Session 5: Biotechnology and Public Policy: Role of the Food and Drug Administration (FDA).

Richard A. Merrill, M.A., LL.B.,
Daniel Caplin Professor of Law and Sullivan & Cromwell Research Professor,
University of Virginia School of Law, and Of Counsel, Covington & Burling, Washington, D.C.

James S. Benson, former Acting Commissioner, U.S. Food and Drug Administration.

PROF. MERRILL: I appreciate the invitation to come and spend the morning with you and discuss these issues.

I don't have any slides. Most lawyers don't. I don't have any PowerPoint presentation. Lawyers are just learning to use that technology.

I do have a speaking outline that I prepared and shared with Mr. Snead, and I understand the members of the counsel have it, and I'm entirely happy to have it shared with any member of the audience if there are copies available.

I should put on the record that in addition to my academic position at the University of Virginia, I am of counsel to the Washington law firm of Covington & Burling, which has a very substantial FDA related practice.

I say that not because it influences, I think, anything I'm about to say, but members of the council and members of the public are entitled to know about that. I have not consulted with any client; I don't have any client that has an interest in the subjects before the council, I believe. At least I'm not aware of it.

So that the comments you hear, to the extent that they're judgmental, are my own views, not the views of anybody else.

Let me say I'm entirely happy to have questions as I go along about anything I have to say, and this outline can be restructured on the fly, you might say, as we proceed.

The central question I think I have been asked was to address the FDA's legal authority with respect to reproductive technologies generally and very particularly with respect to the use of cloning technology to reproduce the human being.

I guess I should start by commenting briefly on what FDA has said about its own authority, and you are familiar with that, perhaps not familiar in detail with the various settings in which the agency or its representatives have spoken to that question, and it's a little hard to address it head on precisely because the expressions of agency authority have been rather informal, spread over a period of three or four years, and have not taken the form that one would ordinarily expect an assertion of regulatory authority to take, which is to say a publication in the Federal Register which analyzes all of the issues and the pros and cons and possibly even invites public comment on the prudence and legitimacy of the exercise of authority.

The FDA's expressions in this field commenced with an answer to a question that was posed to the then Acting Commissioner, Dr. Friedman, on Diane Rehm's radio call-in show here in Washington, and he was, I take it, asked does the FDA have any role in this field, and he says, "Yes, we can regulate cloning technology. It's a form of gene therapy."

I'm using my words, not his. We don't have a transcript or at least I've not seen a transcript.

There have been subsequent statements, communications to IRBs, congressional testimony, and looking at them in aggregate, the substance of the agency position appears to be that any use of cloning technology to produce a human being requires advanced FDA approval in the form of an investigational new drug application, essentially an exemption from the requirement for (FDA prior approval) of marketing and distribution of a drug for administration in clinical trials.

And then the agency quite clearly went on to indicate that it was not at the present time prepared to approve an application for an investigational drug application or in the vernacular of my field, an IND.

That position in substance meant that any application of cloning technology to produce a human being was in the agency's view forbidden by the Federal Food, Drug and Cosmetic Act and thus potentially punishable with the sanctions that that act provides, which include the possibility of criminal prosecution.

Now, the agency didn't spell it out in that detail, but that's the necessary implication of a conclusion that you need approval, and if you don't have it, you violate the statute by proceeding.

The agency has never quite squarely addressed the question whether or not this assertion of authority ought to have taken the form of some pronouncement in the Federal Register at the time it was first made back in 1999, but it appears to be the case that the agency attributes to two earlier statements that did appear in the Federal Register some explanation of its regulatory authority in this field. One is a 1993 statement in which the agency said, "We are going to commence regulation of gene therapy trials and require IND approval before those trials go forward."

At that time, incidentally, it invited public comment on the appropriateness and the legality of that assertion of authority and proceeded to respond to those comments in subsequent issues of the Federal Register.

The other document that the agency has pointed to is a 1997 publication in which it described its future plans for the regulation of so-called tissue and cellular therapies. We can come back to either of those two documents if there's interest in probing their plausibility as sources of, if not authority, at least explanations of authority.

The question then is does FDA have the authority that it has claimed? If it does, it has to be found in the laws and regulations that were on the books prior to the announcement of Dolly's birth because nobody suggests, FDA has never suggested that there is some new law passed subsequent to that time or some new regulation adopted subsequent to that time that provides the legal underpinning for the assertion of FDA's regulatory authority.

In some sense you can say it is law that has been there for some time even though, as everybody would acknowledge, the word "cloning" does not appear in any regulation or in any statute for which the agency is responsible.

There's really only one of the laws that the agency has authority to administer that could purport to give it authority to regulate and prohibit clinical experimentation, and that's Section 505(i) of the Federal Food, Drug, and Cosmetic Act, which is part of the statutory provision that empowers the FDA to require applications for and grant approvals for the marketing of pharmaceuticals, drugs within the meaning of the statute.

Section 505(i), in effect, authorizes the FDA to waive or exempt clinical research from the prohibitions of the statute that say you can't distribute in interstate commerce a drug that the FDA hasn't approved. This is an authority to grant exemptions for the very purpose of permitting clinical investigators to undertake the kinds of studies that will generate the information necessary to support approval.

And it quite clearly is a provision that Congress contemplated would be available to the agency to permit clinical research to go forward to generate information that would be necessary to allow a sponsor of that research to come before the agency and seek approval for the product.

At this juncture it is worth observing for just a moment that FDA's legal authority, in general, is the authority to regulate the distribution of products rather than directly the authority to regulate activity, it regulates a good deal of activity surrounding the distribution of products, including as I've just described clinical research to generate information about drugs and, for example, the process of manufacturing drugs or devices that had been approved.

But the linchpin of the FDA's authority is focused on products. Its jurisdiction is defined in terms of products, and those products for the agency to have authority to regulate them have to have some linkage with interstate commerce. It might not be much of a linkage with interstate commerce, but some.

So let's look a little more closely at FDA's legal theory for regulating and for the present at least prohibiting cloning research involving attempts to reproduce the human being.

For this authority under the Food and Drug Act to attach, there must be involved a drug because it is the authority to exempt from the requirement of approval of drugs clinical research designed to get information about their safety and effectiveness.

It's probably the case that Congress, when it gave FDA this authority, thought of drugs as being things that people made, that were manmade, but I don't think that anybody any longer would disagree with the agency's assertion that a drug can be something that is found in nature or found in human beings and manipulated or adapted for therapeutic use. So that a gene fragment could be a drug or a tissue sample derived from a cadaveric donor could be a drug or a medical device potentially.

Assuming a product is a drug -- and I'll get back to the qualifications that must be satisfied in just a moment, it has to be a new drug. That's a legal technical term for a drug that is not generally recognized as safe and effective, and one would have no difficulty in this context establishing that newness, that novelty that would justify FDA's general assertion of regulatory authority.

More difficult or more problematic is the question of whether or not the material that would be used to accomplish the cloning of a human being would satisfy either of the two prongs of the definition of drug in the statute.

To be a drug or material, let's assume it is the implanted genetic material, it must be intended for use in human beings for one of two purposes, either to treat or diagnose disease or to affect the structure or function of the body of man or woman.

It is probably the case -- and this is where the analysis gets a little murky -- it's probably the case that Congress had in mind the structure or function of an existing individual to whom the, quote, drug was going to be administered or an existing individual whose health was to be protected or improved by the result of the administration of the material.

In the context of human cloning, it's not clear whether you might say the recipient is the clone or the mother in whom the genetic material is implanted to produce the clone, and the agency has not attempted to disaggregate those two possibilities in explaining its authority.

It's not impossible, and let me stress this. I don't think it is impossible that FDA could with careful analysis and careful explication of how this rather arcane language of the Food and Drug Act applies to the technology in question could put forward a plausible legal theory that would withstand judicial review. I don't know that. I reserve judgment partly because I haven't seen that explanation offered at the present time.

And even assuming the agency could characterize what happens when there is an attempt to clone a human being as the administration of a drug to another human, I'm in agreement with Representative Tauzin who said in congressional hearings in 2001, this is something of a stretch. This is something of a square peg/round hole problem.

I received a letter from the council posing a number of questions, including the following question. Supposing FDA's assertion over human cloning were challenged, what would happen in court? And, in particular, the question is posed: would the agency's ability to call on what lawyers refer to a Chevron deference give it an edge up, a leg up in persuading a court that it was entitled to exercise the authority it has asserted?

If you'll indulge me for just a minute, this is arcane legalism. Chevron is a reference to a case decided by the Supreme Court in 1980 which involved the authority of regulatory agencies generally to administer and interpret, to interpret critically, the meaning of their own statutes.

And the Court in the Chevron case said that in addressing the question whether an agency's interpretation of its statute is legitimate, is lawful, the Court should ask two questions.

The first question is: has Congress spoken to the precise question? If it has, that ends the matter. The agency is not entitled to reject the congressional expression.

But if Congress hasn't spoken to the precise question, and that surely is the case we face, no one would argue -- I think FDA has never suggested -- that Congress has spoken to the precise question of whether FDA can regulate cloning. Then according to the Court in the Chevron case, the question for the Court is whether the agency's interpretation of the statutory language is reasonable.

And the Court was quite clear in saying that as between us, the judiciary and the Executive Branch, in cases of statutory ambiguity the weight of the preference ought to go to the Executive Branch. They're politically responsible for the administration of the law.

So the question in this context would be whether FDA's interpretation of Section 505 of the Food and Drug Act as applying to cloning, attempts to clone a human being, is a reasonable interpretation of the statutory language.

I don't think anybody could argue that Congress has spoken to the question, as I said before. So we really are at what is know as Step 2 of Chevron, and I think there are two difficulties that FDA would encounter in trying to rely on this so-called Chevron deference to support its interpretation.

One is that it is not at all clear that the Supreme Court meant to include in its granting of agency discretion interpretations of an agency's jurisdiction. That is to say it's not at all clear that the Court was prepared to say that executive agencies are entitled to decide what they can regulate as opposed to how they can regulate what is clearly within their dominion.

Second and more importantly, I think, in a more recent case two terms ago, a case called Mead v. United States, the Court said that Chevron deference to an agency's interpretation is to be given only when the interpretation is proffered in the context of a proceeding that has the force and effect of law, which is to say in the context of proceeding to apply law to a particular product or enterprise in an adjudicatory proceeding or in the context of a rulemaking proceeding in which the public is invited to comment on an agency proposal and the agency makes a final determination.

FDA has done neither of these to proffer its assertion of authority to regulate human cloning, and so at least Mead would cast doubt on its ability to invoke Chevron deference in case of a challenge that came up in Court.

I think as I've suggested in a pair of articles, one of which is in the materials, I think that the agency would have been wiser if it had asserted its regulatory jurisdiction in the form of a document in the Federal Register and explained how the statutory language fit the phenomenon it sought to regulate and offered the opportunity for members of the public who wished to support that interpretation or wished to question it to submit comments to which the agency would then at a later stage be obligated to respond.

They didn't do that, and I think that that's an additional difficulty that they would have to surmount if there were a challenge to the agency's legal authority.

Now, let me take a few more moments, if you will, and just comment on some of the other questions that were put to me in the letter from the council. I've addressed a couple of them in the context of this presentation, including the Chevron deference question.

But there are some others that perhaps would help the council for me to address. The first is essentially the question, is FDA's authority limited to products or activities surrounding products that are commercial in nature? Do drugs have to be or things that might be drugs have to be commercial, intended to be marketed and sold?

The answer is no. There needs to be an interstate connection. There needs to be -- the agency's authority is couched in terms of its authority to regulate shipments in interstate commerce, but it can regulate shipments in interstate commerce of drugs that are not approved whether or not there is a commercial interest either on the part of the sender or the recipient.

So if a researcher at University X wishes to send a material to a researcher across a state line at another university with neither researcher having in mind the ultimate commercialization of that material, if that material is a drug, the Food and Drug Act would apply.

The second question I was asked was whether FDA has authority to take into account in addition to safety and effectiveness the sort of linchpin criteria of the Food and Drug Act, the morality of products or activities surrounding products, and if so, where does that authority derive from the statute?

That's a harder question to answer in general terms. The statute that the agency invokes, Section 505 and its exemption authority for clinical research on drugs, quite clearly contemplates that FDA will take into account the ethical dimensions of the proposed clinical trial, the safeguards of the participants in the trial, the elicitation of informed consent and the like. That's explicit in the statute.

It's also entitled to take into account other unmentioned criteria designed to support the public health, and it's not farfetched to think that one might use that language as a jumping off place for exploration of questions that begin to approach the moral and at least depart from safety and effectiveness.

But I think it's fair to say, and I don't think FDA would argue to the contrary, that it has some over arching obligation or authority to take into account the question of whether or not it is moral to undertake a particular investigation, assuming there are no safety and effectiveness questions.

And Dr. Zoon was forthright in congressional testimony a year and a half ago when she was asked essentially: if you were satisfied that a proposed research project did not raise any questions of safety and effectiveness, would you still withhold approval?

And she said no. That is, she seemed to be saying that the benchmarks for our authority were safety and effectiveness. I don't think she would have disagreed that if there were some questions about the adequacy of informed consent, the adequacy of protections for the participants, that the agency couldn't take that into account. It surely could.

The next question had to do with FDA's authority to regulate a host of other kinds of reproductive technologies and services and products, and I really despair of attempting to provide an answer product by product or technology by technology.

I do suggest that if the question is could FDA regulate research applying these technologies, the question would have to be addressed as I've tried to address it in the context of cloning by examining the language of Section 505(i) of the statute and seeing whether or not that particular activity could be made to fit within the definition of the drug, that is to say, the definition of a product designed to prevent disease or treat disease or affect the structure or function of some individual's body.

Some technologies might be reached; others might not be under that analysis. But that was the core starting place.

It's of some interest, I think, that FDA has not by and large attempted to assert drug-like authority over other reproductive technologies. It has effectively a year ago required the registration of so-called tissue banks that provide reproductive tissue, and it has proposed regulations that would require screening of donors of reproductive tissue and require the observance of so-called good tissue practices in these kinds of facilities.

But notably it is not suggested that the materials that these facilities are providing are drugs or that the clinical experimentation with these materials require FDA approval under the provisions that it has sought to apply to cloning.

Now, there may be a reason for that. There are doubtless a number of good reasons. One that occurs to me that I thought I would call to your attention is that for FDA to say that these services involve the dispensing of drugs that require FDA approval would be to put these enterprises out of business immediately because by definition, none of these technologies have affirmative approval. They might be able to get it, but in the meantime they couldn't lawfully be merchandised, distributed.

FDA encountered this problem about 25 years ago when it was asked why aren't you regulating all IUDs as drugs, requiring them to be proven safe and effective, and the agency's answer was if we were to do it now, all of the IUDs in commercial distribution would be unlawful, and all of the women in whom they had been installed would be you might say repositories of illegal drugs.

So cloning is a little bit different. Presumptively cloning is a technology not yet applied. We may have a recent exception, but let's assume we don't, and so FDA's assertion of authority is not to interrupt an activity that is ongoing, but to forestall an activity that has not yet commenced.

But with respect to the other reproductive technologies in increasingly wide use, the agency's legal instrument is not well calibrated for you might say graduated assertion of regulatory authority.

Let me address just two more questions. One is the question of whether or not it makes a difference whether FDA asserts its regulatory authority in an informal way through a radio call-in show and congressional testimony or a rather more formal way in the Federal Register.

I think it does make a difference for two reasons. One is the latter procedure would give the agency considerably greater standing if its assertion of authority were challenged in court. And, two, the process of publishing a proposal in the Federal Register and eliciting comment often results in an improved end product because you learn from people who comment about problems that you hadn't anticipated and difficulties with your analysis that you had not addressed.

The final question was if FDA's assertion of authority in this or related areas were challenged, would it win or lose. I put my gloss on the question that was posed. That's not the kind of questions that lawyers like to answer, and I won't answer this one directly.

I don't think one can know because the agency has not yet put forward its best case, its clearest explanation.

I would stop simply by concluding that applying the Food and Drug Act is not easy in this context. I think it's something of a stretch, but maybe not an illegitimate stretch to attempt to apply it to cloning, and if we saw a challenge in court, we might get the best explanation that the agency has to offer.

I'd be happy to address any questions.

CHAIRMAN KASS: Thank you very much.

Let me start with a couple of questions of my own and try to generalize from the comments made about the cloning example. And let me shift from, let's say, cloning to uses of genetic technology. For the sake of argument, let's grant that the FDA has some authority to regulate things that would be put into a developing organism, and let's say to begin with it would be able to approve its safety for use in, say, therapeutic purposes.

But the very same techniques could be used for purposes beyond therapy. For example, I mean, to mix cases, we've been talking about the uses of preimplantation genetic diagnosis. This is not genetic intervention, but just screening and selection for the prevention of disease, but also possibly for the selection of sex of offspring and the like.

The question goes to the matter of sort of multiple uses of things for which approval is granted. Is the agency in a position to offer approval for technological developments under its statute and to have any kind of restriction as to what uses might be made of this once this goes forward?

It's even more interesting, I guess, in the case of drugs where multiple uses for the treatment of disease or for behavior control are, you know, notorious, and the question is: is there some way for the agency actually to look at the multiple possible uses of these drugs or products and discriminate amongst them in offering approval or once the thing is out there, it has nothing further to say?

PROF. MERRILL: Let me start by accepting the assumptions you asked me to accept.

CHAIRMAN KASS: Please, yes.

PROF. MERRILL: Which are strong assumptions, if not heroic. So the question is: can the FDA regulate, you might way, the unapproved uses or the unevaluated uses of a particular technology?

Let me make one preliminary comment. The drug definition is not just for products that are aimed at disease prevention, diagnosis or treatment, but products that are aimed at bodily improvement or change because a drug can be something intended to affect the structure or function of the body.

And that can be in quite benign or cosmetic or we might say trivial kinds of ways, but it nonetheless would make it a drug.

But more permanently I think the question is supposing the FDA has evidence of safety and effectiveness for some therapeutic use, but the technology that it is approved for that therapeutic use has potential so-called off label uses in the practice of medicine.

The FDA's position is, and I think well established, that it doesn't have legal authority to interdict a physician's decision to use an approved technology for any purpose he or she thinks prudent for the patient. If the distributor of the technology seeks to encourage or elicit that off label use, the FDA would take the position that that's a promotion of an unapproved product, and it is illegal.

But the FDA would say if it's out there and it is promoted for the use that we've approved it, the fact that doctors are using it for something else again would not be a basis for our taking regulatory action, and there are lots and lots of examples in the therapeutic arena in which drugs are used successfully off label, and indeed, I understand in the treatment of cancer that more than half of the chemotherapeutic agents in widespread use are used off label in ways and in combinations that FDA has not approved.

CHAIRMAN KASS: So could I generalize that you have authority over the producers and the marketers, but not over medical practice.

PROF. MERRILL: That's a fair summary.

CHAIRMAN KASS: That would be a way into this.

PROF. MERRILL: Yes.

CHAIRMAN KASS: Would you light up? Thank you.

MR. BENSON: I just wanted to add to what Mr. Merrill suggested. In the '97 amendments that were primarily aimed at medical devices, there is a provision there -- and, Dick, you can help me with this -- but that basically says if the FDA assumed or thinks that a device might be used in an off label way that would be detrimental, it can require the manufacturer to label, you know, with that.

In other words, this product is contraindicated for a use that they are concerned about, and I don't think that applies to drugs. That's the part --

PROF. MERRILL: No, I think it could. I think the FDA could say if it were concerned about the safety of a use of product that was approved for some other purpose and it wished to warn physicians that they oughtn't to use it for some plausible off label use, it would not be impermissible for the agency to insist that the manufacturer provide labeling to that effect.

CHAIRMAN KASS: Thank you very much.

Comments, questions? Janet Rowley, Frank.

DR. ROWLEY: Could you clarify a little bit more for me? The example that you gave of an investigator providing a drug to another investigator in a different state, for that investigator to use for some purpose or other, that that would actually be subject to FDA scrutiny?

PROF. MERRILL: I did say that. I think that's the right legal answer. If you're asking the question I think you're asking, which is does FDA spend any time worrying about those instances, the answer is probably no.

There's a lot of under enforcement, you might say, of the requirements for investigation of the new drugs in the noncommercial context.

DR. ROWLEY: Right, and you did also include DNA amongst or within the definition of drugs, and of course, people are shipping pieces of DNA all over the world, usually with material transfers, agreements in place, but it never occurred to me that this would even fall within the purview of the FDA.

PROF. MERRILL: Well, I mean, if the FDA were assiduous and intrusive and had a lot of resources, it could make an argument that it was entitled to regulate and require advanced approval for that. It wouldn't prohibit it. It would say, "Come and ask us to do it."

If it were quite clear though that the purpose of the shipment of the gene fragment was to allow another person to treat a patient, that shipment is the shipment of a drug, and if the treatment is experimental, it is an investigational use of the drug, and in theory at least, FDA approval would be required.

I'm sure that the FDA doesn't have a regulation that says it just like that, but if the FDA were to ask a former lawyer could it do something, I'd say yes.

DR. ROWLEY: But then most of this, of course, is just for laboratory experiments.

PROF. MERRILL: In which case the material probably wouldn't satisfy the drug definition.

DR. ROWLEY: Okay.

PROF. MERRILL: Because it is not intended for therapeutic or reconstructive --

DR. ROWLEY: Right, and if it were actually going to be used for a patient, then an individual would have to go to their Institutional Review Board to get approval to use that, I would think.

PROF. MERRILL: Could, could, and it is not unknown for individual physicians at research institutions who have received an agent from a pharmaceutical manufacturer to go before the Institutional Review Board and say, "I'm undertaking essentially an experimental use of this agent."

And the companies increasingly will require the recipients of the agents that they are distributing to do that in order to protect themselves against potential liability.

CHAIRMAN KASS: Frank Fukuyama and then Rebecca.

PROF. FUKUYAMA: Well, thank you. That was very helpful, and it seems to me it underlines the need for Congress actually to express an opinion in this area to clarify the authority.

I have I guess two different questions. If you were back in your old job at the FDA and doing this properly, putting the assertion of authority into the Federal Register and making the best case for it, how would you deal with the following problem?

If you are basing the authority on the FDA's ability to regulate on the basis of safety, it seems to me that there is two very different safety concerns between reproductive and research cloning. In the first case, it's presumably the safety of the mother and of the cloned child, and in the second, it's the safety of the patients that receive the products that are derived from the stem cells that come out of the research cloning.

But they are two completely different safety issues. I mean, do you think that if you were trying to make the case for this assertion of authority, you know, this is something that you could deal with adequately?

PROF. MERRILL: Well, not without difficulty, but I think one could construct a legal theory. I think the protection of the mother, the surrogate mother for the transplanted clone, the implanted clone is the easiest case. If the mother is in jeopardy, potentially at risk by virtue of her exposure to this, quote, drug because it needs to be a drug for her receipt of it to be subject to the drug approval requirements, I think that would cover it.

In some sense, with respect to the safety of the clone, you're asking a question about the safety of the, quote, drug, which is something of an oxymoron. It's an odd fit.

PROF. FUKUYAMA: That's why I'm saying legally can you square that circle?

PROF. MERRILL: Well, I think it's a tough case, a tough case. I think the third case, the concern about the safety of people who might receive the technology that is derived from the stem cells derived from the cloned embryo, I think that is addressable, but not at the time that the embryo is being cloned and the stem cells being derived and then being manipulated to produce a therapeutic agent.

It's at the point where that therapeutic agent is going to be administered to people with the disease it's intended to treat that FDA regulatory authority would operate, and in that context, I think it would not be difficult to make the case that if there is doubt about the safety of that administration, FDA is entitled to withhold approval of an IND and to require an IND as a threshold matter.

PROF. FUKUYAMA: Right. Then a slightly different issue, and this may be beyond your particular knowledge, but at Tab 15 we have this Wall Street Journal article about the FDA intervening in ooplasm transfer, this recent case that occurred, I guess, in July 2001, where they actually intervened with an IVF treatment and said that it couldn't be done.

We have heard testimony from Dr. Opitz yesterday, from Dr. Schatten in our previous meeting in December particularly about ICSI, where you have a clinical procedure that seems to have gotten way out ahead of the underlying science and in which even the practitioners seem to raise some real questions as to, you know, the safety of the procedure, and yet the FDA has not intervened in that area, but then they do intervene in this area of ooplasm transfer.

I mean, is this just completely arbitrary? I mean, is there any grounds on which, you know, you ignore one and you intervene on the other?

PROF. MERRILL: Well, I'm not familiar with the case at all. So I won't comment on the case. I'm not comfortable with the implication that FDA is whimsical. I don't think it is whimsical. I think it regulates fewer activities than it would be entitled to regulate under a strict reading of the statute and, as a result, necessarily it is selective in its regulation.

And I think there are usually plausible reasons for that. I won't speculate on what they might be in this case.

In the case of tissues banks that provide reproductive tissues, sperm and eggs and oocytes, the FDA did not, when it initially entered the field of tissue regulation in 1993, regulate those products. It made a conscious decision, though an unexplained decision, I should add, that it was not going to attempt to regulate, not going to require registration, not going to require donor screening.

They clearly thought about it because it's spelled out in the Federal Register. They stopped short. Then seven or eight years later they decided they could no longer justify that exclusion because these enterprises posed the same kinds of disease transmission risks that tissue banks that provided hard tissue presented and, therefore, ought to be regulated in the same fashion.

That's a self-conscious decision for which I think one could offer quite plausible explanation. States were doing a lot, California and New York, in particular. It may have been in deference to state authority that they ultimately abandoned.

CHAIRMAN KASS: If I might just comment, Frank, I think I'm right about this, that the ooplasm transfer prohibition is, I think, conceived of as a kind of experimental therapy on the child to be where the ooplasm transfer happens to be coincident also with the sperm transfer, which produces the individual at the same time as one somehow altering its make-up, whereas I think ICSI is not understood to be therapy at all, but simply a new form of initiating a new life, and part of this unrelated area, assisted reproduction in general, at least as I've heard the attempt informally, not in print, to explain how one comes to treat cloning to produce a child as a drug is that you regard the cloned embryo as a foreign body, placing the woman at risk rather than to treat it.

So in one case you're treating this thing as if it is a patient subject to harm by genetic manipulation, and in the other case you're treating it as the thing capable of causing harm to the woman who's bearing it.

PROF. MERRILL: Yeah, they have not attempted to in any document I've seen. Now, I may have missed something, but they have not attempted to disaggregate the risks to the to be cloned child from the risks to the carrying mother.

CHAIRMAN KASS: Right.

PROF. MERRILL: And it may well be that they thought it legitimate to entertain concerns about both without explaining how one might be an odd fit with the statute.

CHAIRMAN KASS: Right. Rebecca Dresser, please.

PROF. DRESSER: I had three questions. One was about another group of human beings involved in a form of cloning, and that would be research cloning. If, you know, as California and some other places say they would like to create a cloned embryo to study or derive the stem cells, that would require women to provide the oocytes. I wondered if you had given any thought to -- I believe there have been claims that the FDA would regulate this, and you know, it wouldn't be for a product. It would be the creation of a clone for a research tool.

Do you have any thoughts on that?

PROF. MERRILL: I haven't thought about that, and I'd like to be cautious in responding without knowing more facts. I think that's a stretch, to be perfectly honest.

It's pretty clear if you accept my premise, and I think FDA has accepted my premise, that their authority in this arena stems from this power to grant exemptions for clinical research involving human subjects, from the general requirement that drugs need advanced approval; unless you can fit the activity within that category for which it's entitled to grant the exemption, the FDA wouldn't have the authority to regulate.

PROF. DRESSER: Right. Thank you.

The second question was some claims have been made that if the FDA tries to regulate cloning to have a child, there would be constitutional objections or barriers to that. Do you have any remarks on that?

PROF. MERRILL: The last time I taught constitutional law was 1982. So this is even more treacherous territory.

There was an interesting article by Cass Sunstein in the Hastings Law Journal (53 Hastings Law Journal, 987, 2002) in which he dissected that argument and I thought pretty convincingly. I don't offer an independent judgment, but I've not seen an article that convinces me that there is a congressional or constitutional impediment of that sort.

There is, I think, a constitutional question which nobody has seriously addressed yet, and that is whether the Constitution in Article I affirmatively grants the Congress the authority to regulate, to legislate in an area whose ties to interstate commerce are as remote as this activity seem to be.

PROF. DRESSER: Yeah, we have talked a little bit about that.

And then my third question is you mentioned that you thought that one reason the FDA has not tried to regulate the new ART approaches as, you know, new drugs that would have to go through the study process is because you'd have to put people out of business who are practicing these things now.

And I wondered if there's a mechanism in between the two, you know, not regulating at all or starting as if it were at the beginning where they might say we want you to be following the children to see how they're doing. We want you to submit the uses of this, you know, for an IRB review and start studying without putting them out of business.

PROF. MERRILL: So long as the FDA is viewing these technologies as involving in some fashion the production or administration of drugs subject to the drug part of the Food and Drug Act, I think the agency is probably confronted with this binary consequence. You either don't regulate or you regulate more than you would like.

The medical device law for which Jim Benson was responsible for many years is a more finely calibrated instrument, and it allows the regulation of products that don't necessarily require pre-market approval. I haven't thought through how that legal instrument might be made applicable to these kinds of technologies. I suspect perhaps some people at the agency have thought about it, but if you declared these technologies to involve medical devices, that does not automatically entail the conclusion that they require FDA affirmative approval before they can continue to be used.

PROF. DRESSER: Thank you.

PROF. MERRILL: But I guess it goes without saying that to apply the labeled device to a gene fragment might seem even stranger than to apply the labeled drug.

CHAIRMAN KASS: Thank you very much.

Let me propose that we ask Jim Benson to make his presentation. We'll then discuss it, and then we can discuss this topic as a whole.

Please.

MR. BENSON: Thank you, Dr. Kass.

I want to brag a little bit. I did prepare slides all by myself yesterday, and so you know, Dick was concerned about that. You can withhold judgment on the slides, too.

I appreciate the invitation and look forward to talking with you.

I just screwed up the thing here, you know.

Let me summarize my background. I was in the Public Health Service for 27 years, 20 of those with FDA in various positions. I was Deputy Commissioner from July of '88 through July of '91, and during that time I served as Acting Commissioner for a year, 1990.

From July '91 through December '92, I served as Director of the Center for Devices and Radiological Health, and after retiring from federal service in December of '92, I joined the Health Industry Manufacturers Association, now renamed the Advanced Medical Technology Association, or AdvaMed, as Executive Vice President for Technical and Regulatory Affairs.

I retired from AdvaMed this past July and have done limited consulting and expert witness work since then, and at the present time I'm not engaged in any consulting work or any work that would pose a conflict of interest with this council.

I'm not having too much luck. Why is Computer 1 up there? There we go.

I wanted to just as an aside mention that Mr. Merrill and I didn't collaborate on this, but I think the two presentations dovetail extremely well. I was impressed with that, but it was by accident, not on purpose.

Also, I have a copy of the paper which I supplied to your staff, and that's certainly available to anyone you want to give it to.

As with Dick, the council staff provided me with several questions that they thought would be appropriate for me to discuss with you, and I believe the best way to proceed would be for me to respond to those questions. As I understand that from the format of this session you want to hold the questions until later. That's fine or I would be happy to be interrupted if anyone would like.

Playing games here. I didn't put that part in here. I just want to make that clear.

The first question was: does FDA have the institutional competence and capacity to consider ethical and moral questions as part of its regulatory function?

Let me start with the competence part. I think one of FDA's greatest strengths is its institutional ability to handle scientific issues. Most product approval decisions have at their core whether or not the product is safe and effective for its intended use.

Another way of stating that is to ask does the benefit of the product outweigh the risk.

No other agency in this country or, I believe, in the world for that matter has more experience in weighing risk and benefit issues than FDA. The reviewers in all three medical centers in the agency have decades of experience making these decisions.

The agency requires manufacturers and users of approved products to report problems back to the agency, and as an additional step, this feedback loop, aside from being a warning signal for potential problem products, gives the reviewers an opportunity to gain more experience in that risk-benefit equation.

In addition to the agency's permanent staff, it often calls upon outside experts to advise it in scientific evaluation of a product under review. So when you combine the internal staff's scientific knowledge and experience with outside panels of experts, you have a highly competent mix.

Aside from its scientific expertise, one of FDA's greatest strengths is its ability to oversee and coordinate the regulatory process, In addition to scientific decisions it makes, it's critically important to make those decisions transparent where the law allows.

For example, it must assure that outside experts are free of conflict of interest, that investigators are held to informed consent guidelines and conflict of interest rules, that panel meetings are open, that the public has an opportunity to observe and comment, and that proprietary information is not released in accordance with the FD&C Act.

This gives you a sense of my views on competence.

As far as capacity goes, I believe that FDA isn't as strong, is not as strong. FDA's budget has remained virtually constant over the past decade, and when you contrast that against the exciting evolution of technology in all areas over the same time period, I think one should be concerned with that capacity.

A mitigating factor to this budget dilemma is the agency's authority to charge user fees for product approval applications. That authority has been in effect for about ten years for drugs and biologics and since this past October for devices.

The fee schedule varies for different types of applications, and it does provide the agency with the ability to hire additional review staff when needed.

Even more important, it allows the agency to fund an outside expert program to aid its internal review staff. This outside expert program, as I've named it, hasn't been fully utilized. For example, it could fund outside experts to work with the staff of the various review divisions within the agency on specific product applications. This would not only give added expertise to the agency for the new technologies, but it would also give the internal staff appropriate on-the-job training that they might not otherwise get because of work load priorities.

I believe this ability to bring in outside experts can be an enormous aid to the agency.

Let me now turn or address the moral portion of the question. This presents quite a different problem. Whereas I believe FDA is highly competent to handle the kind of issues that I just addressed, I don't believe it should be responsible for moral decisions. Usually it doesn't have to be.

Direction of the agency comes from the Congress. It lays out for the agency what it expects from the agency. For example, it mandates which products require what level of application and scientific data gathering.

The agency then promulgates rules and guidances based on the laws that Congress passes and the President signs. This process is straightforward, although rather cumbersome, but what happens when a new technology springs forth that Congress didn't anticipate, such as the case with technologies and practices that touch the beginnings of life.

The agency can, as it has done extend the law to cover new areas. I think Dick referred to that as pushing the envelope. It's a good concept.

It holds public meetings to get input, which can aid in the moral decision making, but this is not the primary mission of FDA. I believe that the moral decisions of this nature should be made by elected officials. Once made, FDA can implement those decisions quite competently.

The second question, does FDA have the institutional competency and capacity to regulate practices such as assisted reproduction, human embryo research, preimplantation genetic diagnosis, genetic modification of human embryos and gametes, cloning and related practices?

First, let me say I'm not technically competent to judge others' competency in these areas. I think it's important to separate competence in two parts. The first and most obvious is the technical competence. The second is the regulatory practices that I mentioned earlier or regulatory process.

I think FDA has been highly successful in the coordinating of regulatory processes. The capacity to accomplish this is a function of budget, and as far as technical competence goes, FDA and the Biologics Center, in particular, has been able to bring together technically competent people to address evolving technology for many years, many of them brought in as outside experts or as Fellows for one or two years. Many of these have become part of the permanent staff.

As I mentioned before, the ability to bring in experts to work with staff can greatly enhance the agency's ability to tackle the practices mentioned in the question.

In addition, the Biologics Center has already established a liaison committee with NIH. I'm not sure that's the right name for it, and by collaborating with other agencies, such as NIH, the FDA's technical competence can further be broadened. I should add that the Biologics Center, in particular, does have a Fellow program, but I would like to see that greatly expanded, and I think also made available to the other medical centers.

The third question is an institutional matter. Does FDA have the flexibility to respond to rapidly evolving technologies and practices that touch on the beginnings of human life?

Flexibility at FDA can be thought of with the following part: scientific competence, no moral decisions to be made, and a healthy attitude towards change.

Reviewers in the biologics area have considerable experience in working with new technologies, as I discussed before. I do believe this process could be expedited if a program were established and implemented to broaden staff exposure to outside experts.

The knowledge and experience gained from their work would contribute to the agency's flexibility in this area. As I discussed earlier, when a moral dilemma exists in a specific area, the agency has trouble reviewing products intended for use in that area. Therefore, an intended use moral dilemma will decrease flexibility.

Regarding attitude toward change, I hope that most reviewers at the agency support the evolution of technology. The excitement of evolving technology, I think, makes the job a lot more attractive.

The fourth question, would the practices in biotechnology that touch the beginnings of human life fall within the domain of the practice of medicine? How does this affect FDA's willingness and ability to regulate these activities?

FDA's policy, and I think Dick mentioned this as well, over the years has been to not regulate the practice of medicine. This policy was articulated in the most recent amendments to the FD&C Act where they specifically addressed the fact that FDA was not to regulate practice of medicine.

I believe that the appropriate approach for FDA reviewers to take is to oversee the products used in the practices that touch the beginnings of human life or any other practice, for that matter. Most fundamentally, this means that the review process must answer the question do the benefits of this product outweigh its risk for its intended purpose part of the question is a function of medical standards or federal or state law.

If the specific practice is illegal, then the question of a product approval becomes moot. If the practice is fully legal and it's considered a standard of medical practice, then FDA product review is straightforward.

If, on the other hand, the legal standard of practice issue is clouded, FDA has a dilemma. How can it make a risk-benefit decision when the intended purpose of the product is in question?

The ideal answer, in my opinion, is that it should not. Absent clear laws in a specific area, there needs to be a mechanism that gives FDA help on this intended use issue. In the case at hand, I would suggest a permanent commission or council composed of members who can make recommendations with a moral base.

I would further suggest that if FDA is confronted with an application for product review that falls into this dilemma, that it be directed by the Secretary to seek direction from such a commission or council before proceeding with the product review.

Let me just underscore that. I think -- and, again, Dick made this point strongly -- the best way for this kind of moral decision to be made is through laws created by Congress. If that doesn't work and we still have the dilemma in front of us, then I think some sort of politically appointed commission that has some ties to elected officials obviously with appropriate background should then be brought into play.

The fifth question is: in your experience how politically insulated is the FDA, that is, to what extent do its priorities and values change with a change in administration?

The amount of insulation varies, in my opinion, as a function of several factors. I've experienced and observed some of these. The most obvious is the appointment of a Commissioner. In recent years, it has taken as long as two years to make an appointment after a new President is elected.

In the interim an Acting Commissioner is usually appointed from the ranks of career employees, as was the case when I served as Acting Commissioner. Absent other factors, this situation means little or no change in priorities or values. In my direct experience, congressional oversight both through formal hearings and through more informal means, including letters, phone calls, meetings, et cetera, had a great deal of influence over the agency's priorities.

This factor, as the congressional oversight, combined with media attention or media attention alone also affected priorities. In fact, I think media attention, especially if it's prolonged, may be the biggest factor.

A good example of how priorities can be changed was the decision by the agency in '93 to regulate tobacco. This decision was taken with no congressional mandate, but managed to generate enormous media attention. That attention served to fuel the priority of getting regulations in place.

Ultimately the regulations for the most part were overturned by the courts, and today FDA has little to do with regulating tobacco. This example, I think, points out the importance of congressional direction to assure the FDA is implementing the law of the land and to avoid a change in priorities or values that are not based in law.

The sixth question, how does FDA as an institutional matter resist being co-opted by the institution it regulates?

I think the fundamental answer to this question is through professional pride. The reason FDA exists is to protect and promote the public health. That goal must be instilled in all employees. It's the job of upper management to keep that part of FDA mission in the forefront of all employees' minds.

On a more day-to-day level, there are proper conduct ground rules in place that govern employee behavior, and if that behavior is not proper, it's the role of management to deal with it.

There are many other checks and balances that come into play on this issue. FDA is surrounded by observers who never hesitate to point out when the agency tilts in what they consider to be in the wrong direction.

These observers include trade associations, consumer groups, patient groups, professional societies, the lay press, trade press, and certainly not the least the congressional oversight. So working in a fish bowl certainly, I think, contributes to not being coopted.

The seventh question is as a matter of institutional competence and capacity. Is the FDA the best suited administrative agency for regulating the biotechnologies that touch the beginnings of human life?

My simple answer to that is yes. I think that the most important factor to consider in this issue is the regulatory process in conjunction with the scientific decision making. The Biologics Center has had a full century of experience in the biologics area, and as I mentioned before the job of coordinating the regulatory process is fundamental to successful decision making.

Process mistakes along the way can be devastating years later.

I also think that the existing competence of the biotech staff is high. If augmented by outside experts and through joint efforts with other agencies like NIH, you have the best of all worlds, coordinated by an agency with 100 years of experience.

The last point I would like to make under this question, as a summary point to the paper, is the critical nature of the moral decision. Absent a congressional mandate signed by the President, no agency within the existing structure of our Executive Branch can be successful. Unless or until Congress acts, I think it's critical that a commission or council be established with the full support of the administration behind it and hopefully the support of Congress to make the moral decisions, that is, the intended use decisions that we talked about earlier to give FDA or whatever agency the basis it needs to make the scientific and process decisions.

And I think it goes without saying that the agency must be adequately funded in order to carry out that mission.

CHAIRMAN KASS: Thank you very much for a precisely responsive presentation.

MR. BENSON: Thank you.

CHAIRMAN KASS: And dealing with the questions that we have put before you.

Let's direct the beginning part of the question to Mr. Benson's presentation, and then we can sort of generalize the conversation about the FDA as a whole.

Frank Fukuyama.

PROF. FUKUYAMA: Yeah, I want to get you to expand on your answer to the seventh question about whether -- it's the question of institutional competence to deal with ethical questions. You said at the conclusion that you thought that Congress will -- I think we all agree that Congress ultimately, you know, would be the source of those kinds of decisions.

Would it be possible, do you think, to modify the FDA's statute to include kind of on an institutional basis consideration of ethical and moral questions and not simply safety and efficacy questions? Do you think that the agency could handle that shift in its mandate so that it's not as if, you know, Congress makes a one time moral decision, but it actually delegates the need for a new institutional capability to consider, you know, moral factors like this, you know, council has been created to do on an ongoing basis?

And would that, you know, be something with adequate funding and so forth? Do you think the FDA would be capable of handling or does that change kind of the self-understood mission of the agency in ways that might, you know, lead to internal confusion or, you know, other kinds of problems?

MR. BENSON: Well, I think, first off, the answer is, yes, it could be done. Certainly that's straightforward, and basically I think you're saying should it be done or does this make sense, and I would be much more cautious in answering that.

I think, as I tried to point out in the paper, FDA has enormous competence, I think, in handling regulatory processes, and we tend to kind of say that's no big deal, but it really is because doing things right and making sure that the proper process is in place really is critical to successful outcomes both for patients primarily, for the industry that it regulates, the public in general.

As far as the practicality of that kind of delegation, again, I think there needs to be some mechanism that is, you know, perhaps coordinated or hosted by the agency, but removed from the agency in some way to address whatever moral -- and I use the word "moral" instead of ethical because I think I'm not sure the definition is there, but moral I think says it clearly -- can make those kinds of decisions and allow the agency to implement.

And so I would be a little cautious in saying, yeah, let's kind of go for that or let's make that recommendation. I think there needs to be separation.

CHAIRMAN KASS: Janet Rowley and Michael Sandel.

DR. ROWLEY: Can I ask you a question about the relationship of the FDA with the Recombinant Advisory Committee at NIH? And I'm not sure who it's most appropriate to discuss because for some of us we've looked on the RAC as the kind of national review panel that looks at not only science, but efficacy and safety, but clearly you've already indicated that what it involves is putting DNA into cells and into patients.

That then falls within the purview of FDA. So there is already experience at least in that arena of two different groups presumably one hopes working together, but I'd like your comment.

MR. BENSON: I'll start and Dick can certainly comment.

I'm not familiar with the specific interaction between the committees, but in my understanding that is a good model. I'm not sure how the RAC is actually appointed. I think if you draw the connection between the RAC and the kind of council that I was talking about, I think as long as that is truly a political appointment, you know, so that the elected official really is responsible for what goes on. I think that kind of system can work.

DR. ROWLEY: Well, I think, and I'm not sure that anybody here has full knowledge of this, the RAC is appointed by the Secretary of HHS, and it includes not only scientists, but also members of the community.

MR. BENSON: Right.

DR. ROWLEY: And ethicists as well.

MR. BENSON: Dick?

PROF. MERRILL: One of the people in this room, Gail Javitt, and I wrote a short article on you might say the forced marriage of the FDA and the RAC in the regulation of gene therapy. I think at the end of the day it has worked reasonably well within a cabined arena.

DR. ROWLEY: Within what kind?

PROF. MERRILL: A cabined arena. It's not given a charter to look at all of the biotechnologies that have moral or ethical implications. I think that has probably helped. It is now a dozen years old, this collaboration, and a lot of the wrinkles have been worked out.

Dr. Noguchi is the person whose judgment I would credit most about the success of this enterprise. I think the FDA was not initially content with the relationship and neither was Dr. Varmus who wanted to terminate it at one point, but it is an example of a collaboration between you might say the ethical community and the technical community that might be looked at in this arena.

MR. BENSON: I think the -- were you finished?

PROF. MERRILL: Yes.

MR. BENSON: Just looking at the logistics, the Biologics Center is headquartered as I'm sure you all know on the campus of NIH, and historically I had mentioned that from a device perspective, which was another five or ten miles away, it's like that five or ten miles is a lot further than the actual distance, if you will, in terms of collaborative efforts.

But I think it's important in general not only in this issue, but I think there needs to be more effort spent on creating an environment where those two agencies -- and I could name a few others -- really do work collaboratively as opposed to kind of, well, this is my turf and you stay away and that kind of stuff.

And I think that's improving, and again, I want to make sure since I'm on record here. I think it has worked well with the Biologics Center, especially the Biologics Center and the various elements of NIH.

CHAIRMAN KASS: Michael Sandel.

PROF. SANDEL: In the U.K. they have a regulatory body, the Human Fertilization and Embryology Authority, and it was established by parliament to license fertility clinics and to regulate embryonic stem cell research and to regulate the proper uses of preimplant genetic diagnosis and things like that.

MR. BENSON: In doing a little bit of reading in preparation for this, I noted the system in Great Britain. I don't know how successful that has been.

Again, I'll come back to the point that I had made before. I think FDA is the ideal agency for carrying out the or implementing what authority it is given. I would separate though -- and I think this goes back to the earlier question about the delegation -- that there needs to be a body that's to some extent moved from the agency, that can really make decisions that involve morality issues. I would have a separation at least.

PROF. SANDEL: So at least a separation and maybe a completely separate body mandated by Congress.

MR. BENSON: Not that would be responsible for carrying or for implementing the law, but, you know, for making the kinds of decisions that we're talking about here.

PROF. SANDEL: Could I just address a question to Frank and other colleagues?

Is that what you would draw from this discussion? Rebecca?

PROF. DRESSER: I'm not sure.

CHAIRMAN KASS: Professor Merrill, please.

PROF. MERRILL: I don't know whether this is helpful or not. I hope it would be. I've done a little thinking about sort of design of regulatory systems. I don't know that it answers the question of what role FDA should have, but it does strike me that there are probably four -- maybe there are more -- levels of decision making that would be involved in the creation of an oversight enterprise, assuming for the moment that the decision has been made that it should be a federal oversight enterprise.

One is the set of questions about whether activities should be permitted at all on moral grounds, and I think Jim Benson and I would agree that that's a political decision, a congressional decision.

There's a second tier of questions having to do with what limits there ought to be on activities that are permissible on some grounds, but not unregulated. I think that's a political exercise, too, but it could be informed by a regulatory body such as FDA because administrability of limits is an important consideration in addition to their content, you might say their moral content.

Then there is the third tier of questions or a third tier of activities involving monitoring of compliance with the limits that have been set. It seems to me that when you get into that arena, that a body like this or a new body is not ideally equipped, and a body familiar with that you might say monitoring that kind of activity, like FDA, has a superior claim.

And there's a fourth set of questions about what do you do with miscreants, people who are not obeying the limit, and if FDA has superior claims to any of these activities, it surely has claims to superiority in the area of enforcement and sanction implementation.

I just observe finally that the resource implications of thinking about the problem in that tiered sense are sort of in reverse order. That is, the resources involved in making a decision about whether or not to allow something is not going to be very great. It might be abnormally anxiety producing, but it's not going to involve fleets of people.

As you get down to the enforcement and monitoring activity, you've got to have a lot of cops. FDA is a cop, and if you're concerned about the willingness of people to observe limits that are not flat prohibitions, you need to deploy the resources that that requires.

MR. BENSON: I think as I thought through this, and this, I think, goes to the points Dick was making, what I realized was that most of the time FDA gets in trouble either for making the wrong decision or much more the case, drawing out a decision on a product approval -- and I'm not talking about these kinds of products necessarily -- the reason for that is because of uncertainty about the intended use. Is it proper?

And once that decision is made, then I think the agency can go forward in a very straightforward way.

If I can just make a brief tongue-in-cheek statement, I think, that occurred to me in one of the points that Dick was making in terms of how FDA would go about regulating products like this as drugs, they would have to define the mother in the case that came up as a manufacturing plant.

And although I say that tongue in cheek, I think it's probably what they would end up doing. So good manufacturing practices would be applied and so on.

I don't say that only to try to be cute, but I think that, again, it points out the importance of having a clear mandate because, I mean, that's silly perhaps, but those kinds of ways of gerryrigging the implementation of a program would happen and will happen.

So that comes back to the importance of really having clarity on the moral issue, morality issue.

CHAIRMAN KASS: Could I follow up on this last set of questions not so much with respect to new institutional design,b ut it seems to me part of the reason that we're having this conversation is that unlike so many of the things that have been the bread and butter questions that come to the FDA, the kinds of questions that we've been dealing with are new in at least two respects.

One, those things that are connected with the beginning of life often raise questions about the ethics of the means insofar as they affect nascent human life, which is vulnerable to practices, and there's disagreement on the morality of that. And the other reason that I think we're concerned is that there are intended uses, intended uses from the start that might be beyond what is traditionally understood as treatment.

Now, it seems to me that the FDA probably has some experience in dealing with things like the latter in terms of the way in which it has gone about dealing with devices for cosmetic surgery, breast implants, and the things of that sort, and it probably has some experience in thinking about things not unrelated to the former insofar as the concern for the well-being, at least the limited well-being under the heading of safety of fetuses at risk and pregnancy with the uses of drugs where you've got a third patient involved.

That's part of the difficulty, another patient is involved here, and I wondered if we could have some help perhaps especially on the question of intended use coming out of, let's say, the area of cosmetic surgery and devices that are involved there, particularly as just yesterday in one of our discussions there was a discussion about devices or means for, say, choosing in advance the sex of children and to make the case simple, let's not talk about the ones involving destruction, but let's say talking about sperm sorting questions.

I don't know whether something like that would come before the FDA approval since there might be some risk involved in the procedure for doing the separation.

The other question, I suppose of intended use might come up as it might come up in the devices.

I talk too long. I mean, the question really is could we get some help on the way in which intended use might function? Because the moral considerations do come in there.

MR. BENSON: I think just out of my own experience on the cosmetic side, I lived through the breast implant problems that we came to, and it kind of, I think, underscores one of the points I made before, and that is when the media gets involved, you know, you have much more of a crisis. You no longer have an issue or problem. You have a crisis as a result of -- I'm certainly not blaming the media here, but just the controversy that gets stirred up.

Dick may want to take me to task on what I'm about to say, but for breast implants, here's a clear-cut case of a product that's clearly a device, the implant itself, but the decision as to whether its intended use is appropriate is what caused all of the problems.

Now, there were safety concerns. Looking back on it, I think those safety concerns were misinterpreted in many cases. Let's not get into that.

To me the decision on breast implants should have been one that the intended use part of that formula should have been made between a woman and her physician. The agency had no business, in my opinion, getting involved there. That's a very private decision and should be made that way.

What the agency did do and should have done maybe exclusively is make sure that the risks associated with that product were carefully articulated and based as best they could be in science. In that way then the patient could, with the knowledge of the physician, make a risk-benefit decision.

So I think that's the role that the agency should have played and still can play in that sense, and maybe there's an analogy there to this, where I think the point I would make is that, again, the intended use is not something that the agency makes a moral decision about. It's not the agency's business as to whether or not a woman should have a breast implant, in my opinion.

I want to make sure that this is a very personal opinion.

CHAIRMAN KASS: And then by analogy, it would not be the agency's decision whether or not people should use technologies to choose in advance the sex of their children. The agency's decision would be to make clear what the risks of doing that are, and then its job would be finished.

MR. BENSON: No, I think in addition in that case, I think you would include this in what you said, if there are specialized products or new products, let's say, drugs or devices that would be involved in that process, then the agency can make those kinds of risk-benefit decisions on the value of the product, not on the intended use.

CHAIRMAN KASS: Okay.

PROF. MERRILL: I couldn't agree more.

MR. BENSON: Thank you.

CHAIRMAN KASS: Well, Bill May.

DR. MAY: I simply wanted to return to the earlier questioning from Leon Kass of you, Mr. Merrill, just to get clear about it for my own benefit.

Once the FDA approves a drug for a specific use, I gather, it retains the power to regulate the marketing of the product to insure that the company does not promote the product as a treatment for other uses, but it doesn't regulate actual medical practice, perhaps the disposition perhaps of some doctors in the course of time to prescribe the drug for other uses even though those uses were off label, perhaps treating other illnesses or perhaps using it for purposes of enhancement rather than the treatment of illness.

Now, is review and regulation, therefore, irrecoverably beyond FDA control as long as the pharmaceutical firm is careful not to advertise and market the drug for these other uses?

And if that's the case, what recourse then does the public have for its protection as information grows that these other uses are either inefficacious or harmful or perhaps offer short term benefits, but may expose people to long term harms?

Does one simply rely on the following: the educational impact of published studies about such inventive uses, professional self-regulation and discipline, or resort to the courts in the form of malpractice suits and so forth? But the FDA as such remains silent.

PROF. MERRILL: I think that is in general terms an accurate depiction, but with important qualifications. The FDA is not forced to remain silent. It can require changes in the labeling of the drug if it is aware of hazards associated with its off label use.

I think it has taken the position that it can and there may be examples of its doing so withdraw approval of the drug on the ground that the risks associated with its off label use are too great to justify the benefits of its use for the labeled purpose. I think one could argue that a drug that was recently allowed to be reintroduced for the treatment of irritable bowel syndrome was in that category, a drug whose hazards when misused or inappropriately used were great enough to offset the benefits of its appropriate use.

So the FDA can intervene. It may run into a dispute with the manufacturer about that risk-benefit judgment, but with respect to lack of efficacy, it could require relabeling of the drug, but I suspect in the case of lack of efficacy for the off label use, it would be much slower to act ordinarily.

And then the civil justice system is not likely to provide much of a remedy because it's very hard for an individual patient to make a case in court that "I was given this drug and it didn't work." What is your harm from it not working if you can prove that it didn't work.

DR. MAY: That's very helpful. Thank you.

DR. GÓMEZ-LOBO: I'm going back to the question originally raised by Frank, and may I ask a quick question to Frank?

What did you have in mind when you mentioned the possibility of somebody making moral decisions under the purview of the law? Did you have the U.K. Fertilisation and Embryology Authority in mind, something like that?

Yes. Okay. I have problems with that, first of all, because I'm not sure that the U.K. Fertilisation and Embryology Authority is making moral judgments. From the exposition we had here, I understood that what they did was simply take the law and apply it. In fact, it's hard for me to think that there might be, say, a majority in that authority at one point in time who might say, "Oh, by the way, the human embryo deserves protection before 14 days. Therefore, we're not going to authorize this on this experiment."

I think that's totally inconceivable because they are under the mandate of the law. So I would be very conscious of calling that a body intended to make moral decisions.

I agree with our speakers today that the morality should be embodied in the law. I think that's the right place for more considerations, more deliberation. That should be something that the political community should discuss, you know, which kinds of actions are morally permissible, which are not, and that that should be the body of the statute.

Now, in a way that's exactly what happened in Great Britain to some extent. As we all know, the bill, the fertility and embryology bill, "act" as they call it, was very, very strongly informed by the Warnock Commission's report, which was to a great extent a philosophical document with, in my view, very, very serious flaws. I mean, I could point to many defects.

But it seems to me that that's the -- structurally that's how things should go. There should be a national debate about, say, the morality of some forms of embryo research or research cloning, and that, finally, this should take a form as law, and that there be no moral decisions to be made by a lower appointed body. I find that really very strange.

CHAIRMAN KASS: Frank, do you want to respond?

PROF. FUKUYAMA: Well, yes, if I could just clarify, obviously big moral decisions could not be delegated to an administrative body. So you could not possibly delegate the decision on whether an embryo is a human being, you know, to a technical agency. So nobody is arguing that.

In the British case, parliament decided to legalize abortion, does not consider embryos to be, you know, persons under the law, and the HFEA operates under that mandate.

But their statute explicitly allows them to take moral and ethical questions into consideration within the broad parameters of that delegation. So they had a couple of instances, you know, of parents, you know, where they had to apply general principles and, you know, did it benefit the child; you know, was the procedure being done for the benefit of the child or simply the parents and this sort of thing, and those are cases where it seems reasonable that too detailed really for legislatures to -- and they're going to come up so frequently that it's not really a practical matter for legislatures to, you know, make decisions and vote, you know, on those kinds of things.

And so the delegation of moral authority is, you know, within a fairly restricted framework, and I think that's what we're talking about because I think fairly clearly from the two presentations that has not been within the purview of the existing statutory authority of the FDA to introduce those kinds of considerations.

And so then the institutional design question is, you know, can the statute be modified if Congress wants to make that kind of delegation or would it be better to try to segregate that institutional capacity into a different kind of agency that works with the FDA.

Obviously the FDA will monitor and enforce and do all of those other things, but can it also, you know, take on this delegated function in addition? I think, you know, that's really the question that we're facing.

DR. KRAUTHAMMER: Frank, could you explain what you mean by that delegated function? I'm not sure I follow it. In other words, what would be the role of this body or what would be the function you'd be asking of the FDA?

The law is passed. It has got moral implications. It has mandates. You seem to be saying there might be a need for an intermediary body between the law and something like the FDA which normally would administer the law. Can you explain what the need is for that intermediary body?

And then I'd like to get the reaction of our guests.

PROF. FUKUYAMA: Well, I guess the need is to address, you know, a lot of the ethical -- I mean, you're not going to address the big ethical issue about, you know, the moral status of embryonic life. That's going to be, you know, set for you, but within that broad parameter, a lot of the kinds of questions that we have been addressing in this council, you know, concerning -- I mean you have, you know, considerations about psychological harms. You have considerations about the relative weighing of the interests of parents versus children. You have, you know, the weighing of long term, somewhat intangible harms versus, you know, clear cut more tangible ones. I mean all of those things, you know, which I think have a certain ethical dimension to them where you would have -- and they would be constantly raised by the generation of new technology. They would be quite, you know, I think detailed and really beyond the competence of a legislative body, you know, to deal with on any kind of routine basis.

DR. KRAUTHAMMER: I'm sorry. What I'm puzzled about is there would be a need for something. As I understand it you're saying other than an FDA like body, which is purely technical to deal with this because they would have to introduce moral considerations in making their judgments.

I'm just trying to think of an example. If Congress passes a law, let's say, banning reproductive cloning, allowing it up to 14 days, can you give an example of what kind of lower level moral question we're -- I'm just --

PROF. FUKUYAMA: Somebody is going to have to help me, but we have an example of that.

CHAIRMAN KASS: Preimplantation genetic diagnosis, and that's the thing that the agency there now deals with. What are the appropriate uses of this?

PROF. FUKUYAMA: Yeah, okay, yeah. Well, enhancement. For example, all of the questions we -- you know, the boundary between enhancement and therapy is a very murky one. You know, it seems to me plausible that Congress may say in general, "We want to permit therapeutic uses," and then the question is what constitutes an appropriate therapeutic use. So that might be a kind of judgment that, you know, would have to be delegated to a body that was not simply a technical body.

DR. KRAUTHAMMER: You would see that the resolution of the issue of what would be appropriate preimplantation diagnosis; you would want to see that handled by an administrative body rather than by legislation?

CHAIRMAN KASS: Well, I don't yet have myself a position on what -- I was simply providing an example of what might be a task for an ethics assessment body that would set guidelines, could set guidelines and might even have some kind of monitoring and enforcement powers as the British agency, in fact, does.

DR. ROWLEY: Well, I would like to just follow up on this because I think Frank brought up an important point that we're really in many respects at the beginning of an area of science and practice where we don't know what all the ramifications are going to be or what all of the uses are going to be and which ones may transgress certain moral guidelines or certain boundaries. And I think that to expect Congress now to write a law in such detail that will govern practice for the next ten years is probably inappropriate because it's going to change and the law just may not be effective or have thought of such things.

PROF. FUKUYAMA: I mean, if I could, Charles, should growth hormone be prescribed for somebody in the 50th percentile with regard to height? Do you want Congress to legislate on that or do you want that kind of decision to be made by, you know, an administrative agency under a broad mandate to, let's say, promote therapeutic uses of medicine?

DR. KRAUTHAMMER: But you'd presume that Congress would have to make a judgment as to whether that issue ought to be something that society or the government or the law ought to speak about in the first place. So I'm assuming if Congress is silent on it, I don't see why an administrative body ought to be regulating it.

If Congress is not silent about it, I think it would set the guidelines now.

CHAIRMAN KASS: Let me ask. Jim Benson, do you want to respond on that?

MR. BENSON: Go ahead.

CHAIRMAN KASS: No, please, first.

MR. BENSON: I think the thing we're discussing is or the essence of it is in the absence of congressional action, what do

DR. KRAUTHAMMER: Would it be advisory or regulatory?

MR. BENSON: Well, I'm not sure I've thought deeply enough to give you a good answer, but I think on the moral side of it, it would have some kind of binding responsibility, not regulatory as such, but you know, this would, like I say, be a surrogate for a fairly general bill that Congress might pass.

I would suggest, and the point I wanted to make in the context of what you were just discussing is the system is already in place if Congress asks, I think. You have varying degrees of advisory committees and panels that work with the agency, and I'm not familiar with the example you gave, but I mean, that would be the kind of thing that I would see coming out of a panel of experts that could give the agency, whatever agency, presumably FDA, the guidance it needs then to go forth, you know, and make some of the risk-benefit decisions based on that criteria.

CHAIRMAN KASS: Richard Merrill.

PROF. MERRILL: Just a couple of comments. One is I don't find it helpful to think about these questions in terms of what changes you would make in the Food and Drug Act. There are a lot of changes necessary, it seems to me, if you visualize a different kind of role for government, and the exercise ought to focus on what kind of role for government you anticipate.

I think Dr. Krauthammer had it right. I think the first question is whether or not the kinds of decisions about use of technologies are to be made governmentally or at the level of social interaction between individuals or between physicians and patients. If they are to be made governmentally, that means they're going to be made legally by law, whether it's statutory law or regulatory law.

I'm not very enamored -- I should continue for just one moment. Then the question is how do you insinuate the new criteria, the new sensitivities, the new standards for judgment into the decision, the legal decision making process, and I'm not very enamored of a sort of a third component. It strikes me that one is probably going to be better off trying to equip the administrative body with the personnel and the sensitivity that needs to be part of the decision making process so that FDA enlarges its advisory committees, and to include people who are going to say, "Yeah, it might be safe, but it's dumb or unwise or imprudent."

And the law permits dumbness or un-wisdom to be criteria, the agency can incorporate that in its decisions whether or not or on what terms to approve the technology.

CHAIRMAN KASS: Let me see. That was Gil and Michael and then Janet.

PROF. MEILAENDER: Yeah, I just wanted to note, I mean, the discussion remains at a level that I have a hard time quite knowing what to say about it because it seems to me that a great deal would depend on what sort of legislative action, if any, one got. After all, if what you got was legislation saying that a certain kind of activity is prohibited, one wouldn't need a complicated discussion about the possible adjudication of various possible uses.

So that it remains at a certain level of abstraction when we discuss it in this way. I mean, I do think a great deal depends on what the sort of legislative authorization was, what boundaries it did or did not set. That would have an awful lot to do with what range of, you know, possibly moral decisions needed to be made.

CHAIRMAN KASS: Yeah, except that I think I won't say that there's a consensus on this, but that the general feeling around the room has been in previous discussions that the realm of activities whose ethical dimensions we have concerns about far exceed those that could be handled by simple legislative proscription. I mean, that's a blunt instrument, and for rare cases at best, and therefore the regulatory model of discriminating better and worse uses has always been the more attractive one, even if it has its own difficulties and concerns.

PROF. MEILAENDER: Granted, although I think there's far less agreement around the room about among the various activities we have discussed which ones are properly so characterized.

CHAIRMAN KASS: To be sure, to be sure.

Michael Sandel and then Janet, and then I think we're coming up on a break.

PROF. SANDEL: Well, this is just a reply. Frank gave the answer I would have given to Alfonso exactly. I think that's exactly right.

And to respond to the kind of ardent legal positivism of Justice Krauthammer, that's wildly implausible and impractical to think the law works that way, and also to Gil. In his case I wouldn't call it wildly implausible, legal positivism, but in any case, just to prohibit something --

PROF. MEILAENDER: We have two Justices now.

PROF. SANDEL: -- just to prohibit something --

DR. KRAUTHAMMER: It seems I'm a doctor and a Justice.

PROF. SANDEL: -- doesn't remove interpretive questions that have a moral dimension. Congress tomorrow could pass a law prohibiting non-medical uses of preimplantation genetic diagnosis, and that would not remove but create a whole range of questions about what counts as a non-medical use of pre implantation genetic diagnosis as we know from our discussions.

And so there would have to be a body. Unless you want to go back to Congress each time with all of the issues we've discussed here and say, "Well, what about this? Will you pass a law about this? For example, what about using PGD to screen for genetic defects? Is that medical or not?"

Well, it is.

What about if in the course of screening for genetic defects you're also trying to screen for a child who will be a narrow match to save the life of an existing child? Is that medical or non-medical?

Sex selection, and the like. Are we going to go to Congress to pass a law on each of these cases to distinguish, to take -- here the U.K. case is very instructive. They're wrestling with the distinction between two uses of PGD for donor match, and they drew a distinction. Some may say it's casuistry. It may be right; it may be wrong between a case where you do the screening because the new child will be in danger of inheriting a disease as against a case where the existing child won't be, but they just want to have a donor match.

Well, are you going to go to Congress and say, "Is there a morally relevant distinction between these two even if they've enacted that general law?

CHAIRMAN KASS: Michael, actually as a technical matter I think over here it sounds like they were engaged in some kind of Jesuitical activity, but it was a matter of statutory interpretation. I think I've been corrected on that.

I can't quote you the text of the statute, but I think their hands were tied. I mean, one case fell on one side of the statute and the other case fell on the other.

PROF. SANDEL: Well, that may be, but the point is that the statutory interpretation, whatever that statute is, prescribing nonmedical uses of PGD, of course there are going to be questions about applications that are not purely administrative, purely technical, that raise all sorts of normative questions. That's the range of question, and I think Frank is quite right. We can't rush back in every case to Congress and say, "Please pass a law about this, whether this counts as non-medical or not."

CHAIRMAN KASS: Janet Rowley.

DR. ROWLEY: I just want to come back and ask. You raise the question of using experts to help in certain questions, and are there examples where you've actually taken questions to the National Academy of Science or to the NRC and have they looked at issues for you and is that a worthwhile way for expanding your access to expert advice?

MR. BENSON: Yes, I think that's a very good point. I think IOM, NRC, we've had at various times different round tables that were established that dealt with issues, and it was a very good forum for at least, you know, getting something out on the table, having it discussed, and getting at least some sense of direction.

In other cases, there have been reports that have been commissioned. Unfortunately, it comes back to a budget issue. The academies aren't cheap, and FDA usually doesn't have enough money, you know, to go for for a half million dollar study, for example.

But, yes, that's exactly the kind of thing I was talking about, as well as more formal panels, you know, that are set up to specifically advise the agency in the various areas.

CHAIRMAN KASS: I have one last questions just for information. Professor Merrill, you talked about the registering of eggs, sperms, oocytes, embryos. Could you say something more about the sort of legal treatment of these reproductive tissues? Because that bears in part on the question of our concerns.

PROF. MERRILL: Well, it's part of a larger now decade long effort by FDA to come to grips with the use of cadaveric donor tissues, mainly cadaveric donor tissues in surgery, which is now quite common, and the agency's original concern was with the transmission of infectious disease, aids, and hepatitis.

And it established a set of controls for all tissue banks save those that dealt in reproductive tissues in 1993.

In 1997, it announced a plan to incorporate this developing scheme of controls for tissue banks generally to include the reproductive tissue banks, and subsequently the agency has required one thing essentially, which is everybody who is in the business needs to register with the agency, just as a drug manufacturer does. Those requirements are in effect.

It has proposed a parallel set of requirements for donor screening and testing that would apply to cadavers from whom organs and soft or hard tissues are harvested, as well as donors to reproductive tissue services, and it has proposed a set of requirements that they label "good tissue practices" that have to do with quality control inside the facility to assure cleanliness, integrity, and traceability.

But in no instances yet has it gone the next step, dropped the next shoe and said some of these technologies are drugs and require individual assessment and approval under the drug approval system, although it has said that could come.

CHAIRMAN KASS: Thank you very much.

I want to thank our guests for excellent presentations and wonderful discussions. This has been very, very helpful, I think, to our understanding of the FDA and thinking about where we might go further in our own thinking.

We, council members, have 15 minutes. We have scheduled a roughly 45 minute discussion amongst ourselves on psychotropic drugs and their assessment and regulation, and then we'll have a short public session. We should adjourn probably by noon.

(The foregoing matter went on the record at 8:32 a.m., off the record at 10:36 a.m., and went back on the record at 10:55 a.m.)