EU confirms suspension of 700 products hit by Indian CRO issues
This article was originally published in Scrip
Around 700 generic drugs will no longer be available in Europe from 21 August after the European Commission issued a decision confirming the products' suspension in light of concerns over data manipulation by the Indian CRO GVK Biosciences.
Products considered of critical importance to patient needs can remain on the market for now, but only if the company concerned can provide the relevant justification.
Among the drugs affected are atorvastatin, candesartan, clopidogrel, desloratadine, donepezil, escitalopram, esomeprazole, fluconazole, metformin, repaglinide, rizatripan, ropinirole and tacrolimus.
The move will clearly affect sales of the products, but evaluating the impact of the decision in Europe and on the companies concerned (including GVK) is difficult, partly because not all the products are marketed in all the member states, and partly because some of them have already been suspended in some countries.
Concern over the products was first expressed by the French regulatory agency ANSM after it conducted an inspection of GVK's Hyderabad facility, which found instances of non-compliance with Good Clinical Practice with respect to bioequivalence studies.
In an inspection report published on 21 July last year, ANSM cited "critical deficiencies" in GVK's quality system, specifically evidence of systematic manipulation of electrocardiogram records during nine generic medicine studies over a period of at least five years.
The commission asked the European Medicines Agency to launch a review into the matter, which it did in September 2014, looking at some 1,000 pharmaceutical forms and strengths.
Pending the outcome of the review, in December 2014 the German regulator, BfArM, decided to suspend some 80 products whose bioequivalence testing had been conducted by GVK Biosciences. In about 20 cases, the manufacturers launched legal challenges, and in a few cases the suspension was lifted after companies filed new clinical data. Other countries including France, Belgium and Luxembourg also suspended some products.
In January 2015 the EMA issued its opinion recommending the suspension of some 700 of the 1,000 products, with the remainder being given the all-clear on the basis of data from alternative sources.
The agency said the length and systematic nature of the studies conducted by GVK "cast doubt on the integrity of the way trials were performed at the site generally and on the reliability of data generated at that site", although there was no evidence that the products posed a risk to human health or were ineffective.
The companies affected included Actavis (now Allergan), Dr Reddy's, Glenmark, Generics (UK), Lupin, Mylan, Ranbaxy, Ratiopharm, Sandoz, Teva, Torrent Pharma and Wockhardt.
GVK itself was greatly displeased, arguing that the action was "unprecedented and highly disproportional", and that the observations should not be extrapolated to other trial-related activities at the same site.
Some marketing authorization holders asked for re-examinations, which the EMA duly conducted, but it concluded that concerns remained about the reliability of the clinical studies, and maintained its January recommendation, which has now been confirmed by the commission's decision.
Commission decision
The decision, which follows an opinion of the EU member states' Standing Committee on human medicines, is accompanied by two lists of products: those that can stay on the market because their bioequivalence with EU reference medicines has been shown, and those that are to be suspended because BE data or justifications were not submitted or were considered insufficient to establish BE.
BfArM said its list of suspended products, which was updated in May, would remain in force until the commission's decision took effect on 21 August. In the meantime it said it would inform the companies involved about the commission's decision, noting that while they can appeal against suspensions, it will have no immediate effect and the products will remain suspended pending any further decision.
It’s difficult to judge the effect of the commission's decision on the market for these products. As already mentioned, their availability varies from country to country, and moreover suspensions can be lifted if a satisfactory BE study is conducted versus the EU reference drug.
Products can also stay on the market if the company concerned demonstrates to the relevant member state that they are "critical", based on an evaluation of any potential unmet medical need, the availability of suitable alternatives, and the nature of the disease.
In such cases the suspension will be deferred for up to two years pending submission of the data; the manufacturer must submit a bioequivalence study within 12 months of the publication of the commission decision.
Effect on GVK
It's also not clear what the effects will be on GVK itself. The company told India's Business Today that it was "disappointed with the fact that even after multiple appeals, a deeper scientific dialogue was not undertaken", and that it would continue working with the Indian government and its customers to help resolve the issues.
But suggestions that the government may yet be able to wield influence in the EU on this matter are questionable. Some leading Indian industry experts told Scrip recently that not everyone was sure that a protest by the government on behalf of the industry was warranted, suggesting that companies would do better to ensure they complied with global regulatory requirements. The sources also said that claims of significant effects on Indian exports as a result of the EU's action might be overblown.
Business Today suggests that GVK itself will take a big reputational hit, but that the financial effects may be limited because the clinical trials division constitutes only a small proportion (around 10%) of its business. The Times of India says GVK may be considering pulling out of clinical trials, citing "people familiar with the development" as suggesting that GVK is already in talks over a possible sale of the business.