India’s Micro Therapeutic says EMA’s ‘Sweep’ Suspension Will Hurt; CRO Industry Shuns ‘Bad Eggs’

Data integrity concerns continue to cloud outlook for India’s contract research sector. The European Medicines Agency’s latest action against Micro Therapeutic Research Labs suspends more than 300 products in the EU over “unreliable” data and the firm tells Pink Sheet this will result in a “considerable dent” in its operations.

Indian contract research organizations continue to be pulled up over dirty data submissions, scarring further the already struggling domestic industry and piling up challenges for marketing authorization holders.

The European Medicines Agency has now recommended the suspension of a range of nationally approved medicines for which bioequivalence studies were conducted by Micro Therapeutic Research Labs at its sites in Chennai and Coimbatore in India over untrustworthy data.

The EMA’s Committee for Medicinal Products for Human Use (CHMP), in its review, held that data from studies conducted at the sites between June 2012 and June 2016 were “unreliable” and “cannot be accepted” as a basis for marketing authorization in the EU.

There is, however, no evidence of harm or lack of effectiveness of medicines authorized and being evaluated in the EU on the basis of studies at the sites, an EMA statement dated Mar. 24 said.

Micro Therapeutic’s managing director, Munyandithevar Ganesan, told the Pink Sheet that the EMA referral decision was “spread to the studies done unto June 2016” and that based on the EU initial inspection and the “acceptance” by the inspectors in their audit reports, the firm was “confident” that concerns raised on the “acquired data” at its site was “mitigated since January 2015”.

“We presented our case as well as supporting data to EMA through written response. However, to our disappointment EMA could not accept the same. For the studies and the marketing authorizations (MA) that have got affected due to this final EMA decision, we are working with MA holders to do repeat studies and submission to respective national authorities,” Ganesan said.

The Micro Therapeutic’s official maintains that he is “fully confident” of the firm’s studies meeting compliance levels of all international regulations; he referred to the firm having “faced” around nine US Food and Drug Administration inspections at regular intervals successfully in the past.

He admitted that the “EMA sweep decision” of “comprehensively” acting on the studies till June 2016 is a “setback” for the firm.

“Going by the customer perception of any site having faced regulatory action, we expect a considerable dent in operations especially for EU studies. It would take time for our esteemed customers to come back,” he admits.

Medicines Suspended

The EMA has recommended for suspension over 300 products in varying strengths whose marketing authorization holders include, among others, Aurobindo Pharma BV (amlodipine-valsartan, among other products), Sandoz N.V./S.A. (betahistine, among other products), Alternova A/S (prednisolone, among others) and Sanofi Aventis (hydroxyzine). Reactions to the EMA suspension from the marketing authorization holders could not immediately be got.

The EMA statement said that the suspensions can be lifted once alternative data establishing bioequivalence are provided.

Certain products including Mylan NV’s tadalafil, memantine from multiple marketing authorization holders and paracetamol from Dawa Ltd can, however, stay on the market.

“Alternative supporting data have already been provided for several of the medicines reviewed. Therefore, the CHMP recommended that these medicines can remain on the market,” the EMA statement added.

Micro Therapeutic’s Ganesan explained that paracetamol (all studies) had been accepted as MA holders had provided alternative data.

“Other alternative data acquisition is confidential information between us and the MA holder/applicant and as soon as they are acquired, the agency would know of it,” he said, when asked which are the other drugs for which Micro Therapeutic expects to provide alternative supportive data on a priority basis.

Pipeline Approvals

The EMA has also recommended that medicines not yet authorized but which are being evaluated on the basis of bioequivalence studies from the tainted Micro Therapeutic sites should not be approved until bioequivalence is demonstrated using alternative data.

Ganesan indicated that the number of applications which were under review by various national agencies in the EU are around 15.

“[The] rest all were approved studies/licenses,” he added.

The EMA also said that since some of the medicines which have been recommended for suspension may be of critical importance in certain EU member states, the 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.

The CHMP’s recommendation will now go to the European Commission for a legally binding decision valid throughout the EU.

Rebuilding Confidence

The EMA’s latest action clearly comes as a setback for the Indian clinical research industry that has been keen to shrug off any impression that data integrity issues or other deviations are a deep-rooted systemic malaise.

The Indian Society for Clinical Research, whose members include several large multinational firms and clinical research organizations, said that it does not condone “any action of malpractice or data integrity violations” by any organization but added that it cannot comment on the specifics of Micro Therapeutic’s case as it does not have enough information to do so.

“It is unfortunate that this is coming at a time when we are striving hard to rebuild confidence and trust in a more evolved and balanced Indian regulatory environment. While these instances are far and few, they tarnish the image of our country and the pride of ‘Make in India’ which the Indian government has invested in,” ISCR president Suneela Thatte told Pink Sheet.

Launched in 2014, Prime Minister Narendra Modi's pet "Make in India" initiative, aims to make India a global manufacturing hub, thereby upping the contribution of the manufacturing sector to the country's gross domestic product (GDP).

One Bad Egg

Thatte, though, maintained such instances of violations have been confined primarily to a “cross-section of BA/BE players” and it is incumbent upon the Indian regulator to investigate these allegations “thoroughly and take action as appropriate” so that it would act as a deterrent while also communicating India’s seriousness about such issues to global stakeholders. (Also see "Data Integrity Failures Undermine Trust That Can’t Easily Be Won Back, EMA Official Says" - Pink Sheet, 28 Feb, 2017.)

The ISCR also underscored the high quality of clinical research being done in India, referring to “collated data” of all the US FDA and EMEA GCP inspections to date in India which show “no critical findings”.

“One bad egg should not be indicative of an entire industry and as in any industry, there will always be players operating at both ends of the spectrum. We need to highlight this, while using a data-driven approach to communicate that we have a very highly qualified and competitive clinical research ecosystem in our country,” she maintained.

India's clinical research sector has, in general, been dented amid uncertainties and delays caused by evolving regulations and ongoing trial-related litigation among other factors. Compliance deviations have only added to these pressures. (Also see "India Global Trial Hub Dreams Still Distant As Concerns Linger" - Pink Sheet, 15 Aug, 2016.) India’s GVK Biosciences and Quest Life Sciences were earlier hauled up over data integrity issues. In July 2016, the EMA suspended over 200 products based on a clutch of actives that relied on flawed bioequivalence studies done by the Bengaluru-based Semler Research. The latest position on these cases could not immediately be ascertained. (Also see "Semler Dirty Data: EMA Suspends Over 200 Products; Stings Indian CROs" - Scrip, 25 Jul, 2016.)

From the editors of Scrip Regulatory Affairs.