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Focus on Regulation

EMA publishes draft Guideline on clinical investigation of haemophilia B medicinal products


The EMA has published a draft Guideline on clinical investigation of recombinant and human plasma-derived factor IX products.[1] The purpose of this guideline is to provide applicants and regulators with harmonised requirements for applications for marketing authorisation of haemophilia B medicinal products. In July, a similar guideline was adopted concerning haemophilia A medicinal products.

The draft describes data that needs to be collected during clinical trials for a haemophilia B medicinal product prior to application for an application for Marketing Authorisation (MA).

The data described in the draft is necessary for new medicinal products and for medicinal products that are subject to a significant change in the manufacturing process. The draft introduces general principles on efficacy and safety. It also provides that some of the principles formulated could also apply to non-factor replacement therapies used to treat an underlying deficiency.

In non-factor replacement therapies, the haemophilia B is not treated directly with factor IX. An underlying condition, such as the patient developing inhibitors, is addressed through other medicinal products and therapies. Inhibitors can bind to factor concentrates preventing them from working and thus making the factor therapy less effective. The draft refers to the use of monoclonal antibodies and gene-therapy as examples for non-factor replacement therapies.


The draft

The draft provides information concerning which data to be collected and how collection should be made, to prove the efficacy of the medicinal product. It provides guidance regarding haemophilia B medicinal products and adverse events, safety with respect to viruses and other transmissible agents. The draft also provides guidance on immunogenicity and thrombogenicity.

In previous years it had become apparent to the EMA that the number of Previously Untreated Patients enrolled in clinical trials is too low and poses a challenge for manufacturers. The obligation to perform clinical trials with Previously Untreated Patients for marketing authorisation purposes has been deleted.

The draft further provides guidance regarding general aspects on the collection of clinical data for “new” marketing authorisations. This includes guidance concerning the minimum number of participants in a pre-authorisation trial. The minimum number of participants is to be 40 patients. The guideline acknowledges the limited availability of patients but considers this to be a relatively low number. Additional data on the medicinal product must, therefore, be gathered through post-marketing investigations.

Post-marketing data can be gathered by using patient disease registries. The EMA envisions an increased role for patient disease registries to collect clinical data. It launched an “Initiative for Patient Registries”. The EMA has launched a public consultation for a discussion paper that is to provide guidelines on the use of patient disease registries for regulator purposes. More information about this is available in our previous blog post.

Changes in the manufacturing process may alter the structure of the medicinal product’s activity. The possible effects of these changes on the medicinal product should be investigated. The draft also provides guidance regarding the collection of clinical data on medicinal products subject to significant changes in the manufacturing process.

 The draft further refers to the use of a risk management plant and provides three annexes. The first annex includes an overview of a clinical trial concept. The second annex provides an overview of patient population and trial parameters for an intended investigation goal, such as “safety” or “clinical efficacy”. The third annex provides more specific guidance on post-marketing investigations for haemophilia B.

 Consultation deadline

The draft will be open for public consultation until 30 June 2019.


[1]               The draft was agreed upon by the EMA’s Blood Products Working Party (BPWP) and Committee for Medicinal Products for Human Use (CHMP)