Industry Trend Analysis - India Will Need To Take Action To Restore Confidence In Medicinal Data Reliability - MAY 2017

BMI View: The Indian Government is likely to be disappointed by this latest medicine suspension recommendation, the third issued by the EMA in recent years after inspecting Indian contract research organisations. Whilst previous actions have drawn rebuke from the Indian Government and impacted EU-India trade negotiations, it is unlikely that this recommendation will have the same effect, as negotiations have been stalled for some time. Nonetheless, a damaging picture of doubt over Indian contract research companies is emerging; India will need to take firm action to restore its reputation.

The EMA has recommended suspending a number of nationally-approved medicines, the bioequivalency studies for which were conducted by Micro Therapeutic Research Labs (MTR) at two sites in India. The suspensions can be lifted once alternative data establishing bioequivalence are provided. MTR is a contract research organisation (CRO) which conducts the analytical and clinical parts of bioequivalence studies, some of which are used to support MAAs for medicines in the EU. The review of medicines studied by the company was started after inspections to check compliance with GCP initiated by Austrian and Dutch authorities in February 2016 identified several concerns at MTR's sites regarding misrepresentation of study data and deficiencies in documentation and data handling.

The review, conducted by the EMA's CHMP, concluded that data from studies conducted at the sites between June 2012 and June 2016 are unreliable and cannot be accepted as a basis for marketing authorisation in the EU. However, the EMA stressed that there is no evidence of harm or lack of effectiveness of medicines authorised and being evaluated in the EU on the basis of studies at the sites. The CHMP's recommendation concerning the affected medicines will now be sent to the EC for a legally binding decision valid throughout the EU.

The review covered one medicine, Mylan's tadalafil, authorised centrally through the EMA, as well as medicines authorised by national procedures in EU Member States (including decentralised or mutual recognition procedures), the MAAs for which included data from studies conducted by MTR at two sites in India, in Chennai, Tamil Nadu and Coimbatore, Tamil Nadu. The review also included ongoing MAAs for medicines which use study data from these sites.

The suspended products are marketed in some 25 countries in Europe. Companies that have been affected by the suspensions include Aurobindo Pharma, Sandoz ( Novartis), Mylan and its subsidiary, Famy Care, Orion, Sanofi, Teva Pharmaceutical Industries, Strides Arcolab ( Strides Shasun), Bluefish Pharmaceuticals, Lupin and Zydus Cadila. However, in some cases alternative supporting data have already been provided; in these instances, the CHMP has recommended that the medicines can remain on the market. The EMA also recommended that medicines not yet authorised but which are being evaluated on the basis of bioequivalence studies from the two MTR sites should not be authorised until bioequivalence is demonstrated using alternative data.

National authorities in the EU will need to consider how critical individual medicines recommended for suspension are in their countries and make final decisions on whether to suspend or allow them to remain available, while new data are generated. The EMA noted that some of the medicines which have been recommended for suspension may be of critical importance, for example because of a lack of available alternatives, in certain EU countries. In these cases, national authorities can temporarily postpone the suspension in the interest of patients. Countries should also decide whether recalls of the affected medicines are needed in their territories.

Growing History Of EU Concerns Over Indian CROs

This is now the third case in recent years where the EMA has recommended suspending medicines with studies originating from India-based firms. At the start of 2015, the EMA recommended suspending products for which authorisation was primarily based on clinical studies from GVK Biosciences, based in Hyderabad, India. This inspection was carried out by the French medicines agency; the inspection revealed data manipulations of electrocardiograms during the conduct of some studies of generic medicines. In May 2015, the EMA recommended suspension of some 700 medicines linked to GVK studies.

In July 2016, the EMA recommended suspending a number of nationally-approved medicines for which bioequivalence studies were conducted at Semler Research Centre, based in Bangalore, India. The EMA's review of Semler was initiated on April 28 2016 at the request of Denmark, Germany, the Netherlands, Spain and the UK.

In that case, the EMA's review followed an FDA inspection that identified several issues at Semler's bioanalytical site, including the substitution and manipulation of subjects' clinical samples. The FDA reported in June 2016 that it was notifying NDA and ANDA sponsors that clinical and bioanalytical studies conducted by Semler were not acceptable as a result of data integrity concerns and would need to be repeated. The FDA took this action as a result of an inspection conducted between September 29 and October 9 2015. The inspection found what the FDA termed 'significant instances of misconduct and violations of federal regulations'.

The EMA noted that even before the FDA's inspection, the World Health Organization (WHO) had raised concerns about Semler. In a letter to Semler, the WHO reported that it had conducted inspections at Semler between January 27 and 31 2015, and conducted a follow-up between December 2 and 5 2015 in order to verify compliance with Good Laboratory Practice and Good Clinical Practice standards. The inspections revealed major deviations from both standards.

Suspensions Have Sullied EU-India Relations

Whilst the response to the Semler suspension was more muted, the effects of the GVK action were far reaching. In August 2015, the Indian Government announced it was deferring talks with the EU over the India-EU Broad based Investment and Trade Agreement (EU-BTIA) to mark its displeasure with the decision. At the time, the Indian Ministry of Commerce and Industry noted that the pharmaceutical industry is a flagship sector for India, and stressed that it had developed its reputation through strong research and safety protocols over the years.

Negotiations over the EU-BTIA have been underway for several years. As its name suggests, it is a broad bilateral trade agreement encompassing many business sectors, and grew from summit meetings in 2005. At the time, bilateral trade in goods between India and the EU were worth some EUR40bn (USD44.6bn). India exported some EUR3.8bn (USD4.26bn) worth of services to the EU, and the EU was India's largest source of foreign direct investment. Negotiations have stalled in the years since, the situation having been exacerbated by the financial crisis from 2008, coupled with concerns over the nature of the trade agreement and implementing an agreement that will benefit both sides. An agreement had originally been expected to have been concluded some years ago, but after several rounds of negotiations, agreement has yet to be reached.

In March 2016, the EU hosted the 13th EU-India summit, during which both sides welcomed the re-engagement in discussions on how to move forward trade and investment agreements and endorsed the EU-India Agenda for Action 2020. This sets out a road map for the EU and India to reach agreement on a number of issues including trade, security and human rights.

Given the stalled nature of talks between the EU and India, this latest suspension recommendation is unlikely to have much impact on trade negotiations between the two, as India cannot again defer talks. However, the Indian Government is likely to be alarmed that a third CRO has been identified by the EMA as having questionable data. Given the emphasis that India places on the quality of its pharmaceutical industry, it will be in the country's interests to tackle this issue head on to reverse a damaging pattern of doubt that is emerging.