Semler Dirty Data: EMA Suspends Over 200 Products; Stings Indian CROs

Dirty data issues continue to plague Indian contract research organizations, denting the reputation of the beleaguered local industry and piling up challenges for marketing authorization holders. The European Medicines Agency (EMA) has now suspended close to 300 products that relied on flawed bioequivalence studies done by the Bengaluru-based Semler Research.

The EMA on July 22 recommended for suspension a long list medicines in various strengths based on a clutch of actives including erlotinib, saquinavir, celecoxib, eletriptan, duloxetine, amoxicillin and eprosartan for which bioequivalence studies were conducted at India's Semler Research Centre Private Ltd; marketing authorization holders for the suspended products include Sandoz NV, Teva Pharma Belgium NV, Mylan AB, Sanofi Aventis France, Zydus France, Ratiopharm GmbH and Glenmark.

But the Agency's action was not really entirely unexpected – both the FDA and the World Health Organization (WHO) had earlier pulled up Semler over compliance deviations.

The EMA said its review followed an FDA inspection that raised several issues at Semler Research Centre Private Ltd's bioanalytical site, including the "substitution and manipulation of subjects’ clinical samples". The FDA had earlier said that Semler engaged in practices and processes that undermined the analytical methods used at the firm which resulted in the submission of "invalid" study data to the agency.

Semler was also previously pulled up by the WHO for "critical and major" deviations from good laboratory practice (GLP) and good clinical practice (GCP), resulting in a stinging notice of concern (NOC) against the Indian CRO in April.

The NOC referred to an "indicator of fraud" and manipulation of at least five studies over an extended period of time suggesting that this is a "common practice". The WHO at the time said it believed that to execute such manipulation, several staff members on various levels of the organization had to be "collaborating and co-ordinating".

"The issue is thus not confined to a single person operating outside of the quality management system," the WHO had said.

Semler had, the NOC said, acknowledged that four FDA studies and one WHO study had "questionable" data and these trends were not "physiologically explainable" and that there were system gaps identified during the retrospective investigative audit in the system due to which the firm was not able to identify "who and why this happened". (Also see "Foreign Regulators Rap More Indian Firms Over Data Integrity" - Scrip, 25 Apr, 2016.)

The WHO had questioned the validity of studies for a range of pre-qualified products and those under assessment at the time including fixed dose combinations of efavirenz, lamivudine and tenofovir, azithromycin and isoniazid.

The EMA said that the findings from FDA and WHO inspections call into question the quality management system in place at Semler, and thus on the reliability of the data of all bioequivalence studies, including those used to support marketing authorization applications in the EU.

"The EMA’s Committee for Medicinal Products for Human Use (CHMP) has concluded that the studies conducted at Semler cannot be accepted in marketing authorization applications in the EU. Thus, no medicines can be approved on the basis of these studies," the EMA statement said.

The Agency has also recommended that medicines currently being evaluated for authorization and which rely only on bioequivalence studies from this site should not be authorized until bioequivalence is demonstrated using alternative data.

There is, however, currently no evidence of "unexpected harm or lack of effectiveness" with any medicine approved on the basis of studies conducted at Semler, the EMA statement noted.

Semler could not immediately be reached for a comment over the weekend.

Alternative Studies

The EMA, however, said that certain products, essentially abacavir/lamivudine combinations from multiple companies, could stay on the market in view of alternative studies provided for some of these.

"These studies show bioequivalence, and therefore, the CHMP has recommended that these medicines can remain on the market."

The EMA also said that some of the medicines that had been recommended for suspension may be of critical importance given the "lack of available alternatives" in a given EU Member State and hence national authorities can temporarily postpone the suspension in the interest of patients.

"Member states should also decide whether recalls of the affected medicines are needed in their territories".

Setback For Indian CROs

Action against Semler, industry experts say, comes as a setback for Indian CROs that have been keen to shrug off any impression that data integrity issues are a deep rooted malaise. GVK Biosciences and Quest Life Sciences were earlier hauled up over data integrity issues. (Also see " GVK India Row: Stalled EU Trade Talks And ''Vendetta'' Claims " - Scrip, 6 Aug, 2015.)

An industry expert told Scrip that a section of the Indian CRO industry (he estimates around 40-50 CROs) have significant bioequivalence-related activity driving business and foreign companies could now get jittery about having these studies done out of India. (Also see "Indian CRO segment in throes of a shakeout?" - Scrip, 15 Feb, 2015.)

"Some could consider switching off from India; even Indian firms that use local CROs for bioequivalence studies for exports could be cautious, though cost economics are a factor," he said.

Bioequivalence studies typically form the basis for approval of generic medicines.

Dilip Shah, secretary general of the Indian Pharmaceutical Alliance (IPA), which represents leading domestic drug firms, however, maintained that while the "local unknown CROs" may suffer, the established global ones with "good internal oversight" may even benefit following the EMA action.

"India still continues to be cost effective, providing access to a large patient pool and trained doctors," Shah told Scrip.

The expert quoted previously also indicated that much of Indian regulatory action appeared "re-active" and it was perhaps time for "proactive and systematic" regulation of CROs, and the rest of the industry.

Industry bodies were quick to swing into damage control mode. The Indian Society for Clinical Research (ISCR), whose members include several large multinational firms and clinical research organizations, told Scrip that it would be "short sighted and damaging" to the reputation of many high quality Indian CROs to tarnish the image of the Indian CRO industry based on a "few, isolated" incidents.

"The quality of clinical research work done in India is comparable to that of any other country. Clinical trials, no matter where they are done, are usually part of multi-country global trials and generate data for submission to multiple regulatory agencies around the globe. Therefore the standards followed are in compliance with international and local guidelines and that is true of clinical research done in India as well," ISCR president Suneela Thatte told Scrip.

ISCR noted that there have been over 40 US FDA clinical trial inspections in India with no critical findings reported; there have also been several all clear European regulatory audits of Indian clinical trial sites.

While the ISCR does not condone any wrongdoing, it does take serious note of any non-compliance by organizations in India, Thatte added.

ISCR expects the developments to impact the prospects of the Indian CROs particularly at a time when "so much has been done" by Indian regulators to strengthen the Indian regulatory environment for clinical trials; Thatte maintains that India already has robust guidelines in place for the conduct of clinical research in India.

"What we really need is a more vigilant governance system to ensure compliance as also a system to ensure corrective action is taken against organizations that may be in violation of these guidelines. We should not have to depend on external regulatory bodies to identify these incidents," she underscored.

GVK was in the eye of a storm after the French Agency on medicinal products (ANSM) detected data manipulations of electrocardiograms (ECGs) following an inspection in 2014. Last year, the EU confirmed the suspension of the products linked to the GVK issue. (Also see "EU confirms suspension of 700 products hit by Indian CRO issues" - Scrip, 29 Jul, 2015.)

The UK MHRA had recently suspended marketing approval for an antibiotic that was based on studies done by Quest Life Sciences following data integrity concerns. Quest had previously been issued a NOC by the WHO over critical deviations from GCP pertaining to studies concerning certain AIDS drugs. (Also see " The ECG curse: India's Quest under lens in ''retrospective'' finding " - Scrip, 7 Jul, 2015.)