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Executive Summary

An optional, alternative ANDA review process that would provide for public workshops on application standards and batch approvals for the first round of applications was proposed by the Blue Ribbon Panel on Generic Medicines at a Nov. 15 press conference in Washington, D.C. The recommendation calls for FDA to identify drugs for the alternative process based on such considerations as patient benefit, industry interest in the product, the drug's medical importance, and potential problems in chemical and bioequivalence reviews. The agency would then convene a workshop to consider review criteria; establish a deadline for ANDA submissions under the alternative review process; and then announce "all approvals of successful applications in the group simultaneously and well in advance of patent expiration for the innovator's product." Products not chosen for this process would be reviewed under the current first in/first out approach. The alternative ANDA review process was one of three panel recommendations highlighted at the press conference. The recommendation is contained in the panel's report, which culminates a nine-month review by the committee. The committee was established as an independent body by the Generic Pharmaceutical Industry Association to examine both the industry and FDA's generic drug approval process and to make recommendations on changes aimed at restoring the public's "confidence" in generic drug products. The committee was chaired by Lewis Engman, an attorney with Winston & Strawn and a former president of the Pharmaceutical Manufacturers Association. The report now will be sent to the Edwards Advisory Committee on the FDA, the agency itself, Capitol Hill, and the pharmaceutical industry. GPIA has asked member firms for written comments on the report and is expected to review the document at a Dec. 19 board meeting. The workshop/batch review approach was contained in a draft proposal that the committee issued for discussion at its June public hearing ("The Pink Sheet" June 25, p. 16). However, the committee decided against another approach discussed in June -- setting up a monograph system for generic drugs. the monograph system envisioned earlier would have required FDA to issue a monograph that defines standards for ANDAs referencing that product as soon as an innovator product is approved. The innovator company might be required to disclose data needed for the monograph. In its report, entitled "Generic Medicines: Restoring the Public Confidence," the committee cites several problems with the monograph system. The panel anticipated that FDA may face difficulties in specifying chemistry review criteria, which would include a review of the applicant's formulation, manufacturing equipment and process. In addition, monographs would be written without improvements in the science of bioequivalence and knowledge gained after the pioneer product is approved. Also, the committee was concerned that the "development of a monograph system as suggested would pose trade secret problems." With the existing ANDA review process, the committee's report notes, "the chemistry and bioavailabilty databases available are usually sparse when the initial ANDAs are evaluated. Under the optional proposal, FDA would have the advantage of simultaneously reviewing chemistry and bioequivalence studies for several products." In addition, the optional review mechanism "would put a premium on submitting the best possible application rather than cutting corners to submit the earliest because an applications's merits would be judged against a number of other applications." Under the alternative review mechanism, a team of FDA reviewers would be responsible for the entire batch of ANDAs. "The group review would minimize such differences [between reviewers] because the group would be expected to reach a consensus on the criteria for acceptability of the first group of applications," the report suggests. "This would be particularly helpful in the chemistry review area in which reviewers would have to agree on the adequacy of the Drug Master File that may be referenced in several applications for a particular drug product and to make consistent determinations on stability testing and interpretation of the [good manufacturing practices] requirements." Near the end of the evaluation, the staff would hold an "ANDA Day," modeled on NDA Days, to discuss remaining issues. At the June meeting, FDA officials indicated the alternative approach could provide helpful information, but expressed reservations about the many unresolved practical issues and administrative complexity...GPIA at that time also objected to the batching approach as penalizing firms willing to invest in earlier development of a product. Under the proposal, a firm could still submit an application before the deadline but would be subject to the traditional first in/first out process without access to the guidance and other advantages of the alternative mechanism. At the press conference, the committee also highlighted its recommendation that generic firms be required to meet many of the same regulatory standards as innovator companies for taking responsibility for all phases of product development, including work done by contract testing labs. "Perhaps the most relevant portion" of the IND regulations direct that "sponsors are responsible for 'selecting qualified investigators, providing them with the information they need to conduct an investigation properly, ensuring proper monitoring of the investigation(s), [and] ensuring that the investigation(s) is conducted in accordance with the general investigational plan and protocols'" contained in the application, the report states. The committee also is recommending that Congress give FDA authority to impose or seek from the judicial system a greater range of penalties for misconduct. The committee suggested that criminal penalites include a requirement for "disgorgement of profits resulting from criminal misconduct." Committee Chairman Engman said the forfeiture of profits has been used by criminal sentencing commissions and in the antitrust area. Other recommendations in the enforcement area include debarment of individuals from the FDA approval process, increased fines and jail terms for misconduct, and requiring a corporation whose employees engaged in misconduct related to the approval process to show its products are safe, effective, and "untainted by the misconduct". The committee concluded that additional authority to debar corporations is "unnecessary" because FDA could debar individuals who control the firm, and those actions, combined with increased fines on the corporation, could lead stockholders to demand a change in management. This strategy could "be more effective than debarment of corporations, which could harm the public interest by denying consumers products whose safety and effectiveness are unaffected by the specific illegal actions," the panel concluded. Rep. Dingell's (D-Mich.) FDA enforcement bill, which was left pending when Congress adjourned in October, contained many similar proposals, but was directed only at the generic scandal, on the basis that the need to take "emergency action" related to the generic industry warranted a limited approach this year. The blue-ribbon group states that any "future legislation should address FDA's enforcement authority over all of its regulated industries." The committee also recommends that firms be required to disclose publicly any financial arrangements with contract testing labs other than standard fee-for-service contracts, but stopped short of urging a ban on contract arrangements, such as a percentage of future sales. Engman said there may be some situations where a new company could not otherwise afford to develop a product. He suggested that "public awareness" is the greatest safeguard against wrongdoing. Among other specific recommendations, the committee proposed that FDA issue a Summary Basis of Approval document for each ANDA that describes how the review was conducted and the basis for FDA's key decisions; that firms be required to report results of all bioequivalence studies, including failures, in ANDAs and ANDA supplements; that product labels be required to include the name of the manufacturer, name of the NDA or ANDA holder and name of the repackager; that industry develop a model code of conduct and urge member firms to report adverse events to FDA; and, that FDA refer to the Federal Trade Commission any "frivolous" complaints brought by innovator firms against generic products. FTC "has recognized that frivolous complaints against a competitor may be a form of non-price predation that violates the antitrust laws," GPIA explains. Regarding narrow therapeutic range drugs, the committee said that based on current scientific evidence, "the existing bioequivalence standards are adequate." Evidence to the contrary is "Anecdotal" and "insufficient to warrant changing the standards at this time," although the committee recommended that FDA continue to "monitor closely" these products.

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