Vioxx and the FDA Advisory Committees: Yesterday, Today, and the Search for Tomorrow

Amid a cacophony of wailing and gnashing of teeth decrying the Food and Drug Administration's (“FDA's”) failure to protect the public from unsafe drugs, the FDA held an emergency advisory committee meeting, which included consultants, to address the safety issues associated with the use of COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (“NAIDs”). The meeting was scheduled and held at warp speed. It provided a transparent dispassionate opportunity to address the safety issues for scientists, affected parties and the public. The decisions of the advisory committee were to some extent, unexpected. This accelerated review process differs from the current advisory committee process of reviewing limited data in a product pre-approval setting. However, this use is a natural extension of the FDA's historic use of advisory committees, ie, analysis of voluminous data on any active ingredient over a period of years and application of the analysis to specific drug products containing the active ingredient.

For marketed drug products, the FDA has traditionally acted unilaterally when the risk/benefit calculation for drug approval has been undermined. Today, as the agency's credibility in protecting the public is coming under repeated attack, the advisory committee meeting is providing a variant approach that is another step in the growing importance of advisory committees at the FDA. The advisory committee process increases the transparency of the scientific debate, and the openness demystifies the process. Passions are tempered. The process forces a dialogue on the known facts, and it exposes the voids of data. Transparency stabilizes the process. Nevertheless, the advisory committee meeting remains only one element in the decision-making process. Because the FDA remains legally responsible, it controls that process, including the timing of the meetings, the preparation of briefing documents, and the ultimate decision.

For the COX-2 selective inhibitors, this process permitted thoughtful analysis of the risks and the benefits of the drugs. Its expedited scheduling helped diffuse the matter. Further, the meeting helped provide an answer to the often-unanswered question that arises in product liability suits ' what was the invisible man in the courtroom (FDA) thinking? A review of the process shows that the FDA improved its use of this tool, and that its use has proved invaluable, historically. If the FDA continues to come under attack for failing to protect the public from specific drugs, more such meetings will be held, and a strategy for dealing with them is necessary. Accordingly, it is useful to trace the past use and project future use.

Yesterday: Retrospective Review of Data

Drug Efficacy Study Implementation Review

The genesis of the FDA's contemporary use of scientific advisory committees was the Drug Efficacy Study Implementation (“DESI”) Review. The DESI Review started in the mid-1960s with a contract between the FDA and the National Academy of Sciences/National Research Council to review the data available on all drugs approved for marketing between 1938 and 1962 to determine if they had been shown to be effective for the indications on their labeling. Congress had created the pre-market approval (“PMA”) process for new drugs (ie, drugs that were not generally recognized as safe (“GRAS”)) with enactment of the Federal Food, Drug, and Cosmetic Act in 1938 (“FDC Act”). The Drug Amendments of 1962 added the proof of effectiveness by adequate and well-controlled clinical investigations requirement. The FDA was also directed to review all drugs approved between 1938 and 1962 to ensure that they met the new statutory standard. Several hundred thousand drug products were being marketed containing the active ingredient marketed as GRAS under old New Drug Applications (“NDAs”) as well as drug products that were identical, similar, or related (“ISR”) to those drug products.

Two-dozen independent expert panels were created based on therapeutic areas to review the data. A multistep public process was created for only this work. NDA holders were requested to submit all relevant data. These data were privately evaluated by the relevant expert review committee. Each panel made a report to the agency determining which claims were supported by adequate and well-controlled clinical investigations. At this point, the panel's work was done.

The Agency then announced the conclusions, which it applied to all drug products containing the same active ingredient and all ISR products, and it gave companies the opportunity to respond through the formal legal procedures applicable to the approval and withdrawal of approval of the NDAs.

In sum, a group of independent medical experts over a period of years privately reviewed the data supplied, and they made across-the-board decisions about drugs in their areas of expertise. Of particular interest was the unwritten rule that the experts were to reach a conclusion on the basis of the data submitted supplemented by their expertise. Not all of the labeling claims were supported by data meeting a punctilious reading of the regulatory standard. The experts, who numbered in the hundreds, used their judgment and experience to determine which claims were appropriate. No formal time frames governed the process. Forty years later, the FDA is still completing the process, but the expert decisions achieved indisputable status because of the reputation of the independent experts and the process.

GRAS Review

The cyclamates crisis led to the next creative advisory committees use in the early 1970s. Enactment of the Food Additives Amendment of 1958 created a pre-market approval requirement for articles used initially in or on food after 1958 that were not GRAS. Thus it did not apply to a significant number of articles because they were considered GRAS. With a report implying that cyclamates were an animal carcinogen, the FDA concluded that cyclamates were no longer GRAS and had to be removed from the market immediately because they lacked a food additive regulation.

As a result, then President Nixon ordered a review of all of the GRAS substances, and the FDA contracted with the Federation of American Societies of Experimental Biology (“FASEB”) to review all of the substances marketed as GRAS. FASEB created the Select Committee of GRAS Substances (“SCOGS”) to review the safety data of all GRAS substances. Rather than create multiple advisory committees, however, one committee comprised of pre-eminent individuals with complementary areas of expertise was utilized. For almost 2 decades this committee remained essentially intact reviewing scores of substances.

The stable nature of the advisory committee membership was unique. Individual members were comfortable with their roles. Recommendations about substances were dispassionate, thorough, and credible. Time was not a factor, but the SCOGS committee provided another positive paradigm for future advisory committee use by the FDA.

OTC Drug Review

The success of the DESI Review and the GRAS Review led to the FDA's most ambitious undertaking in 1972 ' a review of the active ingredients in all drugs then marketed as over-the-counter (“OTC”) drugs. The legal basis for marketing these products was often muddled. Without a comprehensive plan, the FDA was faced with regulating 300,000-500,000 products on a case-by-case basis. It concluded that an ingredient-based multistep review process utilizing renowned experts was the only pragmatic approach. Accordingly, it created a replica of the DESI Review. Two-dozen expert panels, again broken out by therapeutic area, reviewed the data on the active components of these drug products, and they determined if the drugs were generally recognized as safe and effective and therefore did not require approved NDAs for marketing. The expert panels only reviewed the data at an initial series of meetings, which culminated in the Panel Reports or Advanced Notices of Proposed Rulemaking. The legal standard of adequate and well-controlled clinical investigations was satisfied at the initial stage by the panels' analysis of historic use, literature, and data submitted by manufacturers and others. Again, the experience of the panel often superseded the absence of data for many older drugs dating from the early 20th century.

The FDA controlled the subsequent steps in the rulemaking, and the agency thoroughly assessed the data against the adequate and well-controlled clinical investigations regulatory standard.

More than 30 years later, this unfinished program is an albatross. Nonetheless, the independent data review by scores of experts over a quarter of a century ago has created a foundation of decisions that has satisfied the agency and the public.

FDA Procedural Regulations

The widespread use of advisory committees by the FDA and throughout the government led to enactment in 1972 of the Federal Advisory Committee Act, which imposed criteria for establishment of federal advisory committees as well as procedures for conducting advisory committee hearings. Subsequently, the FDA issued a comprehensive set of procedural rules governing the conduct of advisory committees. Integrated into these procedural regulations was a clearer recognition of the conflict of interest rules and requirement for special government employees.

Today: Prospective Decision-Making Committees

The successful use of advisory committees to rule retrospectively on products logically led to their use in the pre-approval process, and this expanded drastically in the 1970s and 1980s with the chartering of advisory committees to correspond to the therapeutic review groups in the FDA drug review process. Utilized as a mechanism to vet difficult or novel scientific issues as they arise in the drug development process, advisory committees play a new role. The luxury of unlimited time to review reams of historic data and to use each luminary's experience with the drug product to assess decisions does not exist in these circumstances. Today, advisory committee members face a more truncated scenario.

Pre-market approval data on a drug are limited. Few drug products are studied in more than 5000 patients, which is designed to detect a 1% adverse reaction rate with 95% confidence. Although drug companies are urged to work closely with the FDA in creating drug development plans, the recent speeches by senior FDA officials decry the failure of so many new chemical entities. The time frames created by the user fee deadlines dramatically shorten the FDA's deliberative opportunities. Furthermore, the FDA prepares the data package for the advisory committee shortly before the meeting. That package is strongly influenced by FDA statisticians and clinical design considerations. These skill sets are unique, and they frame the advisory committee debate, which is usually 2 days at a maximum.

The advisory committee members serve overlapping 3-year terms; thus, few long-term relationships exist among the members. If special expertise is necessary, the FDA hires consultants as special government employees who are screened for conflicts of interest as rigorously as the advisory committee members.

The FDA is the decision maker; the advisory committee can only make recommendations. The members lack long-standing relationships. Caution in the review process is the watchword. Nevertheless, the patient/consumer atmosphere has changed dramatically in the past decade. Concerns about the so-called drug lag caused by purported excessive FDA caution in the drug review process led to enactment of user fee amendments to accelerate the drug review and approval process. This change corresponded to an explosion of information availability through numerous new media outlets, eg, cable television and the Internet. Consumer demand for information of all types increased by orders of magnitude. Patients became more knowledgeable and more demanding. Patient advocacy has grown, especially in the areas involving serious or life-threatening diseases.

Patients are fickle, however. They want the benefit of therapy, but their perception of risk is easily distorted. No drug is absolutely safe. The drug approval process is a balancing of the risks learned in the drug approval process balanced against the projected benefits, and the advisory committee is asked to solve the risk/benefit equation for hundreds of thousands of patients on the basis of data in a few thousand patients. All of these factors created a cautious, but pragmatic, approach among the advisory committee members. The decisions thus are in some sense hypothetical, but the public discussions of these considerations are invaluable, particularly for new categories of drugs.

The criticism of the FDA's handling of drug approvals has increased dramatically in the past 5 years, but the use of advisory committees in the process has provided a tool to diffuse some of that criticism and provided at least a modicum of protection for the agency.

Issues that have led to withdrawal of approvals in this critical period have arisen on the basis of new evidence gathered from the widespread use of the drugs in exponentially more patients than were studied. This new evidence has fundamentally changed the risk/benefit calculation, and the FDA has normally acted on its own to remove the drugs from the market. The world, however, is changing.

The Search for Tomorrow

Information availability and product liability litigation are compressing the time frame for decision making on product safety issues, and Congressional oversight shrinks that time even faster. The furor caused by the studies that undermined safety of the COX-2 inhibitors was unparalleled, and it was fueled by those factors. Actions were taken by individual companies; the FDA made announcements; the National Institutes of Health made announcements. In this information age, patients inundated their physicians with questions, who in turn raised more questions. The media and Congress raised questions not only about the drug, but of equal importance, the FDA's handling of the drugs from their inception. Lawsuits were filed all over the country. The FDA's credibility, which has been taking a continuous barrage of criticism, took a direct hit. All eyes turned to Washington (or Rockville).

The scientific review process is a multistep process that normally involves a series of studies that are designed to address issues; the results are then used to build a body of information to resolve the questions that sequentially arise as more is learned about the initial issue. This process, whether it pertains to drug development or resolution of another scientific issue, is long and tedious. It is trial and error.

No such measured scenario was available here; nor will it be in the future if such problems arise. Rapid action was needed to address the issues, stabilize the storm, and reach a credible solution. Unilateral FDA action was not an option.

The agency turned to an advisory committee in hopes that the transparency of these independent voices would stabilize the hysteria and restore some of the FDA's faded luster. In fact, it is one of the few options available to the agency in its current state. Public airing of the data before independent experts who know the disease state, understand drug development, and understand the therapy used for the treatment of the disease in question is the only way to provide the public and now Congress with the confidence that FDA decisions will consider all the relevant factors. Crises make strange bedfellows. Therefore, short-term working relationships and other limitations of the system are subsumed by the public process. This public process assures that the seriousness of the diseases in question and alternative therapies with their risks are taken into consideration. With the current state of affairs, the search for a better tomorrow will continue. As yet, this is the only practical approach.

Conclusion

Members of the industry must prepare for crises and public debate over the safety of their drugs. As we enter the new millennium, more crises will occur, and the FDA's credibility is under attack and will remain so for the foreseeable future as a surrogate for the current polarized political debate. Under these conditions, scientific, legal, regulatory, and public relations strategies for dealing with the public advisory committee process must be poised for implementation because the situation resembles a code red alert in a hospital. If the adrenaline is not on the crash cart, it is too late.

Amid a cacophony of wailing and gnashing of teeth decrying the Food and Drug Administration's (“FDA's”) failure to protect the public from unsafe drugs, the FDA held an emergency advisory committee meeting, which included consultants, to address the safety issues associated with the use of COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (“NAIDs”). The meeting was scheduled and held at warp speed. It provided a transparent dispassionate opportunity to address the safety issues for scientists, affected parties and the public. The decisions of the advisory committee were to some extent, unexpected. This accelerated review process differs from the current advisory committee process of reviewing limited data in a product pre-approval setting. However, this use is a natural extension of the FDA's historic use of advisory committees, ie, analysis of voluminous data on any active ingredient over a period of years and application of the analysis to specific drug products containing the active ingredient.

For marketed drug products, the FDA has traditionally acted unilaterally when the risk/benefit calculation for drug approval has been undermined. Today, as the agency's credibility in protecting the public is coming under repeated attack, the advisory committee meeting is providing a variant approach that is another step in the growing importance of advisory committees at the FDA. The advisory committee process increases the transparency of the scientific debate, and the openness demystifies the process. Passions are tempered. The process forces a dialogue on the known facts, and it exposes the voids of data. Transparency stabilizes the process. Nevertheless, the advisory committee meeting remains only one element in the decision-making process. Because the FDA remains legally responsible, it controls that process, including the timing of the meetings, the preparation of briefing documents, and the ultimate decision.

For the COX-2 selective inhibitors, this process permitted thoughtful analysis of the risks and the benefits of the drugs. Its expedited scheduling helped diffuse the matter. Further, the meeting helped provide an answer to the often-unanswered question that arises in product liability suits ' what was the invisible man in the courtroom (FDA) thinking? A review of the process shows that the FDA improved its use of this tool, and that its use has proved invaluable, historically. If the FDA continues to come under attack for failing to protect the public from specific drugs, more such meetings will be held, and a strategy for dealing with them is necessary. Accordingly, it is useful to trace the past use and project future use.

Yesterday: Retrospective Review of Data

Drug Efficacy Study Implementation Review

The genesis of the FDA's contemporary use of scientific advisory committees was the Drug Efficacy Study Implementation (“DESI”) Review. The DESI Review started in the mid-1960s with a contract between the FDA and the National Academy of Sciences/National Research Council to review the data available on all drugs approved for marketing between 1938 and 1962 to determine if they had been shown to be effective for the indications on their labeling. Congress had created the pre-market approval (“PMA”) process for new drugs (ie, drugs that were not generally recognized as safe (“GRAS”)) with enactment of the Federal Food, Drug, and Cosmetic Act in 1938 (“FDC Act”). The Drug Amendments of 1962 added the proof of effectiveness by adequate and well-controlled clinical investigations requirement. The FDA was also directed to review all drugs approved between 1938 and 1962 to ensure that they met the new statutory standard. Several hundred thousand drug products were being marketed containing the active ingredient marketed as GRAS under old New Drug Applications (“NDAs”) as well as drug products that were identical, similar, or related (“ISR”) to those drug products.

Two-dozen independent expert panels were created based on therapeutic areas to review the data. A multistep public process was created for only this work. NDA holders were requested to submit all relevant data. These data were privately evaluated by the relevant expert review committee. Each panel made a report to the agency determining which claims were supported by adequate and well-controlled clinical investigations. At this point, the panel's work was done.

The Agency then announced the conclusions, which it applied to all drug products containing the same active ingredient and all ISR products, and it gave companies the opportunity to respond through the formal legal procedures applicable to the approval and withdrawal of approval of the NDAs.

In sum, a group of independent medical experts over a period of years privately reviewed the data supplied, and they made across-the-board decisions about drugs in their areas of expertise. Of particular interest was the unwritten rule that the experts were to reach a conclusion on the basis of the data submitted supplemented by their expertise. Not all of the labeling claims were supported by data meeting a punctilious reading of the regulatory standard. The experts, who numbered in the hundreds, used their judgment and experience to determine which claims were appropriate. No formal time frames governed the process. Forty years later, the FDA is still completing the process, but the expert decisions achieved indisputable status because of the reputation of the independent experts and the process.

GRAS Review

The cyclamates crisis led to the next creative advisory committees use in the early 1970s. Enactment of the Food Additives Amendment of 1958 created a pre-market approval requirement for articles used initially in or on food after 1958 that were not GRAS. Thus it did not apply to a significant number of articles because they were considered GRAS. With a report implying that cyclamates were an animal carcinogen, the FDA concluded that cyclamates were no longer GRAS and had to be removed from the market immediately because they lacked a food additive regulation.

As a result, then President Nixon ordered a review of all of the GRAS substances, and the FDA contracted with the Federation of American Societies of Experimental Biology (“FASEB”) to review all of the substances marketed as GRAS. FASEB created the Select Committee of GRAS Substances (“SCOGS”) to review the safety data of all GRAS substances. Rather than create multiple advisory committees, however, one committee comprised of pre-eminent individuals with complementary areas of expertise was utilized. For almost 2 decades this committee remained essentially intact reviewing scores of substances.

The stable nature of the advisory committee membership was unique. Individual members were comfortable with their roles. Recommendations about substances were dispassionate, thorough, and credible. Time was not a factor, but the SCOGS committee provided another positive paradigm for future advisory committee use by the FDA.

OTC Drug Review

The success of the DESI Review and the GRAS Review led to the FDA's most ambitious undertaking in 1972 ' a review of the active ingredients in all drugs then marketed as over-the-counter (“OTC”) drugs. The legal basis for marketing these products was often muddled. Without a comprehensive plan, the FDA was faced with regulating 300,000-500,000 products on a case-by-case basis. It concluded that an ingredient-based multistep review process utilizing renowned experts was the only pragmatic approach. Accordingly, it created a replica of the DESI Review. Two-dozen expert panels, again broken out by therapeutic area, reviewed the data on the active components of these drug products, and they determined if the drugs were generally recognized as safe and effective and therefore did not require approved NDAs for marketing. The expert panels only reviewed the data at an initial series of meetings, which culminated in the Panel Reports or Advanced Notices of Proposed Rulemaking. The legal standard of adequate and well-controlled clinical investigations was satisfied at the initial stage by the panels' analysis of historic use, literature, and data submitted by manufacturers and others. Again, the experience of the panel often superseded the absence of data for many older drugs dating from the early 20th century.

The FDA controlled the subsequent steps in the rulemaking, and the agency thoroughly assessed the data against the adequate and well-controlled clinical investigations regulatory standard.

More than 30 years later, this unfinished program is an albatross. Nonetheless, the independent data review by scores of experts over a quarter of a century ago has created a foundation of decisions that has satisfied the agency and the public.

FDA Procedural Regulations

The widespread use of advisory committees by the FDA and throughout the government led to enactment in 1972 of the Federal Advisory Committee Act, which imposed criteria for establishment of federal advisory committees as well as procedures for conducting advisory committee hearings. Subsequently, the FDA issued a comprehensive set of procedural rules governing the conduct of advisory committees. Integrated into these procedural regulations was a clearer recognition of the conflict of interest rules and requirement for special government employees.

Today: Prospective Decision-Making Committees

The successful use of advisory committees to rule retrospectively on products logically led to their use in the pre-approval process, and this expanded drastically in the 1970s and 1980s with the chartering of advisory committees to correspond to the therapeutic review groups in the FDA drug review process. Utilized as a mechanism to vet difficult or novel scientific issues as they arise in the drug development process, advisory committees play a new role. The luxury of unlimited time to review reams of historic data and to use each luminary's experience with the drug product to assess decisions does not exist in these circumstances. Today, advisory committee members face a more truncated scenario.

Pre-market approval data on a drug are limited. Few drug products are studied in more than 5000 patients, which is designed to detect a 1% adverse reaction rate with 95% confidence. Although drug companies are urged to work closely with the FDA in creating drug development plans, the recent speeches by senior FDA officials decry the failure of so many new chemical entities. The time frames created by the user fee deadlines dramatically shorten the FDA's deliberative opportunities. Furthermore, the FDA prepares the data package for the advisory committee shortly before the meeting. That package is strongly influenced by FDA statisticians and clinical design considerations. These skill sets are unique, and they frame the advisory committee debate, which is usually 2 days at a maximum.

The advisory committee members serve overlapping 3-year terms; thus, few long-term relationships exist among the members. If special expertise is necessary, the FDA hires consultants as special government employees who are screened for conflicts of interest as rigorously as the advisory committee members.

The FDA is the decision maker; the advisory committee can only make recommendations. The members lack long-standing relationships. Caution in the review process is the watchword. Nevertheless, the patient/consumer atmosphere has changed dramatically in the past decade. Concerns about the so-called drug lag caused by purported excessive FDA caution in the drug review process led to enactment of user fee amendments to accelerate the drug review and approval process. This change corresponded to an explosion of information availability through numerous new media outlets, eg, cable television and the Internet. Consumer demand for information of all types increased by orders of magnitude. Patients became more knowledgeable and more demanding. Patient advocacy has grown, especially in the areas involving serious or life-threatening diseases.

Patients are fickle, however. They want the benefit of therapy, but their perception of risk is easily distorted. No drug is absolutely safe. The drug approval process is a balancing of the risks learned in the drug approval process balanced against the projected benefits, and the advisory committee is asked to solve the risk/benefit equation for hundreds of thousands of patients on the basis of data in a few thousand patients. All of these factors created a cautious, but pragmatic, approach among the advisory committee members. The decisions thus are in some sense hypothetical, but the public discussions of these considerations are invaluable, particularly for new categories of drugs.

The criticism of the FDA's handling of drug approvals has increased dramatically in the past 5 years, but the use of advisory committees in the process has provided a tool to diffuse some of that criticism and provided at least a modicum of protection for the agency.

Issues that have led to withdrawal of approvals in this critical period have arisen on the basis of new evidence gathered from the widespread use of the drugs in exponentially more patients than were studied. This new evidence has fundamentally changed the risk/benefit calculation, and the FDA has normally acted on its own to remove the drugs from the market. The world, however, is changing.

The Search for Tomorrow

Information availability and product liability litigation are compressing the time frame for decision making on product safety issues, and Congressional oversight shrinks that time even faster. The furor caused by the studies that undermined safety of the COX-2 inhibitors was unparalleled, and it was fueled by those factors. Actions were taken by individual companies; the FDA made announcements; the National Institutes of Health made announcements. In this information age, patients inundated their physicians with questions, who in turn raised more questions. The media and Congress raised questions not only about the drug, but of equal importance, the FDA's handling of the drugs from their inception. Lawsuits were filed all over the country. The FDA's credibility, which has been taking a continuous barrage of criticism, took a direct hit. All eyes turned to Washington (or Rockville).

The scientific review process is a multistep process that normally involves a series of studies that are designed to address issues; the results are then used to build a body of information to resolve the questions that sequentially arise as more is learned about the initial issue. This process, whether it pertains to drug development or resolution of another scientific issue, is long and tedious. It is trial and error.

No such measured scenario was available here; nor will it be in the future if such problems arise. Rapid action was needed to address the issues, stabilize the storm, and reach a credible solution. Unilateral FDA action was not an option.

The agency turned to an advisory committee in hopes that the transparency of these independent voices would stabilize the hysteria and restore some of the FDA's faded luster. In fact, it is one of the few options available to the agency in its current state. Public airing of the data before independent experts who know the disease state, understand drug development, and understand the therapy used for the treatment of the disease in question is the only way to provide the public and now Congress with the confidence that FDA decisions will consider all the relevant factors. Crises make strange bedfellows. Therefore, short-term working relationships and other limitations of the system are subsumed by the public process. This public process assures that the seriousness of the diseases in question and alternative therapies with their risks are taken into consideration. With the current state of affairs, the search for a better tomorrow will continue. As yet, this is the only practical approach.

Conclusion

Members of the industry must prepare for crises and public debate over the safety of their drugs. As we enter the new millennium, more crises will occur, and the FDA's credibility is under attack and will remain so for the foreseeable future as a surrogate for the current polarized political debate. Under these conditions, scientific, legal, regulatory, and public relations strategies for dealing with the public advisory committee process must be poised for implementation because the situation resembles a code red alert in a hospital. If the adrenaline is not on the crash cart, it is too late.