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European drug applications 'stable but more complex in 2012'

Despite austerity measures, EMA's annual report shows signs of biopharma resilience

Pharma regulatory 

The European Medicines Agency (EMA) saw the number of marketing authorisation applications (MAAs) it received in 2012 stay pretty much in line with the previous year, with an uptick in the complexity of new submissions.

The maintained rate of applications came despite ongoing austerity in the EU and increased public scrutiny of areas such as conflict of interest and transparency, according to the regulator's chief executive Prof Guido Rasi.

The EMA annual report for the year was published last week and it reveals there were 96 MAAs in 2012, compared to 91 in 2010 and 100 in 2011, and the agency issued 59 positive opinions for new human medicines, suggesting that the drug industry is at least maintaining its R&D output despite the tough operating environment in Europe.

One of the main highlights of the year was the EMA's first approval for a gene therapy, namely UniQure's Glybera (alipogene tiparvovec) for the treatment of patients diagnosed with lipoprotein lipase deficiency who suffer severe or multiple pancreatitis attacks. 

Glybera uses an adeno-associated virus (AAV) vector to deliver working copies of the LPL gene into muscle cells to enable production of the enzyme in cells, and the EMA report notes that its review was challenging with a green light eventually given for a more restricted patient population than originally sought.

Nevertheless "the lessons learnt from this case are multiple and pave the way for approval of similarly complex medicines in the future, as more gene therapies for rare diseases, personalised medicines and nanomedicines are on their way," says the agency.

Adaptive regulation

One of the main messages gleaned from the Glybera review process was the need for an evolving, adaptive regulatory framework that can introduce different degrees of licensing beyond the approved/not approved system used at present.

"The agency is committed to exploring new ways that would facilitate timely access to innovative treatments," says the report, adding: "progressive marketing authorisation is an option mentioned in the … road map for 2015."

The trend towards greater complexity observed during the year was also shown in a significant increase in the number of applications for orphan drugs used to treat rare diseases, with an 18 per cent increase over 2011 to 19 MAAs and a 25 per cent increase in positive opinions issued by the Committee for Orphan Medicinal Products (COMP).

Among those backed by the COMP last year was Vertex Pharma's Kalydeco (ivacaftor), which is designed to cystic fibrosis by restoring the function of a defective protein called CFTR and is the first therapy to address the underlying mechanism of CF, and Takeda's Revestive (teduglutide) for treating adults with a rare but debilitating condition known as short bowel syndrome.

Given the increasing complexity of applications, it is perhaps unsurprising that average assessment times for MAAs lengthened to 188 days from 179 days in 2011 and 167 days in 2010, although a reduction in the number of applications for generic drugs also played a part. 

There was also an increase in the duration of 'clock stops' - prompted by requests for clarifying or additional data from applicants - which are not counted to the EMA's commitment to review applications in 210 days.

More than two thirds (68 per cent) of orphan applications were submitted by small and medium-sized enterprises (SMEs), and there was a healthy rise in the number of SMEs interacting with the EMA, with more than 1,050 businesses on its books in 2012, a rise of 58 per cent over the prior year.

Once again, the increased activity among smaller companies suggests that suggestions the EU biopharma sector is in decline may be premature.

In fact, it was notable that in 2012 - for the first time - an SME submitted a request for EMA qualification of a biomarker to support clinical development of its medicinal product. Overall there was an increase in proportion of SME's seeking advice from the agency ahead of filing an MAA, reaching 64 per cent of applicants versus 41 per cent in previous years.


One of the biggest changes faced by the EMA last year was the introduction of the EU's new directive on pharmacovigilance, which required the creation of a new Pharmacovigilance Risk Assessment Committee (PRAC) and other initiatives such as the creation of the first EU database of all authorised medicines - which by the end of the year had 300,000 entries - and the formulation of guidelines on good pharmacovigilance practices.

The year was also marked by the start of the first infringement investigation against a pharma company (Roche) for allegedly failing to comply with pharmacovigilance obligations.

In 2012 the total number of adverse drug reaction (ADR) reports received was up by a third over 2011, with a marked increase (60 per cent) for those coming from areas outside Europe. The rise is attributed to an increased commitment of stakeholders in the healthcare sector to provide ADR data.

There was also increased evidence that companies are starting to embrace risk-management principles in the MAAs in accord with the new directive, with a 24 per cent hike in the number of applications including risk-management plans.

More activity in this area is expected, as earlier this year the EMA unveiled plans to produce new guidance on patient reported outcomes, improve its analysis and understanding of data and information, and increase the coordination of pharmacovigilance inspections.

Meanwhile, 2013 is shaping up to be equally challenging for the regulator as it gears up for the implementation of the falsified medicines directive and, in particular, the introduction of tighter controls on active pharmaceutical ingredient (API) imports.

22nd April 2013

From: Sales, Regulatory



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