Squeezing Drug Authorization at Both Ends

Wherever the European Medicines Agency winds up after Brexit (and that is a subject so widely discussed elsewhere that I'll leave that out for the moment), the reality for anyone working on drug development is that the strains and constraints of their job are not going to get any easier.

The late-March meeting of the EMA's senior scientific committee offered plenty of evidence. Alongside the customary rigorous evaluation of routine marketing authorization applications, it revealed how tight conditions are becoming for early development – and how hard it is to join fast-track schemes. At the same time, it showed how tough the authorities are becoming on demonstrations of scientific validity throughout the entire application process.

The tight conditions appear particularly clearly in the figures released on how many further applicants have been successful in joining the fast-track PRIME scheme last month. None, to be precise.

PRIME is important. Set up just a year ago, it provides early and enhanced support to medicines that are judged to have the potential to address unmet needs. The eligibility criteria are the offer of a major therapeutic advantage over existing treatments, or of benefit to patients currently without treatment options, and the judgment is made on the basis of early clinical data.

Once a candidate medicine has been selected, EMA appoints an expert from its pool to support development and help to build knowledge about the medicine ahead of a marketing authorization application – particularly through improved clinical trial designs. Sponsors receive advice on how to optimize development plans, collect robust data and submit high quality marketing authorization applications. Guidance from EMA is provided on planning and regulatory strategy, and scientific advice is offered at development milestones. The additional pay-off is that medicines in the PRIME scheme are also potentially eligible for accelerated assessment for marketing authorization.

So far, EMA has considered 82 applications, and the scheme is becoming a valuable tool for sponsors who manage to get their products into it. But not everyone can. EMA has granted PRIME status to just 19. And last week it reviewed another four applications, and turned them all down. They were able to provide non-clinical data and some exploratory clinical data – but not enough.

Recognizing the disenchantment this generates, EMA has also decided to hold a review meeting in London on May 19, bringing together drug firms, patients, healthcare professionals, academics, industry representatives and health technology assessment bodies. It will be looking for feedback from users and potential users of the scheme. And it will crucially provide information on how the rules on eligibility have been applied.

The squeeze at the other end of the authorization process affects rather more than four products. More like 300.

The EMA has recommended suspending a draft of medicines because of concerns over misrepresentation of bioequivalence study data, and deficiencies in documentation and data handling. The products, marketed by companies that include Mylan, Sandoz, Sanofi, and Orion have mostly been authorized through national procedures in the EU member states. But bioequivalence studies were conducted by a contract research organization in India - Micro Therapeutic Research Labs – and investigations have found that studies are unreliable because of problems in the way data and documents were managed at two of the CRO's sites. "Data from studies conducted at the sites between June 2012 and June 2016 are unreliable and cannot be accepted as a basis for marketing authorization in the EU," the EMA said.

Although "there is no evidence of harm or lack of effectiveness of medicines authorized", the EMA says they should be taken off the market until alternative data establishing bioequivalence is provided. As a gesture towards pragmatism, the EMA conceded that "national authorities can temporarily postpone the suspension in the interest of patients" if some of the medicines recommended for suspension are "of critical importance", because no alternatives are available. But the red flag is up, not just on Micro Therapeutic Research Labs, but on the probity of CROs everywhere. And not just on bioequivalence studies. These concerns came to light in the wake of identified problems with compliance with good clinical practice at the CRO. Inspectors are going to be redoubling their scrutiny just as the sifting process becomes finer and more demanding at the downstream end of drug development too.

Peter O’Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.