Friday, January 17, 2003
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
University of Virginia School of Law, and Of Counsel, Covington
& Burling, Washington, D.C.
James S. Benson, former Acting Commissioner, U.S. Food and
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
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
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
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
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
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
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
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
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
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
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
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
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
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
PROF. MERRILL: Yes.
CHAIRMAN KASS: Would you light up? Thank
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
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
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
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
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
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
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.
And there seems to be at least some incoherence in the understanding
of the material at hand, but it would be nice, I think, to see
this argued through, and I don't think — if I understand part
of the brunt of Professor Merrill's comments, is that maybe
they could give a justification, but one hasn't been attempted
at least in writing where we could look at and see the various
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.
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
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
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
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
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
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
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
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
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.
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
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
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
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
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
If we wanted a regulatory body to perform those functions, would
the best way to do it be to try to amend the mandate of the
FDA or would it be better to try to establish a new regulatory
authority with that mandate?
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
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
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
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.
CHAIRMAN KASS: Alfonso Gómez-Lobo.
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
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
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
you do, and there is where I was suggesting, you know, some
kind of politically appointed commission that could do the next
best thing. So that would be a surrogate for Congress, an unfortunate
one, I think, but nonetheless ?-
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
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
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
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
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
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
PROF. SANDEL: — just to prohibit something
DR. KRAUTHAMMER: It seems I'm a doctor and
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
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
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 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
Thank you very much.
(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.)