To      :  Mr. Carl Sharp                           Date: Nov. the 4th, 1976
From    :  M. Adrian Gross
Subject :  Draft Agreement for Validation of Searle Aspartame Studies


The following are some comments which you requested on the document
under reference as well as on the cover memorandum Wylie/Gardner dated
November 1, 1976.

I must confess that I became deeply disturbed on reading this effort -
last July 14th in a telephone conversation I had with Commissioner
Schmidt during which I stated my reservations about this entire plan, he
assured me that whatever is being contemplated in this area will be
undertaken in full knowledge of and consultation with some of us who
were intimately involved with the Searle investigations and that whatever
is finally accepted will be of such nature as not to jeopardize or
undermine all of our previous work. Given this kind of background I
suffered a rude shock by the proposed plan in front of us at this time.

Let us put this matter in some perspective by establishing the basic
facts here.  The Searle investigation which started in the Fall of 1975
can be viewed as an investigation "for cause" following the discovery of
certain improprieties in the conduct of animal studies during preliminary
inspections in the 1974 and in the first half of 1975.  The report of the
Task Force submitted in March of 1976 in essence constituted a stinging
indictment of Searle and it contained various recommendations for
regulatory action including referral to the Justice Department for
review of possible criminal violations of the law.

The Aspartame studies to which we have reference here are nothing but an
extension of the studies which were reviewed by the Task Force.  I see
no essential difference between them and any of the studies already
investigated.  In the meantime this Agency as received a substantial
amount of additional funding for the express purpose of monitoring the
quality of research carried out by regulated industry in a much expanded
fashion.  As part of this program, there has been a marked degree of
effort, time and money expended on setting up sundry task forces, steering
committees, training courses for investigators, "surveillance"
inspections, regulations for good laboratory practices, compliance
programs, etc.

Yet, notwithstanding any of this, now that the Agency is confronted with
the need of completing what it started out to do in this Searle matter,
we seem to be turning to an outside group of questionable capability in this

area:- the UAREP.  I know absolutely nothing of the past experience of this
outfit to carry out investigations of this sort - perhaps, whoever it was
that selected this group to carry out our responsibilities for us might be
as kind as to enlighten us on this point.  I noted the name of Dr. Stowell
associated with this organization - I have known Dr. Stowell for many years
now from the time he was Scientific Director of the Armed Forces Institute
of Pathology and I can readily agree that he has impeccable credentials and
a remarkable achievement in his own field of pathology;  as far as investigations
of the sort that we are concerned with here, however, I would judge him to
be a complete neophyte in this particular area.  I also know nothing of the
others at UAREP to do the actual "hands-on" part of the investigation -
we need additional details here but I would doubt very much that UAREP could
come up with a number of workers who are both experienced and competent in
matters of this sort.

Speaking as a pathologist, I seriously question the wisdom of selecting a group
of pathologist to oversee the kind of investigations that are called for here;
pathology problems do not constitute but a small part of the difficulties
involved in situations such as these.  My own experience is that, as a rule,
controversial technical aspects in pathology proper (such as whether any
particular characterization of any given lesion is a proper one or not) are
seldom an important factor in a determination whether any study contains
serious flaws.  This has been amply demonstrated in the extensive Searle
investigation as well as in other investigations currently under way in the
Bureau of Drugs.  I have great difficulties in visualizing pathologist
conducting a searching examination of a variety of records which have nothing
to do with pathology or closely question a number of administrators,
laboratory technicians or aids, animal caretakers, etc., on their practices, on
detail of their tasks, adequacy of their observations and so on.

I would not like to generate the impression here that scientific expertise
in pathology or in any other scientific field associated with studies like
these could or should be totally ignored.  Far from it.  However, the
concept under which we have operated ever since I can remember is that
investigations are best handled by trained and experienced investigators.
Where there is a need to address certain scientific problems which transcend
the capabilities of the investigators, the practice has always been for
the appropriately qualified specialists from the various Bureaus of the FDA
to assist the investigators; in those few cases where outstanding technical
difficulties beyond the capabilities of Agency scientists are required, we
have not refrained in the past from using help from outside and I should
hope we shall continue to do so in the future.  But this help provided by
scientists on an ad-hoc basis and only where it is required is an entirely
different matter than having scientists direct the actual course of the
investigation.  While I believe it is entirely proper (in fact preferable)
to have scientists evaluate the scientific impact of a set of findings,
I cannot see professional scientists do the job of professional investigators
any more than I could see members of a legal society doing the work of
detectives or policemen in investigating various aspects of a specific crime.

It disturbs me to see from the draft we have here that the role of what is
termed the "FDA Monitor" will be reduced to little more than having this
person be present during communications between UAREP and Searle; I find
this kind of prospect ludicrous and I do not understand the need for it.

What I understand even less is why Searle should offer or be asked to pay
the cost of this entire operation to the investigative agent in a direct
manner;  why is there a necessity for this body, UAREP, to enter into any
kind of formal contract with Searle and why are we expected to co-sign
such a contract?  The fact that Searle will pay for this cannot but give
them some kind of decision-making role as is evident from merely reading
the terms of this proposed contract.  It seems to me that no-one except
the FDA can have the responsibility for undertaking this kind of work -
this is our mission and we are being paid from public funds to carry it
out.

Although, as expressed above, there is much I do not understand about this
entire plan, particularly its basic raison d'etre, there is something here
that I appreciate fully:-  this is the statement at the top of page two of
Wylie's memorandum:-  "Searle understandably continues to press for the
expediting of this agreement."

I would suggest that  implementation of this contract can have only one
of two predictable outcomes which are mutually exclusive:-

a)  There are serious improprieties in the conduct of these studies.
   If this is the case, I would submit that inexperienced outside
   scientists selected by an outside agency under contract to the
   firm which is the object of the investigation, will have a
   markedly  reduced probability of detecting such improprieties;

b)  There are no serious improprieties in the conduct of these studies.
    IF this is the case, it would necessarily follow that any report
    written by the "investigators" would not signal the presence of
    any such improprieties.  But, if so, for exactly the same reasons
    as listed above, such a report may well be interpreted as being
    nothing short of an improper whitewash.

My recommendation is simply that this entire plan be aborted forthwith,
and that we proceed with this matter in a way we are supposed to;  this
is the way we have handled things like this in the past and the way we
anticipate to operate in the future.

                                                    M. Adrian Gross
                                                    HFD-108

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