Welcome to our European Regulatory Roundup, our weekly overview of the top EU regulatory news.
EMA Creates Simplified Transfer Process for Some MAHs Affected by Brexit
The European Medicines Agency (EMA) has created a simplified process for transferring marketing authorizations in response to Brexit. The process is open to companies that want to move marketing authorizations between organizations registered under the same EudraVigilance headquarter profile.
EMA’s old advice on transferring product registrations assumed the former marketing authorization holder (MAH) and the new MAH were different entities. In this model, the original MAH invalidated the authorized medicinal product (AMP). The new MAH then reinstated the AMP. This process places multiple responsibilities on each MAH but ensures both parties have agreed to the transfer. MAHs must still follow this process when transferring AMPs to other companies.
However, in light of Brexit, the assumption that AMP transfers will involve two distinct entities is no longer valid. MAHs are moving AMPs from affiliates based in the United Kingdom to affiliates based in one of the other 27 member states to ensure they are compliant with the regulations when Brexit happens in March. The precautionary steps built into the normal transfer process are of less value to these companies.
Recognizing that, EMA has created a simplified process for internal transfers. The process eliminates several of the steps involved in transfers between companies. In the new process, MAHs change the authorization status, enter the new and old EV Codes and submit the information to transfer an AMP to an affiliate.
Updating details in EudraVigilance is just one part of moving a marketing authorization to another member state, and the time savings offered by the new process may be limited. However, with the industry needing to move thousands of authorizations, even small time savings can add up.
EMA presented the new process in updates to its detailed guidance on the electronic submission of information and a related document that answers questions submitted by industry. The updates include new information related to AMP transfers. Notably, the guidance explains that the Qualified Person Responsible For Pharmacovigilance must be registered at the affiliate that is receiving an AMP.
, XEVPRM User Guidance
EMA Adopts Factor VIII Guideline, Ending Need to Run Trials in Treatment-Naïve Patients
EMA has adopted a revised guideline on the clinical development of factor VIII products. The update eliminates the need for developers of the hemophilia drugs to enroll previously untreated patients in clinical trials.
Data on previously untreated patients used to be an essential component of filings for approval of factor VIII drugs. However, studies on the development of inhibitory antibodies in patients receiving factor VIII products for the first time led EMA to conclude its prior position was “problematic.” That led EMA to seek feedback on a revised approach late in 2017.
EMA has only made a few changes as a result of the consultation. Changes include the removal of ethnic background and genotype from the list of factors that influence inhibitor occurrence. EMA has also removed ethnicity from a subsequent list of factors to help classify the risk of developing factor VIII inhibitors, and from the information registries should gather. Type of gene mutation is still on the list of risk factors.
Other changes include the softening of the language around registries. The final guideline states patients “should be encouraged” to enroll in disease-specific registries. EMA has also amended the text to clarify that both previously untreated and treated patients are of value to registries.
EMA released the final guideline alongside a document on summary of product characteristics (SmPC) for factor VIII products that was also affected by its rethink on previously untreated patients.
Factor VIII Guideline
, SmPC Guideline
EMA Proposes Reducing Data Requirements for rG-CSF Biosimilars
EMA is planning to reduce the data requirements for developers of recombinant granulocyte colony stimulating factor (rG-CSF) biosimilars. The proposed changes echo broader shifts in EMA’s approach to biosimilars by reducing the need to run animal tests and clinical trials.
Backed by more than a decade of experience of regulating biosimilars, EMA has dropped some of the requirements it placed on developers in its original guidelines. Specifically, EMA adopted a risk-based approach to in-vivo
animal studies in a guideline on the development of biosimilar proteins, and gave companies the option to skip confirmatory clinical trials through an update to its overarching position on the sector.
Those changes have caused EMA’s broad biosimilar documents to diverge from the position set out in its rG-CSF guideline. To close the gap, EMA is proposing to update its guideline on medicinal products that contain rG-CSF.
The draft released for consultation states developers of rG-CSF products can show biosimilarity through physicochemical, functional, pharmacokinetic and pharmacodynamic comparisons with the reference product. EMA’s confidence in the validity of these comparisons means it has dropped the requirement for comparative efficacy trials.
EMA has also reconsidered its position on nonclinical data. While the adopted version mandates the use of in-vivo
rodent studies to compare the pharmacodynamics of a biosimilar and reference drug, the draft states in-vitro
tests are sufficient. EMA has previously said in-vitro
tests “are usually more specific and sensitive to detect differences between the biosimilar and the reference product.”
Other differences between the adopted and draft guidelines include the addition of considerations specific to pegylated rG-CSF. The adopted version refers to biosimilar filgrastim and lenograstim but lacks specific guidance for developers of pegylated products. EMA has addressed this shortcoming in the draft by detailing the different pharmacokinetic requirements for pegylated and non-pegylated products.
EMA is accepting feedback on the draft until 15 February.
EMA Updates Atorvastatin Product Information to Reflect Interaction with Antivirals
EMA has updated the product information for atorvastatin products following a safety review. The review found plasma levels of the drug, better known as Lipitor, increase when it is given alongside hepatitis C drugs sold by AbbVie and Merck.
There is long-standing evidence of the interaction between atorvastatin and antivirals, such as HIV protease inhibitors. The old product information for the lipid-lowering agent reflected this evidence.
More recently, EMA’s Pharmacovigilance Risk Assessment Committee has reviewed information from studies that analyzed the interaction between atorvastatin and the antivirals Mavyret and Zepatier. The studies found co-administering the drugs increases atorvastatin plasma concentrations, raising the risk of adverse events including the muscle disease myopathy.
The finding led EMA to revise the SmPC for atorvastatin. The revised SmPC states the statin is contraindicated in patients who are taking AbbVie’s Mavyret. EMA took a softer line on Merck’s Zepatier, merely limiting the dose of atorvastatin to 20 mg a day when it is administered alongside the hepatitis C drug.
has updated its post-authorization procedural advice for users of the centralized procedure to clarify that companies should give it six months notice when they plan to file an extension application. The agency wants the prior warning as the assessment of extension applications requires “significant” resources. EMA also wants six months’ notice before MAHs file some type II variations. EMA Advice
has adopted a revised guideline on the core SmPC for human albumin solution. In revising the text, EMA has removed a statement about the factors that influence the choice between albumin and artificial colloid. The revised guideline will come into force on 1 February. EMA Guideline