Pfizer’s warning letter for pediatric Geodon trials could impact patent extension

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Pfizer’s (NYSE:PFE) recent FDA warning letter could jeopardize the marketing exclusivity extension - worth up to USD 500m - on its blockbuster antipsychotic Geodon (ziprasidone HCl), as well as potentially impact the timeliness of future drug applications, industry experts told Pharmawire.

As this news service first reported, an FDA warning letter issued to Pfizer on 9 April cited violations in adherence to good clinical practice (GCP) in the conduct and monitoring of two Geodon trials in 2006 and 2007 in children with bipolar disorder and schizophrenia. Pfizer has said it will outline its response to the agency’s concerns within the next two weeks.

Geodon is currently approved in the US for the treatment of adults with schizophrenia and acute bipolar disorder. Four pharmaceutical industry regulatory consultants pointed out that Pfizer’s purpose in running the Geodon pediatric trials was to take advantage of The Best Pharmaceuticals for Children Act. The act allows a company to receive six months of extra marketing exclusivity if it conducts the particular studies in pediatrics that the FDA requires to establish dose, safety, and efficacy.

“Pfizer is counting on the pediatric trial data for the extra six months patent exclusivity on Geodon and it would be a big blow not to get this,” one consultant said. According to the Biopharm Insight database, Geodon is expected to achieve peak sales of around USD 1.1bn in 2011, tapering off after the drug loses its formulation patent in 2012.

In response for comment, Pfizer said it believes the clinical integrity of the trial was maintained. “We are responding to the FDA’s queries around the study and continue to plan to seek a pediatric indication for Geodon,” Pfizer said, adding that Geodon may offer an important treatment option for pediatric patients with manic or mixed symptoms of bipolar disorder. ‪

The Phase III bipolar disorder trial was the main study cited in the FDA’s warning letter. One of the key violations noted by the FDA was the prolonged overdosing errors that were not recognized or reported in a timely manner by the study monitors between March and July 2006. Forty out of the 245, or 16% of, patients were subjected to an overdosing error and half of these were exposed to higher than the maximum tolerated dose for the trial.

There was also insufficient documentation to support the qualification of some of the trial’s principal investigators to recruit patients for the trial and to administer these patients with the study drug, according to the FDA’s report. In addition, there was a problem with informed consent at some sites, among other GCP violations, the FDA said.

The trial was conducted at 50 Pfizer investigational sites across the US and this news service previously reported that K-Force Clinical Research (NASDAQ:KFRC) is understood to be a contracted vendor involved in providing Pfizer with monitoring staff for the pediatric Geodon trials. A person familiar with the situation claimed information that the FDA also inspected K-Force as part of its investigation.

K-Force declined to comment on the situation.

The GCP breaches were identified during FDA inspections between May and June 2009 after Pfizer submitted an application for the approval of Geodon for the treatment of pediatric patients with bipolar disorder in October 2008. Subsequent to these FDA inspections Pfizer was issued a 483 form - a detailed list of significant regulatory compliance deviations. Pfizer responded to the FDA’s 483 in a timely fashion, it is understood, yet the FDA issued a formal warning letter nearly a year later.

The issuance of the warning letter could have real implications for Pfizer’s chances of gaining the Geodon marketing exclusivity extension, aside from delaying or costing the approval of the drug in pediatrics, the consultants said.

The first consultant noted that it has been 18 months and the FDA has still not approved Geodon for children, even though an FDA Psychopharmacologic Drugs Advisory Committee tentatively agreed to its use in pediatrics in June 2009, pending more safety data.

The data Pfizer has submitted might not be considered reliable by the FDA, the same consultant said, adding that the FDA may request an additional trial, especially to gather more safety data. A second consultant explained that if 40 out of 245 patients were given an overdose, Pfizer may not be able to prove to the FDA’s satisfaction that the dose it investigated is safe and effective. If the FDA does request further trials, it may be too late for Pfizer to complete them in time to gain the extra marketing exclusivity before Geodon’s patent expires, the same consultant added.

It is understood that Pfizer has already excluded three clinical sites from the Geodon pediatric data set that the FDA is reviewing. A third consultant noted this move could impact the power of the trial. It is understood that Pfizer stated to the FDA that the primary efficacy endpoint still achieved statistical significance, despite the data exclusion.

Yet the first and third consultants noted that FDA could still reject the data as unsatisfactory, citing the recent example with Johnson & Johnson (NYSE:JNJ) and Basilea Pharmaceutica’s (SWF:BSLN) antibiotic ceftobiprole, which the FDA declined to approve in the US based on the uncertainty of data quality of its current Phase III programme. Both J&J and Icon – the clinical research organization responsible for monitoring the trial – received FDA warning letters over the matter. It was also suggested by the consultants that the contractor involved in the Geodon trials could yet receive an FDA warning letter as Icon did.

The FDA commented that the marketing exclusivity determination under The Best Pharmaceuticals for Children Act does not hinge on positive trial results; rather, it hinges on the completion of the studies as requested by the agency in a manner consistent with good scientific practices. The agency confirmed that a study not conducted following good scientific principles may be recognized as too flawed to meet the objectives required by the FDA and would thus be grounds for denying exclusivity.

The third consultant also noted that there is already a well documented heightened sensitivity within the FDA and the public in general over the potential adverse effects associated with the use of antipsychotics in children.

Two consultants said that the warning letter signals that Pfizer is very much “under the FDA microscope” and this could slow down future drug applications from the company as the FDA will want to “double check everything” and conduct more inspections in the future which could potentially lead to more 483 forms.

This news service previously reported that an FDA inspection of Pfizer’s US headquarters – which occurred in mid-2009 – identified a number of violations in the pharma giant’s reporting standards for adverse drug events (ADE). The FDA identified several findings that called into question Pfizer’s quality assurance/quality control processes for the ADE reporting on its marketed drugs such as Viagra, Lipitor, Bextra, Chantix, Lyrica, Cerebyx, Provera and Selzentry, it was reported.

Pfizer was subsequently issued a 483 form and pharmacovigilance/regulatory compliance consultants interviewed at the time suggested that Pfizer could be issued an FDA warning letter over the matter, although it has yet to materialise.

As previously also reported by this news service, Pfizer is understood to be aware of a number of oversight failings of its monitoring of K-Force monitoring staff that have lead to GCP breaches in some of its other clinical trials. Some of the oversight failings were of high importance and persistent, drawing concern over Pfizer’s internal quality control processes regarding its clinical trials and the integrity of the data for not only the trials it is aware of, but potentially other trials run by K-Force monitors, as reported.

Two of the consultants recently interviewed pointed to the case of J&J’s ceftobiprole as an example of a situation Pfizer may yet face. The consultants claimed that J&J has still not resolved its warning letter situation with the FDA and is still liaising with the agency on how it will satisfy the agency’s concerns and move forward. The warning letter is having a wider impact on J&J than just ceftobiprole and the situation is partly responsible for holding up its application of another cardiovascular drug, rivaroxaban, they claimed.

When asked to comment, J&J said these are distinct applications under review in different divisions of the FDA.

The third consultant stated that “word spreads quickly within the FDA,” yet the second consultant did not necessarily think that the FDA would use “delay tactics” on future drug applications of companies that have received a warning letter.

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