Regulatory news - April 2017

Keep up to date with regulatory news from around the world with the Cell and Gene Therapy Catapult regulatory newsletter.


European Medicines Agency (EMA)

New framework published for collaboration with academia on human (and veterinary) medicines

As part of the EMA’s platform of stakeholder interactions, the agency recently published a formalised framework for interaction with academic institutions in an effort to increase academic engagement.

“This framework of collaboration takes into consideration both organisations and their representatives pursuing education and research in all fields relevant for regulatory activities, and operating primarily at European level. In particular, it addresses organisations such as public or private education establishments awarding academic degrees, public or private non-profit organisations entities whose primary mission is to pursue research, European research infrastructures, European research consortia, and European learned societies. National Competent Authorities will continue to play a central role in managing interaction with academia at national level.”

This new framework follows a targeted survey carried out by the agency last year as well as a dedicated workshop and includes four key objectives:

1. To raise awareness of the mandate and work of the European medicines regulatory network as a means to increase academia’s engagement and trust in the regulatory system that addresses society’s needs;

2. To promote and further develop the regulatory support to foster the translation of academic research into novel methodologies and medicinal products which meet the regulatory standards required to address patients’ and public and animal health’s needs;

3. To ensure that the best scientific expertise and academic research are available to support timely and effectively evidence generation, regulatory advice and guidance, and decision making in regulatory processes;

4. To work in collaboration with the regulatory network in developing regulatory science addressing e.g. novel approaches, novel endpoints, methodologies, adapting to scientific progress whilst affording appropriate patient safety.

Upon endorsement by EMA’s Management Board, the framework will be implemented based on the three year action plan.

The EMA has also recently developed a page on it’s website covering academic collaborations under the ‘Partners & networks’ tab which contains more information.

Click here to view the framework of collaboration.

EMA drafts updated guideline on handling multiplicity in clinical trials

Multiplicity of inferences can lead to unsubstantiated claims for the effectiveness of a new treatment based on an inflated rate of false positive conclusions. Once a clinical trial expands beyond having two treatment groups, one predefined null hypothesis and a single primary variable - or adds an interim analysis - developers should control for false positives.

The EMA first published its position on multiplicity in clinical trials in 2002, through a points to consider text. Different methods of control may lead to different conclusions and therefore the method used is dependent on the study circumstances. The latest guideline generally expands on topics covered in previous versions including interpretation of data from multiple secondary endpoints as well as drawing reliable conclusions from a subgroup analysis or from composite endpoints (multiple events treated as one endpoint). The document also incorporates advances in understanding since the first document was released 15 years ago, including a further section on multiplicity in estimation of treatment effects and accounting for new approaches in dose finding.

The draft guideline is out for consultation until 30 June 2017, click here to view it online.

Draft reflection paper; statistical methodology for comparison of quality attributes

The EMA frequently receives questions concerning the adequacy of inferential statistical approaches to compare critical quality attributes (CQA) for biosimilars or for determinatiing comparability of a particular biologic pre- and post-manufacturing change. In response, the agency has worked on producing a Reflection Paper with a potential of useful application in the context of the comparison of quality attributes.

The draft reflection paper published last month raises open issues from a methodological perspective related to quality comparison objectives, sampling strategies, sources of variability, acceptance ranges and statistical analysis approaches to conclude on the similarity of two drug products based on quality attribute data.

The overall objective of the paper however is to establish a framework and a common language to facilitate future discussion among stakeholders and to invite comments in relation to the issues raised.

Click here to view the draft reflection paper, out for consultation until March 2018.

Final report on joint EMA-FDA QbD pilot program

In March 2011, the EMA and FDA launched a joint pilot program for the parallel assessment of applications containing Quality by Design (QbD) elements; an approach that aims to ensure the quality of medicines by employing statistical, analytical and risk-management methodology in design, development and manufacturing. The pilot aimed to share knowledge, support consistent implementation of quality by design concepts and promote the availability of medicines of consistent quality throughout the EU and the US.

More specifically, the programme facilitated the implementation of concepts introduced in the International Council for Harmonisation (ICH) Q8, Q9 and Q10 documents. In total, two Marketing Authorisation Applications (MAA)/New Drug Applications (NDA), three variation/supplements and nine scientific advice applications were evaluated under this program. Based on the learnings, FDA and EMA jointly developed and published three sets of Question and Answer (Q&A) documents.

The report goes onto say:

“The FDA/EMA QbD pilot program opened up a platform for continuous dialogue which may lead to further communication on areas of mutual interest to continue the Agencies’ support for innovation and global development of medicines of high quality for the benefit of patients.”

Interestingly, the document then goes on to say that;

“Both agencies are currently exploring potential joint activities with specific focus on continuous manufacturing, additional emerging technologies, and expedited/accelerated assessments (e.g. PRIME, Breakthrough).”

Click here to view the joint EMA-FDA report.

Good clinical practice (GCP) draft guideline on trial master file (TMF) released for public consultation

The EMA has published a new draft guideline for public consultation to assist sponsors and investigators in complying with the requirements of the new Clinical Trials Regulation (EU) No 536/2014, concerning the trial master file (TMF). The TMF contains the essential documents that facilitate the conduct and management of a clinical trial and may be subject to regulatory agency oversight.

ICH-GCP lists the documentation which is considered essential in section E6 which will already be familiar to sponsors including the Investigator’s Brochure, Clinical Protocol and Informed Consent Forms. However, the guidance also includes some further documents not included in ICH GCP E6 which it would consider essential:

  • Forms, checklists and reports etc. generated from following quality system procedures
  • QP certification of the IMP
  • Assay method validation report for analysis of IMP or metabolite(s) in clinical samples
  • ATIMP traceability records
  • Documentation to demonstrate validation of trial-specific builds of computer systems (e.g. e-CRF 199 and IRT).

For ATIMPs (Advanced Therapy Investigational Medicinal Products), the study sponsor, the tissue establishments/procurement organisation, the manufacturer and the investigator/institution where the ATIMP is used, should keep their parts of the traceability records for a minimum of 30 years after the expiry date of the product. This includes the relevant documentation contained in the sponsor and investigator TMF as well as the trial subjects’ medical records.

Beyond the guidance on structure and content of the TMF, the document includes sections on security and control, scanning or transfers of data and inspection readiness.

Click here to view the draft consultation.



GMP inspection deficiency data trends for 2016 published

Last month the MHRA published an overview of it’s inspection deficiency trends for 2016 with a view to allowing stakeholders to perform their own assessments against the findings as part of self-inspection and continuous improvement.

The MHRA carried out 324 inspections in 2016, 21 more than in 2015 with 82 of these on manufacturing sites overseas. In a repeat of the preceeding year, the most common deficiency issues by a large margin related to companies’ quality systems. This was followed by sterility assurance which interestingly, did not appear in the MHRA’s top 10 deficiences in 2015.

The 100-page report offers a number of deficiency examples related to corrective and preventive action (CAPA), staff training, a lack of management oversight of pharmaceutical quality systems, equipment issues, temperature-controlled storage facilities, and document control and completion, among others.

Click here to view the MHRA GMP Inspection Deficiency Data Trend for 2016.

MHRA releases 2017/18 strategy with a focus on preparing for post-Brexit activity

The UK MHRA has published its detailed business plan for 2017-18 whch includes the agency’s top ten strategic objectives for the year.

These include:

  1. Develop a proposed model for future regulation of medicines and medical devices in the UK, post-Brexit
  2. Develop an international and enhanced national strategy for collaboration and engagement with key partners and stakeholders
  3. Develop the next five year corporate plan for the Agency
  4. Play a key role contributing to the Government’s Life Science Strategy
  5. Expand the Clinical Practice Research Datalink (CPRD) further to support research and innovation
  6. Deliver the new Patient Safety and Vigilance Strategy
  7. Secure global supply chains for medicines and medical devices
  8. Deliver our operational transformation programme
  9. Secure sustainable funding for medical devices regulation
  10. Make the Agency a good place to work for our staff and manage a seamless transition to our new accommodation at the Government Hub at Canary Wharf in 2018

As expected, progressing a post-Brexit strategy is a high priority for the agency.

Our aim, post-Brexit, is to develop a world-leading, financially stable, medicines and medical devices regulatory system that gives patients timely access to safe, effective medicines and supports a flourishing life sciences sector.”

The model will aim to protect public health, facilitate innovation, minimise burden on industry and make the UK an attractive global regulator. The main compenents to achieve this are related to Brexit negotiation, european engagement and stakeholder communication as well as ensuring optimal strategies for regulation and commercial development in the UK.

Whilst Brexit planning takes central stage, the agency has confirmed its commitment to its role within Europe which including:

  • Implementing existing EU legislation
  • Influencing / leading work within the EMA, taking a leading role in the development of Co-ordinated Clinical Trial assessment in Europe for multiple Member State Clinical Trials
  • Contributing to the EU regulatory network throughout the year, ensuring that we remain within the upper quartile in our contributions to (co) rapporteurship appointments, scientific advice appointments and the preferred Reference Member State (RMS) for DCP (decentralised procedure) work in cases where the UK is involved, and remain actively involved with the various EU committees

Click here to view the UK MHRA business plan for 2017-2018.

Australia (TGA)

TGA progresses orphan drug program following consultation period

The Therapeutic Goods Administration (TGA) which is responsible for regulating medicines, devices, blood and tissue products has released feedback it received in response to the orphan drug program consultation in October 2016. The agency had 39 responses of which 20 were affiliated with the pharmaceutical industry, 10 from consumer, industry or health profressional bodies and 9 from individuals.

The program aims to align more closely with the European Medicines Agency’s criteria for orphan designation. This includes raising the population threshold for a rare disease to 5 in 10,000 from a more restrictive threshold of 2000 Australians (approximately a 6-fold increase) as well as taking into account the seriousness of the condition when making designations and requiring sponsors to demonstrate significant benefit over existing treatment options.

Click here to view the submissions received by the TGA and the agency response.

Public consultations