Schering-Plough's pending supplemental NDAs to switch Claritin (loratadine) OTC appear to be unaffected by the company's GMP consent decree with FDA.

The ¹ consent decree notes that the approval of Schering's NDAs "shall be in accordance with 21 U.S.C. 355(b)(4)(F)," which states that "no action by the reviewing division may be delayed because of the unavailability of information from or action by field personnel unless the reviewing division determines that a delay is necessary to assure the marketing of a safe and effective drug."

"The process validation and equipment certification requirements" of the consent decree "shall not apply to applications approved by FDA after the date of this decree," states the agreement, which was approved by a Newark, N.J. federal court May 20. "These requirements will be addressed by FDA in accordance with its new drug(s) pre-approval inspection program."

The section appears intended to avoid any ambiguity about whether FDA has the authority to delay reviews of Schering products based on general GMP concerns. In past cases of extensive GMP difficulties, FDA has delayed action on NDAs for agents not considered "medically necessary."

At a minimum, the clause is a clear indication that Schering is not being placed on the FDA Application Integrity Policy list, although FDA is conducting a criminal investigation related to the GMP issues (² Also see "Schering GMP Criminal Investigation Continues After Consent Decree" - Pink Sheet, 20 May, 2002., p. 4).

FDA already demonstrated that it is not putting a general hold on Schering applications when the agency approved the Rx antihistamine Clarinex before the final terms of the decree were negotiated.

The Claritin switch NDAs are among the company's most important pending new drug applications; Schering has said the first batch of products submitted for certification under the consent decree procedures will include the loratadine 10 mg dose (³ Also see "Schering Claritin Awaits FDA Certification; Correctol SKUs To Be Discontinued" - Pink Sheet, 20 May, 2002., p. 3).

Under the consent decree, Schering agrees to cease manufacturing and marketing more than a dozen OTC drug SKUs, including Gyne-Lotrimin 3-Day Combination Pack, Gyne-Lotrimin three- and seven-day inserts, two Correctol products and four Afrin SKUs (see chart: " ⁴ Schering's Discontinued OTCs ").

The company characterized the discontinued OTCs as "minor," less commonly used SKUs that have not been promoted. By discontinuing the OTCs, in addition to numerous Rx agents, Schering avoids the costs of undergoing the consent decree's certification process for each drug and the penalties for missed deadlines.

If Schering decides to resume production of any of the discontinued products, it must provide 30 days notice to FDA and then complete the consent decree process.

The consent decree picks up on a number of themes from recent good manufacturing practices enforcement actions, including disgorgement penalties, hefty fines for failure to come into compliance and an emphasis on management structures.

Schering will pay a disgorgement penalty of $500 mil. under the decree. That payment is significantly larger than FDA obtained previously in any GMP case. The company also will be subject to penalties and royalty payments if it fails to meet deadlines spelled out in the decree.

Schering will reimburse FDA the cost of all inspections undertaken by the agency under the decree, including payment of close to $500,000 to reimburse FDA for inspection costs so far.

As the number of companies operating under consent decrees proliferates, the agency may find itself with a new category of funding: "abuser fees" collected to reimburse for the cost of repeat GMP inspections.

FDA is relying on a combination of outside consultants and clearly defined internal accountability to ensure compliance at Schering.

The decree is signed by CEO Richard Kogan on behalf of Schering, and "in his individual capacity." Schering Senior VP-Worldwide Technical Operations Steven Chellevold also signed the decree in both capacities. Covington & Burling attorneys Peter Barton Hutt and Richard Kingham are representing Schering and Kogan respectively. Kleinfeld, Kaplan & Becker attorney Peter Safir is representing Chellevold.

The decree requires Schering to hire consultants to conduct an inquiry into "the adequacy of management controls of the manufacturing and laboratory operations" at the four affected facilities - the Las Piedras and Manati facilities in Puerto Rico, and Kenilworth and Union sites in New Jersey.

Schering must appoint a top quality control exec for each plant, reporting directly to the senior VP-worldwide quality. The plant managers will be directed to file written reports simultaneously to the CEO, senior VP-worldwide quality and senior VP-technical operations.

The CEO "will take action necessary to ensure that all adverse findings included in these reports are promptly and appropriately addressed by the appropriate personnel in the relevant facilities," the decree says.

Schering is working with numerous consultants on the GMP issues, including Lachman Consulting and Quantic.

The Manati facility will be governed by an extra tier of requirements beyond those for the other three plants.

Products manufactured at Manati will be subject to compliance under a cGMP protocol identified specifically for that facility. On March 6, FDA approved the cGMP protocol put together by Schering's consultants. Production at Manati will remain suspended until the consultants find that "Manati is in compliance with the requirements of the March 6 protocol," the decree says.

The consultants "may certify the Manati facility in its entirety or on a building-by-building basis, or it may certify the part(s) of the facility used to manufacture sterile drug(s) separately from the part(s) used to manufacture non-sterile drug(s)," the decree says.

The cGMP protocol for Manati is in addition to the requirement that Schering develop a comprehensive "cGMP workplan" for each of the four facilities.

The workplan is "designed to ensure that the methods, facilities, and controls used to manufacture drug(s) at each of these facilities are, and will be continuously in compliance" with FDA requirements.

Schering "shall obtain written FDA concurrence of the cGMP workplans and timetables," the decree says. The agency is required to respond to each submission of the workplan within 60 days.

The decree requires validation of all products manufactured at the four facilities, although 12 "medically necessary" Rx drugs are exempt from the requirement.

The consultants are required to assess "whether the process validation protocol clearly states how the validation study was to be conducted, including test parameters, relevant characteristics of the drug(s) or API(s), production equipment used, and decision points on what constitutes acceptable test results."

The consultants are also asked to certify that "there is reasonable assurance" that the validated drugs and APIs "will consistently meet all applicable specifications established in its approved" applications.

If the consultants are "unable to certify that a manufacturing process validation...is adequate," they are required to report the inadequacy to the senior VP-worldwide quality. Schering is required to provide a proposal on how to correct the deviations found by the consultants within 30 days of the report.

FDA provides an alternative to the validation process: consultants may provide "a product quality review" for products manufactured at the four facilities.

Schering NDAs Not Subject To Extra Scrutiny Under FDA Consent Decree

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