European procedure for registration of medicines

The evaluation of medicines in the EU can be through single national submissions (in the first instance then a mutual review lead by the country who made the first assessment) but in the case of medicines of high importance like neurodegenerative disorders, paediatric medicines and those for rare disease it is normal that the medicines is registered Centrally. Here assessors from the National Agencies work together under the coordination of the European Medicines Agency to make an evaluation which is accepted across all countries in the EU. This is the Centralised Marketing Authorisation and it is issued by the European Commission on behalf of all Member States. In Iceland and Norway they participate closely in the review and will issue a National Licence once the European Marketing Authorisation is issued.

SPINRAZA (nusinersen) was approved in the US over an unprecedented few months of review. The FDA advised that this decision was based on a number of reasons: “The FDA granted this application fast track designation and priority review. The drug also received orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. The sponsor is receiving a rare paediatric disease priority review voucher under a program intended to encourage development of new drugs and biologics for the prevention and treatment of rare paediatric diseases.”

Also important to this decision was many years of working closely with the FDA through the efforts of the TreatNMD, Charities like CureSMA and most importantly the day to day interaction with families with SMA children and adults.

In a similar way the EMA has held a series of meetings closely working with TreatNMD and with SMA charities like SMA Europe and National groups. There is a good understanding of the need for treatments for SMA children and adults. However, there are differences to the legislation in the US and EU which mean specific steps need to be achieved before approval. These steps are advancing rapidly and if all questions raised by the Agency on the development of nusinersen can be met then approval maybe as soon as the second quarter of 2017.

In this review we look at some of the steps that have already taken place to accelerate the review and approval of nusinersen.

Orphan designation

Drugs for illnesses with a prevalence of less than 5 in 10,000 patients across the EU population can receive an Orphan Designation. As spinal muscular atrophy is a rare disease with a prevalence approximately 0.4 in 10,000 (20,000 people across the EU), nusinersen was granted an Orphan Designation.

This is important as it allows the company to seek advice (Protocol Assistance) and this allows the company to start to build the case for the assessment of the medicine. Experts from Europe will be involved in the assessment and advice given on the best way to study the medicines in clinical trials, which early studies are needed in cells or animal models as well as detailed guidance on issued related to manufacture and production.

Paediatric medicine

As these treatments are partially focused in children (though adult use is also expected), there are panels of European experts who work closely with the company to focus on the needs for studies in children as well as possible formulation development so that the drug can be used in children. A detailed Paediatric Investigation Plan will be developed with the EMA and experts across the EU to ensure that adequate data are provided on the safety and efficacy of the medicines especially in children.

Accelerated Assessment

To help companies with urgent new treatments for life threatening conditions like spinal muscular atrophy, there are processes in place to allow for the rapid assessment of the treatments by the EMA and experts across the EU. This accelerated assessment is part of the advantages from the European PRIME (Priority Medicines) scheme.

Nusinersen has been discussed with the EMA as a possible treatment needing accelerate assessment. This information is what is available in the public domain communication between the Agency and Company are confidential.

Highlights

• 8 November 2016 – Applications received for assessment by the Centralised Procedure.
• 17 November 2016 – CHMP referenced that nusinersen EMEA/H/C/004312 for the treatment of Spinal Muscular Atrophy (SMA) has been accepted for accelerated review.
• 5 January 2017 – CHMP Committee discussed nusinersen.
• 9 January 2017 – PRAC (Committee on the safety of medicines) had nusinersen on the agenda as part of the accelerated review.
• 16 January 2017 – COMP (Committee for Orphan Medicines) had nusinersen on the agenda for discussion.
• 23- 26 January 2017 – CHMP had nusinersen on the agenda for the adoption of a list of questions that would be sent to the company to answer as quickly as possible. If this is sent across to the company there is a “clock stop” as the assessment by the Agency is held until the company responds. This may be few weeks or longer depending on the complexity of the questions though as an accelerated review the pressure will be on the company to address these questions as quickly as possible.

Once the responses have been received the clock will be switched back on as the Agency will review the responses to see if the concerns have been addressed. It is difficult to determine how soon a decision would be issued by the EMA (CHMP Positive Decision) that allows the application to go to the European Commission for formal issue of the Marketing Authorisation. If the responses are quickly provided in February and the Agency is happy with the company’s responses there is a chance that the product will be for review again end March – April which could mean that a decision is sent to European Commission for issue of the Marketing Authorisation. This would be one of the quickest reviews on record and as explained based on the many years of discussion with the EMA and EU Experts before the submission was made.