Visible Genetics, the first company expected to submit a kit-based genotypic resistance assay to the FDA for marketing approval , has announced its plans to stop enrollment in its clinical trial, SEARCH. This long-term study of the clinical impact of genotypic resistance testing was initially designed to evaluate 300 patients with a one-year follow-up. At the time the study was closed to enrollment in December 1999, 128 patients had been enrolled. The company will continue to follow those patients as originally planned; however, the protocol has been modified to include new endpoints that would trigger unblinding and access to open label resistance tests.
The original study was designed with 80% power to detect a difference in mean HIV RNA levels between the two groups, prior to a change in antiretroviral medication, of 0.5 log10 copies/mL (one group was randomized to receive resistance testing while the other group did not). Fortunately, new power calculations using more robust data from recently presented short-term clinical trials of resistance tests suggests that, even with only 128 subjects, the study will have 80% power to detect a difference of 0.7 log10 copies/mL between the two groups. Although all investigators were immediately notified of the changes in enrollment and endpoints, Visible Genetics has not yet prepared a letter for study subjects explaining these changes. They are currently planning to prepare such a letter.
Visible Genetics decided to stop further enrollment in the SEARCH protocol after a recent meeting with officials from the FDA regarding preparation of their pre-market submission. The FDA currently holds the position that there are adequate clinical trials data to support the licensing of resistance test for certain well-defined (but not yet specified) mutations. Companies wishing to secure FDA approval will apparently no longer be required to supply clinical trial data; instead, they will need to demonstrate acceptable performance characteristics of their assay for the specified mutations for which they are seeking approval. The FDA has not yet notified Visible Genetics about which mutations it will consider for marketing approval. Currently, Visible Genetics is completing their proficiency and performance characteristics studies. They plan an FDA submission in the first half of 2000.
The FDA's Center for Biologics Evaluation and Research (CBER) recently held an advisory committee meeting to consider the regulatory requirements for genotypic resistance tests (see related article, "FDA's CBER Defining Regulatory Requirements for Genotypic Resistance Tests"). At that time, FDA indicated that they would be preparing a draft Guidance Document outlining requirements for a new device application-known as 510(k)-for publication in the Federal Register. After a public comment period, a final Guidance Document would be published. There was significant discussion at the September 1999 advisory meeting regarding the amount of clinical trial data that would be required in new device applications for genotypic resistance tests. The FDA indicated that even with the proposed revision of regulatory requirements from class III to class II, clinical trials data could still be required in certain circumstances. The relevant draft Guidance Document has not yet been published.
It appears that the current process for an application for a kit-based genotypic assay will include: 1) definition by the FDA in a Guidance Document of specific mutations for which data will be considered for marketing approval and 2) data provided by the company demonstrating proficiency and acceptable performance characteristics of their assay for each of the defined mutations. FDA is also considering allowing manufacturers to incorporate data on mutations that are not established to be clinically relevant (but do meet performance criteria) into their resistance algorithms, but would require the use of disclaimer language in the package insert, label and test report for these mutations. It is unclear at this time how new information regarding existing or newly defined mutations with clinical relevance will be incorporated into the approval process, allowing companies and laboratories using approved assays to extend the use to new mutations for which approval was not originally sought. Manufacturers will likely be required to submit applications for new claims that include citations from the literature supporting the clinical relevance of the mutation, as well as performance data if that has not already been submitted.
For more information regarding the SEARCH protocol or Visible Genetics refer to their web site: http://www.visgen.com.
For more information regarding the FDA meeting held in September refer to their web site for minutes: http://www.fda.gov/ohrms/dockets/ac/99/transcpt/3548t2a.pdf.
For more information about resistance assays and regulation, refer to related articles published by HIVresistanceWeb.com:
FDA's CBER Defining Regulatory Requirements for Genotypic Resistance Tests
FDA Considers the Uses of Resistance Evaluation in New Drug Development and Product Labeling
California State Office of AIDS ad hoc Advisory Committee Considers State Reimbursement Policy for Drug Resistance Assays
Clinical Availability and Reimbursement Status of Antiretroviral Drug Resistance Assays
