5th Annual Biopharmaceuticals Meeting Report 2015
Once again, Munich served as the host city for the 5th Annual Biopharmaceuticals Meeting on February 5-6, 2014, which gathered 110 participants from 16 countries that are actively involved in regulatory affairs of biopharmaceuticals. Participants were welcomed by Prof. Johannes Löwer, Past President of Paul-Ehrlich-Institut and Past President of BfArM, and Gabriele Dallmann, Study Director of EUCRAF who both chaired the meeting. A total of 11 agencies speakers presented key insights, concepts, and news on the rapidly changing regulatory environment. In addition, academic and pharma speakers presented on the recent developments in the industry, thereby successfully achieving the theme of the conference “What currently matters for Biopharmaceuticals”.
Prof. Joyce Tait delivered a thought provoking lecture entitled “Regulation and other factors influencing the development of biopharmaceuticals - The innovator’s perspective”. Prof. Tait is the Co-Director of the Centre for Social and Economic Research on Innovation in Genomics, also known as Innogen, and a professor at the University of Edinburgh. She has an interdisciplinary background in natural and social sciences covering technology development strategies in the chemical, pharmaceuticals and life science, translational medicine, governance, risk assessment, risk communication and regulation, policy analysis, stakeholder attitudes and influences. She started off by describing two approaches to innovation – the Disruptive Innovation and the Incremental Innovation. The Disruptive Innovation is an innovation that is usually not accommodated within a company’s current business model and the Incremental Innovation is the typical working business models of pharma industry. The main difference between the Disruptive and Incremental innovation is that there is no clear regulatory precedent in the disruptive innovation model whereas the incremental innovation is usually set on a clear regulatory precedent. It is important to identify at the early phase on the choice of regulatory system for a new area of pharma related development. Prof. Tait then spoke about how stratified medicine business model offers opportunities to the conventional business models to drive pharmaceutical R&D. She gave the audience a flavor of how this is applied at Innogen, where considerations were given to the complex collaboration, coordination and regulatory interactions for co-development of a therapy and diagnostic.
SESSION 1: ROUNDUP OF THE LAST YEAR ON REGULATORY ACTIVITIES IN EUROPE AND THE US
Christian K. Schneider is the Medical Head of Division Medicines Licensing and Availability at the Danish Medicines Authority. He is CHMP member and CHMP Working Party on Similar Biological Medicinal Products (BMWP) Chairman. Between 2009 and 2013 he was the Chairman of the Committee for Advanced Therapy (CAT). He gave us an update on the statistics of marketing authorization (MA) and development of recent guidelines at EMA. He mentioned about whether regulators would be in favor for a more staggered approval for situations not covered by conditional marketing authorization or marketing authorisation under exceptional circumstances and discussed whether this can be achieved via adaptive licensing, which was one of themes of last year’s European regulatory scene. Christian Schneider also shared his personal takes on the monthly highlights of CHMP recommendation of approval for biopharmaceuticals in the form of “biotech calendar of 2014” and this was really appreciated by the participants.
Sol Ruiz is one of the agency expert heavily involved in regulatory activities related to biological and advanced therapy medicinal products (ATMPs). She is the Head of Sector of Biotechnology and Advanced Therapies at the Spanish Medicines Agency. She is also the chair of the BWP (Biologics Working Party) at the EMA and the Spanish representative in the group since 1997, member of the CAT at EMA and a co-opted member of the CHMP since 2007. Sol Ruiz presented an update of ATMP in the EU and CAT activities. She elaborated on the challenges for the development of ATMP, requirements for marketing authorization, classification of ATMP and its implications, and ensuing commitments and follow up activities from CAT. She also highlighted additional guidances available at the EMA website. The EPAR of Glybera and ChondroCelect were discussed during her presentation.
SESSION 2: AN UPDATE ON THE PAEDIATRIC COMMITTEE (PDCO) ACTIVITIES
Dirk Mentzer is medical doctor and is the Chairperson of PDCO at EMA and he works at the Paul-Ehrlich-Institut (PEI) as Head of Section Pharmacovigilance. He gave an update on the most recent work by the PDCO. The overall trend shows that there is a growing number of marketing authorization applications submitted for paediatric indications. He noted that paediatric expert teams are now more commonly established in pharmaceutical companies and there is a growing interest in paediatric formulation development. In addition, there is an increase in clinical trial infrastructure, expanding paediatric pharmacological knowledge and frequent multilateral cooperation between stakeholders from industry, patients, academia and regulators. Dirk Mentzer listed several challenges within the paediatric research environment. As the 10-year report on the Paediatric Regulation is coming up, he proposed an opportunity for fine-tuning of the regulation in areas such as modification procedure of agreed PIP opinion and the pediatric reward system. There is a need for systematic and consistent approach to provide a framework and predictability for applicants and regulators at PDCO in the determination of the condition(s) for a Paediatric Investigation Plan or its waiver condition.
SESSION 3: BIOSIMILARS
Martine Weise is a member of the CHMP and Vice-chair of the CHMP-BMWP. She is the Head, Unit on Diabetes/Cardiovascular Disorders at the BfArM. She presented an update on the EMA Biosmilar Medicinal Products Working Party. As of January 2015, a total of 30 MAAs on biosimilar products were received by EMA. The highlights of the year 2014 for BMWP was the finalisation of 3 guidelines:
- Guideline on similar biological medicinal products (CHMP/437/04 Rev 1), adopted October 2014
- Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (EMA/CHMP/BWP/247713/2012), adopted May 2014; main work performed by BWP
- Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues (EMEA/CHMP/BMWP/42832/2005 Rev1), adopted December 2014.
Martine Weise spoke on the principle of extrapolation of indication in the comparability exercise of biosimilars. She highlighted that it is an established scientific and regulatory principle that has been exercised for years in the case of changes in manufacturing process of originator biologicals. Additional clinical studies have not been considered necessary by regulators or by the marketing authorization holders for changed product of other approved indications when extrapolation through additional functional data and scientific justification is sufficiently conducted. But when the change of product has an impact on safety and efficacy, additional clinical test may be required. Among the activities anticipated for 2015 is the revision of the biosimilar interferon-alfa and filgrastim guidelines, the immunogenicity guideline and the finalization of revision of the biosimilar insulin and low molecular weight heparin guidelines.
Steven Kozlowski is the Director of the Office of Biotechnology Products, Office of Pharmaceutical Science, at the Center for Drugs Evaluation and Research, FDA. He has been involved in all phases of the regulatory process as a reviewer, from pre-IND product development through inspections, licensing, and post-approval supplements. Dr. Kozlowski served as acting Director of the Division of Monoclonal Antibodies from 2004 to 2005. He has also served as an instructor and as an adjunct clinical reviewer at the FDA. He gave an update on biosimilars in the US. He explained how the FDA evaluation of biosimilarity must consider the product's manufacturing process complexity, expression system, structure of protein and its mechanism of action, the usefulness of biochemical and functional characterizations tools and how to incorporate these factors into a risk-based approach. FDA’s scientific evaluations and decisions are based on reducing residual uncertainty to an acceptable level in any given clinical setting. He mentioned the first biosimilar filgrastim by Sandoz recommended for approval in the US and that there are increasing number of applications under review. These include application for biosimilar of infliximab by Celltrion, biosimilar of pegfilgrastim by Apotex and biosimilar of epoetin alfa by Hospira. Steven Kozlowski added that in the coming future, the FDA intends to finalize the current six draft guidances and to develop the following new guidances:
- Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009
- Considerations in Demonstrating Interchangeability to a Reference Product
- Labeling for Biosimilar Biological Products
As part of FDA’s education initiative, the agency intends to reach out the stakeholders including other regulatory agencies through education working groups, webinars and presentations at professional society and clinical specialty meetings. Topics such as the tansition to biological products and interchangeability remains as issues that need to be further discussed.
Jian Wang is the chief of the Clinical Review Division in Centre for Evaluation of Radiopharmaceuticals & Biotherapeutics, Biologics and Genetic Therapies Directorate at Health Canada. His division has regulatory responsibility, including pre-submission consultations and premarket reviews, over the biological drugs for haematological, oncological, infectious, cardiovascular and renal diseases, radiopharmaceuticals, gene therapies, subsequent entry biologics (biosimilars) and therapeutic vaccines. He gave a Canadian perspective on the extrapolation of indications for biosimilar of infliximab. The Canadian regulatory decision to grant approval for part of the indications only as opposed to EMA’s decision to approve the biosimilar infliximab for all the indications as Remicade (reference product) was discussed. Health Canada could not recommend extrapolation pertaining to inflammatory bowel disease indications due to quality and clinical concerns. He mentioned that regulatory agencies may render different regulatory decisions based on the same data package for biosimilars as it has always been the case for other decisions in the past. The Health Canada’s decision is in line with the Canadian regulations. This topic has set off a lively debate during the panel discussion.
SESSION 4: HEALTH TECHNOLOGY ASSESSMENT (HTA)
Beate Schäfer has been working for more than 20 years in different areas of Regulatory Affairs and pharmaceutical Quality Assurance in national and European positions. Since 2011, she is the Head of Regulatory Sciences and Pharmaceutical Quality Assurance at Bristol-Myers Squibb Germany. She presented specifically on how the SmPC is understood by the HTA bodies and discussed practical examples in relation to the Act on the Reform of the Market for Medicinal Products (AMNOG) process in Germany. Beate Schäfer identified that there is a difference in the interpretation of the subpopulations in the dossier by the license holder and HTA body. Therefore, it is important to align data requirements from both regulators and HTA bodies. The definition of in-label population and how this is reflected in the SmPC was discussed in details.
Jan Mueller-Berghaus is a CHMP member and clinical assessor at the Paul-Ehrlich-Institut. He presented on what needs to be considered while making an indication in the target population and how it could be incorporated in the SmPc. He said that ultimately it is the perceived benefit/risk balance for the population that is described in section 4.1 of the SmPC. But he also acknowledged the importance to carefully consider the wording details of the indication as this has obviously significant impact on the decision of the HTA bodies later on.
SESSION 5: APPROVAL OF DRUG-DEVICE COMBINATION
Ilona Reischl joined the Austrian Medicines and Medical Devices Agency in March 2006 and currently holds the position of a Senior Expert in the Institute for Assessment and Analysis with a focus und the quality assessment of biological medicinal products including advanced therapy medicinal products. She is the Austrian member of the CAT and the BWP. She presented on the trend in marketing authorisation applications for biological covering drug-device combinations and how these are dealt with. The combination products pose legal, procedural and scientific issues. The classification determines the legal path and organization that takes the lead in authorisation. Ilona Reischl also posed a few important questions during her presentation: What is the timing required to comply with Medicial Device and Medical Product legislations? Which requirements apply to medical device for clinical investigation? What happens on the clinical trial level? Using several case studies, Ilona Reischl addressed these with clear examples and concluded that the drug-device combination dossier has to be adapted so that it can be reviewed by both the medical device and medical product assessors.
SESSION 6: UPDATE ON THE CLINICAL TRIAL REGULATION
Surendra Gokhale serves as Senior Group Manager in Global Regulatory Affairs at Roche in Basel. He leads the Clinical Trials regulatory management group, finding the alignment between different regional regulatory aspects in the EU, United States, Asia and Latin American countries, as well as global development plans. He is Roche’s representative on the Regulatory Affairs group (ERLC), and EU Clinical Trials subgroup of the European Pharmaceutical Association (EFPIA). He also represents Roche in the IFPMA Regulatory Group (RPTS), as well as the ICH M5 subgroup. In his presentation entitled “Preparedness for the Clinical Trial Regulation (CTR) in the EU – a company perspective”, he discussed key aspects of the implementation of the future EU CTR. Surendra Gokahle recognized that change may create uncertainty, but if managed will present itself as an opportunity for optimization. Indeed, the success of the Clinical Trial lies in the joint responsibility of the regulators, ethics committees and sponsors, which Gokhale defined as the ‘an opportunity to work together in the CTR implementation’. He presented from Roche’s experience an example roadmap on how to manage alignment of internal processes and avoid compliance gaps during the transition to the CTR.
SESSION 7: UPDATE ON THE PRAC ACTIVITIES
Doris Irene Stenver is the Chief Medical Officer at the Danish Health and Medicines Authority. She joined the Danish regulatory authority and the EU Pharmacovigilance Working Party in 1998. In 2002, she became member of the European Risk Management Strategy Facilitation Group. As of July 2012, she is member of the PRAC. Doris Irene Stenver spoke about the outcome of PRAC activities in the EU, the PRAC “toolkit”, referral procedures, periodic safety update reports, risk management plans, the EU signal management process and the Eudravigilance data as well as the post-authorization efficacy studies. The availability of wide range of tools help PRAC in all aspects of risk management activities, committing to proactivity, transparency and compliance with legal time frames. Biopharmaceuticals are particularly challenging from a safety perspective and this was indeed another take-home message of this meeting.
SESSION 8: SCIENCE AND STRATEGY OF DEVELOPMENT
Jennifer Sims has 25 years experience in preclinical drug development with an emphasis on biotechnology products (monoclonal antibodies, therapeutic proteins, vaccines, gene and cell therapies and xenotransplantation). She is the Past Vice Chair of the BioSafe leadership group and was the EFPIA topic leader and Rapporteur for ICH S6 revision. She presented the summary of the NC3R workshops held in June 2014. The NC3Rs is a UK-based scientific organisation dedicated to replacing, refining and reducing the use of animals in research and testing. A change in nonclinical testing paradigm is beginning to emerge. Jennifer Sims called for reduced and refined usage of animal models, with more careful evaluation of in vivo study designs, particularly with respect to its predictability in human. It is important to understand the limitations of species for predicting clinical effect in humans and opportunities for greater use of cell and tissue based technologies for mAbs should be encouraged. She presented how case studies were discussed during the NC3R workshop to illustrate whether it is eventually possible to phase out non human primates for safety testing of mAbs.
Michael Pfleiderer was another agency speaker present this year at the meeting. He is the Chairman of the Vaccine Working Party, Chairman of the Pandemic Task Force as well as Chairman of the CHMP/BWP Influenza ad hoc Working Group. He is the Head of the section reviewing virus vaccines at Paul-Ehrlich-Institut. He gave an overview on the currently discussed Ebola treatment options and presented how the EMA ad hock expert task group was created to identify the most appropriate regulatory pathway to ensure accelerated approval of potential Ebola treatment. Three vaccines candidates are currently under clinical evaluations. One of the key milestones is the initiation of phase 3 trials schedule in February – March 2015. There is a possibility that the early results of vaccine efficacy would be available by the 3rd quarter of 2015. In parallel with accumulation of efficacy data, the planning for large-scale use, including systems for vaccine financing, allocation and vaccine usage is going on concurrently.
SESSION 9: LOOKING AT OTHER REGIONS: CANADA
One of the meeting aims for this year was to look at regulatory development of different region outside of EU and Canada was selected for this session. Jian Wang presented on Health Canada (HC) Regulatory Framework and how it regulates biopharmaceuticals and biotech products and reviews submissions of drug approval application in Canada. Under the Health Products and Food Branch (HPFB) of Health Canada there are 7 operational Directorates with direct regulatory responsibilities: Therapeutic Products Directorate; Food Directorate; Biologics and Genetic Therapies Directorate; Natural Health Products Directorate; Marketed Health Products Directorate (with responsibility for post-market surveillance); HPFB Inspectorate and the Veterinary Drugs Directorate. Through its Therapeutic Products Directorate and the Biologics and Genetics Therapies Directorate, HC determines the initial approval and labelling of all prescription drugs. HC is one of few regulatory authorities that conducts independent evaluations for drug submissions according to Canadian regulatory requirement and guidance. HC is an active participant in the International Conference on Harmonization (ICH), is committed to the adoption and implementation of ICH guidances and standards. HC may consider FDA, EMA and WHO guidances for decision-making. HC also encourages the review staff to use foreign review documents to perform part of the evaluation or help with decisions.
SESSION 10: NEWS IN CMC OF BIOPHARMACEUTICALS
Steffen Gross is the Head of the section Monoclonal and Polyclonal Antibodies, Laboratory Head as well as Scientific Assessor at the Paul-Ehrlich-Institut. He presented on the current topics related to CMC of biopharmaceuticals. After introducing the Variation Regulation and its principle of classification of variations, Gross laid out several concerns from the industry. One of the concerns revolved on the call for flexible implementation of ICH Q8 (Pharmaceutical Development), Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality System). The ICH Q8, Q9 and Q10 are linked together to provide a systematic, modern risk- and science- based approach to pharmaceutical manufacturing and development. The guideline on process validation for finished products – information and data to be provided in regulatory submissions were discussed in this session. Sponsors are required to provide production scale validated data in the marketing authorization dossier. A matrix approach of validation may be acceptable and it should cover all manufactured strengths and all manufacturing sites used for production of the marketed product. Continuous Process Verification (CPV) is an alternative approach to traditional process validation in which manufacturing process performance is continuously monitored and evaluated. Companies should also monitor product quality and process performance to ensure that a state of control is maintained throughout the commercial part of the product lifecycle. Design of Experiment, small scale studies, model verification, control strategy, real time release testing, critical steps and critical process parameters, post approval change management protocol, single use systems were the other CMC related topics discussed in this session.
SESSION 11: NEWER DEVELOPMENTS EXPECTED DUE TO CURRENTLY PENDING COURT CASES
Geneviève Michaux is a Belgian and French qualified attorney (Hunton & Williams) who focuses on issues surrounding the regulation of drugs, biologicals, medical devices, cosmetics and food in Europe, both at the Union and national level. She started off her presentation by distinguishing between patent protection and regulatory protection. Marketing authorization can be granted despite patent protection. The supplementary protection certificates (SPC) provide protection for specific defined medicinal products beyond the term of the original ‘basic patent’ as a way of recompensing the patentee for the time taken to obtain regulatory approval. Data exclusivity for medicinal product is the period of time during which a company cannot cross-refer to the data in support of another marketing authorization. Several interesting court cases were presented to illustrate how decisions were implemented. For example, in the recent judgment, Case C‑631/13, Arne Forsgren versus Österreichisches Patentamt, the Court of Justice of the European Union had to consider a referral about an SPC. The judgment was about whether an SPC could be obtained to a product per se in ‘separate’ form when the marketing authorisation was for a medicine in which the product is covalently bonded to other ingredients. The ruling was that in principle, an active ingredient can give rise to an SPC where the active ingredient is covalently bound to other active ingredients which are part of a medicinal product. The other judgement was whether the SPC could rely on a marketing authorisation which only described the product as a ‘carrier protein’ and did not provide any information about an independent therapeutic effect (such as the one described in the patent on which the SPC was based). The ruling was that an SPC may not be granted for an active ingredient whose effect does not fall within the therapeutic indications covered by the wording of the MA. This is one of the few court cases presented by Michaux on the latest development of protection of biological medicinal products.
From the top (left to right): Dr. Gabriele Dallmann, Prof. Johannes Löwer, Prof. Joyce Tait, Dr. Doris Irene Stenver, Dr. Ilona Reischl, Dr. Steven Kozlowski, Dr. Christian Schneider, Geneviève Michaux, Dr. Dirk Mentzer, Dr, Michael Pfleiderer, Dr. Surendra Gokhale, Dr. Sol Ruiz, Dr. Jennifer Sims, Dr. Martina Weise, Dr. Jian Wang and Dr. Jan Müller Berghaus.
Overall, the 5th Annual Biopharmaceuticals Meeting was a great success. The speakers provided in-depth insights and a lot of interesting take-home messages were gathered during the engaging Q&A sessions. There were also a lot of positive feedback from participants on the selection of topics for the meeting. The atmosphere during the social event held at a traditional Bavarian restaurant at the Augustiner Schützengarten was relaxed and was one of the many occasions to talk to the speakers and other experts. Gabriele Dallmann and Johannes Löwer concluded the meeting and announced the upcoming 6th Annual Biopharmaceutical Meeting in February 2016.
Here are some of the positive feedback from the participants:
"Excellent, stimulating programme!"
"Great variety of topics, very informative, well organized meeting, relaxed, pleasant atmosphere"
"Excellent content, speakers, organisation and location!"
"High level of quality of presentations and speakers. Very good choice of topics"
"Good agenda, good discussions! Very well organised team - Thanks!"
"Very well organised meeting. Good overview of regulatory developments. Compliment!"
"This was a wonderful event in every aspect ranging from its scientific topics covered up to the organisation"