STANFORD UNIVERSITY MEDICAL CENTER

STANFORD, CALIFORNIA 94305

 

 

November 17, 1975

STANEORD UNIVERSITY SCHOOL OF MEDICINE
Department of Genetics
(413) 497-5052

 

Dr. Giuseppe Benagiano
Human Reproduction Unit
World Health Organization
1211 Geneva 27, Switzerland

Dear Dr. Benagiano,

As you know I have been preparing an assessment of the current status
of toxicity control studies on the Alza erodible implant systems, I am happy
to submit this interim report at the request of Dr. Edward E. Schmitt of Alza
Research,

Dr. Schmitt has given me extensive proprietary information concerning
the erodible norethisterone implant system and has discussed with me in detail
the nature of the erosion products. I have not seen, nor did I consider it
necessary at this stage to review, the original laboratory data on which the
present picture of the chemical process of erosion is based. However, Dr. Schmitt
did give me a most detailed account of the chemical nature of the products
and their quantitative distribution under various conditions. They appear to
have made a very wise choice indeed in their selection of constituents as
being a priori most unlikely to present significant toxicity problems.

I have also reviewed a pathology study that they have conducted to date
and their descriptions of the fate of implants in experimental animals. I
believe that other experts can readily be found who would have more experience
with conventional toxicity-pathological studies and might be able to uncover
problems that were not evident to me, Although a slight inflammatory reaction
and connective tissue incapsulation has: been noted with some implants, these
reactions are most unlikely to be avoidable with any implant at all and do
not appear to pose any significant problem that would hinder the further
development of this therapeutic approach on the basis of the present evidence.
Needless to say, such studies will eventually have to be conducted over very
much longer pariods of time and with human subjects in order to erase any
conceivable doubt. There would appear to be no impediment on the basis of the
studies so far to proceeding with clinical trials on human subjects.

I have offered Dr. Schmitt a list of suggested studies that I believe
should be carefully studied for selection of the highest priority items for
further investigation. They include:

1. The whole area of low-level chronic toxicity in mutagenesis and
teratogenesis regimes. This must be proposed as a general precautionar:
measure in view of the scope of intended application of the systems,
rather than because there is any manifest suspicion on the basis of
current evidence. Protocols for these kinds of studies are already

LT. J.P. KRENNEDY, JR. LARORATORIES FOR MOLECULAR MEDICINE, DEDICATED TO RESEARCH IN MENTAL RETARDATION

MOLECULAR BLOLOGY HEREDITY NEUROBIOLOGY DEVELODAMLENTAL MEDICINE
Dr. Giuseppe Benagiano ~2- 11/17/75

sufficiently well crystallized to be generally accepted. They would
include dominant lethal mutation assay in mice, in vitro bacterial
mutagenesis and host-mediated bacterial mutagenesis, inactivation of
DNA and of bacterial phage in vitro, and teratology studies on a few
laboratory mammals. The test reagents for these studies should be
chosen so as to give a very large scale amplification of potential
toxicity and we discussed such measures as the use of finally divided
polymer-hormone complexes; injections with the known oligomers; and
with some of the other known degradation products of the polymer.

2. I did not as yet see specific documentation of purely chemical studies
on the possible interaction of the steroids with the polymer as may
occur during the fabrication of the implant. This should include
consideration of all of the process steps that will be used in the
final manufacture, There is a theoretical possibility of the occurrence
of a small percentage of new chemical complexes between polymer
constituents and steroid and it would be important to isolate and
identify such complexes in order to permit a more aggressive analysis
of their potential toxicity.

Similarly, more studies of the potential chemical reactions between the
polymer constituents and amino acids and other body fluid constituents should be
conducted at a purely chemical level, not withstanding the evident lack of
toxicity of the systems as studied empirically so far.

The question of halegenicity of the implant materials and the possibility of
occasional idiosyncratic sensitivity to them has not so far as I know been addresse
If such reactions do appear - as may well be conceivable after repeated and
perhaps interrupted implantations - this will not necessarily vitiate the use of
the systems but may require the development of skin testing or other diagnostic
procedures to identify such sensitivity. In a related vein I would urge that blood
clotting and platelet function studies be included in further hematological analysi

More closely connected with the therapeutic efficacy than with the safety of
the implants, I would recommend further studies on: (1) tne preconditioning of
implants by emersion in water so that they are available for immediate initiation
of release, and (2) more detailed studies on the terminal rate of release of
hormone at the end of the life-time of the implant - a stage which is dealt with
only by a rather shaky extrapolation at this time. To conduct these studies it will
be necessary to use tracer-labelled agents and to make direct analyses for the
blood levels and metabolic disposition of the agent and of the implant material.

Not withstanding, these critical considerations which will have to be pursued
in unusual detail because of the enormous potential and equally enormous range of
subjects at risk, the approach does indeed to be a most promising one and I
would judge deserves continuing attention by WHO. I would be happy to continue in
a consulting role on this project and believe that I can contribute to a continuing
critical evaluation of the therapeutic systems. However, I believe it important
that I place on the record that I have a long history of personal association with
Dr. Alejandro Zaffaroni and that for this reason alone it would be inappropriate
for me to be in a critical adjudicatory role with respect to WHO's continued
investment in this particular direction.

Sincerely yours,

Joshua Lederberg
cc: De. Edward E, Schmite Professor of Genetics