Regulatory news - May 2016

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EMA news

EMA announces 8th annual European Network of Paediatric Research workshop on 2 June 2016

On 2 June 2016, the “European Network of Paediatric Research at the European Medicines Agency” (Enpr-EMA) will hold its 8th annual workshop at the European Medicines Agency’s (EMA) London offices.

Specific legislation applies to the development of paediatric medicines in recognition of the fact that clinical protocols need to be tailored to these patients rather than them being treated according to an adult trial protocol. In the European Union, the Paediatric Investigation Plan (PIP) procedure is the mechanism by which clinical trials in children and adolescent patients are authorised, and there is a legal requirement for a PIP to be agreed by the EMA’s Paediatric Committee (PDCO) before a paediatric clinical trial can begin. The role of Enpr-EMA is to bring together research networks, investigators and centres in Europe with recognised expertise in performing paediatric clinical studies in accordance with the legislation such that more medicines are authorised for use in children.

According to the press release on the EMA website, the first day of the workshop will be open to all stakeholders including patients/parents organisations, regulators, Enpr-EMA network representatives, academia, clinical investigators and representatives from the pharmaceutical industry for paediatric studies. This will include a panel debate on how the ethical aspects of paediatric clinical studies will be handled in the context of the implementation of the new European Union Clinical Trial Regulation.

The second day of the workshop will involve discussions between the members of Enpr-EMA and the Enpr-EMA coordinating group to define priorities for 2016-2017.

Registration for the first day of the workshop is open until 24 May via the EMA website.

CAT publishes minutes of February 2016 meeting and March 2016 monthly report

Within the European Medicines Agency (EMA), the Committee for Advanced Therapies (CAT) is the expert committee with responsibility for the scientific evaluation of Advanced Therapy Medicinal Products (ATMPs). In this role, the CAT provides input into a number of EMA procedures, including, among others:

  • Evaluation of marketing authorisation applications (MAAs) with the Committee for Medicinal Products for Human Use (CHMP);
  • Scientific Advice with the CHMP and Scientific Advice Working Party (SAWP);
  • Innovation Task Force (ITF) meetings (early dialogue ahead of formal scientific advice);
  • Orphan Drug Designation with the Committee for Orphan Medicinal Products (COMP);
  • Evaluation of Paediatric Investigation Plans (PIPs) with the Paediatric Committee (PDCO).

The CAT is also uniquely responsible for certain procedures, including ATMP Classification and certification of quality and nonclinical data for SMEs developing ATMPs.

CAT members meet monthly and minutes and reports of their meetings are published afterwards on the CAT website.

Minutes of CAT meetings are made available online following approval which always takes place during the next CAT meeting. Therefore, CAT monthly reports are always published ahead of the minutes for any one monthly meeting.

CAT meeting minutes February 2016

February 2016 minutes cover information of CAT decisions including:

  • Day 180 list of outstanding issues for GSK’s ADA-SCID autologous CD34+ cells transduced with retroviral vector (Strimvelis; note that this product has subsequently received a positive opinion from the CHMP);
  • Adoption of post-authorisation activities for Glybera;
  • Scientific Recommendations on Classification of ATMPs (four new requests, six day 30 first reports, two day 60 revised reports, seven finalisations of procedures);
  • Organisational, regulatory and methodological matters.

Below are highlighted some of the topics referring to procedural guidance and interactions of CAT drafting groups with associated working parties:

Mandate and organisation of the CAT

The update/revision of the guidance document “Procedural advice on the evaluation of ATMPs (EMEA/630043/2008)” was discussed. This document covers procedural advice for pre- and post-authorisation activities and for re-examination.

Cooperation within EU regulatory network

Following the first February update between the CAT drafting group and the GMP inspectors working group, scheduling of a second virtual drafting group was noted for information. The sections that will be discussed will cover premises and equipment.

Orphan similarity for ATMPs was discussed on the basis of comparison between the pharmaceutical concept of “similar active substance” and the designation criteria for “similar medicinal product” and “clinical superiority”. In particular, the report states that “for (cell-based) ATMPs, it is felt that it will not be possible to work on basis of the Principal Molecular Structural Features (PMSF): for these complex products, the PMSF cannot be defined. For the determination of orphan similarity of two ATMPs, the proposal is to take into consideration the structural and functional characteristics that (could) have an impact on the biological activity of the product.”

National requirements for licensed medicinal products containing microorganisms (GMOs) were discussed and it was confirmed that for storage, culture, transport, destruction, disposal and use of GMO-containing authorised products, there could not be national requirements related to release in the environment as laid down in Directive Dir/2009/41/EC. Consequently, “there should be no reference in SmPC (see this link for more details) of authorised medicines to National requirements for biological safety with regards to GMOs”. However, the situation is different for GMOs evaluated in clinical trials, as “there is no similar derogation from the GMO directive, so national approval for deliberate release in the environment is necessary”.

Cooperation with international regulators

An ATMP cluster teleconference with the United States and Canadian competent authorities (FDA and Health Canada) was scheduled for 22 March.

CAT minutes of the 79th meeting which was held on 18–19 February 2016 were published on 23 March 2016. The document can be found here.

CAT monthly report for March 2016

The CAT publishes metrics relating to its activities each month in a monthly report on the CAT website. The CAT Monthly Report includes information on the following:

  • Recommendations for, or the refusal of, marketing authorisations for ATMPs. Of note, the March 2016 report includes a recommendation for granting marketing authorisation to a paediatric gene therapy medicinal product for the treatment of ADA-SCID, Strimvelis, which was then issued a positive opinion by the CHMP (as detailed in the minutes of the February meeting above);
  • Recommendations on ATMP classifications;
  • Organisation, regulatory and methodological matters (for example, input into the development of new/revised scientific guidelines and regulatory procedures);
  • Numbers of procedures (ongoing and completed MAAs, variations for authorised ATMPs, ATMP classifications, SME certifications, Scientific Advice for ATMPs, PIPs for ATMPs).

The CAT monthly report for March was published on 31 March 2016 following the CAT’s 80th meeting on 22–23 February 2016.

The full report can be found here.

EMA publishes draft reflection paper on development of paediatric medicines

The European Medicines Agency (EMA) has published a preliminary draft reflection paper outlining how clinical trial data from adults can be extrapolated to children to support the authorisation of new paediatric medicines

Specific legislation applies to the development of paediatric medicines in recognition of the fact that clinical protocols need to be tailored to these patients rather than them being treated according to an adult trial protocol. In the European Union, the Paediatric Investigation Plan (PIP) procedure is the mechanism by which clinical trials in children and adolescent patients are authorised, and there is a legal requirement for a PIP to be agreed by the EMA’s Paediatric Committee (PDCO) before a paediatric clinical trial can begin. The draft reflection paper is being developed to investigate how available data from adult clinical trials can be used most effectively, by extrapolation, to develop paediatric medicines.

According to the EMA press release, “the draft reflection paper outlines a systematic approach to extrapolation of data from adults or other paediatric populations to children that is considered scientifically sound and reliable to support the authorisation of a medicine. The framework sets out when, to what extent, and how extrapolation can be applied and validated.

The principal steps of the extrapolation framework are:

  • Extrapolation concept: this consists of a systematic synthesis of all available data, including the use of modelling and simulation approaches, which aims to predict the differences with regard to pharmacokinetics/pharmacodynamics, disease progression, and clinical response to treatment between adults and children;
  • Extrapolation plan: this aims to propose optimal studies in the paediatric population in line with predictions identified by the extrapolation concept;
  • Confirmation and extrapolation: this phase aims to confirm the extrapolation concept on the basis of the data collected in children and adults. If the extrapolation concept cannot be fully confirmed, it should be updated and the extrapolation plan revised accordingly;
  • Mitigating uncertainty and risk: the limited data generated in the paediatric population may not be sufficient to resolve all uncertainties and assumptions of the extrapolation concept by the time of marketing authorisation. Additional follow-up data may be necessary to address uncertainties and to further evaluate assumptions. Measures to generate these data need to be proposed.”

The reflection paper has been drafted for discussion at an EMA workshop being held on 17–18 May 2016, specifically for the purposes of clarifying extrapolation of data from adult to paediatric clinical studies where scientific knowledge is fast evolving or experience is limited. Following the workshop, a final version of the draft reflection paper is expected to be released for public consultation by the end of July 2016. The workshop will be broadcast live on the EMA website.

EMA publishes draft guideline on medicinal product sterility: applicability to ATMPs

Many medicinal products for human and veterinary use must be sterile in their final formulation, but the method of assurance of sterility is dependent on the type of medicinal product being manufactured. For non-biological medicinal products, it may be possible to terminally-sterilise them by methods such as steam sterilisation, ionising radiation or sterile filtration without compromising their pharmaceutical activity. However, this is not possible for cell-based Advanced Therapy Medicinal Products (ATMPs) and so their sterility must be assured by aseptic processing. One aspect of this is encompassed by the Good Manufacturing Practice (GMP) requirements for sterile, biological medicinal products described in Annexes 1 and 2 of Eudralex Volume 4. In addition, medicinal product sterility must be demonstrated by appropriate sterility testing at appropriate points in the manufacturing process, with the tests being performed in accordance with European Pharmacopoeia (Ph. Eur.) methodology unless justified. Tests applicable to ATMPs are described in Ph. Eur. chapters 2.6.1, 2.6.27 and 5.1.

Although aseptic processing contributes significantly to the sterility of ATMPs, other precautions also need to be taken. In particular, the sterility of the raw materials and excipients used in the manufacturing process, and the container in which the final product is packaged, additionally need to be controlled. Sterile filtration can be used to prepare many of the raw materials and excipients used in ATMP manufacture, and if this is used then for regulatory submissions it is important to document that the methods used are validated and produce acceptable results. ATMPs must also be packaged in containers that have been sterilised according to a validated process.

The European Medicines Agency (EMA) has recently published a draft scientific guideline on “the sterilisation of the medicinal product, active substance, excipient and primary container”.

Although much of the content is applicable to those medicinal products which can be terminally sterilised, it does contain sections on aseptic processing (applicable to ATMP manufacturing processes), sterile filtration (applicable to raw materials) and physical sterilisation methods applicable to containers. that not only should sterile filtration methodology used for raw materials be performed in accordance with Ph. Eur., but bioburden testing should also be performed pre-filtration to ensure that the sterilisation method used is capable of clearing the bioburden (“the population of viable microorganisms in a product prior to sterilisation”) to acceptable limits. In this respect, the recommendations of another EMA scientific guideline, “Manufacture of the finished dosage form” (currently under revision), are applicable.

The draft scientific guideline on the sterilisation of the medicinal product, active substance, excipient and primary container has been published through an open consultation procedure which allows interested parties to comment on the content and suitability of the guideline up until 13 October 2016. See the EMA website for more details.

EMA-EUnetHTA collaboration publishes report of joint 2012-2015 work plan

The outcome of the 3-year collaboration between the European Medicines Agency (EMA) and the European network for Health Technology Assessment (EUnetHTA) has been announced online through a joint press release earlier this month.

EUnetHTA is an established network for scientific cooperation to produce Health Technology Assessment (HTA) procedures in the European Union. It is composed of organisations from EU Member States, EEA and accession countries, and a large number of relevant regional agencies and not-for-profit organisations.

The overall aim of the EMA–EUnetHTA work plan was to integrate regulatory evaluation and health technology assessment throughout the lifecycle of medicinal products developed within the European Union. The initiative paralleled the ongoing synergistic activities between EMA and HTA to accelerate new medicine commercialization and is expected to continue its activities to further expand areas for cooperation, which will include aspects on marketing authorisation applications, improvement of regulatory reports in support of later HTA, and generation of scientific guidelines on the design of specific clinical development studies.

Between November 2012 and December 2015, EUnetHTA has finalised 15 joint assessments which are the output of collaborative efforts with EMA to prepare shared products or agreed outcomes.

A number of key achievements obtained in the 3-year cooperation programme are highlighted in the press release, and they include:

  • Joint regulatory/HTA scientific advice and early dialogue for medicine developers to reduce duplication and to streamline and optimise the whole medicine development process for the benefit of patients;
  • Improved EMA assessment reports (in the form of EPARs – an explanation on EPARs is can be found at this link on our blog) to address the needs of HTA bodies;
  • Approaches for collection of robust data post-authorisation (which need to be performed according to European scientific guidelines as previously covered in our blog);
  • Facilitating EUnetHTA’s pilot projects on rapid relative effectiveness assessment of pharmaceuticals;
  • Discussion on the therapeutic indication for medicines.

With no doubt, the European Union ATMP development and commercialisation sector will tremendously benefit from initiatives which aim to foster and affirm collaborations between regulatory agency bodies and HTA networks, such as the EMA–EUnetHTA synergy.

The complete final report can be found here.

PROTECT project publishes key findings for improved safety of European patients

The Innovative Medicine Initiative (IMI)-funded Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) project was established with the main aim to improve patient protection through the assessment of the benefit–risk of medicinal products approved in the European Union throughout their life-cycle. IMI is the largest public-private initiative present in the European Union aiming to accelerate the development of better and safer medicinal products through collaborative research projects and the generation of industrial and academic networks.

The PROTECT project was coordinated by EMA and GSK from September 2009 to June 2015 and within this period it produced a consistent amount of scientific research across the European Union. All material is available online on the PROTECT website and on the PROTECT benefit-risk website. Additionally, some of the key findings (covering topics such as framework for pharmacoepidemiology studies, identification of methods for signal detection and new methods for direct data collection from patients, benefit-risk integration and representations and replication studies) have already been published in peer-reviewed medical journals and results of the PROTECT project are being implemented in routine pharmacovigilance and regulatory practice.

EMA has recently announced that a final document with key findings and recommendations of the project has been published. The EMA press release contains links to the scientific papers on the main recommendations from the project studies.

The EMA document containing a description of the main results of the PROTECT project can be found here.

Other EU news

European Commission Publishes Quality and Safety Standards for Human Blood, Tissues and Cells

On the 26th April 2016, the European Commission (EC) published two reports on the implementation of the European Union (EU) Directives that set the standards for the quality and safety of human blood (2002/98/EC) and human tissues and cells (2004/23/EC).

Donation of human blood or human tissues and cells should be voluntary and unpaid in all EU Member States. The aim of such Voluntary and Unpaid Donation (VUD) is to contribute to higher safety standards and therefore protect human health. The EC reports show that VUD has been encouraged and Member States are in compliance with the directives, however the report highlighted a number of differences across the EU regarding compensation and incentives. Twenty-seven of the Member States provided refreshments to donors, 24 gave small tokens such as badges and pens, and around half of the Member States had travel costs reimbursed.

The reports demonstrate adequate compliance with the quality and safety requirements of the Directives by the EU Member States and EEA countries. There has also been significant progress made in many areas, which has been largely supported by EC funded projects and other initiatives. Projects such as EUBIS, DOMAINE, Optimal Blood Use, EUSTITE and SOHO V&S have provided support to Member States to help implement the requirements of the Blood and Tissue and Cells Directives. These actions have brought improvements in quality management and inspection, donor selection, development of guidelines and manuals, and also led to training courses for Member State Competent Authorities and their inspectors.

The reports highlight discrepancies in the way the directives have been implemented in the various member states in areas such as protection of donors, Competent Authority inspections framework, testing, and deferral criteria for new epidemiological and technological developments. The EC suggested that a further in-depth evaluation of the legal framework may be useful.

The full press release can be found here.

European Commission Publishes Results of it’s Blood Donor Testing Requirements Mapping Exercise 2015

On 22 April 2016, the European Commission (EC) published the results of a 2015 mapping exercise to compare blood donor testing requirements across European Union Member States.

European Directive 2004/33/EC defines the technical requirements to meet the quality and safety standards for the collection, testing, processing, storage and distribution of blood. This directive allows Member States to adopt more stringent measures into their national legislation as required, and for some member states these measures are defined by national standards.

However, stakeholders have suggested that introducing more stringent measures could create barriers when sharing blood and blood components between Member States. They can also pose challenges when distributing medicinal products derived from blood.

To provide greater clarity and transparency on these issues, Member State competent authorities and the Directorate-General for Health and Food Safety (DG-SANTE) agreed to map the more stringent donor testing measures and make the mapping results publicly available.

In 2015, a survey was completed by all Member State competent authorities. The preliminary data were presented on the 11th of November 2015 at the “Meeting of the Competent Authorities on Blood and Blood Components”.

This was then clarified, verified with the competent authorities and then organised into individual country sheets. The data have also been combined into one overview sheet.

The full press release can be found here.

Currently Open Consultations

European Medicines Agency
Start dateTitleWebsiteEnd date
13 April 2016Draft guideline on the sterilisation of the medicinal product, active substance, excipient and primary container

More information

13 October 2016
29 February 2016Guideline on good pharmacovigilance practices (GVP) 3 - Module V – Risk management systems (Rev 2)More information31 May 2016
29 February 2016Draft guidance on format of the risk management plan (RMP) in the EU – in integrated formatMore information31 May 2016