know, was not idle. As for the peer review process, we also continue to be concerned that it is no guarantee that the readers receive rigorously accurate and unbiased information. One reason is the fact that the peer reviewer's sources of information about the issue usually are quite limited. For instance, the peer reviewers almost never receive the study protocol: they cannot tell what the initial hypothesis was, or whether the final analysis represents what was originally planned, or whether it is an analysis drawn up with the results in hand. In fact, the main purpose of the peer review process in most cases is to merely determine if an article is worthy of publication.

At its best, peer review can ensure that the reader is provided with enough detail and clarity to make a general judgment about the strengths and weaknesses of the study. It is no substitute for the rigorously examined, truthful and non-misleading labeling information that results from FDA's review.

And this brings me to my last topic today -- FDA's responsibility for the provision of truthful and non-misleading medical product information to consumers, who are increasingly targeted by direct advertising. As most of you undoubtedly know, direct-to-consumer advertising -- DTC -- has undergone a phenomenal growth in this decade, when it began focusing on mass media -- including television and radio -- in addition to direct mail. By 1994, for example, more than 40 prescription drugs had been advertised to consumers, and the year's expenditures for this promotion was $308 million. In comparison, the corresponding figure in 1987 was just $35 million. By now, more than 100 prescription drugs have received DTC promotion -- more than 30 of them are currently advertised on TV and radio -- and the annual spending on this activity exceeds $1 billion.

As you also know, FDA has not been inimical to this phenomenon, and regarded it through the prism of the consumers' need for drug information, and the industry's legitimate interest in disseminating it. In 1985, after examining the practice, FDA lifted a voluntary moratorium on DTC advertising and declared itself satisfied that the then-existing regulations provided "sufficient safeguards to protect consumers." In August 1997, our agency dramatically improved the advertisers' ability to promote drugs DTC on television and radio, by proposing a draft guidance with four relatively simple provisions for ensuring consumers' access to the advertised product's approved labeling. And last month, this proposed guidance was finalized essentially intact, and FDA announced that it will remain in force for at least another two years, when our agency will evaluate the effects of DTC promotion on public health.

I am not going to take your time going over the DTC final guidance, whose provisions are well known and, moreover, will be discussed this afternoon. What I do want to strongly emphasize is FDA's dominant concern in regulating DTC, which is the agency's duty to protect consumers against drug information that is less than truthful, unbiased, and non-misleading.

Earlier in my remarks, I went into some detail to describe FDA's dedication to science, and our agency's determined efforts to enhance activities that result in scientific findings. That is one principal pillar of our endeavor to protect the public health. The other pillar of that same mission is to help ensure that these scientific facts are disseminated to those who need them truthfully, understandably, and without deception.

The pursuit of scientific truth in the service of the public is not a new FDA cause -- indeed, our agency has been dedicated to its throughout its history. Moreover, the principle has been frequently re-invigorated by Congress. The most recent example is the FDA Modernization Act, which was passed after an extensive, two year-long congressional examination of FDA's mission and practices. That law's Section 406(b), which lays down a blueprint for FDA's future, requires the agency -- among other obligations -- to ensure that it has access to the necessary scientific and technical expertise, and to maximize the availability and clarity of information about FDA's processes and regulated products.

When we asked our stakeholders in a series of large public meetings what were the foremost goals they wanted the agency to accomplish, the top measures they endorsed included the strengthening of FDA's scientific and analytical basis for regulatory decisions. In addition, consumer and patient groups strongly emphasized their need for prompt, complete, understandable, and unbiased information about products that FDA regulates, particularly new therapies. Their point was that well-informed consumers are more effective contributors to the management of their own health risks. And last spring, that proposition was echoed in the findings of FDA's task force on risk management, one of Dr. Henney's first initiatives after she was sworn in as the new Commissioner.

The task force of FDA's Centers directors concluded that while the sponsors and FDA are responsible for the product's performance before its approval, once the drug or medical device reached the market, the risk management is shared by the prescribers and the users. It is the patients who take the risk of using the drug, and it is completely unacceptable that they should be assuming that risk on the basis of deceptive promotion.

I said in the beginning that there is no point in speculating about the future of the off-label promotion of medical products to physicians because the WLF case is still pending. But after my fairly full examination of concerns and pitfalls involved in the practice, I want to transgress my own injunction by suggesting that we need to view the current controversy in a long-range perspective.

Anyone who examines the history of public health protection in our country inevitably will find it encouraging. The government, consumer, academic and industrial participants in this very complex and difficult process on the whole have acted with intelligence, imagination, and flexibility, and the results of their efforts have been overwhelmingly positive. Granted that from time to time, there have been setbacks, the recent court decision included.

But we at FDA have no doubt that in the long run, the public health interests will prevail, and the progress that our agency has helped advance for the past 93 year years, will continue.