For many years we’ve taken an active interest in the time required by regulatory authorities globally to approve orphan drugs. Clearly this kind of activity is required for forecasting and planning, but it also helps in communications to give our broader audience a realistic idea of the timelines ahead and some of the hurdles we may face.
Predicting timelines in drug development is an imprecise business fraught – each case or drug needs to be indivudally assessed, there are no comparables – but it is nonetheless one method by which we can anticipate the period of time required before any decision from the European Medicines Agency (EMA) is published.
The EMA has a set process by which orphan drugs are evaluated. Following an orphan designation in Europe – the recognition that a drug may have the potential to treat a rare disease – the EMA will use the Centralised Procedure (CP) to review the drug’s marketing authorisation application (MAA). Under the CP, two ‘co-rapporteurs’ are appointed to review the complete dossier. These are individuals within two of the recognised national EMA authorities (such as ANSM in France, BfARM in Germany, MHRA in the UK and AIFA in Italy) who act as the central contact points for the EMA’s review.
These two individuals (or, more specifically, the agencies they represent) review the dossier in-depth and ask questions of a company along the way on behalf of all EMA agencies represented. The process then follows a set of formal steps, running to a 210 day ‘clock’ in a standard review:
- Validation. Once a MAA dossier is submitted, the first step is to ‘validate’ all the documents in the dossier to ensure they are present and have been formatted according to the EMA’s requirements. This usually takes 1-2 months (but can take longer if there are serious errors or omissions).
- Clock start and initial review. Following validation, the EMA gives the co-rapporteurs 120 days to perform and initial review of the dossier. After 80 days, an Assessment Report is submitted to the sponsor, with a list of unofficial questions which have already been raised by the dossier. At day 120 the co-rapporteurs submit an official list of questions to the sponsor, raising key issues within the dossier, including any found during inspections of manufacturing, non-clinical and clinical study sites.
- Clock stop and up to six month response time. At day 120 the official clock is ‘stopped’ and the sponsor is given three months to respond to all questions submitted by the co-rapporteurs. A further three months can be given..
- Clock start and 60 day review. Once the sponsor has responded, the clock restarts (day 121) and the EMA has a further 60 days to review the response and raise any outstanding issues.
- Clock stop at day 180 and up to three month response time. At day 180 the clock is stopped again when the EMA raises further questions. At this point the EMA can also request an oral explanation of the sponsor – to present before a panel of regulatory authorities and medical experts and discuss the MAA dossier. The sponsor is given up to 3 months to prepare their response (whether in writing or for an Oral Explanation meeting).
- Clock start and preparation of CHMP opinion. When the response is delivered by the sponsor, the clock starts again at day 181 and the EMA’s Committee for Medicinal Products for Human Use (CHMP) is given 30 days to prepare a final opinion on the product’s dossier; the final hurdle to EMA approval. The CHMP can issue one of three opinions: approval, conditional approval and rejection (a negative opinion). An approval may also occur with ‘Exceptional circumstances’ – a situation where data may not prove that a drug is safe and effective beyond all doubt, but recognises that this may not be possible and places further obligations on a sponsor following an approval (16 of the 65 orphan drugs approved by the EMA1 have been approved with Exceptional circumstances).
One final step exists, however, once the CHMP approves a drug, which is to forward the opinion in all languages of the European Union to the European Commission to adopt the drug under relevant laws, finally allowing its marketing across Europe. For orphan drugs this final step can take as little as 48 days, but the reported average is about 88 days.
Next week I’ll look at some of the orphan drug approval statistics in greater depth to gain a sense of how long the approval process for SCENESSE® (afamelanotide) may take.
1 Refers to the 65 orphan drug European Public Assessment Reports (EPARs) available at time of writing for orphan drugs on the EMA’s website. Jakavi, a recently approved drug, is at the moment excluded from these numbers. I’ll explain this analysis process in greater depth next week.
“Skyline Brussel bij zonsondergang” posted to Flickr.com by Erasmushogeschool Brussels on January 7, 2009 <http://www.flickr.com/photos/erasmushogeschool/3179373114/>