Interim Melamine and Analogues Safety/Risk Assessment
Peer Review Report
Introduction and Summary of Comments
On May 24, 2007 FDA sent its Interim Melamine and Analogues
Safety/Risk Assessment (S/RA)(1)
to six experts and asked them to review it by May 31, 2007. The peer reviewers
were:
Georges Benjamin, M.D.
Director, American Public Health Association
Samuel M. Cohen, M.D., Ph.D.
Professor and Chair, Pathology and Microbiology
Havlik-Wall Professor of Oncology
University of Nebraska Medical Center
Elaine M. Faustman, Ph.D.
Professor, University of Washington
School of Public Health and Community Medicine
Institute for Risk Analysis and Risk Communication
Lonnie King, D.V.M., M.P.A.
Director, National Center for Zoonotic, Vector-Borne and Enteric Diseases, CDC
Xavier Pi-Sunyer, M.D., M.P.H.
Director, Columbia University Obesity Research Center
St. Lukes Roosevelt Hospital Center
John Thomas, Ph.D., D.A.T.S., F.A.C.T
Professor, Indiana University School of Medicine
Department of
Pharmacology and Toxicology
We greatly appreciate the peer reviewers' comments and suggestions, as well as their
willingness to provide them on a very tight deadline. The reviewers' responses
to the specific charge questions are provided below without attribution to the
specific reviewer.
Overall, there was consensus
from the peer reviewers that the conclusions of the S/RA were appropriate. In
addition, recognizing the time-sensitive context in which the S/RA was
developed and the time-sensitive need for the S/RA results, the peer reviewers
concurred that the methodology, data, assumptions, and exposure scenarios used
were appropriate.
Several reviewers provided suggestions for FDA to consider
in future revisions of the S/RA. These additional suggestions include the
following:
- There may be other data sources from studies of similar compounds
pertinent for consideration; for example, one reviewer suggested that we
consider studies that were conducted to evaluate the toxicity and metabolism of
"triazine" pesticide compounds.
- Multiple sources of exposure should be considered, as there could
be an additive effect. For example, one reviewer suggested that there may be
exposure to melamine and its analogues from plastic products.
- Although one reviewer stated that "there is no evidence of
bioaccumulation," other reviewers suggested that a scenario focused on possible
chronic toxicity from longer duration exposure should be considered.
- There should be some consideration of possible formation of other
(more toxic) compounds such as might be created during heating.
Finally, there was a consensus among the peer reviewers additional
research is needed. The reviewers identified several areas for future investigation,
including:
- Determine the concentration and crystallization of melamine
compounds (MCs) in urine of different species, including possible co-crystallization
(e.g., melamine and cyanuric acid) at lower concentrations due to hydrogen
bonding effects between the MCs in enhancing crystallization and the effect of
liquid and salt ingestion on the concentration of MCs in urine.
- Method development, such as more sensitive assays to detect low
levels of MCs in tissues.
- Toxicological studies with different species, including the
examination of co-toxicity from exposures to multiple MCs to determine whether
there are other additive or synergistic effects.
- Studies to better understand melamine pharmacokinetics including
the effects of dehydration, common medications (diuretics) and others that
alter renal excretion.
- Determine whether heating MCs forms new compounds in foods with
greater toxicity than the parent compounds.
- Conduct longer term studies to determine potential toxic effects,
including liver, reproductive or endocrine dysfunction.
- Determine whether biomarkers can be identified for predicting renal
failure secondary to exposure to MCs.
Several of these
suggested research studies may provide more extensive and accurate data that
could be used to reduce the uncertainties in future safety assessments of MCs. However,
to some extent the long term testing that this suggested research would entail would
need to be justified by evidence of chronic exposure, and we are unaware of
such evidence at this point.
Peer Review Comments in Response to Charge Questions and
FDA Response
- Question 1. Does the S/RA
report adequately identify the data and methodology used,
and explain how data were identified and what
criteria were used to determine the suitability of the data? Were these
criteria adequate? Was the methodology appropriate?
- Reviewer #1. I found that the report was adequate in both
identifying the data used for the assessment and establishing the criteria and
methodology for the S/RA. While these features were clear, only a single
approach was used that was based on limited studies and data. There may be
other data sources from studies of similar compounds that are pertinent for
consideration and thus a broader approach to create the S/RA.
- Reviewer #2. See response to Question 8.
- Reviewer #3. The S/RA report clearly identifies the data and
methodology used including the assumptions behind the methodology. Because of
the general reported lack of clinical studies, a great deal of assumptions had
to be made. While these may be found to be inexact in the future the authors
make very conservative and reasonable assumptions to construct their
methodology.
- Reviewer #4. Extent of contamination-One of the
interpretation difficulties inherent in an incident such as this is the
representativeness of the analyzed samples. Knowledge about the sampling
strategy used to analyze contaminated media can assist the reader in
understanding the extent of the problem however such information was missing
from this report. Obviously concern for source identification is important and
hence samples were only identified by letter or number however in order for
this reviewer to understand how these samples were chosen for analysis (i.e.
random or were these chosen for most suspected to be contaminated; where these
samples from multiple supplier sources or all from one supplier and thus
representative of downstream variation.). Such information is needed in order
for this reviewer to support the "conservative" characterization of the risk
assessment that is proposed on page 3.
Risk assessment methodology - Standard approaches for using
NOAEL based reference values, uncertainty factors and Margin of safety
assessment techniques were employed. The calculation of the TDI was also
representative of such established methodologies.
Exposure assessment - Based on this reviewers comments listed
above I have concerns about whether the exposure assessment is based on
appropriate estimates.
- Reviewer #5. The S/RA adequately reports the data and
methodology uses. It also explains how data were identified and what criteria
were used to determine the suitability of the data. I believe that the
criteria were adequate and the methodology was appropriate.
- Reviewer #6. Yes.
FDA Response: The peer reviewers generally agreed
that the report adequately identified the data and methodology used and that
the data and methodology were appropriate. One reviewer requested additional
information to better understand the sampling design of the analyzed feed and
tissue samples. It is important to note that the samples were largely of an
investigational nature and were obtained from facilities that were involved in
the contamination incident; as such the reported samples were targeted to the
incident and not "random" samples. We recognized in the S/RA that
there was uncertainty associated with the sample design. However, we believe
that this uncertainty was offset by the conservative nature of the assumptions
in the S/RA. More information will be supplied in the
S/RA to provide a better description of sampling methodology.
- Question 2. Are uncertainties in the S/RA identified and characterized?
- Reviewer #1. Further uncertainties may need to be considered
in the assessment. There should be a factor of 10 used based on interspecies
variability (identified in the interim S/RA) but also an additional factor of
10 should be considered based on variations in human sensitivities and exposure
differences. Combining these premises would produce a lower uncertainty factor
which would also be consistent with most standard RA practices.
- Reviewer #2. See response to Question 8.
- Reviewer # 3. The uncertainties concerning long term
exposure could be strengthened. While Melamine compounds appear to be
relatively inert, the complications of long term exposure remain unclear and
there may be as yet unpredicted immunologic response secondary to some unknown
trigger. I would simply strengthen these unknowns.
- Reviewer #4. Please see comments for Question 1 responses.
In addition, there are several additional issues that need to be addressed in
this report. Please see my responses under question 7 for additional future
data needs.
The report contains material in the appendices that does not
appear to be fully addressed in main section of the report. For example, on
page 9, Appendix 1, under the heading of Hazard and Toxicity both an LD50 and
phrase "Exp. Carcinogen" is listed. The text should provide additional
references and discussion of this listing. On page 10, Appendix 1 for Cyanuric
acid, there are listings under biological use and importance that hint at other
biological activities that could be related to its hazard potential for
example, its use as a herbicide and information that in an ester form it may be
an anticonvulsant or hypnotic. Does FDA have any information on these
properties or potential for these forms to be present under the current
conditions? How potent are these materials? Is there information available
from the Pesticides office of EPA (in RED documents) for cyanuric acid as an
herbicide? This same page also lists this agent as an eye and skin irritant.
Where did this information come from? At what exposures do these effects
occur?
Other missing information includes lack of toxicological
information that this reviewer would believe is present in the toxicological
documents reviewed for this assessment. Since, references were not cited it is
difficult for this reviewer to double-check if this is true. For example, on
page 2 of the report many NOAELs were given from various animal studies however
minimal to no information was provided about complete numbers and dose levels
tested in each study. At a minimum such information is useful for
understanding if the strength of support for the NOAEL being a true NOAEL
rather than just the lowest dose tested. Such information could influence the
size of the uncertainty factor used in the later stages of the risk assessment.
- Reviewer #5. The uncertainties with regard to this S/RA
Assessment are identified and characterized.
- Reviewer #6. Yes.
FDA Response: One
reviewer noted the need to provide more complete references for the S/RA. The
reviewer also suggested including additional ancillary information. In general,
we agree that more information could be provided and that the information
should be properly cited and documented, and will take steps to further develop
the references in this S/RA. Although adding references will enhance this
document, we do not believe that providing such additional information would
have changed our methodology, approach, or results.
One reviewer suggested an
additional uncertainty factor should be considered "based on variations in
human sensitivities and exposure differences." At the current time the
additional uncertainty factor would not be generally considered warranted. Human
variability was considered in the selection of the total uncertainty factor of
100 that was used in the S/RA. Selection of the uncertainty factor of 100 was
done according to typical safety assessment practices; the value was based on a
factor of 10 for inter-species variability and a factor of 10 for intra-species
sensitivity variation. As additional information becomes available through
future research, the magnitude of the uncertainty factor can be revisited.
One reviewer
questioned the information in Appendix I and whether further discussion in the
text of the S/RA was needed on a listed LD50 and a reference to
"Experimental Carcinogen." The same LD50 reference was a part of
and considered in Reference 2. The consideration of MCs as carcinogens was not
considered relevant to short-term exposure to these compounds. There has been
extensive testing of cyanuric acid and melamine; the results of this testing forms
the basis for conclusions regarding the general systemic toxicity of these two
compounds, as discussed in the S/RA. A table of studies contributing
to the S/RA will be added to the S/RA. This table will list dose levels and
durations of studies.
- Question 3. Are there additional scientific/ technical studies available that were not considered?
- Reviewer #1. There are a number of studies that have been
conducted on other "triazine" compounds that are structurally closely related
to melamine and its analogues that should be considered in the analysis and
S/RA.
- Reviewer #2. See response to Question 8.
- Reviewer #3. I have done a brief review of the literature
and have not [sic] found very little covering toxicity with melamine in humans.
One article concerning inhalation of an aerosol including several chemicals one
of which was melamine resulted in pulmonary edema. The causative compound was
not felt to be melamine.
- Reviewer #4. Since very few if any of the studies that were
reported had unique references to specific studies this question was a bit
difficult to answer directly. When RTECS [Registry of Toxic Effects of
Chemical Substances] was reviewed there were additional references listed that
should be specifically cited and discussed in this risk assessment document.
For example the Tox and Applied Pharm article from 1984. Also for transparency
I would have direct links from this document to these review sources. The
RTECS site also lists mutation data and references and these should be
referenced. In addition, IRAC [IARC, the International Agency for Research on
Cancer] reviews should be cross-referenced. For background it may also be
important to document that inhalation studies have been performed even though
this route of exposure and toxicological findings are less relevant than oral
studies they may at least provide some toxicological context. Note that both
reproductive and liver function assessments were done following inhalation
studies and these endpoints should be openly discussed for relevance. There is
also a specific citation for eye irritation that provides limited exposure dose
information. Please add this information.
- Reviewer #5. To my knowledge, the available
scientific/technical studies were referred to. I do not know of additional
data that should have been included and was not.
- Reviewer #6. Studies showing lack of DNA reactivity
(non-genotoxicity). See International Agency for Research on Cancer (IARC)
reference.
FDA Response: Before the S/RA is updated, we will
review the studies identified by the peer reviewers to determine whether they
are relevant to the data and assumptions used for this S/RA. We note that some
of the studies identified by the reviewer concern occupational exposure and may
investigate a route of exposure (e.g., inhalation, dermal) that is different
from the route considered in this S/RA (oral) that may not be applicable to our
analysis.
- Question 4. Is the no observed adverse effect level (NOAEL) used the
appropriate point of departure for calculating the margin of safety (MOS), or
do data support the use of an alternative endpoint?
- Reviewer #1. An alternative end point should be considered
based on toxicity studies of atrazine and similar compounds; some have looked
at occupational human exposures. These studies suggest that reproductive and
developmental hazards and implications need to be considered in the final end
point calculations. The animal study used was based on the carcinogenicity of
calculi-forming pathways. This may or may not be applicable to the human situation.
- Reviewer #2. See response to Question 8.
- Reviewer #3. I think this (NOAEL) is the most appropriate
point to use.
- Reviewer #4. Based on the information provided in the
assessment this review would concur with the chosen NOAEL and endpoint. However
as discussed above, insufficient information about total dose-response curves
for all toxicological studies was given that would allow for a full response to
this question.
- Reviewer #5. I believe that the NOAEL used is the
appropriate point of departure for calculating the margin of safety.
- Reviewer #6. NOAEL is appropriate
FDA Response: In general, the peer reviewers agreed
that the NOAEL chosen was appropriate. It would be challenging to analyze
additional triazines for potential applicable toxicity with regard to expected
effects of the MCs. The rather extensive testing performed with melamine and
cyanuric acid to date do not reveal effects relating to the other toxicological
endpoints mentioned by the outside reviewers at exposures that are relevant to
those potentially received by humans in this instance. The reviewers for this
S/RA felt that the most relevant toxicological data would be provided by that
of melamine and cyanuric acid. Other substances e.g., atrazine, do demonstrate
additional toxicity compared to MCs; however, the central nervous system
toxicity manifested by atrazine may not be applicable to the MCs due to
atrazine's less polar nature. As noted, we will look again at the
literature on triazine pesticides and consider the possibility that other
biological endpoints should be considered in future assessments.
- Question 5. Were scientific
assumptions that are not strictly linked to the data explained and
appropriate?
- Reviewer #1. The S/RA as currently being considered is quite
narrow in its interpretation and data consideration without the additional
consideration of pertinent studies involving atrazine and similar chemical
compounds.
- Reviewer #2. See response to Question 8.
- Reviewer #3. The real challenge is extracting
[extrapolating] rodent data to humans (I understand the studies are mostly in
this species). However, since the event was precipitated by feline illness I
would suggest you discuss what you do know about the pathophysiology of this
exposure in cats and then transition to people.
- Reviewer #4. No, for example the discussion on carcinogenic
potential was not fully explained or sufficiently documented. One of the other
reviewers of this assessment is Dr. Sam Cohen and his research on rodent tumors
with saccharin is very relevant for this study however none of his mechanistic
research is mentioned or summarized for relevance. Also, in order to support a
non-genotoxic mechanism for cancer, the available mutation data and references
would need to be cited. Some of this was listed in RTECS but not fully
described or referenced in this document.
- Reviewer #5. A certain number of assumptions had to be made
in carrying out this assessment. The assumptions made seem reasonable and
sound to me.
- Reviewer #6. Yes.
FDA Response: With one exception, the peer reviewers
agreed that the assumptions were explained and appropriate. The additional
suggested considerations will be evaluated when the interim S/RA is updated.
As stated previously, the potential chronic toxicity and carcinogenicity of the
MCs were not evaluated in this S/RA due to the temporary nature of exposure to
these substances (see FDA Response to research suggestions by the outside
reviewers and FDA Response to Question # 4). One reviewer suggested including
a discussion of the mechanism of action. There are no data found in the
literature on the mechanism of action specific for melamine. We do
not agree that including data on the mechanism of action for the
formation of bladder tumors from ingestion of high doses of saccharin is
useful for the melamine S/RA because it is not known whether the molecular
events which trigger bladder tumor formation from ingestion of high levels
of saccharin would be the same as those for MCs; however, Dr. Cohen was one of
our reviewers and we will follow up on this suggestion with him. Finally, thus
far, little or no experimental data have been found where the cat was used as
the subject of testing.
- Question 6. Are the
scenarios addressed representative and comprehensive, considering the public
health risk evaluated?
- Reviewer #1. The three scenarios are quite useful but may
not be completely representative or comprehensive. There may actually be worse
case scenarios that should be considered in addressing potential public health
risk. There might be a greater additive effect if multiple sources of exposure
are considered. Another factor that should be considered is human consumption
of pet food which does occur in some human populations. The final issue is the
need to consider possible background exposures to melamine and its analogues
likely through plastic products. One scenario should also focus on a longer
duration of exposures and the potential outcome of chronicity.
- Reviewer #2. See response to Question 8.
- Reviewer #3. The three scenarios are appropriate and cover
the scope of risk categories. They are at the macro-level and define the gross
risk of consumption. The scenarios appear to assume no bioaccumulation over
time (This is of course adjusted some by the calculation for Tolerable Daily
Intake but may need to be readjusted if substantial bioaccumulation is found to
occur in future studies).
- Reviewer #4. Please see my earlier comments regarding
representativeness of the exposure media assessment and how this would impact
uncertainty in the exposure scenarios. As a reviewer of this document, I would
need to understand more about the rationale to use 50 ppb for the concentration
of melamine in all edible tissues. Because of the lack of information about
representativeness of the measurements of the tissues and feed, this reviewer
could not determine the "conservative" nature of this assumption as is stated
on page 3, second paragraph.
Note that the text does not specifically state how the contaminant
level in the feed (Table A-3,Source numbers 1-19) related if in any way to the
tissue levels reported in Table A-4. Also, this reviewer noted that on page 3, second paragraph
the text states that the "analogue levels were generally no greater than
melamine levels" however Table A-2 lists multiple examples where this statement
was not true. This reviewer probably did not disagree with the over all
statement but feels that more specific responses and statements are needed
rather than just saying "generally" state the specific number of time the
analogues exceeded the levels of melamine.
- Reviewer #5. I think that the three scenarios presented are
representative and comprehensive, considering the public health risk evaluated.
- Reviewer #6. Yes.
FDA Response: The
additional suggested scenarios will be taken into consideration when the
interim S/RA is updated. The pharmacokinetic data on melamine and cyanuric
acid indicate that both of these substances are absorbed readily, distributed
to the total body water and excreted relatively quickly (half lives of 2-3
hours). There is no evidence of bioaccumulation of these two substances at the
doses tested. One reviewer assumes that the FDA's S/RA used 50 ppb as the level
of contamination by MCs; however, the actual level of contamination was assumed
to be 100 ppb. (See S/RA) Thus, the degree of conservatism with regard
to assumed exposure was even greater than this reviewer suggested. When the
S/RA is updated we will have a more complete analysis of samples for the
compilation of putative exposures and their variation.
- Question 7. What are the
prioritized research needs in relation to melamine and melamine related
compounds, including the research that is needed to reduce the uncertainty
associated with the S/RA?
- Reviewer #1. There is clearly a need to develop and
implement several research studies to help fill in knowledge gaps. These
studies are listed in priority order from my perspective: 1. Identify complete
structural activity to make sure that we are comparing the various compounds
correctly; 2. Take contaminated food stuffs and identify exact chemical
compounds that might result after heating the foods and then evaluate if the
new compounds have greater toxicity; 3. Conduct longer term studies to
determine other potential toxic effects including liver and reproductive or
endocrine dysfunction; 4. Determine the possible additive and/or synergistic
effect of melamine and its analogues that might result from co-exposures.
- Reviewer #2. See response to Question 8.
- Reviewer #3. The most obvious one is to look at other
organs like gut, spleen, liver etc. for sub clinical accumulation or effects.
Also, to better understand the effects of dehydration, common medications
(diuretics and others that alter renal excretion of melamine pharmacokinetics.
- Reviewer #4. This reviewer is supportive of the research
needs listed in the document but feels that additional needs should include
information on kinetics especially as this is directly related to the clearance
issues. Determining whether these compounds breakdown internally or form
esters internally would also be important to confirm. The importance of
determining toxicity under co-exposure conditions is important. The report
contains only a single line regarding reproductive and developmental toxicity
and this would need to be verified or available data more thoroughly
described. Much more exposure information about contaminate sources is needed.
- Reviewer #5. Information on the toxicity of melamine
compounds and on the levels of melamine compounds in edible tissues would be
very useful. It would be important to have more accurate analytical methods to
detect low levels of melamine compounds in tissues. The crystals that have been
found in kidneys should be characterized. Basic toxicological studies should
be done in several species. The toxicity studies should include examination of
co-toxicity when there is exposure to more than one than one melamine
compound. Is there synergism or just additivity? Could biomarkers be
identified that would raise an alert about renal failure secondary to melamine
compounds?
- Reviewer #6. Concentration and precipitation in urine of
different species. Synergistic effects of the 4 chemicals in enhancing crystallization.
More sensitive assay. Effect of liquid and salt ingestion of concentration of
MC's in urine.
FDA Response: Thank you for the suggested research
needs.
- Question 8. Do the S/RA
results adequately support the conclusion (i.e., the low risk to human health
from consumption of fish, chicken, poultry and pork inadvertently fed melamine
contaminated feed)?
- Reviewer #1. While the statement of a low risk to human
health is the likely conclusion, I would hope that a true worse case scenario be
constructed and considered based on exposures mentioned in question # 6. While
the half-life of the compounds is relatively short, there is still a lingering
question about what happens to melamine and analogues after cooking and/or
heating. Are new and more toxic compounds created as they combine with resins?
If this is true, then the current S/RA would seem to miss the most potentially
relevant exposures. It seems that this question needs to be addressed before a
final conclusion is considered.
- Reviewer #2. I have reviewed the document entitled,
"Interim Melamine and Analogues Safety/Risk Assessment", dated May 24, 2007.
The various assumptions used in developing the three (3) Scenarios, coupled
with the analytical results, indicate that melamine and its analogues should
pose no undue risks to human health. The Scenarios appear to be plausible.
While additional investigations may be warranted, there are no overt adverse
effects caused by these compounds that should concern humans who might have inadvertently
ingested melamine-contaminated animal food/feed.
It is noteworthy that melamine was synthesized over 150
years ago, and that it has enjoyed a wide variety of commercial uses for
several decades.
Melamine is minimally toxic, and has an LD-50 in
experimental animals that is similar to that of common table salt or sodium
chloride. There is no evidence of bioaccumulation.
- Reviewer #3. I believe the S/RA adequate supports the
conclusions for short and moderate term exposure. Longer term exposure (years)
should be cautionary until further studies are done.
- Reviewer #4. This reviewer would support that the fact that
the interim risk assessment suggests that the risk is low for humans following
acute exposure scenarios presented. Questions that need to be determined
include the above points regarding lack of completeness regarding the extent of
contamination-for example only livestock, pet and fish food contamination
issues were discussed. Do we really know and can ensure that no contamination of
human food stuffs were directly contaminated? In addition, because of the
uncertainty of the linkage of exposure data and effects in livestock, it
appears that only one of the studies was directly linked (U of California Davis
study) hence significant uncertainty exists yet no additional factors for uncertainty
are included in the margin of safety calculations. If an additional factor of
at least 10 were included the same general risk/safety conclusion could be made
but the MOS values would be more modest and in this reviewers assessment more
reflective of the situation at the current state of knowledge.
- Reviewer #5. The S/RA adequately supports the conclusion
that there has been low risk to human health from consumption of fish, chicken,
poultry, and pork inadvertently fed melamine contaminated food, given the
amounts that were ingested.
- Reviewer #6. Yes.
FDA Response: We will take the suggestion to
consider the toxicity of other potential toxic compounds and implications of
chronic exposure into account when the interim S/RA is updated. We agree that
a separate S/RA to evaluate the risk from exposure to other human food items
would be useful, but note that we are unaware of evidence of direct contamination
of human food items. Scenario 3 was meant to address in part the uncertainty
of whether all potentially contaminated human food items had been identified
when the S/RA was conducted.
- Question 9. Do you have any
additional comments that would assist FDA in refining the S/RA?
- Reviewer #1. My comments and perspectives have already been
stated.
- Reviewer #2. See response to Question 8.
- Reviewer #3. No.
- Reviewer #4. This reviewer felt that a conference call or
face to face meeting with the reviewers could have readily resolved some of the
issues of this risk assessment and could have facilitated a quicker more
comprehensive response.
- Reviewer #5. No. I feel the S/RA is comprehensive,
reasonable, and evidence-based.
- Reviewer #6. Reference to IARC (IARC Monogr. Eval.
Carcinogen. Risks Human, 73:329-338, 1999) and RSI (Crit. Rev. Toxicol.,
33:591-654, 2003) (sponsored by US-EPA and Health Canada) reviews.
FDA Response: We thank
the reviewer for providing the two additional references for our consideration.
One reviewer suggested that instead of a letter peer review, that a panel
review could have facilitated the speed of the responses. We believe that
considering the urgency of the situation, that the letter review was
appropriate. In addition, we note that the June 14, 2007 public meeting of the
Science Board to the FDA will provide an additional opportunity for scientific
review of the S/RA.
- Question 10. Do the
information and data in Appendices II and III support the underlying
assumptions used in the interim assessment?
- Reviewer #1. Yes, the assumptions are supported by data
available and used; the issue remains, should other data sets be considered for
this S/RA? I believe that they should be considered. I am aware of the need to
make decisions with data that are available and there is certainly a paucity of
information. The S/RA was restricted by this reality. Yet at this point,
further work needs to be done to shift this report from an interim status to a
final report and S/RA. My comments are made to be constructive and useful with
an understanding of the difficulties involved in this situational and the need
for timeliness of the analysis.
- Reviewer #2. See response to Question 8.
- Reviewer #3. Yes they do.
- Reviewer #4. See the specific comments above.
- Reviewer #5. I believe that the information and data in
Appendices II and III support the underlying assumptions used in the interim
statement.
- Reviewer #6. Yes.
FDA Response: The peer reviewers concurred that the
data in the appendices support the underlying assumptions. No additional
response is needed.
(1)
Available at http://www.cfsan.fda.gov/~dms/melamra.html.