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PhRMA Letter June 30, 1998 Dr.
Joseph DeGeorge Dear Dr. DeGeorge: Two PhRMA subcommittees, the DRUSAFE Pregnancy Labeling Subcommittee (preclinical) and the Pregnancy Labeling Task Force (clinical) have reviewed the two pregnancy labeling proposals that have been drafted by the FDA. Those two proposals are: 1.
Suggested Changes and Redesign of the Pregnancy Label for Human
Drugs, by J. DeGeorge, A. Ellis, et al. It is was the consensus of these two subcommittees that before writing a labeling proposal, it is important to discuss core priniciples that communicate our position on the pivotal issues in the development of new guidance for pregnancy labeling. We feel that these core principles should be applicable to any pregnancy labeling proposal that is developed. We urge the FDA to adopt them as guiding principles for your works on this project. In addition, we are providing specific comments related to the above two labeling concept papers/proposals (Attachments I and II). CORE PRINCIPLES Key Audience Customer: The primary customer for the pregnancy label is the prescribing health care practitioner/physician. Secondary customers are pharmacists and pregnancy counseling groups. Physicians and other health professionals need better guidance in interpreting the details of preclinical findings and assessing the potential risk based on those findings. We believe that these customers want bottom-line advice presented in a standardized format on the use of a drug in pregnancy. Bottom-Line Advice should be provided using Summary Statements, not categories or standardized language. Custom-written dialog, within general guidelines, is recommended. This should provide the health care practitioner with information for a case-by-case decision as to whether a particular drug should be used during pregnancy, and serve as basis for an individual risk-benefit discussion the patient in the context of the health care practitioner-patient relationship. Summary Statements should provide recommendations for use in pregnancy based on a "weight of evidence" approach. This recommendation should make a conclusive statement about use in pregnancy. For example: "Animal and human data predict a risk to embryo-fetal development, and this risk outweighs the potential benefit; therefore, drug y should not be used in pregnancy." "Studies in experimental animals do not predict a risk to human pregnancy, and there are clinical data supporting safe use in pregnancy." When animal data do not identify a hazard, a cautionary comment should be added: "No adequate human data are available." Additionally, "No risk demonstrated in animal and human trials" may be appropriate. Background risks of drug-induced adverse pregnancy outcomes in humans should only be discussed when the Summary Statement is based on human data. Inadvertent Drug Exposure in Pregnancy: It is not possible to provide general advice applicable to inadvertent exposure during pregnancies. There are too many factors that must be considered on a case-by-case basis. Health-care providers should contact a pregnancy health counselor on the specifics of the individual case and/or the manufacturer for additional scientific information. Narrative vs. Tabular Summaries: We agree that the details constituting the "weight of evidence" should be made available to those customers who want further information and are skilled in interpreting such information. However, a detailed tabulation or presentation of results in the pregnancy label itself is not practical or appropriate. It would make the label too long, would not be helpful to most health care practitioners, and is inconsistent with other agency initiatives to make the labeling easier to use. Moreover, a detailed description of animal findings could be misleading (because of its length) particularly when animal studies are negative. The PhRMA subcommittees would like to work with FDA to find novel and effective ways to make all appropriate information available. Possible options include:
This proposal has the advantage of allowing a virtually unlimited amount of text and tables in which to fully explain the evidence supporting the Summary Statement, including exposure considerations, risks vs. benefits for the various indications for which the drug might be used, and a full discussion of complex issues, however, the workload and planning/implementations resources required of the manufacturers should be thoroughly assessed. Updating Existing Labels will be a massive undertaking. Although it will be fairly straightforward to apply the new label to newly approved drugs, it will be a very difficult and lengthy process to rewrite the labels for existing drugs. Regardless of the format adopted, this will have to be phased in over many years. The implementation timetable for previously approved products would be determined based upon defined criteria (e.g., frequency of use by women with reproductive potential) established by FDA and PhRMA. Products with a well-established safety profile or limited patient populations would have a low implementation priority. Interdisciplinary Oversight Committee: We have some serious concerns about the composition and functions of the proposed committee. For example:
PhRMA appreciates the opportunity to have early input into the proposals for redefining the pregnancy section of the prescribing information. We hope that you will find our comments helpful. Please do not hesitate to contact me if we can provide further information or assistance in this very important effort. {note: The attached comments are summary level comments based on more detailed comments from the reviewers. Should the agency be interested, more detailed comments can be provided at an informal meeting.} PhRMA Subcommittee Members DRUSAFE Pregnancy Labeling Subcommittee (preclinical)
Pregnancy Labeling Taskforce (clinical)
Sincerely your, David A. Shriver, Ph.D.cc. Dr.
S. Kweder
Attachment ISpecific
Comments on "Suggested Changes and Redesign of the Pregnancy
Label for Human Drugs", J. DeGeorge et al. 1.
The proposed format would complicate rather than simplify the presentation
of prescribing information. In particular, the proposed tabul ations
would be restrictive and inflexible.
a. The animal data would be presented cryptically but repetitively.b. Complicated animal data are difficult to summarize in a small box.c. Intermingling of known human effects with animal data, as proposed in the tables, should be avoided. As human data become available, the animal data should be de-emphasized.d. Listing observed reproductive and developmental effects in the table separately from information in the narrative on timing, dose, systemic exposure, biomarkers, etc. could lead to effects being considered out of context. 2.
"Categorical language" will be perceived as "categories",
and categorization should be avoided. From a scientific perspective
and legal perspective, it will be virtually impossibledifficult
to develop standardized interpretations of "not apparent risk",
"low risk" and "significant" risk that sponsors
and FDA can implement across therapeutic drug classes and that health
care professionals can reliably use. Furthermore, from a legal perspective,
these risk categories are problematic in that they appear to be
a basis for FDA advocating that a product's labeling might be required
to advise the health care professional to consider "safer"
therapies.
3. Many different risk-management situations will occur, particularly with multiple indications for one drug, as well as off-label uses. It is not practical to anticipate and address all such situations in the label. 4. The narrative section would be unacceptably large. It requires textual descriptions of every reproductive-toxicity study, including "a complete description of dose, exposure, and the period of drug administration." Prescribing health care practitionerphysicians do not usually need access to this level of detail, and we should be able to find a better way to provide the details to pregnancy counselors. 5. The proposal does not take maternal toxicity into consideration and requires presentation of every adverse effect on the embryo or fetus . This can lead to misinterpretation and misapplication of the developmental findings. Specific Comments on "Proposed Changes to the Pregnancy Section of Labels for New Drugs and Biologic Products", S. Kweder and A. Scialli 2. It is proposed that the label should avoid a consideration of benefits, only describe risks, and avoid medical advice. However, many of the examples of summary statements include implied medical advice or guidance. There are also three exceptions listed which would require benefit-to-risk evaluations. It is likely that many drugs would fall into one of these categories o f exceptions. We believe that health care practitioners want prescribing guidance. 3. Many different risk-management situations will occur, particularly with multiple indications for one drug, as well as off-label uses. It is not practical to anticipate and address all such situations in the label. 4. Advocating labeling for drugs used in labor and delivery (even though such uses are unapproved) to include a discussion of the effects on the mother and fetus. neonate, is not a reasonable request of a sponsor if that use has not been formally studied and postmarking data are the only source of information about pregnancy events. If only positive outcomes are known, would the FDA consider such information to constitute promotion of an unapproved use? 5. It is unclear where the required information on background risks will come from. Does accurate information exist? Are human risks uniform, or do they vary with age, genetics, or economics? How will the human background risk for an anomaly seen in animals be estimated? 6. The required presentation of animal data is similar to t he DeGeorge proposal; i.e., unacceptably long and detailed. Similarly, there is inadequate attention to the presentation and interpretation of maternal toxicity. 7. Regarding lactation and the health benefits of breast feeding, there will usually not be enough information available to support a positive recommendation to continue nursing. This recommendation will put manufacturers in the awkward position of making a representation in the absence of supporting data unless they undertake laction studies. 8. The discussion of "Raising standards for quantity and quality of human data related to drug use in pregnancy" raises concerns. The statement that "For many products, the conduct of clinical pharmacology studies in pregnant women, pregnancy registries and lactation studies should be encouraged" could be interpreted by FDA as setting the stage for population-specific study mandates. 9. If Sample Statements are to be applied, they should evolve subsequently in conjunction with workshops using case studies. 10. PhRMA would like the opportunity to review and comment on the "Preclinical Reproductive and Toxicology Guidance Document" and the "Guidance for Review of Human Pregnancy Outcome Data". 11. There are serious concerns about the composition and responsibilities of the FDA's "Interdisciplinary Committee on Pregnancy Labeling", and in light of the complexity of the current undertaking to redesign pregnancy labeling, FDA and the industry should stay focused on the labeling objective, and not add additional research burdens on manufacturers. 12. Updating the labels of all existing drugs will be a massive undertaking and will have to be phased in gradually over many years. |
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