Saturday, March 28, 2009

Too good to be true?

Typically, the regulatory authority requires two pivotal studied to demonstrate the efficacy. If the results from two studies show the conflicting or inconsistent results, the evidence for efficacy may be considered as not convincing.

On the other side, if two studies show the results almost identical, it could raise the issue with regulatory reviewers for suspicious fraud. In the most recent ASA's biopharmaceutical report, two examples were discussed.

NDA 022145 Merck's Isentress

Nearly identical results were observed in the investigational treatment group in two pivotal phase III trials for the applicant’s primary efficacy endpoint.
As part of the data verification process, the statistical review team requested copies of original source documents (laboratory reports) for HIV RNA data from the four sites that were inspected, from the site with the largest number of patients and from an additional site that had highly statistically significant results in favor of the investigational drug.
Because the applicant used an IVRS, there were no fixed randomization lists available prior to enrollment of the patients in the trial and no treatment codes available in envelopes at the sites that DSI inspected. Therefore the statistical review team also requested that copies of original source documents for treatment randomization schedules be sent directly to the FDA from the external vendors. In addition, the statistical reviewer requested the applicant’s standard operating procedures for randomization schedule generation and certification from the external vendors that the randomization code documents were obtained from the original electronic file sent to the vendors from the applicant prior to study initiation. A sample of treatment codes and laboratory data were compared to corresponding values in the SAS data sets and appeared to match.

Of note, in this NDA, two pivotal studies were allowed to be combined. The final assessment is based on the integrated summary of efficacy (ISE). It appears that the dynamic randomization was used in these two studies even though there was no detail description about the randomizaton procedure (ie, dynamic allocation for baseline covariate or dynamic allocaton for response?)

GSK's Relenza (NDA021036)

Two phase III studies assessed post-exposure prophylaxis in household contacts of an index case of influenza. In the first household study, the index case was treated while the index case was untreated in the second study. The primary efficacy endpoint for the two phase III household prophylaxis studies was the proportion of households with at least one previously uninfected household member who contracted symptomatic, laboratory-confirmed influenza.

Nearly identical rates were observed for the primary efficacy endpoint in the two household studies. Such a high degree of coincidence is rare.

Of note, the biopharmaceutical report is a quarterly report by biopharmaceutical section under american statistical association. Unfortunately, the report was not updated on their website. I have to put the report under a temporary web location.

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