T

he US Food and Drug Administration last week alerted an untold number of drug makers that marketing applications containing clinical trial data prepared by an Indian contract research organization would not be accepted due to concerns about the integrity of the data.

A notice was posted on the FDA web site one day after the agency sent a letter to Semler Research Center, which is based in Bangalore, India, saying that inspections found “significant instances of misconduct and violations of federal regulations, including the substitution and manipulation of study subject samples.” The FDA inspected Semler facilities last fall.

The move comes two weeks after the World Health Organization issued a “Notice of Concern” to Semler for the same reasons. Specifically, the WHO examined company computer servers and found a spreadsheet file containing detailed instructions for manipulating drug samples that were used in clinical trials for its clients. The WHO inspections conducted inspections early and late last year.

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“Manipulation of at least five studies over an extended period of time indicates this is a common practice,” the WHO wrote. “WHO is of the impression that to execute this type of manipulation, several staff members on various levels within the organization have to be collaborating and coordinating. The issue is thus not confined to a single person operating outside of the quality management system.”

The WHO noted that Semler acknowledged there were four FDA studies and a WHO study that had questionable data that could not be explained. Among the companies whose studies were cited in the recent WHO notice are Mylan Laboratories and Lupin, one of India’s largest drug makers. The FDA communications did not mention specific drug companies.

We asked Semler for comment and will update you accordingly.

The implications for the drug makers affected by the WHO and FDA notices may be substantial.

Last year, for instance, the European Union suspended hundreds of drugs that were authorized for use based on what European regulators called “flawed” studies conducted by GVK Biosciences, a clinical research organization based in Hyderabad. The episode triggered protests not only from drug makers but the Indian government, as well.

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Although the FDA says it has not identified reports that raise serious safety concerns with any of the approved medicines, the agency is requiring companies to repeat bioequivalence studies using a different contract research organization. These studies determine the extent to which a generic drug is similar to a brand-name medicine.

This means, of course, that drug makers will have to decide whether it will be worth the expense of conducting new studies for pending or approved applications by the WHO or the FDA, explained Vince Suneja, who heads TwoFour Insight Group, a consulting firm that specializes in the Indian pharmaceutical industry.

The companies will also have to review drugs in their pipelines where studies were being run by Semler and find a new CRO, which could result in delayed filings with the WHO or the FDA. And in the US, he noted, the data integrity issue prompted the FDA to change therapeutic equivalence ratings for any approved drug that relied on Semler testing. This means that such drugs may no longer substituted as easily at pharmacies, which could cause drug makers to pay higher rebates or, perhaps, face product-liability lawsuits.

This is the second time in the past year, by the way, that the WHO has issued a Notice of Concern to an Indian CRO. Last July, the agency cited Quest Life Sciences for a clinical study of different AIDS drugs and recommended rejecting the study, according to the notice.

For this reason, the latest move by the WHO may prompt drug makers to “paint a broad brush toward CROs in India that may result in delayed filings of other products, as well as higher costs for conducting bioequivalence studies in other higher cost markets,” according to Suneja.

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  • To quote a distinguished colleague at Waters in the Boston area when I posted the letter last week: [They must be saying] “If only… That pesky spreadsheet hadn’t been found,…”
    My rejoinder – What a tangled web we weave when first we document how we deceive!

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