April 20, 2000

Robert Cohen

560 Oradell Ave.

Oradell, NJ 07649

  ----------------------------------- -----------------------------------
                                      

                                      Re: Docket No. 99P-4613
  ----------------------------------- -----------------------------------

Dear Mr. Cohen:

This is the final response from FDA to your Citizen Petition dated
October 21, 1999. The petition concerns Posilac®, a recombinant bovine
growth hormone (rbGH) product, sponsored by the Monsanto Corporation
(Monsanto) and approved for marketing by the Food and Drug
Administration (FDA).

Prior to commercial distribution of any new animal drug for use in
food-producing animals, a sponsor must prove its product is safe and
effective when used as described in the proposed labeling of the drug.
Effectiveness simply means that the product does what the labeling
claims. Safety routinely covers the safety of the food products to
humans, and safety to the target animals. In addition to these
requirements, the sponsor must prove that they can consistently
manufacture the drug to a specific purity, potency and quality.

Your petition was filed by the agency on October 26, 1999. The petition
requested "that FDA rescind their approval of Monsanto's Posilac and
immediately remove it from the market" based on "new evidence" that the
product poses "serious health consequences for human consumers." The new
evidence you cite is an article by Robert P. Heaney, et al. entitled
"Dietary changes favorably affect bone remodeling in older adults" which
appeared in the October 1999 issue of the *Journal of the American
Dietetic Association*. You also raised issues in the petition regarding
the effects of rbGH in cattle on the levels of IGF-I in milk, the
purported carcinogenic effects of IGF-I in humans, and the effects of
heat treatment on the presence of rbGH in milk.

You amended this petition by FAX on October 27, 1999, and on November 3,
1999. The first FAX contained, in addition to the original petition, a
document entitled "Docket #99P-4613". The second FAX contained the
original petition and a document entitled "Meeting agenda for November
19, 1999." These documents had identical text but different headings.
The documents recounted the issues raised in the original petition and
raised another one. The new issue was based on an article by B. N.
Violand, et al. entitled "Isolation of *Escherichia coli* synthesized
recombinant eukaryotic proteins that contain epsilon-N-acetyllysine"
which appeared in the July 3, 1994 issue of *Protein Science* and
related to the purity of the rbGH produced by Monsanto.

Page 2 -- Mr. Robert Cohen

On December 2, 1999, you amended your petition by letter, raising an
issue regarding FDA's interpretation of a 90-day toxicology study
(conducted by Richard, Odaglia and Deslex) and raising a new issue that
the study "actually lasted for 180 days" and that the FDA had either
misinterpreted or failed to review the study.

Thus, as amended, your petition raised three primary issues in support
of your request for withdrawal of Posilac. These are: 1) that a recently
reported increase in serum levels of insulin-like growth factor-I
(IGF-I) in humans following milk consumption represents absorption of
dietary IGF-I, invalidating a basic premise of FDA's safety assessment
and proving that IGF-I in milk represents a hazard to human health; 2)
that Monsanto changed the manufacturing process for rbGH after the
studies supporting the New Animal Drug Application (NADA) were
completed, thereby invalidating the research used to support the
approval; and 3) that the 90-day toxicology study and/or the information
derived from the additional 90 days of the study demonstrate both that
rbGH is absorbed and that it is not safe. Finally, as a minor point, you
commented on the potential ability of rbGH to survive the pasteurization
process and thus be available for absorption.

We have thoroughly reviewed the issues you raised in your petition. We
believe that the arguments presented in your petition do not demonstrate
any human food safety issue related to the use of Posilac. Therefore,
your petition requesting withdrawal of the approval of Posilac is
denied. The issues you raised are addressed below.

1)  **The safety of IGF-I.**

One of your main areas of concern is that IGF-I in milk will result in
IGF-I levels that are elevated in humans after they consume milk from
cows supplemented with rbGH. The FDA has previously maintained and
continues to maintain that levels of IGF-I in milk whether or not from
rbGH supplemented cows are not significant when evaluated against the
levels of IGF-I endogenously produced and present in humans. In support
of your position, you cite the *Science* article by Juskevich and Guyer
(August 24, 1990). From this article's review of experimental data, you
conclude that when rbGH is injected into cows, levels of IGF-I in milk
increase by 80%.

IGF-I is normally found in human plasma at concentrations much higher
than those found in bovine milk (Schaff-Blass et al., 1984). The levels
in human plasma range from a low in neonates of 14 ng/mL to a high of
686 ng/mL in late pubertal females. The mean values of IGF-I
concentrations in human blood plasma are between 42-308 ng/mL. The total
daily production of IGF-I (endogenously) in an adult is 10,000,000
ng/day (Guler, H.P., et al., 1989). Additionally, IGF-I is normally
found in human breast milk in concentrations higher than those found in
bovine milk. The IGF-I concentrations in human milk ranged between 13
and 40 ng/mL six to

Page 3 -- Mr. Robert Cohen

eight weeks postpartum (Corps, A.N., et al., 1988) while the milk
samples from 5 commercial dairy herds not supplemented with rbGH had a
mean IGF-I concentration of 2.54 ng/mL (Juskevich & Guyer, 1990).

Reported percentage increases in IGF-I concentrations in milk of rbGH
supplemented cows can be misleading because the levels of IGF-I in milk
are so low prior to any increase. For example, a 1988 study (Torkelson
et al., 1988) indicated that while IGF-I concentrations in milk of rbGH
treated cows could be as much as two-fold higher (a 100% increase) than
unsupplemented cows, the absolute increase was 2-3 ng/mL. The 80%
increase in IGF-I levels you refer to in the petition falls in this same
range of 2-3 ng/mL.

IGF-I is a normal but highly variable constituent of bovine milk with
the concentration depending on the animal\'s state of lactation,
nutritional status and age. While some studies indicate that levels of
IGF-I may statistically increase in the milk of rbGH supplemented cows
relative to unsupplemented cows, reported increases are still within the
normal variation of IGF-I levels in milk. Therefore, while IGF-I levels
in milk from rbGH supplemented cows has been considered to be elevated
by some groups (WHO FAS 31, 1993), IGF-I levels in milk from rbGH
supplemented cows do not differ from those of unsupplemented cows in
general with regard to IGF-I.

You cite new evidence demonstrating that levels of IGF-I increase in the
blood serum after humans consume milk. The new evidence is an article by
Heaney, et al. published in October 1999. This article states that there
is a 10% increase in serum IGF-I levels in the milk groups. (The milk
groups consumed three servings of milk per day for 12 weeks.) However,
the study reported in the article made no effort to identify whether the
milk products consumed by the participants were from dairy farms that
used rbGH treatment. Also, the actual levels of IGF-I in the consumed
milk are not reported. Therefore, while this study reports an increase
in serum IGF-I following increased milk consumption, it does not link
this increase to rbGH supplementation of dairy cattle, nor does it
demonstrate any dietary link to the serum IGF-I levels.

The IGF-I increase observed in this study by Heaney, et al. must be
viewed in light of the total daily adult endogenous production of IGF-I,
which is in the milligram range while daily levels of IGF-I consumed in
milk (by three-glass-a-day milk drinkers) are in the microgram range (a
thousand-fold difference). As detailed below, IGF-I in milk would alter
plasma levels by less than 1%\--even if the entire amount of IGF-I in
1.5 liters (three very large glasses\--an 8 oz. glass is less than a ¼
liter) of milk were totally absorbed. Therefore, the 10% increase in
serum IGF-I reported in this study cannot possibly be due directly to
IGF-I absorption from milk.

Finally, we note a difference between the study by Heaney et al. and
that of Storm et al. (1998). Storm, et al. reported no significant
change in serum IGF-I levels over a 2 year period for women supplemented
with milk. This study utilized three treatment groups: placebo,
non-dietary calcium, and milk supplementation. The milk group of 20
volunteers consumed four 8-ounce glasses of milk every day for the
duration of the trial.

Page 4 -- Mr. Robert Cohen

The presence and the concentrations of IGF-I resulting from rbGH
administration were addressed by the 1992 and 1998 meetings of the World
Health Organization/Food and Agriculture Organization\'s Joint Expert
Committee on Food Additives (JECFA). FDA scientists were invited to
participate in these proceedings. At these independent scientific
meetings of international experts on food safety, concerns about the
biological significance of rbGH-induced increases of IGF-I levels in
milk were thoroughly evaluated.

The 1992 JECFA expert committee reached the conclusion that any
elevation of IGF-I levels in milk resulting from rbGH administration
were not of any human health concern due the lack of significant oral
absorption of IGF-I under normal physiologic circumstances in humans.
The 1998 JECFA expert committee concluded purely on the basis of
exposure that the amount of IGF-I in milk is insignificant compared to
the production of IGF-I in people, (less than 0.09%). This amount, even
if it all survived digestion (and there is insufficient credible
evidence that it does), could not reasonably elevate human plasma levels
by even 1%. The international experts, including those from the FDA,
concluded that IGF-I levels in milk of rbGH supplemented cows do not
produce a biologically significant or deleterious effect in people. This
conclusion of safety is reinforced by the JECFA decision that an
allowable daily intake (ADI) and maximum residual limits (MRL) in food
are not needed for rbGH and that rbGH can be used without any
appreciable risk to the health of consumers.

Your petition also asserts that there is a connection between increases
in levels of IGF-I and cancer. In the last few years there have been
several articles published in the scientific literature that have dealt
with the incidence of breast, prostate, and lung cancer in association
with elevated levels of IGF-I, which you have cited (Chan, J. M. et al.,
1998; Hankinson, S.E., et al., 1998; Yu, H. et al., 1999). These
articles postulate an epidemiological association between significant
increases in the plasma levels of IGF-I and tumor appearance. None of
the articles demonstrate a causal relationship between IGF-I and the
appearance of tumors. It must be noted that while large percentage
increases in IGF-I concentrations in human plasma are reported in
association with some tumors, the authors of these articles do not reach
the conclusion that IGF-I caused the tumors.

Among the growth factors, IGFs play a crucial role in regulating cell
proliferation and differentiation. IGFs\' mitogenic activity (activity
on reproduction of the cell) is regulated by receptor binding, which is
in turn facilitated by IGF-binding proteins. These articles note a
possible dose-response relationship between increased risks of these
cancers and elevated levels of IGF-I, but none of the three articles
empirically demonstrates a causal relationship. The authors' state that
increased IGF-I plasma levels may be part of the phenotype of certain
types of cancer; thus, the cancerous cells themselves may promote IGF-I
to maintain their accelerated cell cycle. That is, the increased IGF-I
levels may be the result of the cancer, and characteristic of the cancer
process, but not the cause.

While clearly debatable, if increased circulating IGF-I levels were
assumed to increase cancer risk, then the interaction between IGF-I and
its receptor and the binding proteins becomes important. The putative
carcinogenic effects of IGF-I would then depend upon receptor

Page 5 -- Mr. Robert Cohen

interaction. IGF-I is not directly genotoxic (i.e., it does not directly
alter the DNA). The ligand-receptor complex is responsible for the
increased DNA synthesis and the acceleration of the cell cycle seen in
the presence of IGF-I. There is no experimental evidence that (1) oral
rbGH impacts the level of circulating IGF-I, or the number of IGF
receptors and (2) there is no evidence that rbGH increases the number of
ligand-receptor complexes. Thus, at present there is no evidence linking
rbGH to any increased cancer risks that might be due to increased IGF-I
and IGF receptor interactions. We agree with your conclusion that bovine
IGF-I and human IGF-I are indistinguishable, and we reiterate that with
respect to potential effects in humans, the amount of IGF-I in milk from
cows (regardless of possible rbGH supplementation) is insignificant
compared to the endogenous production of IGF-I in people (less than
0.09%).

**2) The manufacturing process for rbGH.**

The FDA was, of course, fully aware of the modification of the
N-terminal amino acid of rbGH with a methionine (the established name of
the product, methionyl sometribove, reflects that knowledge). We
recognize that you have not taken issue with the incorporation of the
methionine, conceding that it is not a health concern because it does
not interfere with the tertiary structure of the protein nor does it
impact the biological activity of the protein. FDA was also aware of the
potential for an acetylated lysine at position 144 as well as other
positions as reported by Violand, et al. in 1994. The FDA was informed
of the latter potential difference between natural bGH and the
sponsor\'s rbGH in 1987, six years prior to approval. {We note that you
submitted an FOIA request for documents from January 1, 1990 to the
present (which we considered to be December 20, 1999, the date your FOIA
request was filed) regarding the "five different amino acids created
during the process of genetically engineering \[Monsanto\'s\] bovine
growth hormone". We had no documents from that time period and we so
advised you in our FOIA response.}

With regard to the alteration of amino acid 144, from lysine to
epsilon-acetyl-lysine, and similar potential acetylations elsewhere, we
note that these are post-translational modifications to the molecule. In
other words, once the protein molecule is formed by incorporation of the
appropriate amino acids at the appropriate positions, that is, after
both transcription and translation, some amino acids may be further
modified by the addition of various functional groups. While with rbGH
the concern is over acetylation, with other proteins post-translational
modifications may include glycosylation and disulphide-bridge formation.
Most types of post-translational modification (including acetylation) do
not affect the overall tertiary structure of the protein and thus, do
not affect the biological activity of the protein. However, depending on
the chemical moiety being added to the amino acid component, it is
possible that these post-translational modifications alter the net
electrical charge of the protein.

When Monsanto informed the FDA in 1987 that a small percentage of their
rbGH product contained modified amino acid components, they did so by
reporting on the electrical charge states of the resultant proteins. We
note, in passing, that amino acid modifications of this kind are
probably not appropriately referred to as \"freak amino acids\" as you
refer to them in your petition. Rather, acetylation is a recognized
naturally occuring post-translational event in

Page 6 -- Mr. Robert Cohen

proteins. In any event, only a small percentage of the total rbGH
produced is post-translationally modified in this manner.

We also note that the N-terminal amino acid of natural bGH is either
phenylalanine or alanine\--both of these amino acids occur as natural
variants. Another site for variation in the amino acid sequence that
occurs in natural bGH is position 126 at which valine and leucine are
both known to occur. Thus, natural bGH, itself, is not one substance but
a group of molecularly similar substances demonstrating similar
biological activity. In general, pituitary extracts yield a class of
related growth hormone polypeptides that vary in charge, mass, and
N-terminal amino acids (Breems, D.N. et al., 1985). This heterogeneity
of composition does not alter biological function and, thus, does not
create a public health concern.

You note that Jerome Moore\'s 1988 *Endocrinology* article, comparing
recombinant human growth hormone with natural human growth hormone,
\"warned that a different amino acid in the middle of the sequence of a
protein chain could have significant consequences, quite often
disastrous.\" While we could find no evidence of such a warning in the
Moore article, the FDA fully agrees that substitutions of specific amino
acids in specific proteins have been shown to lead to deleterious
effects on the function of the hormone in some cases. However,
post-translational modifications and N-terminus modifications of bGH
specifically have not been shown to have any adverse effect on the
biological activity of the molecule. Moore, himself, demonstrated this
with respect to two different recombinant human growth hormone forms:
with an N-terminal methionine and without the methionine. Therefore, we
believe that Moore\'s discussion has been misconstrued in your petition
relative to the kinds of changes associated with rbGH.

As previously noted, post-translational acetylation results in a small
change in the electrical charge of the rbGH molecule relative to
non-acetylated rbGH. This charge difference allowed Monsanto to improve
their manufacturing process by separating most of the acetylated rbGH
from the non-acetylated rbGH. (The net charge on the molecule is reduced
by one positive charge due to the binding of the neutralizing acetyl
group to the positive lysine.) The acetylated rbGH has similar activity
to non-acetylated rbGH on the basis of in vitro assays and the
acetylated rbGH never represented more than a small portion of the total
rbGH produced. The improved manufacturing procedure resulted in rbGH
that is of a purity comparable to that achieved in protein products
approved for use in humans.

From statements in your Citizen Petition it appears that you believe
that Monsanto satisfactorily \"fixed\" the problem of post-translational
acetylation, but that in doing so the sponsor invalidated seven years of
research because the pivotal studies supporting the approval utilized
rbGH which was produced prior to the \"fix\". We assume your argument is
that the rbGH used in the studies is not the same rbGH that FDA
approved.

As stated earlier, FDA was aware of the change in the manufacturing
process prior to its approval of the product and believed that the
change did not result in a different product such that the research with
the product prior to the manufacturing change was invalid. We note that

Page 7 -- Mr. Robert Cohen

during the new animal drug development process, it is the usual case
that sponsors make continued improvements in the manufacturing process.
If those changes result in only biologically inconsequential variations,
we consider the products to be the same.

However, to reaffirm that the conclusion we reached in this case was
correct, we re-examined information previously submitted by Monsanto to
their Investigational New Animal Drug file, to their manufacturing
chemistry Master File, and to their New Animal Drug Application to
support the approval of the rbGH product. We also made a site visit to
the sponsor to examine batch records. These records are not required to
be submitted to the new animal drug files.

Based on our examination, we reaffirmed our conclusion that the
manufacturing changes resulted in only biologically inconsequential
variations in the product used in the safety and effectiveness studies
and, therefore, the rbGH product we approved is the same as the product
used in the studies.

**3) The fate and effects of bGH in milk**

You cite the *Science* paper by Juskevich and Guyer and challenge the
article\'s conclusion that pasteurization at 162°F for thirty minutes
destroys bGH. You claim that the heat treatment in the study cited in
the *Science* article, which produced only a 19% decrease, was not truly
\"pasteurization\" because pasteurization at the temperature used in the
study typically occurs for only 15 seconds. A review of the definition
of pasteurization appearing in the Code of Federal Regulations (21 CFR
1240.61) defines pasteurization as the process of heating every particle
of milk and milk product in properly designed and operated equipment to
one of the temperatures given in the following table and holding it at
or above that temperature for at least the corresponding time.

  --------------------------------- -------------------------------------
  Temperature                       Time

  145° F (63° C)                    30 minutes

  161° F (72° C)                    15 seconds

  191° F (89° C)                    1 second

  194° F (90° C)                    0.5 seconds

  201° F (94° C)                    0.1 seconds

  204° F (96° C)                    0.05 seconds

  212° F (100° C)                   0.01 seconds
  --------------------------------- -------------------------------------

The Agency considers all approaches in 21 CFR 1240.61 equivalent in
pasteurizing a product. These alternative definitions of pasteurization
only address the minimal time duration. While there is no indication
that the heating process can not last longer and still be considered
\"pasteurization\", we concede that it may have been more appropriate to
refer to the process utilized in the referenced study as simply
\"heating\" of the milk at the specified temperature for the specified
duration.

Page 8 -- Mr. Robert Cohen

Like most dietary proteins, rbGH is degraded by digestive enzymes in the
gastrointestinal tract and not absorbed intact. *In vitro* studies on
the metabolism of rbGH demonstrate that digestive enzymes readily cleave
the molecule (Heiman & Harris, 1989). The progressive cleavage of
peptide bonds results in the loss of biological activity because both
the C- and N-termini and appropriate tertiary structure are required for
receptor binding. *In vivo* studies confirm that proteolytic fragments
of rbGH produced by digestive enzyme cleavage have no biological
activity (Hammond, B.G., et al., 1990). In fact, one of the most common
techniques for studying the primary structure of proteins is trypsin
cleavage. In this technique, the protein molecule is treated with a
proteolytic enzyme commonly found in the human digestive tract, trypsin,
and the peptide bonds of the protein are broken down such that the amino
acid sequence may be determined.

Your concern regarding the potential oral activity of rbGH leads to the
issue you raised with respect to the "Three-Month (90-day) Oral Toxicity
Study of Sometribove in the Rat." This study is the same 180-day study
that you claim the FDA has not evaluated. This is a study of complex
design and FDA welcomes the opportunity to clarify both the design of
the study and its interpretation. The following discussion will address
the full study.

In this study from Monsanto, conducted by Richard, Odaglia and Deslex,
Charles River VAF rats (30 /sex/treatment group) were administered rbGH
by oral gavage (0, 0.1, 0.5, 5 and 50 mg/kg bw) or subcutaneous
injection (1 mg/kg bw) once daily for 90 days. Clinical observations,
morbidity, mortality, body weights, and feed consumption were recorded
for all rats. Upon cessation of drug treatment, 15 rats/sex/treatment
group were necropsied to determine toxicology endpoints, including
ophthalmology, hematology, clinical chemistry, urinalysis, pathology and
histopathology.

The remaining 15 rats/sex/treatment group were used for the blood
collection/reversibility groups. Blood samples were obtained from all of
these rats prior to drug administration. Of these animals, blood samples
were collected from 10 rats/sex/treatment group during week 7 of
treatment and at week 14 (upon cessation of drug treatment). These rats
were then removed from the study and destroyed without necropsy. The
remaining 5 rats/sex/treatment group (the reversibility group) were also
bled at week 14, and then on study week 28 (recovery week 14). At study
week 28, following the collection of blood and recording of body weight
and feed consumption, these animals were destroyed without necropsy.

Data collected for the 10 rats/sex/treatment group that made up the
blood collection experimental group were limited to serum rbGH antibody
concentration. Data collected for the 5 rats/sex/treatment group that
made up the reversibility experimental group were limited to body
weights, body weight change, feed consumption, and serum rbGH antibody
concentration.

Thyroid cysts were observed in the gross and histopathological
examinations in all treatment groups, including the positive and
negative control groups. Neither the frequency nor severity of the cysts
was attributable to rbGH treatment. Similarly, a prostatitis was
observed in animals from all treatment groups including the positive and
negative control groups and again this was

Page 9 -- Mr. Robert Cohen

not attributable to rbGH treatment. No adverse effects of rbGH were
observed in any animals of the toxicology group.

There were no statistically or biologically significant effects of daily
oral rbGH in clinical observations, body weights, body weight change or
feed consumption, either during treatment or during the recovery phases.
Daily administration of subcutaneous rbGH significantly increased body
weights, body weight change, organ weights, and feed consumption in the
toxicology experimental group. However, body weights, body weight
change, and feed consumption following subcutaneous administration
returned to the \"base-line\" levels found in the control group animal
values over the course of the recovery period.

Administration of subcutaneous or oral rbGH resulted in a significant
increase in plasma antibody concentration. One out of 30 rats (male and
female) receiving 0.1 mg/kg bw oral rbGH per day, 6/30 rats receiving 5
mg/kg bw, and 9/30 rats receiving 50 mg/kg bw per day had a measurable
plasma antibody response following 90 days of continuous oral treatment.
Twenty-seven out of 28 rats showed a significant antibody response
following 90 days of subcutaneous rbGH injection (1 mg/kg bw). Fourteen
weeks after cessation of rbGH administration, 9/10 rats of the
subcutaneous rbGH treatment group, and 2/10 rats of the 50 mg/kg bw oral
rbGH treatment group had measurable titers.

The immunological assay could not distinguish between an antibody
response to intact rbGH or fragments of rbGH. It was also not possible
to distinguish between antibodies produced in response to absorbed rbGH
or gastrointestinal rbGH. While further interpretation of the plasma
antibody response data is not possible, we reiterate that no adverse
effects of rbGH were observed following 90 continuous days of oral
administration or following an additional 90 days of recovery after the
cessation of drug administration.

## 4) Conclusion

For the reasons stated above, FDA denies your Citizen Petition
requesting withdrawal of the approval of the New Animal Drug Application
providing for the marketing of Posilac by Monsanto.

> Sincerely yours,
>
> /s/
>
> Dennis E. Baker
>
> Associate Commissioner
>
> for Regulatory Affairs

cc: HFA-305 (Docket 99P-4613)

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