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July 27, 2000
The TSEAC and VRBPAC were requested to consider appropriate precautions to be taken with regard to the use of bovine-derived materials in the manufacture of vaccines when those materials were obtained from countries in which BSE is known to exist or from countries where the USDA has been unable to assure the FDA that BSE does not exist ("BSE-risk countries"). The committees were also asked to consider the potential risks and possible actions to be taken with regard to licensed or investigational vaccine products that may be affected. The following questions were presented to the committee for discussion and comments. There were no formal votes on any of the questions.
- Please discuss the potential risk presented by the use of bovine-derived materials, sourced from Europe (including the UK), in currently licensed vaccines. In this discussion, please comment on the various risk estimates that have been presented to the Committee. In this discussion, please include:
- Preparation of bacterial and viral master and working seeds; preparation of master and working cell banks (e.g., use of calf serum, fetal calf serum).
Committee members stated that the risk of TSE agents in fetal calf serum is very low, but there could be a potential risk. The committee expressed concern about manufacturers using serum from BSE-risk countries for routine vaccine production and agreed that such manufacturers should switch to appropriate sources immediately. The committee members stated that use of a small amount of fetal calf serum sourced from the UK and used to derive master cell banks presented a negligible (as opposed to a significant) risk. The risk of exposure to the BSE agent is small compared to the possible risks related to changes in a vaccine product due to changes of the master seed material. The risk of calf serum was not specifically discussed.
- Fermentation process (e.g., use of bovine-derived media)
- Formulation of the final products (e.g., use of gelatin, etc.)
For both parts "b" and "c", while the potential risk was acknowledged to be very small, steps in a manufacturing process (e.g., chromatography, filtration) may help reduce any possible contamination with the BSE agent. The committee also discussed the possibility of manufacturers investigating test methods to rule out the presence of the BSE agent.
Additionally, in this discussion, please include risk assessments for bovine materials sourced, at different times, from different European countries (e.g., UK, Germany, France).
The committee stated that 1980 was the cut off date previously decided upon regarding the risk of exposure to the BSE agent for blood donations. In light of that decision, the committee agreed that 1980 would be an appropriate cut-off date for concern about BSE risk in bovine-derived material used in vaccines.
The committee stated that in light of current scientific knowledge, the risk of bovine-derived materials sourced from BSE-risk countries in currently licensed vaccines is a "theoretical" risk. The risk assessment is dependent on the geographic source, the type of tissue, and the processing. None of the current estimates of risk can be precisely quantified. This theoretical risk must be balanced against the benefits of the vaccination program (or the real risk of not being vaccinated).
- The following item pertains to currently licensed US vaccines that contain bovine-derived material obtained from Europe (including the UK).
Please discuss those circumstances, if any, under which FDA should take specific regulatory action regarding these vaccines. Some examples of regulatory actions which are available to the FDA include product recall, modification of the package insert, and/or issuance of a "Dear Doctor/Health Care Provider" letter.
Committee members agreed that some form of notification to vaccine recipients or "public disclosure" should be made regarding vaccines which may be manufactured with bovine materials sourced from BSE-risk countries. The committee discussed but was not in full agreement on what would be the most appropriate means of disclosure. The options discussed included issuance of a Dear Health Care Provider letter, inclusion of such information in the package insert, a joint statement of the agencies within the Department of Health and Human Services, or publication by journal article. The committee agreed that any disclosure should be carefully worded in order to express the theoretical risk of exposure to the BSE agent versus the benefit of receiving the vaccine.
- The following item pertains to investigational (non-US licensed) vaccines that contain bovine-derived material obtained from Europe (including the UK). This includes certain investigational vaccines (used under IND) that contain currently-US licensed vaccines as components (such as components of a new investigational combination vaccine). In addition, this includes the "usual" investigational vaccines without previously US licensed components.
Please discuss those circumstances, if any, under which FDA should take specific regulatory action regarding these investigational vaccines, such as stopping a clinical trial (pending an acceptable remedy of the product) or modification of the informed consent form.
While the theoretical risk of vaccine products under investigation is the same as the theoretical risk of licensed vaccines, committee members agreed that products under investigation do not have a proven benefit as compared to licensed vaccine products. Therefore, investigational vaccines should be considered separately from licensed products. The committee members agreed that participants in clinical trials should be notified through informed consent about the theoretical risk of vaccines produced with bovine-derived materials from a BSE-risk country.
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