SALINE BREAST IMPLANT PMAs MUST INCLUDE CLINICAL ASSESSMENT OF RISKS

SALINE BREAST IMPLANT PMAs MUST INCLUDE CLINICAL ASSESSMENT OF RISKS associated with the devices, including fibrous capsular contracture, deflation and infection, FDA says in a Jan. 8 proposal to call for premarket approval applications for the pre-1976 Class III devices. In addition to the known risks, FDA identifies several potential risks of saline-filled breast implants that should be evaluated in the PMA, including interference with mammography, adverse immunological effects, carcinogenicity, teratogenicity, calcification and cellular reactions to silica used in the silicone shell of the device. The PMAs should describe the randomization techniques used in the study design to minimize biases and list diagnostic criteria used to evaluate immunological and allergic reactions to the device and its components, FDA says. In accordance with medical device law, PMAs containing the clinical trial data would need to be submitted to the agency within 90 days after the rule becomes final. The proposed rule also notes the statutory provision that reclassification petitions will be accepted for 15 days following the proposal's publication. FDA is accepting comments on its proposal until March 9. In addition to assessing risks, the PMAs must address the benefits of the devices. For example, "time course presentations of patient satisfaction with and psychological benefit from the implantation of this device" should be included in submissions. FDA says it "understands that evaluation of...patient satisfaction and psychological well-being" involves assessing "patient expectations and includes subjective factors, which may be transient in nature." The agency therefore recommends that PMA submissions include studies "structured for an objective and standardized recording/measurement of the psychological benefit of the device." Among the proposal's "primary requirements" for these studies are use of appropriate control groups and standardized tests rather than nonvalidated questionnaires. The agency further recommends that psychological studies incorporate "stratification of data according to augmentation versus reconstruction mammoplasty" since "the level of the device's benefit may depend on" the reason for its use in each patient's case. Other factors, such as physical and chemical characterization of the device and its chemical extractions, must be assessed in preclinical studies contained in the PMA. The preclinical section of the PMA should include pharmacokinetic/biodegradation studies of materials used in the finished device that focus on "the ultimate fate, quantities, sites/organs of deposition, routes of excretion, and potential clinical significance of silicone retention and migration." Animal studies that "simulate the intended use of the device in humans" also must be performed to evaluate endpoints including carcinogenicity, teratogenicity and reproductive toxicity. In addition, certain chemicals extracted from the finished device must be tested in animals during preclinical trials. Although the proposed call for PMAs was published in the Jan. 8 Federal Register, on Jan. 5, FDA issued a statement announcing its intent to issue the proposal and granted several lay news organizations interviews on the subject with Commissioner David Kessler. The announcement and interviews appeared to be a preemptive strike designed to mitigate press attention to the Jan. 6 release of a House Government Operations human resources subcommittee staff report that is critical of FDA's regulation of silicone gel-filled breast implants (see following story). Mentor and McGhan are the only firms currently marketing saline-filled breast implants. The companies will be allowed to continue marketing their saline implants while their PMAs are under review. However, if a firm fails to submit a PMA by the designated date, it must either cease to distribute the devices or obtain an investigational device exemption from FDA to use the implants in clinical trials. FDA states in its proposal that saline-filled breast implants may be subject to postmarket surveillance requirements, a determination the agency says it will make during its review of the PMAs. Because "the agency believes that insufficient time has elapsed to permit a direct evaluation of the risk of cancer posed by the presence of silicone in the human body," manufacturers of the implants will be required to conduct long-term postapproval followup of implanted patients. FDA notes in its proposal that "in some instances, the requirements for postapproval studies may satisfy the postmarket surveillance requirements" and that under such circumstances the agency will allow manufacturers to combine these requirements. Saline breast implants are among five types of pre-1976 Class III devices recently designated by FDA as having a high priority for PMA review. The saline implant is the first of the five devices to be the subject of a PMA call proposal. The agency plans to issue a proposal for calling for PMAs for testicular implants during the week of Jan. 11 (see story, p. 5). The saline breast implant proposal is being issued approximately one year after FDA issued a temporary moratorium on the use of silicone gel-filled breast implants. FDA subsequently lifted the moratorium and is allowing sales of the silicone gel- filled devices for use in clinical investigations.