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Ideals and reality in actual regulatory experience
REGULATORY
TOXICOLOGY
AND
PHARMACOLOGY
8,257-266
(
1988)
Ideals and Reality in Actual Regulatory
ALEXANDER
Experience’
M. SCHMIDT
Institute of Governmentand Public Afairs. University of Illinois, Chicago,Illinois 60607
ReceivedFebruary 22, I988
During the past 14 years I have often heard that the purpose of the Food and Drug Administration is to guarantee the purity and safety of America’s foods and drugs. I think that is a pretty accurate expression of what most people expect the FDA to do. Unfortunately, I was asked to become Commissioner of Food and Drugs 143 years ago, before I fully appreciated the meaning of that great expectation of the American people. Nor did I realize that people could become very angry when it was discovered, as it often was, that FDA was not living up to that ideal expectation. In short, I did not realize that I was taking on an impossible job! I gave vent to my resulting frustration in a speech delivered a decade or so ago as we approached another, past, Christmas. Given the season, I suppose I could be forgiven for having entitled that speech, “Great Expectations, or, Giving FDA the Dickens.” It was a pretty good speech, really . . . I am still proud of it. It was widely reprinted and quoted. It was a good speech, as far as it went. But, in retrospect, I am afraid that I missed an important point. In that speech, I described all the products FDA regulated-human foods and drugs and biological products; animal foods and drugs; medical devices, from artificial hearts to tongue blades; things that emitted any kind of radiation, from industrial lasers to light bulbs; cosmetics; pet turtles. Something on the order, at that time, of 30 cents of every consumer dollar. I pointed out that if we were to do what the public expected us to do, we would have to have more resources. My main plea, in that speech, was that the Agency be given the money and manpower needed to do the job it was expected to do. My error, or perhaps better, my omission, was in not being more explicit than I was in that speech that the job many people expected us to do was, in reality, impossible. The public’s ideal, that FDA would guarantee the absolute purity and safety of ’ Presented at the Third Annual Meeting, International Society of Regulatory Toxicology and Pharmacology, December 10-I 1, 1987, Arlington, VA. 257 0273~2300/88 $3.00 Copyright Q 1988 by Academic Press, Inc. Au rights of reprcdwtion in any form men&.
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the products we regulated, did not match the reality of what we-or anyone else, for that matter-could, in fact, do. My intent here is to give you some insight into why the reality of regulation does not always meet the ideal. I will apologize now for using FDA to illustrate my points; but then, that is the territory I know best. On numerous public occasions, when there was the opportunity and time, I attempted to explain to people what the reality behind the regulatory rubric really was, often without much success. Sometimes, the reality can be quite jarring to one’s perception of the ideal. To relate just one example, I shall never forget the successive looks of disbelief, and then shock and horror, that crossed a sweet young woman’s face when I admitted to her query that it was really true that there were pieces of insects and probably other creatures, and maybe some rat hair, in her bread and beans and other veggies; and there were little beetles in her coffee beans. My attempt to jolly her with the old line that a beetle or two was better than no meat at all did not help much. Nor did a more sophisticated argument about unavoidable contaminants and action levels. To her, it was as if we not only permitted a certain number of rat hairs in flour; we actually added a sufficient number to be certain that the standard was met! I think I left that young woman somewhat suspicious of the Agency. I can imagine her thinking, “Well, if they cannot even keep my food clean, how can they keep my medicines safe?” And, interestingly enough, I do not think she will ever change her thinking, no matter how skillfully the Agency tries to educate her and others about natural contaminants and the fact that crops grown on the ground tend to come into contact withdirt. . . and rodents and bugs. So, I come to one of my Great General Principles (GGP), which is: “Few people will ever be happy with rat hair in their bread.” No amount of education of the public will ever change that fact. It is part of human nature. In fact, I always worried about someone putting before Congress an amendment to the Food, Drug and Cosmetic Act prohibiting anyone from knowingly selling food contaminated with rodent hair. I called it the “Mickey Mouse Clause.” I am certain it would pass; after all, a vote against the law would be a vote in favor of people eating nasty bits! A corollary of my GGP is that people will not be happy with carcinogens or other toxins in their food, either. . . unless they are very sweet! My point, of course, is that the public’s expectations are very high, and science and the regulatory arts are not quite up to them. At the same time, I do not believe most people are very discriminating, as yet, with regard to a number of regulatory matters-at least those pertaining to food and drug regulation, environmental contamination, and risk assessment. That is not meant as a criticism; many of the issues are really quite complex, not to be understood without a great deal of study and knowledge of the issues, of scientific studies, of probability theory, and the like. That is why we see the persistence of so many active consumer advocates in the food and drug field. They occupy a public playing field that otherwise would be empty. They are, to a large extent, the voice and conscience of the public. When Sidney Wolfe, one of our prominent “consumer advocates,” decides that he wants the FDA to do something about, say, a food additive, and sues FDA or files a petition backed by his analysis of several scientific studies, it is difficult for the general public to know whether he or the Agency is correct. But if Sidney is “viewing with alarm,” then the public tends also to be alarmed.
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Often, the public has no sound way to determine whether the petition is pro-consumer, anti-industry, or simply pro-Sidney Wolfe. Remember: consumer advocates draw their nourishment from conflict; when there is no conflict, they wither and disappear from view. In general, I think that the Sidney Wolfes of our country get the benefit of the public’s doubt, and so receive the public’s trust, for two principal reasons: it is assumed by the public that consumer advocates generally represent consumer interests; and, second, the communications media generally give the better consumer advocates favorable, and often plentiful, coverage. And, of course, on some occasions, consumer advocates are absolutely correct in their view! Also, the general public, as a rule, does not often have much of a direct or immediate impact on FDA’s regulatory actions. The Agency very much wants the public to think well of it (which, usually, is the case, according to surveys). But there is not much on a day-to-day basis coming from the general public that would command the Agency’s attention. The good consumer advocates do get the Agency’s attention, however. All too often, they have another characteristic that tends to make Agency leadership pay attention. Not only are good consumer advocates usually well-connected with the media, as I mentioned a moment ago, but they are also often “in pretty thick” with members of Congress or their staffs and even, on occasion, with employees of the FDA. Now, I come to another of my Great General Principles, which is: “We tend to pay attention to those who can hurt us, and we give most attention to those who can hurt us now.” The Food and Drug Administration, to succeed, needs several things: over the long haul, it needs public support, which accompanies public perception that the Agency is doing a pretty good job of protecting the public’s health and welfare. This public support is very important, as it is enabling to the Commissioner and his staff, and is more important than a lot of people, even many in the Agency, realize. It is, however, somewhat abstract and distant. More immediate and concrete Agency needs are for people, money, and facilities, which come from certain actions of the administrative and legislative branches of our government. And the Agency needs to be free from political and other interference, as much as possible, in doing its job. And so, hurting the Food and Drug Administration is depriving it of public support, of legislative authority, of money, staff, and independence. It follows, then, that the FDA needs the strong support of the Secretary and Assistant Secretaries of the Department of Health and Human Services (HHS) and their staffs, and the Agency needs the friendly ear of the Office of Management and Budget. Rarely, the Agency needs the direct support of the President and White House staff; but this is unusual, and when it occurs, indicates a problem at the Department level, such as a weak Secretary. As things now stand, since the Secretary of HHS hires and fires the Commissioner and his top staff, there should not be, and there rarely are, dramatic clashes among those individuals. Generally, the Agency gets good administrative support from the Department, and only occasional interference. The Administration does submit a budget to Congress, however; and so a real hurt that can be inflicted upon FDA by the Administration is to recommend a budget cut.
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This is usually in an attempt to control spending, rather than a punitive act; the Secretary always tells the Commissioner, “This hurts me more than it does you.” In practical terms, while FDA is in the Executive Branch of government, the Agency really must serve two masters . . . a serious problem. Congress passed the Food, Drug and Cosmetic Act, and thus, in a real sense, created the Food and Drug Administration. It therefore should not surprise you to hear that Congress considers the Agency its own, and expects it to do what Congress wants ittodo. . . which is to say that each member of Congress wants FDA to do what he or she wants it to do. FDA actually worries much more about being hurt by Congress than by anyone else . . . which, if you think about it for a few minutes, makes sense. Congress can hold well-publicized hearings, which can be painful to those called on the Congressional carpet, and which can seriously erode public perception of the Agency’s effectiveness. Congress can issue reports independent of hearings. Congress authorizes expenditures and appropriates money. And, Congress makes laws, and even can abolish FDA, which would be the ultimate hurt! Of course, there is the legal mandate for the Agency to carry out the provisions of the Food, Drug and Cosmetic Act and the other laws FDA implements; but that, for the most part, is taken for granted by all parties. The problems come in deciding how the Agency will carry out the provisions of the Food, Drug and Cosmetic Act. How swiftly, and on what basis, FDA makes its decisions seems to fascinate all FDAwatchers, each of whom is both curious and opinionated. The advantage held by Congress is that it can haul FDA before it to assuage its curiosity and advocate its position. A major problem for FDA is that Congress rarely speaks with a single voice. And so the Agency, as a practical matter, pays more attention to the most powerful voices . . . those of the Ted Kennedys and Henry Waxmans who either are in power or who will be, sooner or later. The Chairpersons of an agency’s oversight and appropriations committees, of course, have the most power to command Agency attention. Congress likes FDA . . . or, to put it more accurately, perhaps: Congress is very interested in FDA. I like to tell the true story that when I left FDA at the end of the Nixon-Ford administration, I was told by a senior member of Congress that his staff had counted appearances before Congress by administration officials, and had so learned that Henry Kissinger and I had testified more times than anyone else. I was emboldened by the implied compliment to wonder aloud why that had been the case, and was told, “Well, we like Henry because he’s so important, so intelligent, so articulate, so fascinating a person and speaker! He has so much to say!” “And I?’ I rashly enquired. “Well, we hauled you up because you’re such an easy target!” Indeed. It would be foolish to underestimate the effect on FDA of the numerous oversight hearings to which it is subjected by Congress. Congress can and does exert a constant one-sided pressure on FDA, which, in time, can be very wearing, and even cause FDA to tilt away from the ideal in regulation. Of course, the degree of pressure exerted on FDA depends quite a bit upon which political party is in the White House and which party controls Congress. I was in a Republican administration with a Democratically controlled Congress, not the best of worlds. My successor as Commissioner was Donald Kennedy, who served Jimmy Carter and a Democratic Congress. It was obvious to both Don Kennedy and me that he had an easier time of it with Ted Kennedy and his colleagues than I did.
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Even so, I would submit that no matter the political circumstance, Congressional oversight hearings, on balance, have a marked negative effect on the regulatory process. Certainly, they cost both Congress and FDA a lot of time and money. They cost the Commissioner and his staff, and FDA’s Legal Counsel and his or her staff, many weeks out of their work year. I would like to know the dollar value of the time that FDA staff spends in gathering information for Congressional committees, responding to Congressional queries, and preparing for and attending Congressional hearings. It would be a significant number. And yet, that is not the main cost of the way Congress carries out its oversight function. The principal effect of Congressional oversight is to cause the Agency to be overly cautious in carrying out its duties. Most people believe that the proper job of a regulatory agency like FDA is not only to keep unsafe or ineffective products off the market, but also to approve the marketing of safe and effective new and important products in a timely fashion. If you agree, then you should be pleased, as are most people, that Commissioner Frank Young and his staff have assured the American people that they will be prompt but prudent in reviewing new drug applications for therapies for important diseases for which there are no good existing treatments. That is to say, they will put important new therapies on a “fast track.” One of the first drugs successfully to traverse the “fast track” is an important new entity called “lovastatin,” a drug which lowers serum cholesterol and thus will help reduce the appalling incidence of coronary artery disease in this country. Lovastatin is an important new drug, and its arrival on the market was happily hailed by all my cardiologist friends. When speaking to a group of internists a few weeks ago, I rather cynically, I thought, speculated on how long it would be before some Congressman announced an investigation of the process used by FDA in approving lovastatin. The answer turned out to be, “not long.” As you may have read, Representative Weiss is now gathering a lot of information to be used in second guessing FDA’s decision. If FDA gets jerked around for approving lovastatin in a relatively short time, how do you think this will affect the approval speed of the next important drug that should be put on the “fast track”? I am now wondering whether some committee will investigate FDA’s approval of tPA (tissue plasminogen activator), a very important new drug for the treatment of acute coronary thrombosis. The other side of that regulatory coin was shown to us again just last week by another in a series of Wall Street Journal editorials about FDA and our Drug Approval process. The WSJ had been angered by the slow and deliberate pace of FDA action on new drugs, and seemed upset with regard to studies of a new drug for Alzheimer’s disease (THA). FDA had, in the WXI’s words, “. . .stopped the entire (clinical) test when changes in liver chemistry appeared in some patients.” This seems to upset the WSJ editorialists, who apparently would have stopped testing only if all patients had liver damage . . . but I doubt that any Congressional committee will be stirred to investigate the matter. If, however, FDA had permitted the trial to go on, and a significant number of human subjects of the trials had damaged livers as a result, then some Congressional committee would have had a field day raking some poor FDA officials over the coals.
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The point is that Congress applies an unremitting and heavy pressure on FDA to be cautious. . . to avoid risk . . . to be safe . . . to retreat. . . to be negative . . . to say “No”; because if you are going to be publicly excoriated by Congress for making a mistake, the best protection is to do nothing . . . to make no decision . . . to approve no drug. I have pointed out many times that rarely, if ever, has Congress held a hearing to look into the failure of FDA to approve a new entity; but it has held hundreds of hearings alleging that FDA has done something wrong by approving a drug . . . or food additive, or whatever. Why does the Wall Street Journal not say anything about that? If you are the one hauled up before a Congressional committee and accused of having done something terribly wrong, even though you know you have not, the experience will stop and make you think, and one of the things you will think is that you do not want to do that again! Remember my second General Principal: “We tend to pay attention to those who can hurt us!” Congressional hearings are managed by Congressional staffs, who want the hearings to attract the attention of the press, to be widely reported, and to get a lot of attention for their employer, who likes and needs the public exposure generated by the successful hearing. In other words, all too often, to a Congressman, the sensational hearing is the successful hearing. All too often it is not legitimate Congressional oversight, it is show biz! It is very much like the newspaper game, in which the rule seems to be that one does not attract attention-or readers-by reporting good news. It is the bad news that gets the headlines and the long columns on the front page. The investigative reporter wins the prizes. And so, too, Congressional hearings are designed to discover and publicize what can be characterized, rightly or wrongly, as “bad news” for the Agency: an error, a tragedy, dishonesty, or whatever. There is, of course, no scientific way to quantitate the effect that all of this has on FDA, but the effect is real and the effect is significant. I believe the effect is to cause a certain tilt . . . that is to say, a certain amount of deviation, from the regulatory ideal of a balanced process. If nothing else, it accounts for much of the lethargy in the process. I used to meet every few months with my counterparts in England, and always envied their immunity from similar harassment by Parliament. The English seem much more successful than we in being able to separate the business of government from politics. Hearings of the sort we have are not conducted by the British Parliament. When I commented on this once to a Member of Parliament, the reply was that they wanted their government professionals undistracted from their jobs; and that if a MP had something to say about how the job was being done, he would say it to the Minister of Health. I always thought that a marvelous response! The media play an interesting, dual, role in all this. As do consumer advocates, members of Congress tend to play to the media, as they, too, wish to be well known and well thought of by the public, which elects them. The media, as we all know, while informing the public, do much to mold public opinion. Thus, anyone wishing to be well thought of by the public must court the media, so as to be reflected favorably to the American public.
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There is a second aspect to the media, however, which is more problematic to FDA or any regulatory agency, which is that much of the media does not simply report the facts, it advocates a position. Few knowledgeable people are passive about FDA, and this includes knowledgeable reporters and editorialists. Indeed, I have always been impressed that most FDA watchers have quite strongly held opinions about what FDA should and should not do, and are not terribly reticent about expressing those views. This is certainly true for today’s press, and it most certainly is true for the Wall Street Journal, which apparently has yet to conclude a series of irate editorials concerning FDA’s failure to approve tPA in May of this year. (FDA has since approved tPA, and while I have not read that the WSJitself has taken credit for shaming FDA into the action, I have seen stories in other publications giving them that credit.) While I believe the WSJ’seditorials to have been wrong and at times bordering on the scurrilous, I credit them for keeping them on the editorial page . . . for carefully separating their editorial opinions from the fair and factual reporting of both sides of the controversy to be found in the rest of their paper. Not all reporters have the expertise or integrity of those of the WSJ. I have long been distressed by reporters who camouflage, knowingly or not, their strong advocacy of a position as simple reporting of the news. The number of “news reports” concerning FDA that should, in all fairness, have been printed on the editorial page is too large for me to count. Thus, the media often carry on a kind of double function: not only do they convey to the public factual information about FDA and its actions, thus serving an important educational function, the media also will pitch their views, their beliefs, their opinions, as to what is right and wrong about the FDA. And that is not necessarily education, it is solicitation to a certain point of view. Editorializing in a news story may be acceptable, as long as the distinction between that and unbiased, factual reporting is made plain to the public . . . which too often is not the case. Now: how does industry fit into this picture? You all know the story that illustrates the distinction between involvement and true commitment. When it comes to ham and eggs, while the chicken is somewhat involved, the pig is totally committed! And when it comes to FDA regulation, the role of the pig is played by the regulated industry. To industry, ideal regulation is a fair, unbiased, scientific, speedyreview of the data put before the regulatory agency, followed by a timely decision, well explained. Most of the people in the pharmaceutical industry who work a lot with FDA think that the regulatory process falls somewhat short of their ideal a majority of the time, particularly with regard to the time taken by the review process. There are many reasons for slow reviews. Many times the information provided to FDA is insufficient for one reason or another: often, the data given to FDA are questionable or clearly flawed; or the data raise yet other questions and thus more data are requested and more studies needed. Presenting data to advisory committees takes time; there are disputes to be settled, and so on. After all, much of science is the skillful asking of questions. All of this would not be as much of a problem as it now is, if it were not for what I think is a peculiarly American flaw in our regulatory system. The most serious problem affecting the relationship between our industry and our regulatory bodies is cultural: and it has to do with a certain lack of trust, a hearty
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suspicion on the part of Americans as to the integrity of their institutions. Certainly, the last decades of Watergate and Viet Nam and crooked judges in Chicago and other such episodes have not helped ease that suspicion. It is simply that many people do not believe that representatives of industry and government can talk directly to each other without some sort of hanky-panky developing. There is an almost hysterical distrust of industry by many consumer groups; and they and other “watchdog groups,” and much of the press, seem highly distressed whenever regulators and representatives of the regulated industry talk to each other outside of their presence. Now, I am from Chicago; so you do not have to tell me about crooked officials, smoke-filled rooms, or people selling out. And I am aware of instances in the recent past when persons in responsible positions within FDA did not distinguish themselves or the Agency with regard to their relationships with industry. Japan, on the other hand, has a marked advantage over us in that in their culture, it is expected that government, industry, and universities work closely togetherthey are encouraged to do so. There is no concern about a “revolving door” between government and industry in Japan. . . there is no door at all! Yet, in the United States, the fact that the FDA, looking for a specific type of expertise, might hire someone from the industry is cause for alarm. And that an FDA employee leaves government service and goes to or returns to industry is cause for panic, in some circles. Even FDA using as expert consultants individuals who know a lot about the subject because they have worked at it on behalf of industry is viewed as unacceptable. It is as if the only persons who should work for or advise government are individuals who are totally ignorant of the subject at hand, and thus free of any taint. Commissioner Frank Young recently said that the single most effective thing that could be done to speed the approval of good new products by FDA would be to improve communication between the Agency and the regulated industry, particularly early in the process. Were there better communication early on about the design of studies to be performed, what data FDA needed and why, etc., a lot of time could be saved. Such discussions should go on throughout the IND process. Those sorts of valuable discussions do not happen for at least three reasons I can think of right away. First, it would be almost impossible in our culture to have such meetings between regulators and industry. Trade secrets and proprietary information would have to be protected; and Ralph Nader simply would not approve of such closed, “secret” meetings. There would be the old, familiar charges, oft disproved, that FDA had “sold out” to industry. Second, when I did try to encourage such meetings, some FDA personnel resisted. Some resisted for a practical reason: they simply could not find the time. Others, though, had a more serious, philosophical objection: they did not want to have to commit themselves at the front end of the process as to what would be necessary to gain approval of the product. They did not want to go out on a limb, for fear it would later be sawed off by and used as a club on them at some point, probably in a Congressional hearing! In a real way, this relates to my earlier discussion of Congressional scrutiny. It is much safer for regulators to sit back and say nothing, until industry shows up with something. The regulator can then look it over and say, “Yes, this is it,” or, “No, this is not it.”
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If a regulator had committed himself or herself as to what likely would be acceptable, early on in the process, then he or she might feel obligated to accept what was presented, and be less likely to demand additional, needed, information. This, of course, could lead to an error which would increase the risk that the regulator could be hurt by Congress, or even his embarrassed agency. Another problem impedes rational discourse between regulator and the regulated. Often, in my view, industry is simply too meek in its relationships with government. Recently, when I castigated a CEO of a major pharmaceutical firm for being too deferential to sloppy science coming out of FDA, he reminded me of a statement attributed to Voltaire: “It is dangerous to be right, when the government is wrong.” Someone else once said, “People who think they know everything are very irritating to those of us who do”; and industry scientists simply do not want to run the risk of irritating the government know-it-alls. There is a real fear on the part of regulated individuals of offending FDA reviewers and thus suffering their wrath. Remember, it is industry’s ham in the pan . . . and it does not matter too much to FDA if it lays an egg once in a while. Fear ofgovernment retribution increases when everyone reads the kinds of speculative stories that recently have wondered whether FDA’s refusal to approve tPA several months ago was to punish the drug sponsor for its alleged arrogance in refusing to answer some FDA questions, and presenting what FDA considered sloppy data. In my view, that is utter nonsense. It was, after all, an advisory committee that refused to recommend approval of tPA in the first instance. In our society, the only answer I can think of to any of these concerns about the relationship of the regulators and the regulated is relatively simple: it is open government. If a regulatory agency will conduct as much of its business in the open as is legally possible, using a wide range of advisors and consultants, then suspicions and fears such as those I have described can be held to an acceptable minimum, and the substantive issues-moral, ethical, and scientific-can receive the proper attention of all concerned. And now I come to the last of the reasons that the regulatory ideal is not often achieved, which is that the Agency personnel are not perfect, either. No one can work long at FDA without realizing that a large number of the people who work for the Agency are terrific. If they were not, they would not be so eagerly sought after by industry! And yet, all organizations, including the University of Illinois, have some lazy people and some people who are not too nice. But, I do not think that is so serious. There are two other problems, however, that I view with more concern. I was asked once what the most difficult aspect of my role in FDA was. The answer was easy: it was recruiting all the first-rate scientists the Agency needed. I found it hard to recruit against universities and the National Institutes of Health and Industry, and I do not think the situation has changed. To be specific, we simply could not recruit enough clinical scientists in all the disciplines needed by FDA. For a time, we were without an ophthalmologist, as one example. We made up for that lack by using advisors and consultants; but FDA must have a complete complement of terrific people, if the ideal is to be met. And, lastly, if you do have good, bright, well-trained, aggressive people in your organization, you will find that they often have their own strongly held views and
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sometimes their own agendas for action. This can result in serious conflict within the Agency, and, on occasion, be embarrassing. In ordinary circumstances, such conflict can and should be settled within the organization. But, when investigative reporters or Congressional staffs get wind of such a controversy and take sides, then things can get very sticky. Again, a smart industry wants no part of such an internal Agency squabble, and will stay as far away from it as possible. On occasion, a controversy arising within FDA is not ordinary, however, and is worthy of public debate. One such question I dealt with was raised again in another form by the tPA debate. The question was whether it was sufficient for the drug sponsor to demonstrate only that tPA dissolved a fresh clot in a coronary artery, or whether they had also to show improved cardiac function. That FDA’s advisory committee, and FDA, wanted answers to both questions seems to have enraged the WSJ. But, I think, they miss the scientific rationale for the question. A similar discussion years ago revolved around the question of whether demonstrating simply that a drug lowered blood pressure was sufficient grounds for approval of the drug. Some FDA staff argued that it must also be shown that there was some benefit to health in so lowering the blood pressure. This controversy had something to do with the Agency’s apparent difficulties with regard to approving new cardiovascular agents, back then. Again, public discussion of this and other such basic questions is morally necessary, and their resolution can help move us toward the ideal regulatory process by increasing the public’s understanding of the role of the regulator. One would hope that this increased public understanding will change the cultural bias a bit and allow FDA the freedom to work more closely with industry than has been permitted in the past. I could suggest a few other things that might improve the process. Remember, I said earlier in these remarks that what FDA needed to do the proper job was public support, legislative authority, money, staff, and independence. I have talked a lot about public support. To some extent, events, such as the series of editorials by the Wall Street Journal saying the FDA is seriously flawed, or recent efforts in California, stimulated by the AIDS crisis, to set up their own drug review process, erode the public’s confidence in our regulatory bodies. The antidote is information and much more public education . . . and public debate of the issues. I think the Wall Street Journal is correct in saying that the issues it raises need to be discussed. I would think that Congress would be concerned, too; but I do not think we will see anything between now and the next presidential election but another series of hearings into FDA’s failures to protect the American public. In sum, what stands between the ideal of regulation and the reality is the peculiar nature of our culture, with its freedoms and independence of speech and press; and our Congress, which does what it thinks it ought to do; and the checks and balances inherent in the way we govern ourselves. What stops us short of perfection are the imperfections of people and the limitations of our science. I doubt that we will ever achieve the ideal; but we can, and no doubt, will, do better in time, if we pay attention to some of the issues I have put before you today. Thank you.
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Ideals and Reality in Actual Regulatory
ALEXANDER
Experience’
M. SCHMIDT
Institute of Governmentand Public Afairs. University of Illinois, Chicago,Illinois 60607
ReceivedFebruary 22, I988
During the past 14 years I have often heard that the purpose of the Food and Drug Administration is to guarantee the purity and safety of America’s foods and drugs. I think that is a pretty accurate expression of what most people expect the FDA to do. Unfortunately, I was asked to become Commissioner of Food and Drugs 143 years ago, before I fully appreciated the meaning of that great expectation of the American people. Nor did I realize that people could become very angry when it was discovered, as it often was, that FDA was not living up to that ideal expectation. In short, I did not realize that I was taking on an impossible job! I gave vent to my resulting frustration in a speech delivered a decade or so ago as we approached another, past, Christmas. Given the season, I suppose I could be forgiven for having entitled that speech, “Great Expectations, or, Giving FDA the Dickens.” It was a pretty good speech, really . . . I am still proud of it. It was widely reprinted and quoted. It was a good speech, as far as it went. But, in retrospect, I am afraid that I missed an important point. In that speech, I described all the products FDA regulated-human foods and drugs and biological products; animal foods and drugs; medical devices, from artificial hearts to tongue blades; things that emitted any kind of radiation, from industrial lasers to light bulbs; cosmetics; pet turtles. Something on the order, at that time, of 30 cents of every consumer dollar. I pointed out that if we were to do what the public expected us to do, we would have to have more resources. My main plea, in that speech, was that the Agency be given the money and manpower needed to do the job it was expected to do. My error, or perhaps better, my omission, was in not being more explicit than I was in that speech that the job many people expected us to do was, in reality, impossible. The public’s ideal, that FDA would guarantee the absolute purity and safety of ’ Presented at the Third Annual Meeting, International Society of Regulatory Toxicology and Pharmacology, December 10-I 1, 1987, Arlington, VA. 257 0273~2300/88 $3.00 Copyright Q 1988 by Academic Press, Inc. Au rights of reprcdwtion in any form men&.
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the products we regulated, did not match the reality of what we-or anyone else, for that matter-could, in fact, do. My intent here is to give you some insight into why the reality of regulation does not always meet the ideal. I will apologize now for using FDA to illustrate my points; but then, that is the territory I know best. On numerous public occasions, when there was the opportunity and time, I attempted to explain to people what the reality behind the regulatory rubric really was, often without much success. Sometimes, the reality can be quite jarring to one’s perception of the ideal. To relate just one example, I shall never forget the successive looks of disbelief, and then shock and horror, that crossed a sweet young woman’s face when I admitted to her query that it was really true that there were pieces of insects and probably other creatures, and maybe some rat hair, in her bread and beans and other veggies; and there were little beetles in her coffee beans. My attempt to jolly her with the old line that a beetle or two was better than no meat at all did not help much. Nor did a more sophisticated argument about unavoidable contaminants and action levels. To her, it was as if we not only permitted a certain number of rat hairs in flour; we actually added a sufficient number to be certain that the standard was met! I think I left that young woman somewhat suspicious of the Agency. I can imagine her thinking, “Well, if they cannot even keep my food clean, how can they keep my medicines safe?” And, interestingly enough, I do not think she will ever change her thinking, no matter how skillfully the Agency tries to educate her and others about natural contaminants and the fact that crops grown on the ground tend to come into contact withdirt. . . and rodents and bugs. So, I come to one of my Great General Principles (GGP), which is: “Few people will ever be happy with rat hair in their bread.” No amount of education of the public will ever change that fact. It is part of human nature. In fact, I always worried about someone putting before Congress an amendment to the Food, Drug and Cosmetic Act prohibiting anyone from knowingly selling food contaminated with rodent hair. I called it the “Mickey Mouse Clause.” I am certain it would pass; after all, a vote against the law would be a vote in favor of people eating nasty bits! A corollary of my GGP is that people will not be happy with carcinogens or other toxins in their food, either. . . unless they are very sweet! My point, of course, is that the public’s expectations are very high, and science and the regulatory arts are not quite up to them. At the same time, I do not believe most people are very discriminating, as yet, with regard to a number of regulatory matters-at least those pertaining to food and drug regulation, environmental contamination, and risk assessment. That is not meant as a criticism; many of the issues are really quite complex, not to be understood without a great deal of study and knowledge of the issues, of scientific studies, of probability theory, and the like. That is why we see the persistence of so many active consumer advocates in the food and drug field. They occupy a public playing field that otherwise would be empty. They are, to a large extent, the voice and conscience of the public. When Sidney Wolfe, one of our prominent “consumer advocates,” decides that he wants the FDA to do something about, say, a food additive, and sues FDA or files a petition backed by his analysis of several scientific studies, it is difficult for the general public to know whether he or the Agency is correct. But if Sidney is “viewing with alarm,” then the public tends also to be alarmed.
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Often, the public has no sound way to determine whether the petition is pro-consumer, anti-industry, or simply pro-Sidney Wolfe. Remember: consumer advocates draw their nourishment from conflict; when there is no conflict, they wither and disappear from view. In general, I think that the Sidney Wolfes of our country get the benefit of the public’s doubt, and so receive the public’s trust, for two principal reasons: it is assumed by the public that consumer advocates generally represent consumer interests; and, second, the communications media generally give the better consumer advocates favorable, and often plentiful, coverage. And, of course, on some occasions, consumer advocates are absolutely correct in their view! Also, the general public, as a rule, does not often have much of a direct or immediate impact on FDA’s regulatory actions. The Agency very much wants the public to think well of it (which, usually, is the case, according to surveys). But there is not much on a day-to-day basis coming from the general public that would command the Agency’s attention. The good consumer advocates do get the Agency’s attention, however. All too often, they have another characteristic that tends to make Agency leadership pay attention. Not only are good consumer advocates usually well-connected with the media, as I mentioned a moment ago, but they are also often “in pretty thick” with members of Congress or their staffs and even, on occasion, with employees of the FDA. Now, I come to another of my Great General Principles, which is: “We tend to pay attention to those who can hurt us, and we give most attention to those who can hurt us now.” The Food and Drug Administration, to succeed, needs several things: over the long haul, it needs public support, which accompanies public perception that the Agency is doing a pretty good job of protecting the public’s health and welfare. This public support is very important, as it is enabling to the Commissioner and his staff, and is more important than a lot of people, even many in the Agency, realize. It is, however, somewhat abstract and distant. More immediate and concrete Agency needs are for people, money, and facilities, which come from certain actions of the administrative and legislative branches of our government. And the Agency needs to be free from political and other interference, as much as possible, in doing its job. And so, hurting the Food and Drug Administration is depriving it of public support, of legislative authority, of money, staff, and independence. It follows, then, that the FDA needs the strong support of the Secretary and Assistant Secretaries of the Department of Health and Human Services (HHS) and their staffs, and the Agency needs the friendly ear of the Office of Management and Budget. Rarely, the Agency needs the direct support of the President and White House staff; but this is unusual, and when it occurs, indicates a problem at the Department level, such as a weak Secretary. As things now stand, since the Secretary of HHS hires and fires the Commissioner and his top staff, there should not be, and there rarely are, dramatic clashes among those individuals. Generally, the Agency gets good administrative support from the Department, and only occasional interference. The Administration does submit a budget to Congress, however; and so a real hurt that can be inflicted upon FDA by the Administration is to recommend a budget cut.
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This is usually in an attempt to control spending, rather than a punitive act; the Secretary always tells the Commissioner, “This hurts me more than it does you.” In practical terms, while FDA is in the Executive Branch of government, the Agency really must serve two masters . . . a serious problem. Congress passed the Food, Drug and Cosmetic Act, and thus, in a real sense, created the Food and Drug Administration. It therefore should not surprise you to hear that Congress considers the Agency its own, and expects it to do what Congress wants ittodo. . . which is to say that each member of Congress wants FDA to do what he or she wants it to do. FDA actually worries much more about being hurt by Congress than by anyone else . . . which, if you think about it for a few minutes, makes sense. Congress can hold well-publicized hearings, which can be painful to those called on the Congressional carpet, and which can seriously erode public perception of the Agency’s effectiveness. Congress can issue reports independent of hearings. Congress authorizes expenditures and appropriates money. And, Congress makes laws, and even can abolish FDA, which would be the ultimate hurt! Of course, there is the legal mandate for the Agency to carry out the provisions of the Food, Drug and Cosmetic Act and the other laws FDA implements; but that, for the most part, is taken for granted by all parties. The problems come in deciding how the Agency will carry out the provisions of the Food, Drug and Cosmetic Act. How swiftly, and on what basis, FDA makes its decisions seems to fascinate all FDAwatchers, each of whom is both curious and opinionated. The advantage held by Congress is that it can haul FDA before it to assuage its curiosity and advocate its position. A major problem for FDA is that Congress rarely speaks with a single voice. And so the Agency, as a practical matter, pays more attention to the most powerful voices . . . those of the Ted Kennedys and Henry Waxmans who either are in power or who will be, sooner or later. The Chairpersons of an agency’s oversight and appropriations committees, of course, have the most power to command Agency attention. Congress likes FDA . . . or, to put it more accurately, perhaps: Congress is very interested in FDA. I like to tell the true story that when I left FDA at the end of the Nixon-Ford administration, I was told by a senior member of Congress that his staff had counted appearances before Congress by administration officials, and had so learned that Henry Kissinger and I had testified more times than anyone else. I was emboldened by the implied compliment to wonder aloud why that had been the case, and was told, “Well, we like Henry because he’s so important, so intelligent, so articulate, so fascinating a person and speaker! He has so much to say!” “And I?’ I rashly enquired. “Well, we hauled you up because you’re such an easy target!” Indeed. It would be foolish to underestimate the effect on FDA of the numerous oversight hearings to which it is subjected by Congress. Congress can and does exert a constant one-sided pressure on FDA, which, in time, can be very wearing, and even cause FDA to tilt away from the ideal in regulation. Of course, the degree of pressure exerted on FDA depends quite a bit upon which political party is in the White House and which party controls Congress. I was in a Republican administration with a Democratically controlled Congress, not the best of worlds. My successor as Commissioner was Donald Kennedy, who served Jimmy Carter and a Democratic Congress. It was obvious to both Don Kennedy and me that he had an easier time of it with Ted Kennedy and his colleagues than I did.
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Even so, I would submit that no matter the political circumstance, Congressional oversight hearings, on balance, have a marked negative effect on the regulatory process. Certainly, they cost both Congress and FDA a lot of time and money. They cost the Commissioner and his staff, and FDA’s Legal Counsel and his or her staff, many weeks out of their work year. I would like to know the dollar value of the time that FDA staff spends in gathering information for Congressional committees, responding to Congressional queries, and preparing for and attending Congressional hearings. It would be a significant number. And yet, that is not the main cost of the way Congress carries out its oversight function. The principal effect of Congressional oversight is to cause the Agency to be overly cautious in carrying out its duties. Most people believe that the proper job of a regulatory agency like FDA is not only to keep unsafe or ineffective products off the market, but also to approve the marketing of safe and effective new and important products in a timely fashion. If you agree, then you should be pleased, as are most people, that Commissioner Frank Young and his staff have assured the American people that they will be prompt but prudent in reviewing new drug applications for therapies for important diseases for which there are no good existing treatments. That is to say, they will put important new therapies on a “fast track.” One of the first drugs successfully to traverse the “fast track” is an important new entity called “lovastatin,” a drug which lowers serum cholesterol and thus will help reduce the appalling incidence of coronary artery disease in this country. Lovastatin is an important new drug, and its arrival on the market was happily hailed by all my cardiologist friends. When speaking to a group of internists a few weeks ago, I rather cynically, I thought, speculated on how long it would be before some Congressman announced an investigation of the process used by FDA in approving lovastatin. The answer turned out to be, “not long.” As you may have read, Representative Weiss is now gathering a lot of information to be used in second guessing FDA’s decision. If FDA gets jerked around for approving lovastatin in a relatively short time, how do you think this will affect the approval speed of the next important drug that should be put on the “fast track”? I am now wondering whether some committee will investigate FDA’s approval of tPA (tissue plasminogen activator), a very important new drug for the treatment of acute coronary thrombosis. The other side of that regulatory coin was shown to us again just last week by another in a series of Wall Street Journal editorials about FDA and our Drug Approval process. The WSJ had been angered by the slow and deliberate pace of FDA action on new drugs, and seemed upset with regard to studies of a new drug for Alzheimer’s disease (THA). FDA had, in the WXI’s words, “. . .stopped the entire (clinical) test when changes in liver chemistry appeared in some patients.” This seems to upset the WSJ editorialists, who apparently would have stopped testing only if all patients had liver damage . . . but I doubt that any Congressional committee will be stirred to investigate the matter. If, however, FDA had permitted the trial to go on, and a significant number of human subjects of the trials had damaged livers as a result, then some Congressional committee would have had a field day raking some poor FDA officials over the coals.
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The point is that Congress applies an unremitting and heavy pressure on FDA to be cautious. . . to avoid risk . . . to be safe . . . to retreat. . . to be negative . . . to say “No”; because if you are going to be publicly excoriated by Congress for making a mistake, the best protection is to do nothing . . . to make no decision . . . to approve no drug. I have pointed out many times that rarely, if ever, has Congress held a hearing to look into the failure of FDA to approve a new entity; but it has held hundreds of hearings alleging that FDA has done something wrong by approving a drug . . . or food additive, or whatever. Why does the Wall Street Journal not say anything about that? If you are the one hauled up before a Congressional committee and accused of having done something terribly wrong, even though you know you have not, the experience will stop and make you think, and one of the things you will think is that you do not want to do that again! Remember my second General Principal: “We tend to pay attention to those who can hurt us!” Congressional hearings are managed by Congressional staffs, who want the hearings to attract the attention of the press, to be widely reported, and to get a lot of attention for their employer, who likes and needs the public exposure generated by the successful hearing. In other words, all too often, to a Congressman, the sensational hearing is the successful hearing. All too often it is not legitimate Congressional oversight, it is show biz! It is very much like the newspaper game, in which the rule seems to be that one does not attract attention-or readers-by reporting good news. It is the bad news that gets the headlines and the long columns on the front page. The investigative reporter wins the prizes. And so, too, Congressional hearings are designed to discover and publicize what can be characterized, rightly or wrongly, as “bad news” for the Agency: an error, a tragedy, dishonesty, or whatever. There is, of course, no scientific way to quantitate the effect that all of this has on FDA, but the effect is real and the effect is significant. I believe the effect is to cause a certain tilt . . . that is to say, a certain amount of deviation, from the regulatory ideal of a balanced process. If nothing else, it accounts for much of the lethargy in the process. I used to meet every few months with my counterparts in England, and always envied their immunity from similar harassment by Parliament. The English seem much more successful than we in being able to separate the business of government from politics. Hearings of the sort we have are not conducted by the British Parliament. When I commented on this once to a Member of Parliament, the reply was that they wanted their government professionals undistracted from their jobs; and that if a MP had something to say about how the job was being done, he would say it to the Minister of Health. I always thought that a marvelous response! The media play an interesting, dual, role in all this. As do consumer advocates, members of Congress tend to play to the media, as they, too, wish to be well known and well thought of by the public, which elects them. The media, as we all know, while informing the public, do much to mold public opinion. Thus, anyone wishing to be well thought of by the public must court the media, so as to be reflected favorably to the American public.
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There is a second aspect to the media, however, which is more problematic to FDA or any regulatory agency, which is that much of the media does not simply report the facts, it advocates a position. Few knowledgeable people are passive about FDA, and this includes knowledgeable reporters and editorialists. Indeed, I have always been impressed that most FDA watchers have quite strongly held opinions about what FDA should and should not do, and are not terribly reticent about expressing those views. This is certainly true for today’s press, and it most certainly is true for the Wall Street Journal, which apparently has yet to conclude a series of irate editorials concerning FDA’s failure to approve tPA in May of this year. (FDA has since approved tPA, and while I have not read that the WSJitself has taken credit for shaming FDA into the action, I have seen stories in other publications giving them that credit.) While I believe the WSJ’seditorials to have been wrong and at times bordering on the scurrilous, I credit them for keeping them on the editorial page . . . for carefully separating their editorial opinions from the fair and factual reporting of both sides of the controversy to be found in the rest of their paper. Not all reporters have the expertise or integrity of those of the WSJ. I have long been distressed by reporters who camouflage, knowingly or not, their strong advocacy of a position as simple reporting of the news. The number of “news reports” concerning FDA that should, in all fairness, have been printed on the editorial page is too large for me to count. Thus, the media often carry on a kind of double function: not only do they convey to the public factual information about FDA and its actions, thus serving an important educational function, the media also will pitch their views, their beliefs, their opinions, as to what is right and wrong about the FDA. And that is not necessarily education, it is solicitation to a certain point of view. Editorializing in a news story may be acceptable, as long as the distinction between that and unbiased, factual reporting is made plain to the public . . . which too often is not the case. Now: how does industry fit into this picture? You all know the story that illustrates the distinction between involvement and true commitment. When it comes to ham and eggs, while the chicken is somewhat involved, the pig is totally committed! And when it comes to FDA regulation, the role of the pig is played by the regulated industry. To industry, ideal regulation is a fair, unbiased, scientific, speedyreview of the data put before the regulatory agency, followed by a timely decision, well explained. Most of the people in the pharmaceutical industry who work a lot with FDA think that the regulatory process falls somewhat short of their ideal a majority of the time, particularly with regard to the time taken by the review process. There are many reasons for slow reviews. Many times the information provided to FDA is insufficient for one reason or another: often, the data given to FDA are questionable or clearly flawed; or the data raise yet other questions and thus more data are requested and more studies needed. Presenting data to advisory committees takes time; there are disputes to be settled, and so on. After all, much of science is the skillful asking of questions. All of this would not be as much of a problem as it now is, if it were not for what I think is a peculiarly American flaw in our regulatory system. The most serious problem affecting the relationship between our industry and our regulatory bodies is cultural: and it has to do with a certain lack of trust, a hearty
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suspicion on the part of Americans as to the integrity of their institutions. Certainly, the last decades of Watergate and Viet Nam and crooked judges in Chicago and other such episodes have not helped ease that suspicion. It is simply that many people do not believe that representatives of industry and government can talk directly to each other without some sort of hanky-panky developing. There is an almost hysterical distrust of industry by many consumer groups; and they and other “watchdog groups,” and much of the press, seem highly distressed whenever regulators and representatives of the regulated industry talk to each other outside of their presence. Now, I am from Chicago; so you do not have to tell me about crooked officials, smoke-filled rooms, or people selling out. And I am aware of instances in the recent past when persons in responsible positions within FDA did not distinguish themselves or the Agency with regard to their relationships with industry. Japan, on the other hand, has a marked advantage over us in that in their culture, it is expected that government, industry, and universities work closely togetherthey are encouraged to do so. There is no concern about a “revolving door” between government and industry in Japan. . . there is no door at all! Yet, in the United States, the fact that the FDA, looking for a specific type of expertise, might hire someone from the industry is cause for alarm. And that an FDA employee leaves government service and goes to or returns to industry is cause for panic, in some circles. Even FDA using as expert consultants individuals who know a lot about the subject because they have worked at it on behalf of industry is viewed as unacceptable. It is as if the only persons who should work for or advise government are individuals who are totally ignorant of the subject at hand, and thus free of any taint. Commissioner Frank Young recently said that the single most effective thing that could be done to speed the approval of good new products by FDA would be to improve communication between the Agency and the regulated industry, particularly early in the process. Were there better communication early on about the design of studies to be performed, what data FDA needed and why, etc., a lot of time could be saved. Such discussions should go on throughout the IND process. Those sorts of valuable discussions do not happen for at least three reasons I can think of right away. First, it would be almost impossible in our culture to have such meetings between regulators and industry. Trade secrets and proprietary information would have to be protected; and Ralph Nader simply would not approve of such closed, “secret” meetings. There would be the old, familiar charges, oft disproved, that FDA had “sold out” to industry. Second, when I did try to encourage such meetings, some FDA personnel resisted. Some resisted for a practical reason: they simply could not find the time. Others, though, had a more serious, philosophical objection: they did not want to have to commit themselves at the front end of the process as to what would be necessary to gain approval of the product. They did not want to go out on a limb, for fear it would later be sawed off by and used as a club on them at some point, probably in a Congressional hearing! In a real way, this relates to my earlier discussion of Congressional scrutiny. It is much safer for regulators to sit back and say nothing, until industry shows up with something. The regulator can then look it over and say, “Yes, this is it,” or, “No, this is not it.”
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If a regulator had committed himself or herself as to what likely would be acceptable, early on in the process, then he or she might feel obligated to accept what was presented, and be less likely to demand additional, needed, information. This, of course, could lead to an error which would increase the risk that the regulator could be hurt by Congress, or even his embarrassed agency. Another problem impedes rational discourse between regulator and the regulated. Often, in my view, industry is simply too meek in its relationships with government. Recently, when I castigated a CEO of a major pharmaceutical firm for being too deferential to sloppy science coming out of FDA, he reminded me of a statement attributed to Voltaire: “It is dangerous to be right, when the government is wrong.” Someone else once said, “People who think they know everything are very irritating to those of us who do”; and industry scientists simply do not want to run the risk of irritating the government know-it-alls. There is a real fear on the part of regulated individuals of offending FDA reviewers and thus suffering their wrath. Remember, it is industry’s ham in the pan . . . and it does not matter too much to FDA if it lays an egg once in a while. Fear ofgovernment retribution increases when everyone reads the kinds of speculative stories that recently have wondered whether FDA’s refusal to approve tPA several months ago was to punish the drug sponsor for its alleged arrogance in refusing to answer some FDA questions, and presenting what FDA considered sloppy data. In my view, that is utter nonsense. It was, after all, an advisory committee that refused to recommend approval of tPA in the first instance. In our society, the only answer I can think of to any of these concerns about the relationship of the regulators and the regulated is relatively simple: it is open government. If a regulatory agency will conduct as much of its business in the open as is legally possible, using a wide range of advisors and consultants, then suspicions and fears such as those I have described can be held to an acceptable minimum, and the substantive issues-moral, ethical, and scientific-can receive the proper attention of all concerned. And now I come to the last of the reasons that the regulatory ideal is not often achieved, which is that the Agency personnel are not perfect, either. No one can work long at FDA without realizing that a large number of the people who work for the Agency are terrific. If they were not, they would not be so eagerly sought after by industry! And yet, all organizations, including the University of Illinois, have some lazy people and some people who are not too nice. But, I do not think that is so serious. There are two other problems, however, that I view with more concern. I was asked once what the most difficult aspect of my role in FDA was. The answer was easy: it was recruiting all the first-rate scientists the Agency needed. I found it hard to recruit against universities and the National Institutes of Health and Industry, and I do not think the situation has changed. To be specific, we simply could not recruit enough clinical scientists in all the disciplines needed by FDA. For a time, we were without an ophthalmologist, as one example. We made up for that lack by using advisors and consultants; but FDA must have a complete complement of terrific people, if the ideal is to be met. And, lastly, if you do have good, bright, well-trained, aggressive people in your organization, you will find that they often have their own strongly held views and
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sometimes their own agendas for action. This can result in serious conflict within the Agency, and, on occasion, be embarrassing. In ordinary circumstances, such conflict can and should be settled within the organization. But, when investigative reporters or Congressional staffs get wind of such a controversy and take sides, then things can get very sticky. Again, a smart industry wants no part of such an internal Agency squabble, and will stay as far away from it as possible. On occasion, a controversy arising within FDA is not ordinary, however, and is worthy of public debate. One such question I dealt with was raised again in another form by the tPA debate. The question was whether it was sufficient for the drug sponsor to demonstrate only that tPA dissolved a fresh clot in a coronary artery, or whether they had also to show improved cardiac function. That FDA’s advisory committee, and FDA, wanted answers to both questions seems to have enraged the WSJ. But, I think, they miss the scientific rationale for the question. A similar discussion years ago revolved around the question of whether demonstrating simply that a drug lowered blood pressure was sufficient grounds for approval of the drug. Some FDA staff argued that it must also be shown that there was some benefit to health in so lowering the blood pressure. This controversy had something to do with the Agency’s apparent difficulties with regard to approving new cardiovascular agents, back then. Again, public discussion of this and other such basic questions is morally necessary, and their resolution can help move us toward the ideal regulatory process by increasing the public’s understanding of the role of the regulator. One would hope that this increased public understanding will change the cultural bias a bit and allow FDA the freedom to work more closely with industry than has been permitted in the past. I could suggest a few other things that might improve the process. Remember, I said earlier in these remarks that what FDA needed to do the proper job was public support, legislative authority, money, staff, and independence. I have talked a lot about public support. To some extent, events, such as the series of editorials by the Wall Street Journal saying the FDA is seriously flawed, or recent efforts in California, stimulated by the AIDS crisis, to set up their own drug review process, erode the public’s confidence in our regulatory bodies. The antidote is information and much more public education . . . and public debate of the issues. I think the Wall Street Journal is correct in saying that the issues it raises need to be discussed. I would think that Congress would be concerned, too; but I do not think we will see anything between now and the next presidential election but another series of hearings into FDA’s failures to protect the American public. In sum, what stands between the ideal of regulation and the reality is the peculiar nature of our culture, with its freedoms and independence of speech and press; and our Congress, which does what it thinks it ought to do; and the checks and balances inherent in the way we govern ourselves. What stops us short of perfection are the imperfections of people and the limitations of our science. I doubt that we will ever achieve the ideal; but we can, and no doubt, will, do better in time, if we pay attention to some of the issues I have put before you today. Thank you.