BARR LABS OUT-OF-SPEC TEST RESULTS FOR ALL REINTRODUCED PRODUCTS MUST BE REPORTED TO FDA FOR TWO YEARS AFTER VALIDATION APPROVAL, CONSENT ORDER DECREES

Barr Labs is required to inform FDA of every out-of- specification test result concerning any previously suspended product for which the company has received agency approval to reintroduce, according to a Nov. 7 consent order issued by Newark, N.J. federal court Judge Alfred Wolin.

Moreover, the requirement remains in effect for a two-year period following FDA approval of validation for a specific product.

The only exception is out-of-specification test results that are "clearly documented as being attributable to laboratory error."

Barr must report all other results, including those attributed to process error, equipment error, operator error, sample error or an inconclusive cause. The results must be relayed to FDA within three working days of determining the cause or within 30 days of obtaining the initial result, whichever is earlier, the consent order states.

The final court order was negotiated between Barr and FDA and approved by Judge Wolin, Barr said. The order "simultaneously concludes the FDA's case against Barr, and Barr's counter-suit against the FDA," and orders each party to bear its own costs and attorneys' fees. The order comes just more than a month after Barr declared that FDA notified the company it was in compliance with cGMP requirements ("The Pink Sheet" Sept. 26, In Brief).

In an effort to portray the order as a positive development for the company and the generic drug industry as a whole, Barr noted that the firm has been "strengthened by this negotiated process for reintroducing products and the acknowledgment that we meet all cGMP requirements." Barr added that the case "helped redefine the standards of good manufacturing practices throughout our entire industry, which benefits all pharmaceutical consumers."

In addition to outlining post-validation approval procedures that Barr must follow, the agreement identifies all the data Barr must supply to the agency before submitting a validation protocol and the standards the company must follow when conducting validation studies.

The validation procedures set forth in the consent order cover two groups of Barr products, which represent 154 of the approximately 175 products Barr was manufacturing prior to the voluntary and court-ordered suspensions in 1992 and 1993, respectively.

The order categorizes Group 1 products as those among the 39 products the court ordered Barr to validate in a February 1993 decision that subsequently have not been defined by FDA as validated as of the Nov. 7, 1994 court order. In the 80-page 1993 decision, Judge Wolin ordered Barr to cease distribution of 24 products and complete validation studies for 15 additional products ("The Pink Sheet" Feb. 8, 1993, T&G-1).

Group 2 products are "115 drug products whose voluntary suspension as to manufacture and distribution by Barr [in April 1992] was continued" by a July 1992 court order. The voluntary suspension was Barr's response to FDA inspections of the company's Northvale, N.J. and Pomona, N.Y. facilities that resulted in a pair of FD-483 inspection reports listing 75 and 47 critical observations, respectively. The agency's concerns centered on Barr's process validation procedures, lack of follow-up on batch failure investigations and lab analysis.

Since May 1993, Barr has reintroduced 12 products and is "actively working to reintroduce those suspended products that continue to offer the most value to its consumers," the company said.

For any product for which Barr is seeking validation, the company must provide FDA with a written validation protocol along with a timetable for conducting the study, according to the Nov. 7 consent order. Barr is also supposed to try to notify the agency in advance as to when it expects to submit any protocol.

The consent order describes five steps which Barr must complete before submitting a validation protocol for a Group 2 product. The steps appear to require a substantial amount of data that must be submitted to FDA before even starting the validation process.

The first step orders Barr to "identify all out-of- specification test results obtained and identify the process used that produced" each out-of-spec result "based on a batch-by-batch review of all lots" of a product manufactured any time after Jan. 1, 1988 if the previous manufacturing process is identical or similar to the current process.

Barr is advised to rely on sources such as deviation logs, failure investigation reports, annual reviews, management reviews, quality assurance reviews and alert documents. The company must also provide a detailed summary of all documents related to the out-of-spec results.

Additional requirements call for Barr to: present to the agency all existing reports of failure investigations conducted after obtaining out-of-spec results, or the reason for the lack of a failure investigation, and in both cases indicate the disposition of each out-of-spec batch; identify and report on the status of Barr's responses to any product-specific 483 observations by FDA post-Jan. 1, 1989; and "review and, where appropriate, update the analytical methods for the product to ensure that the methods are validated."

The consent order calls for FDA to complete its review of validation protocols "as quickly as possible" and gives Barr two options if the company and FDA cannot agree on a protocol. Barr may "proceed on its own responsibility to conduct a validation study" based on the proposed protocol or ask the federal court to resolve the dispute.

Barr must complete a three-consecutive-batch validation study for each product to be reintroduced and submit the study along with certification that "every test result obtained during the validation process" has been included. The three-consecutive-batch requirement was supported as a standard with which all generic drug companies must comply in Judge Wolin's February 1993 decision.

FDA's responsibilities are also addressed in the court order. The agency is directed to complete its review of the studies and contact Barr as quickly as possible; more specifically, a timetable calls for FDA to review 12 validation protocols and 12 validation studies per year, as of Nov. 7, provided Barr meets all the submission requirements laid out in the order.

If Barr and FDA disagree as to whether a product has been validated, the company may ask the Center for Drug Evaluation & Research to review the matter. Further arbitration recourse is available through the court if CDER concurs with the FDA district office's finding that the validation study is inadequate.

The consent order specifies rates at which FDA may bill Barr for evaluating validation protocols and studies and "all inspections, examinations, reviews and evaluations" conducted by FDA as part of monitoring compliance with the February 1993 order.

The suggested rates include $59 per hour for lab and analytical work and $49 per hour per person for inspection work. FDA will submit an itemized bill to Barr within 60 days of the order and thereafter bill Barr on a quarterly basis.