Schering-Plough Clarinex NDA Approval Awaits Resolution Of GMP Problems

Schering-Plough's Clarinex (desloratadine) NDA will not be approved until the company answers FDA concerns regarding Good Manufacturing Practices compliance at a wide range of Schering operations.

"FDA has advised the company that GMP deficiencies cited in facility inspection reports must be resolved prior to granting approval of the company's pending NDA for Clarinex tablets," the company said Feb. 15.

The Claritin (loratadine) successor product Clarinex reached the "approvable" stage at FDA Jan. 19, and the company "has submitted revised product labeling as requested by FDA." According to Schering, "there are no outstanding scientific or clinical issues that would affect approval of the product."

Schering had hoped to launch Clarinex in time for the spring allergy season. The product has been pending at FDA since Oct. 21, 1999.

The company did not project a timeline for the resolution of the manufacturing problems.

FDA has significant leverage in its GMP negotiations because of the importance of the Claritin follow-on to the future of the company.

Schering needs to reach a speedy resolution in order to allow lead time to establish Clarinex before Claritin goes off patent in December 2002. The company also continues to pursue efforts to extend the Claritin patent legislatively; those proposals could take on even more urgency if the delay for desloratadine is prolonged.

Clarinex may not be the only product delayed by the GMP difficulties. Schering's pending NDA for the asthma inhaler Asmanex (mometasone) is also "approvable" at FDA.

Schering said that FDA has outlined GMP deficiencies at four manufacturing facilities - Kenilworth and Union, N.J., and Manati and Las Piedras, Puerto Rico - in recent inspections. FDA inspections of the two Puerto Rico plants are ongoing, Schering said.

Schering maintains that FDA's concerns do not include its Irish production facility where the alpha interferon line (Intron A, PEG-Intron and Rebetron) is produced.

The immediate impact of the manufacturing compliance issues for Schering is supply shortages for some product lines.

Schering's "ability to manufacture and ship certain pharmaceutical products" has been affected by "the temporary interruption of some production lines to install system upgrades and further enhance compliance, and other technical production and equipment qualification issues," the company said.

Schering would not disclose which products would be affected. The only products for which the company specifically ruled out supply problems are the interferon brands.

The Feb. 15 press release included an estimate by Schering of the impact of the manufacturing disruptions on its quarterly results. First quarter diluted earnings per share are expected to be lower by "as much as 15%" compared to the 42[cents] per share reported for the same period in 2000, the company said.

"Some factors affecting first quarter results also are expected to negatively affect earnings for the full year 2001, although the extent of this impact will depend upon the timing and nature of a resolution of the manufacturing issues," Schering added.

In addition to the need to prepare the financial markets for the commercial impact of the supply disruptions (and the delay in approval of desloratadine), the press release could also be an attempt to preempt the bad publicity of a prolonged quality control wrangle with FDA.

In past situations where FDA has sought broad GMP corrections from major drug companies, the agency has often concluded the quality control effort with a consent decree.

The Schering press release includes a declaration by the company of its commitment to "securing FDA's confidence in the quality and reliability of our manufacturing systems and controls."

Schering said it is creating a quality unit to be headed by a senior VP, which will oversee manufacturing at all of its facilities. The company also said it is adding quality control staff, and plans to have increased its quality-related positions by 30% from 1999 through the end of 2001.

The company plans to spend "more than $50 mil. in new equipment, process and system improvements."

Schering dates the GMP issues from a 1999 albuterol inhaler recall, which followed the release of some albuterol and beclomethasone inhalers (Proventil, Vanceril and Warrick's generic albuterol) which may not have contained active ingredient.

FDA issued a warning letter concerning Proventil and Vanceril production at the New Jersey facilities on July 21, 1999, and two recalls followed (¹ (Also see "Schering Implementing Four-Phase Proposal For Proventil Batch Release" - Pink Sheet, 23 Aug, 1999.)).

"After the company experienced manufacturing problems in the fall of 1999 involving aerosol inhaler products, Schering-Plough took a broad review of manufacturing systems and procedures with the help of outside consultants," Schering said. "From this, Schering-Plough developed a GMP action plan applicable to all manufacturing sites."

"While Schering-Plough has taken extensive measures intended to enhance its manufacturing processes and controls, the company notes that FDA's inspection reports and its own internal reviews indicate that improvements are required," the company acknowledged.

FDA is likely to trace a longer history to the GMP compliance difficulties: Schering received three GMP warning letters in 1998 addressing problems at three different facilities.

A June 29, 1998 warning letter cited manufacturing issues for Theo-Dur and Claritin at the firm's Las Piedras facility.

An Oct. 23, 1998 warning letter cited dissolution failures for Claritin-D 12 hour, Proventil inhaler, Nasonex nasal spray, and Diprolene ointment at Schering's Kenilworth and Union facilities. FDA cited the company for partial releases of batches that had been rejected because of failures.

A Nov. 23, 1998 letter addressed the aseptic processing of Intron A at Schering's (Brinny) Innishannon, Ireland facility.

In response to the 1998 letters, Schering set up a task force to evaluate the manufacturing parameters for the products. The company declared in early 1999 that it had resolved the issues to FDA's satisfaction (² (Also see "Schering's Three GMP Warning Letters In 1998 Counter Industry Decline" - Pink Sheet, 8 Mar, 1999.)).

The November 1998 Intron A warning letter raised the possibility that FDA's concerns could extend beyond the four plants specifically identified by Schering.

FDA generally works with manufacturers to ensure that "medically necessary" products are not disrupted or delayed by compliance actions, and Schering's interferon brands would likely fall in that category even if the agency takes a closer look at the Irish facility.

The agency's most recent warning letter to Schering was issued on May 8 and reported observations from a Nov. 30, 1999 to March 28, 2000 inspection of the company's Manati plant.

The letter cites Schering for its response to out-of-specification stability test results for the ophthalmic agents Gentocin and Garamycin, and for departing from written SOPs for products including Vancenase AQ and Nasonex.

FDA recently concluded a consent decree involving Wyeth-Ayerst's GMP compliance at its Marietta, Penn. and Pearl River, N.Y. injectable manufacturing facilities (³ (Also see "Wyeth Will Lose 18.5% Of Marietta Sales If Firm Does Not Comply With GMPs" - Pink Sheet, 9 Oct, 2000.)).

Wyeth was able to negotiate the consent agreement without significant fall-out in the financial markets, in part because the costs of the manufacturing issues were insignificant in the context of the $12 bil. Redux liability costs.

Wyeth also did not have a significant pending line extension that was vulnerable to a protracted delay due to manufacturing compliance problems.

A closer analogy to Schering-Plough's current position may be the compliance difficulties experienced by Warner-Lambert in 1993. In that case, Warner-Lambert was awaiting a critical line-extension (Lopid SR) which was not approved by FDA because of the pending GMP issues.

A disruption in Schering's financial results for the company could have a silver lining in the long run if it ultimately leads to easier quarterly comparisons during the period when Claritin goes off patent.

The delay in the approval of desloratadine also need not rule out commercial success for the drug. The Claritin review was protracted but may have helped the drug find a niche as a next-generation nonsedating antihistamine.