August 30, 1973

Dr. Marvin 0. Maul

Director, Regulatory Affairs
Syntex Agri Companies
Stanford Industrial Park
Palo Alto, California 94304

Dear Dr. Maul,

I have your letter of August 28th asking for comments on the
FDA draft regulations on assay methods for residues.

Much as I felt I had cause to complain about the AHI task force
approach to these problems, the scientific premises of these draft
regulations are totally illusory. In my view the AHI committee would
have much to criticize but as I think you will already have perceived
I feel they have misdirected their energies.

I am of course referring to the concept of zero tolerance, no
residue. By deciding which methods are acceptable, the FDA is of course
begging the question of regulating a residue to that level which is
socially acceptable. (Note that I did not say as zero risk).

The subheading Exogenous Compounds is fraught with internal
contradictions about the objective intended to be accomplished;
presumably these will be resolved by the exercise of regulatory
judgment under the heading of "The Intended Use Pattern of the Compound".
The real objective evidently is to minimize ‘overall public exposure
to potentially carcinogenic compounds. The FDA simply cannot logically
escape from its dilemma that it is de facto determining levels of
dissemination which it has concluded to be socially acceptable.

But later on the ragulations take on a much more reasonable tone
which at least permit one to examine the premises of the proposal.

The basic argumente seems to be that the risk be held to a level
of 1/100 million; however, this is to be estimated so conservatively
that the probable risk on the basis of the assumptions presented is of
the order of 1/billion. Whether this is an appropriate level in the light
of risks involved in other procedures, and of the expected benefits from
a new additive is a social policy consideration that doubtless deserves
greater debate. But at least for the first time the assumptions are exposed
and this is an enormous advance. (I should think that for most additives
for which there were a sufficient market to wish to parsue thd question
that these risks are far too conservative perhaps by two or three orders
of magnitude.)

 
Dr. Marvin Maul ~2- 8/30/73

Nevertheless I would strongly support the validation of this
approach to regulatory standards as it is the only one that is likely
to lead to rational social policy responses. Plainly, it is quite
inconst&tent with the language of the preamble!

One item, marked 3 in my copy, that makes these assumptions
possibly less conservative, is the standardization by body weight.
Since one cancer is enough to kill a 150 kg man as readily as a
25 gram mouse this may be loading the scales towards underestimating
the human risk if we assume that the 2 species are unknown to be
different in sensitivity.

Paragraph 4 seems to verify that the language of this regulation
is intended to provide a meaningful definition of "no residue".

The subheading Endogenous Compounds seems very reasonable --
if anything it may be too liberal in a way that shows the limitaténas
of trying to solve problems of risk by regulation. The FDA would find it
difficult to justify prohibitions that were directed at risks no different
from 1% of normal animals, in spite of the fact that 1% of normal animals
quite conceivably are generating levels of hormone that we would be
better not to take {n. However, in the absence of any concrete example
of such a phenomenon among life-stock there is no point pursuing this
issue and I suggest you just give this entire section your wholehearted
Stamp of approval. Once again I would recommend taking a few mild knocks,
although I imagine it may even be to Syntex's own advantage, in order to
help rationalize the overall procedure which I think this section does.

The heading Assay Evaluation Criteria I find rather difficult to
read and understand. Perhaps other documents’contain the definition of
"sensitivity" of assay methods. I should have thought that one would want
to have sensitivities that were capable of measuring with some precision
whether the level of residue was below or above the regulatory action
level. If that ws what is meant by sensitivity then my remark can be
withdrawn. Or perhaps they are waffling, for the sake of taking a rational
position, against the legal requirement of zero residue. The language about
residues being two positives or not Suggests that interpretation.

Summary line 2 also appears to be an answer to my question.

The word drug seems to have krept in at mark 5 -- I leave that to
you for legal analysis.

All of this seems to be preamble. In the actual draft regulation text
the Mantel Bryan extrapolation is mentioned but no social criterion, like
one per 100 million is explicitly mentioned. Again this may require some
legal analysis to determine whether this makes a difference, whether it
leaves it to the discussion of the FDA without further procedures to change
that objective criterion.
Dr. Marvin Maul -3- 8/30/73

Very important and very encouraging is item 6. For the first
time it would seem to be possible to introduce other relevant data to
refute prima facie evidence of carcinogenicity levels as determined in
some particular animal. It may then be possible to rebut experiments
that are done on hypersensitive bitches for example provided that one
can obtain relevant experimental information to justify adjusting the
parameters from that special experiment. It is not clear who will have
the final responsibility of determining whether the data indicate the
applicability of other methods of extrapolation, and this may be the
main point that I would recommend you consider further in your comments
on the proposal.

By and large the actual language of the new regulation seems to me
a considerable improvement over current practice, and one that one might
hope might be extended to other areas like food additives and drugs
in clinical testing. Some of the explanatory and introductory language
is self-contradictory but this may represent the efforts of some reasonable
man within the agency trying to find formulations consistent with the
letter of the law on the one hand and with the possibility of scientific
validation on the other.

I do not intend to make any personal filing on this matter. Needless
to say, please feel free to use any of the arguments that I have
communicated here but I trust you will consult me before they are
attributed to me,

Sincerely yours,

Joshua Lederberg a
Professor of Genetica

JL/rr
Enclosure