Final Report Summary - ACADEMIC GMP (The impact of Regulation (EC) No 1394/2007 on the development of Advanced Therapy Medicinal Products (ATMPs): an academic perspective)
Executive Summary:
Advanced Therapy Medicinal Products are gene therapy, somatic cell therapy or tissue engineered products. Regulation (EC) 1394/2007 has defined ATMPs to be drugs; at the gap between medicinal products and medical devices, these complex medicines promise innovative treatment options for complex diseases. Regulation (EC) 1394/2007 was intended to ensure their free movement within the European Union while guaranteeing the highest level of health protection for patients, and forms part of the European project of breaking down barriers and allowing free trade and movement of products. In this, the central role of academic institutions as drivers not just of the development but also of the manufacture of ATMP has been overlooked. Many products may only reach clinical application by relying exclusively on academic facilities. Compliance with industrial standards in an inherently non-industrial environment creates particular financial, managerial and cultural pressures. At the same time, ATMP relying on a highly individualized, labour-intensive therapeutic approach challenge established concepts of regulating medicines innovation.
The Project Academic GMP (www.academic-gmp.eu) has been funded among the FP7 Coordination Action or Support Actions for a duration of 30 months (01 September 2010 –28 February 2013). We have assessed the impact of Regulation (EC) No 1394/2007 on academic GMP facilities by: a) conducting a European survey among non-industry facilities in this sector; b) organising workshops and a major conference for targeted, collaborative discourse; c) establishing a web-based platform for information exchange; d) analysing publications and guidance from the perspective of better regulation principles; e) analysing innovation statistics in relation to ATMPs.
Project Context and Objectives:
Advanced Therapy Medicinal Products (ATMPs) are medicinal products for human use, based on gene therapy, somatic cell therapy or tissue engineering. A rapidly growing area in translational research, they represent the ‘next generation’ of complex medicines for complex diseases and pose particular challenges to medicines regulation.
Regulation (EC) No 1394/2007 has been designed to ensure the free movement of ATMPs within the European Union (EU), to facilitate their access to the EU market and to foster the competitiveness of European pharmaceutical companies while guaranteeing the highest level of health protection for patients. The regulation extends standards of Good Manufacturing Practice (GMP) to ATMPs to ensure their quality, safety and efficacy.
Advanced Therapy Medicinal Products present an area of strategic importance for the European Community. Collectively, these therapies represent the full spectrum of challenges and opportunities of truly disruptive innovation. Some of these therapies need to be integrated speedily and smoothly into existing innovation trajectories, others are set to transcend established marketing and business models in therapeutic medicine.
Academic GMP facilities are major contributors to the development of ATMPs. They respond to clinical needs and provide medicinal products in an environment which, albeit compliant with industrial standards, is by definition not industrial. They find themselves in a challenging position between various, sometimes conflicting interests in the transition of ATMPs from bench to bedside. European investigator-initiated multicenter trials on ATMPs critically depend on academic GMP facilities.
We have assessed the impact of Regulation (EC) No 1394/2007 on academic GMP facilities by: a) conducting a European survey among non-industry facilities in this sector; b) organising workshops and a major conference for targeted, collaborative discourse; c) establishing a web-based platform for information exchange; d) analysing publications and guidance from the perspective of better regulation principles; e) analysing innovation statistics in relation to ATMPs.
The consortium has pursued its objectives in time. The following achievements deserve to be mentioned:
- The results of the survey on Academic GMP facilities in the European Union have been collected, analysed, published and presented to a broad audience on several occasions (see below);
- In-depth interviews have been performed with selected experts in ATMP development in each Member State of the European Union, irrespective of whether they had responded to any of the questionnaires. The interviews provided the most detailed information regarding the heterogeneous implementation of the Directives and the Regulation across the EU and the impact this heterogeneity has on development.
- A Public Conference was held in Brussels on October 11, 2012, as a Joint conference of two FP7-funded Research consortia, entitled: „ The Impact of EU legislation on Therapeutic Advance“. The conference was extremely well attended, with members of National Agencies, of the European Commission and of the European Parliament among the participants;
- A position paper of the consortium was presented to the European Commission, with extracts of the consortium’s work, facts, figures and analyses as well as with proposals for improvement (Annex 1). Several other professional societies have used this position paper as a basis for their contributions to a public consultation on ATMP regulation held by the European Commission. The European Commission has published the summary of the responses recently (cf.: http://ec.europa.eu/health/human-use/advanced-therapies/developments/2013_pc_atmp.html) and the impact of our consortium’s position as brought forward by other stakeholders is evident and satisfactory.
- A Joint Session with the EBMT (European Blood and Marrow Transplantation Group) and Federal Agencies was organized, held and sponsored by our consortium on the occasion of EBMT’s 39th Annual Meeting in London, UK, April 7th to 10th, 2013. As a part of the 2nd Cell Processing Day (April 8th, 2013), this session attracted a surprisingly high number of attendees and provided an opportunity to elaborate on pathways to first-in man clinical trials with ATMPs. In another session, Academic GMP was offered to present the results of the consortium’s work to members of the Joint Accreditation Committee ISCT- EBMT (JACIE).
- Other occasions for „going public“ were sought, found and used extensively. This includes a position paper submitted to the European Commission in response to a public consultation (DG Health and Consumers), submitted to key contacts and professional societies who welcomed the opportunity to use our expertise, and invited presentations in front of the House of Lords, Federal Institutions and Industry Stakeholder Meetings. Details are given in the list of dissemination activities.
- The establishment of an electronic tool in terms of Mapping of the ATMP landscape has been initiated, as a basis for a repository of openly accessible data for the perusal of policy makers and researchers.
We gratefully recognize that, with the help of colleagues, policy makers, partners from industry, patient organizations, clinicians and professional societies, and above all, the European Commission, our efforts in research, analysis, interpretation, communication and dissemination have yielded the following results:
- A solid basis of facts, figures and trends that were brought to public attention,
- An awareness amongst ourselves that the political implications necessitate a more pronounced presence among and interaction with the decision-makers on the political level,
- A growing European network of scientific Institutions involved in all levels of ATMP Development, manufacture and clinical application, reaching out to Industry partners and policy makers on a European level.
In the stakeholder consultations performed as part of our work, and as an expression of the dynamics in the field, we have accumulated evidence in support of our hypothesis that, in the Regulation 1394/2007/EC, Academia has not been sufficiently taken into consideration as a major contributor to ATMP Development and Manufacture. Moreover, there is little harmonisation at the level of delivery across the Member States and uncertainty about the regulatory process which, when combined, are stifling academic research and commercialisation of these promising therapies. Most disturbing appears to be the detrimental effect this has on translation to early phase trials which remain largely academic investigator-led. Regulatory uncertainty remains a barrier to commercial investment and market development in the EU.
At project conclusion, we have seen the following outcomes emerging from our work:
1. We have submitted a comprehensive report reviewing the success of the ATMP regulation, drawing out important trends, potential unforeseen consequences, benefits and opportunities. The regulatory landscape has been delineated, with the Regulation 1394/2007/EC placed in context. With Academia emerging as the major contributor to ATMP Development and Manufacture, we have exposed the developmental trajectory, and highlighted obstacles to successful manufacture of ATMPs, reaching beyond the academic perspective that has been laid down in the title of our project.
2. We have provided a repository of openly accessible data for the perusal of policy makers and researchers, forming the evidence base on which to base strategic decisions not just in medical regulation, but also in business modelling, forecasting and innovation policy . The format for this database is an interactive map of the European Union, its member states and associated countries. This web-based tool allows visitors to obtain information pertinent to the development and manufacture of ATMPs in Europe, to the application of Regulation 1394/2007/EC and to country-specific differences in the implementation of the Regulation.
3. In our position paper and in public reports and presentations, we have issued recommendations aimed to assist the European Commission and other bodies to anticipate the needs for further developing of current EU legislation. By doing so, we propose to regard Regulation 1394/2007/EC as an example as to how the identification of and interaction with stakeholders relevant to the field contributes to the establishment, to the applicability and success of European Regulatory concepts. As such, the results of our project are intended to serve as a case study in Better Regulation practice in the EU innovation policy.
4. As a side effect to our project, we have begun to establish a network that is dearly needed (and hitherto non-existent) for sharing advice, regulatory issues and best practice among the academic GMP community in Europe. We are most delighted to see that the structure for this network as laid down in another FP7 project proposal has found a positive opinion for funding within the European Commission’s Framework Programme, with contributions from other European Centers, industrial partners, and with scientific advice from large umbrella organizations . Clusters of topics addressed are the need for common standards in Quality Control and the extension of an Academic Perspective beyond the standards of Good Manufacturing Practice (GMP) into the world of Good Clinical Practice (GCP) and Clinical Application of ATMPs.
Project Results:
1 Introduction
Advanced Therapy Medicinal Products (ATMPs) are medicinal products based on gene therapy, somatic cell therapy or tissue engineering. Regulation (EC) No 1394/2007 has been designed to ensure the free movement of ATMPs within the European Union (EU), to facilitate their access to the EU market and to foster the competitiveness of European pharmaceutical companies while guaranteeing the highest level of health protection for patients1.
Academic GMP facilities are major contributors to the development of ATMPs. We have assessed the impact of Regulation (EC) No 1394/2007 and related Directives on academic GMP facilities by: a) conducting a European survey in this sector; b) organising workshops for a targeted, collaborative discourse; c) establishing a web-based platform for information exchange; d) analysing publications and guidance from the perspective of better regulation principles; e) analysing innovation statistics in relation to ATMPs.
The work packages (WP) had been designed with these objectives in mind, with each work package specifically addressing one predefined goal.
Work Package 1 (WP1): Coordination and Project Management
Work Package 2 (WP2): Data gathering
Work Package 3 (WP3): Workshops & conference
Work Package 4 (WP4): IT infrastructure
Work Package 5 (WP5): Outreach
WP1: After initially implementing a Consortium Agreement (CA) and establishing guidelines for communication and reporting between the beneficiaries, the coordinator managed the project and kept track of its progress. The management team organized periodic project meetings, emphasized the need for an appropriate internal communication strategy by holding regular video conferences, and requested WP leaders to generate periodic reports by listing achievements and eventual delays. The Coordinator also kept a steady contact with representatives of the European Commission.
WP2: The principal objectives of the teams at Newcastle University and University College London were to generate and analyse quantitative and qualitative data on the impact of advanced therapies and related legislations specifically in the academic and hospitals sector.
After data had been gathered by performing a survey of key actors in this sector, the data have been compared, and supplemented with, interpreted in the light of and contextualised with other data elements that have been procured by the leader and participants of the WP. In addition, a selection of academic GMP facilities from each Member State was contacted for in-depth semi-structured telephone interviews by University College, London (UCL) - the result of which complemented the statistical analysis. A contextual analysis was completed by UCL of the data arising from the telephone interviews.
WP3: As outlined in Annex I to our grant proposal, the consortium has performed a series of GMP workshops, a public conference and a special session on the occasion of the 39th Annual Meeting of the EBMT (European Blood and Marrow Transplantation Group).
Workshop 1 ("Academia meets Industry") was held on March 4, 2011. At the kick-off meeting in Belgirate, we had agreed upon performing the workshop in Newcastle upon Tyne, i.e. at the center of one of our members, Prof Anne M Dickinson. The idea behind this was to visit different centers of the beneficiaries and to learn about their GMP facility, their work and their specific environment.
Workshop 2 was held in Vienna, Austria, on September 23, 2011. The focus on ethical issues was brought forward by speakers, participants and by members of the consortium, with discussions circling around critical questions prepared by Prof. Hildegard Greinix and Prof. Nina Worel who hosted the workshop.
Workshop 3 took place in Frankfurt am Main in March 2012; the conference on ATMPs was held in Brussels in October 2012, and the last workshop, organized in conjunction with the 39th annual EBMT meeting, took place in London in April 2013.
During the work of this project, the need to give more space to a broader political exchange had become more evident. For this reason, the scheduled working conference was shifted from the original venue in Hannover, Germany, to Brussels, Belgium. Furthermore, the event was performed as a joint conference, together with a consortium that addressed a topic closely related to ACADEMIC GMP (“CONTRACT”, Consent in a Trial & Care Environment, FP7 project No. 261412). The conference hosted members of the European Parliament who were asked to carry the critical issues emerging from the consortia’s work forward.
WP4: The Lund University team was assigned the task to efficiently implement a comprehensive web-based project platform and to maintain and update the website on a regular basis. The subcontractor that had been selected by the consortium to perform these tasks was also in charge of controlling and verifying data entry and, together with members of WP2, performing data extraction and data reporting.
WP5: After initially introducing the project to regulatory authorities, scientific organizations and the scientific community, with detailed information about activities of the consortium, the project objectives for this work package were the following:
- Presenting outreach activities at the conference
- Describing outreach activities in the proceedings volume of the conference and in the final report
- Organising the joint session with the EBMT at the 2013 Annual Meeting of the EBMT in London
2 Work Package 2: Data gathering
This study focused on European Academic Good Manufacturing Practice (GMP) facilities involved in the manufacture of Advanced Therapy Medicinal Products (ATMPs). The aim of the study has been to investigate, through survey analysis, how these facilities are operating, how they differ (within and between countries) and establish which factors appear to be influencing ‘success’. Work Package 2 has been concerned with respondent identification, data gathering, construction of survey questionnaires, analysis and interpretation of data.
Distribution of a short questionnaire to members of professional societies, regulatory bodies, coordinating scientists of all identified FP-funded projects related to cell therapy, stem cells, regenerative medicine and/or gene therapy, members of the Stem Cell Users Group (SCUG) and personal acquaintances enabled us to approach more than 700 contacts, of whom 85 respondents declared their willingness to participate in a detailed on-line questionnaire comprised of 71 facility and regulatory questions. In addition, 83 respondents said that they would be interested in “establishing a network, developed over the next 2 years, of non-industrial GMP institutions in Europe – giving Academic GMP a voice”.
In the second, more detailed questionnaire, respondents were asked about ATMP production/development, collaboration, facility size, consultation with regulatory bodies and opinion on implementation of current directives. After a six week period, 50 complete surveys had been received in total from 11 European countries.
The statistical data analysis of the GMP questionnaire was completed in December 2011 - thereafter the report was circulated to the Co-ordinator to and University College, London (UCL) for comment. Further ideas and suggestions were subsequently incorporated.
Selected recipients from each Member State were contacted for in-depth semi-structured telephone interviews by University College, London (UCL) - the result of which complemented the statistical analysis.
Additionally, a contextual analysis was completed by UCL of the data arising from the telephone interviews. In brief, the conclusion was that the EU Regulation of ATMPs is broadly recognised as essential for the future development of the field and there is, as yet, no evidence that this regulation is putting EU scientists and clinicians at a disadvantage to colleagues in the US and other developed countries. However, the additional cost and complexity of ATMP manufacture to GMP compliance does add very significant costs and is thus an indirect negative factor on development of novel therapies in the EU. Furthermore, the lack of consistency in the interpretation of Regulation (EC) 1394/2007 across EU Member States is a barrier to cross-border collaboration in the development, manufacture and clinical application of ATMPs, be it among academic institutions, within “conventional” clinical trials or within the so-called Hospital exemption clause (Art. 28(2)) or for industry if commercialisation is being considered.
The work has been disseminated to a wide audience. Currently a paper has been accepted by Cytotherapy subject to minor revision. Additionally, the results of the study have been discussed at the joint conference in Brussels (October 2012): “The Impact of EU legislation on Therapeutic Advance” and at two workshops at the 39th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT) in London (April 2013). Over 250 delegates attended each of the two sessions at EBMT and the feedback was very favourable.
2.1 Data entry and analysis
A short questionnaire was distributed to 747 relevant European contacts asking if their facilities currently produced ATMPs and/or intended to produce ATMPs in the future. In addition, potential respondents were asked if they would be interested in establishing a network, over the next 2 years, of non-industrial GMP institutions in Europe – giving academic GMP a voice. This questionnaire was made available through email and was accompanied by a covering letter explaining the purpose of the survey and data protection policy. University of Newcastle upon Tyne (UNEW) was responsible for the generation of the email questionnaire. E-mailed (short) questionnaires were entered into a database manually by a data manager based at UNEW.
A representative sample of 50 European facilities subsequently replied to a detailed questionnaire which asked about ATMP production/development, collaboration, facility size, consultation with regulatory bodies and opinion on implementation of current directives. Respondents were from the following countries: Germany (15), UK (10), Spain (7), Italy (4), Netherlands (4), Belgium (3), Austria (2), France (2), Republic of Ireland (1), Romania (1) and Turkey (1).
The analysis investigated how the facilities are operating, how they differed (within and between countries), and established which factors appear to be influencing ‘success’.
The questionnaire responses provided clear evidence that:
1. Those centres which are involved in the initial development of new ATMPs are also those which successfully achieve GMP-grade production for clinical trial.
2. Centres which successfully translated to clinical trial were those which interact with appropriate regulatory authorities for advice.
3. Experienced facilities in ATMP development regularly pass inspections – these facilities understand how to be compliant with GMP standards and are comparable with (and potentially competitive with) industry.
4. Experienced facilities in ATMP development mostly have a pre-existing background in manufacturing non-medicinal, minimally manipulated cell therapies (e.g. haematopoietic stem cell transplant products and associated lymphocyte infusion).
5. It is difficult for new centres to enter the field under existing regulations because of the investment required in facilities and expertise.
6. There is a general paucity of and need for quality control programmes for qualification and standardisation of these products as they progress through development in an attempt to attain marketing authorisation in the EU and beyond.
2.2 Interviews
Following preliminary analysis of the questionnaires, specific questions or areas of anomaly were chosen to be explored in greater depth by telephone interviews with one or more experts in ATMP development in each Member State. The interviews were performed in English or the native language of the interviewee in a semi-structured fashion to address procedures implemented in their facility, regulatory problems encountered and general understanding of implementation of the relevant regulations in their Member State. Interviewees were approached in all Member States of the EU, irrespective of whether they had responded to any of the questionnaires. In the end 20 scientists from 16 member states agreed to participate in the telephone interviews.
After conducting the interviews, there was evidence of uncertainty about the regulatory process and it was clear that this impacted on ATMP development. The inconsistencies in the implementation of Regulation (EC) No 1394/2007 are a considerable barrier to development of ATMPs across the European Union but this is largely due to the myriad of differences in national drug laws which underpin the ATMP Regulation. It was also noted that definitions of a cell-based medicinal product, a gene transfer medicinal product or a tissue engineered product as an ATMP are not harmonized.
It was established that the majority of ATMPs in development are patient-directed or intended to be produced in very small batch sizes, but there is widespread concern that problems with regulation will lead to patients travelling out of their Member State for novel therapies.
As regards interaction with local regulatory authorities, some interviewees reported extreme difficulties in obtaining manufacture approval of specific products. A further problem – particularly for small academic manufacturers -was the immense amount of paperwork associated with GMP and Good Clinical Practice (GCP) compliance. Also, whilst all interviewees supported the concept of a high standard of GMP for ATMPs, there was a common belief that a risk-based approach to compliance with pharmaceutical standards is required in the development of ATMPs.
Three additional issues were of repeated concern:
(1) the use of very contrived animal models in the development of ATMPs,
(2) the lack of training of pharmacy Qualified Persons (QPs) in the manufacture of ATMPs,
(3) heterogeneous implementation of the Hospital Exemption Clause (HEC) in Regulation 1394/2007/EC across the Member States.
2.3 Other data
A comprehensive literature search showed that the EU lags behind the United States (US) with regard to cell therapies in clinical trials; both academic and industry-led. In contrast to the EU, US cGMP facilities licensed by the Food and Drug Administration (FDA) for manufacturing for phase I/II and phase II trials are not subject to regulatory inspection and the burden of compliance is lower. The most active countries in this field outside of EU/USA are South Korea and Brazil where the burden of GMP compliance is also lighter. For example, EU GMP requires all “open” manufacturing steps to be performed in a class 100 (grade A) environment within a class 100 laboratory (grade B) which is extremely expensive to attain, requires excessive gowning and is often incompatible with the use of the equipment routinely used in ATMP manufacture such as floor mounted centrifuges. In contrast, cGMP requirements applied in the US, South Korea and elsewhere stipulate that this type of production step need be performed in a class 100 environment within a class 10,000 laboratory (grade C) with associated cost savings and ease of process design. EU GMP manufacture of investigational ATMPs in clinical trial requires formal release by an accredited “Qualified Person” which is unique to the EU and an added expense and complication.
2.4 Dissemination
The results of the surveys and the interviews have been widely disseminated at national meetings in EU MS, international conferences and are now about to be published in the international scientific journal Cytotherapy. They have been part of a written submission to the UK House of Lords Committee on Regenerative Medicine and of a submission to the European Commission impact assessment of Regulation 1394/2007. A detailed list of dissemination activities is attached to this report.
3 Work package 3: Workshops & Conference
Work package 3 (WP 3) was devoted to the organization and performance of workshops and conferences as outlined in the project description. After the first two workshops I (“Academia meets Industry”, Newcastle/ UK, March 2011) and II (“Ethics involving Advanced Cellular Therapies”, Vienna/Austria, September 2011), workshop III was performed in March 2012 in Frankfurt/M., Germany, followed by the Joint Conference: “Impact of EU Legislation on Therapeutic Advance” in Brussels, October 2012, and the workshop and regulatory session co-hosted by the Academic GMP Consortium and the EBMT on the occasion of the 39th Annual Meeting of EBMT in London, April 2013.
3.1 Workshop I: “Academia meets Industry”, Newcastle, UK, March 4, 2011
Workshop I was performed in Newcastle upon Tyne, i.e. at the center of one of our members, Prof Anne M Dickinson. The idea behind this was to visit different centers of the beneficiaries and to learn about their GMP facility, their work and their specific environment.
Prof Dickinson and Dr Sethe, both in Newcastle, were of tremendous help in organizing the workshop. We were surprised about the interest and positive feedback that we received from well-known experts, especially from national regulatory authorities, GMP experts and Industry at all levels, ranging from small enterprises and university spin-offs to "big pharma".
A detailed report on the workshop has been uploaded. However, some impressions of special importance shall be given here:
− Academia is not unequivocally understood as a professional in terms of GMP. Concern was raised from the side of industry that people coming from academia should not be regarded as competitive or even as potential employees.
− „Exemptions“ were said to form most academic experience, rendering academic centres less risk averse. Costs and time in ATMP manufacture were dramatically underestimated, with „money going to research first“.
− Quality management structures were often rudimentary, and scientific curiosity was perceived as a poor structured counterpart to the planned exploitation cultivated in Industry. Academia were said to be focused to own ideas, refractory to counseling, and reclusive with regard to scientific and technical exchange.
− Academia and Industry were perceived as belonging to different cultures, with different languages, and different currencies: publications and "impact factors" vs. financial balance or even bargain.
Academia took some serious cuffs in the dialogue, albeit in a friendly atmosphere. The sometimes overt condescension was a first hint at the validity of our general hypothesis: Academia is rather seen as a stranger in the field of pharmaceutical production, also and especially with regard to ATMPs, and has not been taken into account when the idea of a harmonized structure for marketing authorisation was pursued, leading to the current legislation.
3.2 Workshop II: “Ethics involving Advanced Cellular Therapies”, Vienna/Austria, September 2011
The second Workshop was held in Vienna, Austria, on September 23, 2011. The focus on ethical issues was brought forward by speakers, participants and by members of the consortium, with discussions circling around critical questions prepared by Prof. Hildegard Greinix and Prof. Nina Worel who hosted the workshop. The relatively high number of representatives from regulatory bodies was greeted as a sign of growing awareness of problems in the field.
After an introduction to the spectrum of potential therapeutic applications for Advanced Therapy Medicinal Products, the issue of safety emerged as a central topic in most of the presentations and discussions. Some aspects of the workshop shall be presented briefly:
- Given that the history of GMP is a history of reactions to scandals from the very beginning of drug manufacture, it was to be expected that representatives from the regulatory bodies would translate the risks associated with ATMPs into regulatory requirements. Here, regulatory questions have proven value in unmasking critical weaknesses of drug development which often had fatal consequences for the patients. Unfortonately, these questions were addressed insufficiently in the development and before the application, as proven in several saddening cases that were presented.
- Notwithstanding the regulatory concern, some incidents were “adverse events” that need to be studied, also were studied, and that pave the way for new scientific information and improvements to drug development. This, by the way, extends beyond ATMPs and is also confronted with the risk of withholding therapy. Some of the cases presented were rather examples of the power of patients’ despair than of scientific soundness.
- Patients nowadays take information on ATMPs from publicly available sources, such as the internet. Unfortunately, most of the responses are miracle cures whereas there are very few scientific publications. Medical articles are also very hard to read for the public. There are also unrealistic fears associated with advanced therapies.
- It is true that clinical studies have to comply with a lot of regulations but they intend to protect the patients. It is not realistic to have 2 levels for clinical studies: a lower standard for academia and a higher standard for the industry because patients' safety cannot be underestimated. Academic investigators face certain challenges because most of the advanced therapies are classified as medicinal products and thus are bound to adhere to standards of GMP and other regulations. Today, not all academic centers are capable of fulfilling these standards; this, however, points at a political problem that cannot be addressed by the regulators.
- A risk-based approach as laid down in the Guideline on human cell-based medicinal products (EMEA/CHMP/410869/2006) is not only a translation of risks into the regulatory requirements: A preemptive assessment of risks on all levels is considered as the most appropriate way to include expert knowledge from basic science to clinical application in a truly scientific manner, to achieve a sound decision based on a risk-benefit assessment and on current schientific knowledge that will always be limited.
- In response to a comment on the disastrous standards of some university laboratories, it was acknowledged that there is insufficient financial support for the academic centers, lack of infrastructure and lack of coordination between laboratories. Furthermore, the regulators saw the difficulty associated with ATMPs in the switch from conducting a clinical trial with a licensed product to drug manufacturing. Standards apply to both of these different roles and investigators have to adhere to these standards.
Dr. Nikolaus Forgó, Chair of Legal Informatics and IT-Law, Institute of Legal Informatics at the Gottfried Wilhelm Leibniz University of Hannover in Germany, gave an assessment of the ATMP regulation from a legal point of view: An interpretation of law as defined by Niklas Luhman as a transformation of uncertainty to certainty by the usage of time appeared hard to be applied in the case of the Directive 1394/2007/EC which rather turned uncertainty into uncertainty at a higher level, as proven by taking the legal environment of this legislation under scrutiny. However, law is not only the transformation from uncertainty to certainty by usage of time but also by communication between parties.
This workshop was the starting point for a most fruitful cooperation between two similar projects funded within the 7th Framework Programme, Academic GMP and CONTRACT headed by N. Forgó, and resulted in a joint conference in Brussels to reach out to policy makers in the very political heart of Europe.
3.3 Workshop III: “Regulation of Advanced Cell Therapies”, Frankfurt/M., Germany, March 16, 2012
Workshop III differed from the previous workshops in that it was embedded in the joint Conference of the18th Annual Meeting of the German Society for Gene Therapy (DG-GT), a Perspective Conference of the Stiftung Hämotherapie-Forschung on the Role of Haemotherapy and Transfusion Medicine, and the 1st Symposium of the LOEWE Center for Cell and Gene Therapy Frankfurt (CGT)), and therefore received broad attention. A copy of the entire conference programme (Annex 1) and the Academic GMP Workshop (Annex 2) have been attached to this report.
With a focus on the regulation of ATMP manufacture, the all-day workshop was divided in three sessions including plenary talks, round-table discussions and pro-con debates that were as vivid and fruitful as they were controversial. Regulators from local, national and EU authorities joined the debate as well as clinician-scientists, stakeholders from Industry and basic scientists. A questionnaire on the topic was distributed at the end, and an extract of the responses to this questionnaire has replenished a report from this conference published recently.
In many aspects, the workshop brought forth more questions than answers. In spite of all the criticism and different points of view, panel discussions as performed in this workshop could make a significant milestone to improve the regulatory landscape. The close cooperation between local and national authorities as well as the physicians and researchers of academia in some member states, especially in Germany and in the UK, could be a role model to initiate the next steps to improve the legislation at EU level.
Consensus existed about the medical necessity to develop advanced therapy medicinal products. However, it remains to be defined how the EU wanted their citizens to provide innovative therapies which the pharmaceutical industry for reasons of profitability (currently) is not interested in, and therefore are provided only by academic institutions for many years to come. In the past, relatively few individual patients have drawn benefit from the medical and scientific progress represented by ATMPs, but the future development is uncertain, in the face of the immense investment needed for the production of ATMPs in academic institutions and, moreover, investigator-initiated clinical trials, a challenge that brings academia to the limits, both financially and administratively. In most academic institutions, appropriate structures do not exist. Small and careful steps will be the only way to establish networks among academic centers, to facilitate the application process for clinical trials for the academic centers, and to draft funding policies to sustainably promote drug development in academic centers, also in view of the Horizon 2020 programme. It was also discussed to what extent cell therapy for individual therapy might at all go through the same development as conventional bulk pharmaceuticals, only for the purpose of leading to an EU marketing authorization. ATMPs, especially when intended as an individualized patient treatment, cannot uniformly be subject to the procedure of an EU-wide approval which is unlikely to be feasible for academic institutions. In this way, the development of life-saving therapy would succumb to EU legislation. It is particularly painful to see patients in critical situations turning to obscure therapists or into poorly controlled situations abroad, although the technical and clinical expertise is available for experimental cell therapies.
3.4 Joint Conference, Brussels, Belgium, October 11, 2012
With a growing recognition of the political dimension of our project, the working conference was shifted from the original venue in Hannover, Germany, to Brussels, Belgium. Furthermore, the conference has been performed as a joint conference, together with a consortium that addresses a topic closely related to ACADEMIC GMP (“CONTRACT”, Consent in a Trial & Care Environment, FP7 project No. 261412). The conference hosted members of the European Parliament who have been asked to carry the critical issues emerging from the consortia’s work forward.
It is with deep gratitude and respect that we acknowledge the continuous, inspiring and most forthcoming support by Dr. Joana Namorado who endorsed the idea to hold this conference in the very political heart of Europe, Brussels, and in a manner that might encourage other FP7 consortia to seek the interaction with policy makers; to my knowledge, other consortia are planning to follow this example.
Reaching beyond the topics of both consortia, the „Joint Conference: The Impact of EU legislation on Therapeutic Advance“ became a broader forum for an exchange of thoughts on the effects of current practice of European Regulation on Clinical Research and Innovation. Among the discussants were MEP Maria da Graca Carvalho (European People’s Party, Portugal), MEP Dr. Eva Lichtenberger (European Free Alliance, Austria), MEP Dr. Peter Liese (European People’s Party, Germany), Dr. Joana Namorado, European Commission Horizontal Aspects Coordination – Ethics and Gender Issues, and Dr. Cornelius Schmaltz, DG Research and Innovation, Policy Officer and Coordinator of FP7 Operations.
The conference touched another point of importance: the fact that, apparently, more and more directives are being repealed by regulations which, as is the case with the Regulation on ATMPs, have been endowed with immediate effect upon introduction. Keynote speakers highlighted the current status in the field and exemplified how dramatically current legislation can impinge on clinical practice. Patient advocacy groups requested partnership in development of novel therapies, and recognition of the fact that even seemingly small effects of innovative therapies may have a substantial impact on the reduction of disease burden and associated morbidity. Issues of informed consent were discussed with a specific focus on pediatric oncology and implications of informed consent procedures on participation in clinical trials in this patient population.
Among the conclusions arising from this conference, it became evident that technology and knowledge must be and can be transferred across member states. Bringing Europe forward, the most distinguished task of the European institutions, requires them to foster a change in thinking: ATMPs are a brilliant example for the fact that reclusive behavior does not bring scientific excellence to Europe, nor does it lend a hand to European citizens in need. Instead, collaboration in networks and with Industry is the only efficient way to endorse Europe’s competitiveness and welfare in a time when other parts of the world move at a much faster stride. Most and above all, Academia should show more self-confidence as being the only one minding the gap and responding to the just demand for therapeutic innovation in rare and complex diseases where industry is not present, making this a structural and political issue where political discourse, interaction and also lobbying for a just cause should not be a field left to Industrial stakeholders alone.
The results of this Conference have been made publicly available in a report, and the list of participants in this event is available for download at the homepage of the consortium.
3.5 “Cell Processing Day” in conjunction with the 39th annual EBMT meeting, London, United Kingdom, April 8, 2013
Together with the conference held in Brussels, this event marks the other of two definite highlights of our work within this consortium. The European Blood and Marrow Transplantation Group (EBMT) is one of the major key player organizations in all facets of current Stem Cell Transplantation and Cell Therapy. One of the participants of our consortium, Prof Jane Apperley (Imperial College London), is among the most distinguished Haematologists in Europe and beyond; she hosted this year’s Annual Meeting as Conference President, while other members of ‘Academic GMP’ contributed to the organizing committee. The meeting attracted about 6800 participants from all over the world.
As a part of the 2nd Cell Processing Day (April 8th, 2013), the sessions organized by our consortium attracted a surprisingly high number of attendees and provided an opportunity to elaborate on pathways to first-in man clinical trials with ATMPs. The consortium thus contributed and co-hosted an entire session and a workshop, thus covering 50% of the 2nd Cell Processing Day, a facet of EBMT’s Annual Meeting that was introduced only recently but has become an integral and widely appreciated part of the EBMT Annual Meetings. In another prominent session of the EBMT Annual Meeting, Academic GMP was offered to present the results of the consortium’s work to members of the Joint Accreditation Committee ISCT- EBMT (JACIE). All slides have been made publicly available on the homepage of our consortium. As a most distinguished way of going public, the consortium couldn’t have had a better conclusion of our work. A copy of the conference program can be found at: http://www.congrex.ch/fileadmin/files/2013/ebmt2013/ebook/ebmt2013-final-programme/flipviewerxpress.html.
4 Work package 4: IT Infrastructure
WP4 comprised a total of 3 tasks: Task 4.1 Requirement analysis and specification; Task 4.2 Design and implementation of IT platform, maintenance and updating of IT platform, and Task 4.3 Database updating, data extraction and reporting. All tasks were successfully completed.
The setup, maintenance and updating of the IT platform was conducted by our subcontractor as planned. The platform could be used without any problems and for all intended purposes. In addition to these tasks, the IT platform was amended by an open forum for questions and answers related to the focus of the Academic GMP project. Furthermore, a member restricted area for Academic GMP documents was established and as well as an interactive map of ATMP regulation in Europe.
With the project “Academic GMP” coming to an end, the website and all the information contained therein will continue to be available. As authorized by the Pharmaceutical Committee of the EC/ DG Health & Consumers, the interactive map of ATMP regulation in Europe was supplemented with data on the implementation of the Hospital Exemption Clause in the Member States. Please refer to the homepage at: http://www.academic-gmp.eu/map.html.
5 Work package 5: Outreach
Headed by the Medical University of Vienna, WP 5 was in charge of presenting the project to regulatory authorities, patient organizations, the scientific community, and the general public. A list of tasks was consequently defined to meet the objectives:
• Publication of a press release at the start of the project, introducing the Academic GMP Consortium and the aim of the project to the public.
• Communication with professional societies, patient organisations and regulatory authorities to inform them of our activities and invite them to the workshops.
• Creation of a list of GMP facilities in Europe, which might be interested in responding to the Academic GMP survey. A list of more than 800 relevant contacts has been compiled and has been used for the survey and other purposes along the project.
• Preparation of a brochure on the Consortium’s activities that would be produced and distributed at professional events. The brochure is publicly available on the homepage of the consortium.
5.1 Outreach to professional societies
The presidents of professional societies in the field, EBMT, ISCT and JACIE were informed about the research activities of our consortium. They were also sent the project survey along with invitations to our workshops and were asked to distribute this information to the members of their respective societies. These European and international societies were invited to participate in the conference and the Joint Session with EBMT at the 2013 Annual Meeting of the EBMT in London.
5.2 Contact details
A list with contact details of academic GMP facilities in Europe, their clinical partners and regulatory authorities was created in order to contribute to a closer communication between the partners in ATMP development and regulation. These contact details have already been used to invite respective institutions to the Academic GMP workshops and to encourage them to participate in our survey. Contact details of national and regional regulatory authorities were used for inviting them to the conference and the Joint Session with EBMT at the 2013 Annual Meeting of the EBMT in London.
5.3 Communication with the European regulatory authorities
The consortium was registered at the CAT office and was accepted as an interested party as of March 2011. Information about the research activities including workshops, surveys and the conference were also sent to the CAT. We sent additional information about the conference and the Joint Session with EBMT at the 2013 Annual Meeting of the EBMT in London to the CAT office. The information sent included the program agenda, venue and main objectives of the conference and joint session. Unfortunately, EMA could not allow members of the agency to participate in the joint session with EBMT as originally intended, for reasons of internal reorganization. However, members of the British Authorities (MHRA) were so kind as to substitute for their EMA colleagues.
5.4 Communication with patient organizations
Contact details of patients organizations that operate on a national and European level were collected in a list. Communication with these organizations was established and they were sent information about our research consortium including invitations to workshops and the conference. After providing a list with contact details of patients’ organizations that operate on a national and European level and informing them during the first reporting period about our research consortium, these patients’ organizations were invited to the workshops and the conference. Among these, several national umbrella organizations (ACHSE e.V. in Germany, Genetic Alliance, UK, and others) participated actively in the workshops, in the Joint Conference in Brussels and in the joint session with the EBMT.
5.5 Joint session on ATMP regulation, EBMT annual meeting, 2013
The president of the 39th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT), Prof. Jane Apperley, agreed to have a Joint EBMT session with our consortium. Two sessions with internationally renowned chairs and speakers were organized by our consortium.
The two EBMT – Academic GMP sessions were announced on the official homepage of the EBMT, as part of the 2nd Cell Processing Day, inviting all members including physicians, nurses, data manager, associated researchers, patients and patients’ advocacy groups and the public to the Annual Meeting and thus, also to the consortium’s workshops.
The two sessions (Workshop and plenary session) took place during the 39th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT) and were a Joint EBMT session with our consortium on April 8, 2013 at the ICC ExCel London. The first workshop was entitled “EBMT – Academic GMP Workshop: ATMP clinical trials” and was located within the Cell Processing Day and thus, had an ideal target audience consisting of clinicians and preclinical scientists performing research not only in the field of hematopoietic stem cell transplantation but also in areas of regenerative medicine and regulatory issues. Our consortium organized four presentations consisting of the following:
- Introduction of ATMP, ATIMP and CTD regulations: Prof. Mark Lowdell, London, UK
- How to produce an IMPD for regulatory submission: Dr. Pauline Meij, Leiden, NL
- First in patient: regulatory options, gaps and suggestions (Academic GMP):
Prof. Martin Hildebrandt, Munich, DE
- A regulator’s perspective of an ATMP specification file: Dr. Ian Rees, London, UK
During the workshop an actively participating audience of approximately 100 participants challenged definitions of ATMPs, discussed regulatory issues limiting progress in the clinical application of ATMPs and the role of academic facilities performing research in this very innovative field of advanced cellular therapies. The Chairs of the Joint EBMT session, Prof. Martin Hildebrandt and Prof. Gunnar Kvalheim from our research consortium entertained numerous questions and finally summarized the most important aspects of the discussion for incorporation into the position paper of the consortium.
The second workshop during the Cell Processing Day of the 39th Annual Meeting of EBMT on April 8, 2013 was chaired by Prof. Ulrike Köhl, Frankfurt, Germany from our research consortium, and was entitled “Quality control of ATMPs”. It was also supported by Academic GMP as clearly stated in the program booklet and during the scientific session. Our consortium organized three presentations consisting of the following:
- Enumeration and characterization of circulating cells (in vivo), viability of cell products, residual cell enumeration: Dr. Johannes Fischer, Düsseldorf, DE
- QC on ATMPs (GMP) and non-ATMPs with examples: Dr. Ineke Slaper-Cortenbach, Utrecht, NL
- Standardisation of cell counting, single versus dual platform approach, expanded cells (ex vivo); advantage in ATMPs: Dr. Albert Donnenberg, Pittsburgh, US
During this workshop, important issues on quality control of ATMPs were discussed including:
a. attempts to standardize the characterization of different cellular subpopulations for clinical use,
b. enumeration of different cellular fractions in the circulation and
c. options for ex vivo expansion of cellular subpopulations for clinical use.
The audience of approximately 130 participants from the fields of cell collection, processing, preclinical and clinical cellular research interacted lively with the Chairs and speakers of this workshop and finally agreed on important definitions and standardisation.
6 Dissemination of project results
The knowledge generated within the project has been monitored and managed with diligence and care. The gained knowledge was made available to the project partners on a regular basis through electronic emails, telephone calls and project meetings. It has also been shared with the public, the GMP/ATMP community and other stakeholders through publications, workshops and participation of consortium members to professional meetings. Please refer to WP5 for main activities performed in this area. A list of dissemination activities can be retrieved at the end of this report.
7 Communication with other consortia
Within the FP7 programme, several projects showed similarities or offered opportunities for a collaboration in several ways. For this reason, we explored these opportunities and used them for a better achievement of common goals as extensively as possible.
The CONTRACT Consortium (grant agreement no. 261412) investigated the impact of EU legislation on informed consent (Clinical Trials Directive, Data Protection Directive) on translational research with a view to informing future policy-making in this area. For complex medicines such as ATMPs, this was seen as of utmost interest to the development and application of ATMPs in clinical trials, exemplifying the close proximity of GMP (Good Manufacturing Practice) and GCP (Good Clinical Practice) in the challenging area of cellular therapies. In several meetings, mutual participation in workshops and, most importantly, in the Joint conference on the Impact of EU Legislation on Therapeutic Advance, this collaboration resulted in a most fruitful and recognizable joint effort. To a lesser extent, this held true for other projects that addressed other EU Regulations and directives, including the Tissues and Cells Directive (2004/23/EC), with the TISS.EU project (grant agreement no. 202204) coordinated by Dr. Christian Lenk and Prof. Dr. Claudia Wiesemann (Dept. for Ethics and History of Medicine, University of Göttingen) in cooperation with Dr. Nils Hoppe (Centre for Ethics and Law in the Life Sciences, University of Hannover). Other projects addressing the impact of EU legislation on health research were approached but declined to participate.
The expertise gathered in Academic GMP was welcomed by other projects funded within the FP7 framework programme who asked the consortium as a whole or members thereof to help in terms of investigational medicinal products, regulatory issues and manufacture. This includes the projects: BIOHYBRID (grant agreement no. 278612), T-CONTROL (grant agreement no. 601722), CellEurope (grant agreement no. 315963), AGORA (grant agreement no. 602366), and others.
8 Publications
As planned in the beginning, the results of our work are being published in a major scientific journal (Pearce et al, Cytotherapy 2013, in press). Other publications will be published soon or have been published already. The results communicated haven’t been easy to adopt to a classical format of publication, but were taken up by the peer reviewers and editors with profound interest. Some have been cited already to serve as proof for the challenges inherent in the field and the critical role of academia.
1. K.F. Pearce, M. Hildebrandt, H. Greinix, S. Scheding , U. Koehl, N. Worel, J. Apperley, M. Edinger , A. Hauser , E. Mischak-Weissinger , A.M.Dickinson M.W.Lowdell. The Regulation of Advanced Therapy Medicinal Products in Europe and the Role of Academia. Cytotherapy 2013, in press.
2. M. Hildebrandt, N. Forgó. Short Report: Joint conference on the Impact of EU Legislation on Therapeutic Advance. Cytotherapy 2013, in press.
3. U. Köhl, A. Hauser, M. Hildebrandt. Einfluß der EU-Verordnung 1394/2007 auf Arzneimittel für neuartige Therapien. Dt. Zeitschr. f. Klin. Forschung: 3/2013; 17(2): 57-62.
4. S. Sethe, M. Hildebrandt. Caught in the Gap: ATMP Manufacture in Academia. ISCT Telegraft 19(1), 2012.
5. S. Sethe, A. Dickinson, C. Batkai, M. Hildebrandt. Manufacture of Advanced Therapies: Academia meets Industry. Reg Rapp 8(7/8), 9-11, 2011.
In addition, Insight Publishers are currently preparing a report on the work of the Academic GMP consortium which is expected to appear in autumn 2013. This report will be made publicly available, as all publications emerging from our work.
9 Acknowledgement
In the performance of the management and coordination tasks, the value of the assistance by Ms. Carole Batkai cannot be overestimated. With her friendly and forthcoming attitude as well as with a high degree of professionalism, her continuous support to the tasks of coordination and management are acknowledged most gratefully.
We are gratefully indebted to our external advisors, Stefan Miltenyi, Volker Huppert, Murat Aktas and Marc Barthold, who participated actively in the events organized by our consortium, showing their interest, contributing their view from an industry perspective with close associations with the academic world, and by all means endorsed the project on every opportunity.
We wish to thank the European Commission for entrusting us with the financial and logistic support to perform this project. It is gratefully acknowledged that this project has led us far beyond the original concept, and into a constellation at the interface of science and policy/ public decision making, where the presence of scientists is requested and expected, for good reason.
Most and above all, it is with deep gratitude and respect that we acknowledge the continuous, inspiring and most forthcoming support by the scientific officer, Dr. Joana Namorado, who endorsed our work in a most favourable way, putting this project into a broader perspective. Dr. Namorado ignited an apprehension of the political dimension and responsibility of science, especially in the field of Health research, where European politicians need scientists to develop, to communicate and to explain politics and decisions from a scientific perspective.
Dr. Namorado supported vigorously the idea to hold a conference in the very political heart of Europe, Brussels, and in a manner that might encourage other FP7 consortia to seek the interaction with policy makers. This conference would never have been conceivable if we, the participants of this consortium, hadn’t had the opportunity to be supported by, and to interact with, the political Europe as an integral part of this project. I haven’t been fully aware of the political dimension of our project before, and I cannot be grateful enough for this opportunity to give academia a voice in this complex and dynamic field.
Potential Impact:
The survey gave proof of the existence of Academic and Non-Industry facilities that develop and produce ATMPs successfully. Successful institutions share distinct features that are independent from the country of origin. There is still a lack of academic facilities capable of contributing to the field of translational research, and it is difficult for new facilities to enter the field. Interestingly, those facilities who manufacture ATMPs in a University/Medical School apparently would benefit from collaboration/co-operation with other centres. However, the degree of implementation of EU Regulation varies between member states, with evidence of substantial differences in the criteria used to define ATMPs and in the approved manufacturing environment. This regards genuine academic facilities versus third party contract manufacturers, but also a country-specific interpretation of GMP standards.
In the interviews, topics were addressed such as experiences with the Regulatory classification of products, national practices of licensing, GMP requirements, the availability of Qualified Persons required to release batches and products for clinical use, cost implications and competitiveness. A focus was set on the application of the Hospital Exemption Clause, a highly disputed section of Regulation 1394/2007/EC that might be regarded as an apprehension of the role of Academia, especially in the “niche” of rare diseases and small patient populations that is not in the focus of Industry. In fact, it is evident that, apart from the “conventional” chain of product development, there are ATMPs that never have been intended to reach marketing authorisation, never will do so, and never will be in the scope of Industry. If, however, a therapy is available and a valid option for patients with unmet clinical need, who will provide these patients with a medicine they have the right to accede? And: How does the current regulation cover this field of products which, inadvertently or not, are in the main focus of Clinical interests in Academia?
Member states are handling Regulation 1394/2007/EC in an irritating way. Although the regulation as such took immediate effect upon publication, the 2-year exemption rule for manufacturers had been used apparently by many member states as a lag period for the implementation of the entire regulation. Beyond ATMPs, 1 one member state has no process of allowing hospitals or academic institutions the manufacture of call-based products; indeed,Academia is sometimes claimed to be incapable of handling the manufacture of such complex products and simply should not be allowed to do so. However, a valid alternative is not being offered. Even more so, no industry branch has the experience that some academic partners have accumulated in manufacture of ATMPs so, in this field, academic facilities may even outcompete industry.
Costs are an issue, mostly related to GMP-grade starting materials, the personnel required to run a facility efficiently and in compliance with current regulation, and to the infrastructure needed for aseptic manufacture and proper quality control of medicinal products. Costs are beneficial when adequate standards of quality are assured; on the other hand, a risk-based and less costly approach could allow for the manufacture of a certain product even when GMP compliance is not entirely maintained as long as the safety of the product is not affected.
The workshops and conferences exposed a surprisingly high support for an open-minded, collaborative discourse on the development, manufacture, and regulation of ATMPs and the challenges related to this field. Among the many results, this was among the the most striking ones since it demonstrated the need for an exchange that is quite uncommon to Academia; for good reason, academic researchers have been blamed to accept a reclusive behaviour as a necessity for survival in the highly competitive field of health research. Consequently, the following characteristics of the academic world require attention when Academia decides to grow up to the expectations that accompany the obvious role of academic institutions as the main procurer of ATMPs:
1) With limited, short-time employment, scientific success being measured in publications, and a planning perspective of only few years, the timelines inherent in Academic life are far shorter than needed for the lifecycle of product development and clinical application;
2) The financial resources needed are different from ‚conventional‘ research grants in that much more investment is needed;
3) The infrastructure needed in Academia to develop ATMPs successfully is growing, but still not available in sufficient amounts;
4) The field of GMP has not been incorporated fully into Academia as an opportunity for teaching and career development, while specialists in the field are daringly sought (and hunted) by Industry.
5) Academia has an approach to the manufacture of ATMPs that is not necessarily inferior to the Industry perspective, but different: it is about embedding the GMP structure into an Academic Culture, rather than using the GMP structure for Business development and expoitation. Both approaches are justified, they have similar goals in terms of quality standards, but arise from a different culture.
We see a convergence of interests with the regulators in terms of consumer protection: there is only one standard of safety, which is assured by the Standards of Good Manufacturing Practice. Risk awareness may be different in Academia, especially when a clinical background is present and the lives of patients are at stake; but risk knowledge is the fundamental basis for a risk-based approach and a responsible management of the challenges inherent in these complex medicines and the high public attention.
In spite of dramatic adverse events and scandals that have accompanied the development of these drugs, and will continue to do so, cell-based therapies show a safety profile that is not entirely different from what we see in other pharmaceuticals. Rather, there seems to be a problem in efficacy than in safety.
Academia and Advanced Therapy Medicinal Products: Conclusions
In ATMP Development and Manufacture, academic Institutions fill an ill-defined gap especially where Industry’s interests are not at stake, such as small populations of patients. The current regulation has actually improved the situation; it is not seen as a disaster, it has forced every member state to deal somehow with the manufacture of ATMPs, and, as a consequence, GMP facilities can actually be found in hospitals and/or academic institutions of all member states. However, current regulation does not address Academia. Moreover, there is uncertainty about the regulatory process and little harmonisation at the level of delivery across the Member States which are stifling development and commercialisation of these promising therapies. Most disturbing appears to be the detrimental effect on translation to early phase trials which remain largely academic investigator-led.
Proposals
- On the level of legislation, the performance of phase I/II trials needs facilitation. Here, the European Medicines Agency has a growing sense for the specific characteristics of ATMPs and a strong interest in the interaction with stakeholders, including Academia, as interested parties in a constant dialogue. Beyond conventional early-phase clinical trials, first-in-man proof of principle studies which are not phase I/II trials should be facilitated, for instance by omitting a high workload required for documents such as a full-length IMPD (Investigational Medicinal Product Dossier) or a Common Technical Document (CTD) at this stage, and by adopting the pharmacovigilance requirements to the small-scale scenario.
- Academia has to be recognized as a major contributor and partner in ATMP development, given the fact that this field is currently >90% academic led. With Academia being the only one to fill the gap in this field, universities depend on reliable resources to invest in GMP and GCP infrastructures needed to provide a therapy that practically no one else will provide at this stage. Small facilities could be endorsed also by a more risk-based approach as fostered by the FDA and offered by Annex 2 of 1 the European GMP guide.
- The interaction between Academia and Industry needs a better definition in the manufacturing trajectory. It should be noted that a network of GMP-compliant academic/hospital units is being established across the EU that work to the same (and sometimes higher) standards as Industry.
- The regulation of ATMP development in the EU must address both pathways of development: commercially viable products and non-commercial products. Here, legislators, regulators, funding bodies, universities and commercial sector must work together to develop this field with patients.
Technology and knowledge must be and can be transferred across member states. Bringing Europe forward, the most distinguished task of the European institutions, requires them to foster a change in thinking: ATMPs are a brilliant example for the fact that reclusive behavior does not bring scientific excellence to Europe, nor does it lend a hand to European citizens in need. Instead, collaboration in networks and with Industry is the only efficient way to endorse Europe’s competitiveness and welfare in a time when other parts of the world move at a much faster stride. Academia should show more self-confidence as being the only one minding the gap and responding to the just demand for therapeutic innovation in rare and complex diseases where industry is not present, making this a structural and political issuewhere political discourse, interaction and also lobbying for a just cause should not be a field left to Industrial stakeholders alone.
List of Websites:
http://www.academic-gmp.eu
For Contact details, please refer to the website and to the brochure (attached to this report). Thank you!
Advanced Therapy Medicinal Products are gene therapy, somatic cell therapy or tissue engineered products. Regulation (EC) 1394/2007 has defined ATMPs to be drugs; at the gap between medicinal products and medical devices, these complex medicines promise innovative treatment options for complex diseases. Regulation (EC) 1394/2007 was intended to ensure their free movement within the European Union while guaranteeing the highest level of health protection for patients, and forms part of the European project of breaking down barriers and allowing free trade and movement of products. In this, the central role of academic institutions as drivers not just of the development but also of the manufacture of ATMP has been overlooked. Many products may only reach clinical application by relying exclusively on academic facilities. Compliance with industrial standards in an inherently non-industrial environment creates particular financial, managerial and cultural pressures. At the same time, ATMP relying on a highly individualized, labour-intensive therapeutic approach challenge established concepts of regulating medicines innovation.
The Project Academic GMP (www.academic-gmp.eu) has been funded among the FP7 Coordination Action or Support Actions for a duration of 30 months (01 September 2010 –28 February 2013). We have assessed the impact of Regulation (EC) No 1394/2007 on academic GMP facilities by: a) conducting a European survey among non-industry facilities in this sector; b) organising workshops and a major conference for targeted, collaborative discourse; c) establishing a web-based platform for information exchange; d) analysing publications and guidance from the perspective of better regulation principles; e) analysing innovation statistics in relation to ATMPs.
Project Context and Objectives:
Advanced Therapy Medicinal Products (ATMPs) are medicinal products for human use, based on gene therapy, somatic cell therapy or tissue engineering. A rapidly growing area in translational research, they represent the ‘next generation’ of complex medicines for complex diseases and pose particular challenges to medicines regulation.
Regulation (EC) No 1394/2007 has been designed to ensure the free movement of ATMPs within the European Union (EU), to facilitate their access to the EU market and to foster the competitiveness of European pharmaceutical companies while guaranteeing the highest level of health protection for patients. The regulation extends standards of Good Manufacturing Practice (GMP) to ATMPs to ensure their quality, safety and efficacy.
Advanced Therapy Medicinal Products present an area of strategic importance for the European Community. Collectively, these therapies represent the full spectrum of challenges and opportunities of truly disruptive innovation. Some of these therapies need to be integrated speedily and smoothly into existing innovation trajectories, others are set to transcend established marketing and business models in therapeutic medicine.
Academic GMP facilities are major contributors to the development of ATMPs. They respond to clinical needs and provide medicinal products in an environment which, albeit compliant with industrial standards, is by definition not industrial. They find themselves in a challenging position between various, sometimes conflicting interests in the transition of ATMPs from bench to bedside. European investigator-initiated multicenter trials on ATMPs critically depend on academic GMP facilities.
We have assessed the impact of Regulation (EC) No 1394/2007 on academic GMP facilities by: a) conducting a European survey among non-industry facilities in this sector; b) organising workshops and a major conference for targeted, collaborative discourse; c) establishing a web-based platform for information exchange; d) analysing publications and guidance from the perspective of better regulation principles; e) analysing innovation statistics in relation to ATMPs.
The consortium has pursued its objectives in time. The following achievements deserve to be mentioned:
- The results of the survey on Academic GMP facilities in the European Union have been collected, analysed, published and presented to a broad audience on several occasions (see below);
- In-depth interviews have been performed with selected experts in ATMP development in each Member State of the European Union, irrespective of whether they had responded to any of the questionnaires. The interviews provided the most detailed information regarding the heterogeneous implementation of the Directives and the Regulation across the EU and the impact this heterogeneity has on development.
- A Public Conference was held in Brussels on October 11, 2012, as a Joint conference of two FP7-funded Research consortia, entitled: „ The Impact of EU legislation on Therapeutic Advance“. The conference was extremely well attended, with members of National Agencies, of the European Commission and of the European Parliament among the participants;
- A position paper of the consortium was presented to the European Commission, with extracts of the consortium’s work, facts, figures and analyses as well as with proposals for improvement (Annex 1). Several other professional societies have used this position paper as a basis for their contributions to a public consultation on ATMP regulation held by the European Commission. The European Commission has published the summary of the responses recently (cf.: http://ec.europa.eu/health/human-use/advanced-therapies/developments/2013_pc_atmp.html) and the impact of our consortium’s position as brought forward by other stakeholders is evident and satisfactory.
- A Joint Session with the EBMT (European Blood and Marrow Transplantation Group) and Federal Agencies was organized, held and sponsored by our consortium on the occasion of EBMT’s 39th Annual Meeting in London, UK, April 7th to 10th, 2013. As a part of the 2nd Cell Processing Day (April 8th, 2013), this session attracted a surprisingly high number of attendees and provided an opportunity to elaborate on pathways to first-in man clinical trials with ATMPs. In another session, Academic GMP was offered to present the results of the consortium’s work to members of the Joint Accreditation Committee ISCT- EBMT (JACIE).
- Other occasions for „going public“ were sought, found and used extensively. This includes a position paper submitted to the European Commission in response to a public consultation (DG Health and Consumers), submitted to key contacts and professional societies who welcomed the opportunity to use our expertise, and invited presentations in front of the House of Lords, Federal Institutions and Industry Stakeholder Meetings. Details are given in the list of dissemination activities.
- The establishment of an electronic tool in terms of Mapping of the ATMP landscape has been initiated, as a basis for a repository of openly accessible data for the perusal of policy makers and researchers.
We gratefully recognize that, with the help of colleagues, policy makers, partners from industry, patient organizations, clinicians and professional societies, and above all, the European Commission, our efforts in research, analysis, interpretation, communication and dissemination have yielded the following results:
- A solid basis of facts, figures and trends that were brought to public attention,
- An awareness amongst ourselves that the political implications necessitate a more pronounced presence among and interaction with the decision-makers on the political level,
- A growing European network of scientific Institutions involved in all levels of ATMP Development, manufacture and clinical application, reaching out to Industry partners and policy makers on a European level.
In the stakeholder consultations performed as part of our work, and as an expression of the dynamics in the field, we have accumulated evidence in support of our hypothesis that, in the Regulation 1394/2007/EC, Academia has not been sufficiently taken into consideration as a major contributor to ATMP Development and Manufacture. Moreover, there is little harmonisation at the level of delivery across the Member States and uncertainty about the regulatory process which, when combined, are stifling academic research and commercialisation of these promising therapies. Most disturbing appears to be the detrimental effect this has on translation to early phase trials which remain largely academic investigator-led. Regulatory uncertainty remains a barrier to commercial investment and market development in the EU.
At project conclusion, we have seen the following outcomes emerging from our work:
1. We have submitted a comprehensive report reviewing the success of the ATMP regulation, drawing out important trends, potential unforeseen consequences, benefits and opportunities. The regulatory landscape has been delineated, with the Regulation 1394/2007/EC placed in context. With Academia emerging as the major contributor to ATMP Development and Manufacture, we have exposed the developmental trajectory, and highlighted obstacles to successful manufacture of ATMPs, reaching beyond the academic perspective that has been laid down in the title of our project.
2. We have provided a repository of openly accessible data for the perusal of policy makers and researchers, forming the evidence base on which to base strategic decisions not just in medical regulation, but also in business modelling, forecasting and innovation policy . The format for this database is an interactive map of the European Union, its member states and associated countries. This web-based tool allows visitors to obtain information pertinent to the development and manufacture of ATMPs in Europe, to the application of Regulation 1394/2007/EC and to country-specific differences in the implementation of the Regulation.
3. In our position paper and in public reports and presentations, we have issued recommendations aimed to assist the European Commission and other bodies to anticipate the needs for further developing of current EU legislation. By doing so, we propose to regard Regulation 1394/2007/EC as an example as to how the identification of and interaction with stakeholders relevant to the field contributes to the establishment, to the applicability and success of European Regulatory concepts. As such, the results of our project are intended to serve as a case study in Better Regulation practice in the EU innovation policy.
4. As a side effect to our project, we have begun to establish a network that is dearly needed (and hitherto non-existent) for sharing advice, regulatory issues and best practice among the academic GMP community in Europe. We are most delighted to see that the structure for this network as laid down in another FP7 project proposal has found a positive opinion for funding within the European Commission’s Framework Programme, with contributions from other European Centers, industrial partners, and with scientific advice from large umbrella organizations . Clusters of topics addressed are the need for common standards in Quality Control and the extension of an Academic Perspective beyond the standards of Good Manufacturing Practice (GMP) into the world of Good Clinical Practice (GCP) and Clinical Application of ATMPs.
Project Results:
1 Introduction
Advanced Therapy Medicinal Products (ATMPs) are medicinal products based on gene therapy, somatic cell therapy or tissue engineering. Regulation (EC) No 1394/2007 has been designed to ensure the free movement of ATMPs within the European Union (EU), to facilitate their access to the EU market and to foster the competitiveness of European pharmaceutical companies while guaranteeing the highest level of health protection for patients1.
Academic GMP facilities are major contributors to the development of ATMPs. We have assessed the impact of Regulation (EC) No 1394/2007 and related Directives on academic GMP facilities by: a) conducting a European survey in this sector; b) organising workshops for a targeted, collaborative discourse; c) establishing a web-based platform for information exchange; d) analysing publications and guidance from the perspective of better regulation principles; e) analysing innovation statistics in relation to ATMPs.
The work packages (WP) had been designed with these objectives in mind, with each work package specifically addressing one predefined goal.
Work Package 1 (WP1): Coordination and Project Management
Work Package 2 (WP2): Data gathering
Work Package 3 (WP3): Workshops & conference
Work Package 4 (WP4): IT infrastructure
Work Package 5 (WP5): Outreach
WP1: After initially implementing a Consortium Agreement (CA) and establishing guidelines for communication and reporting between the beneficiaries, the coordinator managed the project and kept track of its progress. The management team organized periodic project meetings, emphasized the need for an appropriate internal communication strategy by holding regular video conferences, and requested WP leaders to generate periodic reports by listing achievements and eventual delays. The Coordinator also kept a steady contact with representatives of the European Commission.
WP2: The principal objectives of the teams at Newcastle University and University College London were to generate and analyse quantitative and qualitative data on the impact of advanced therapies and related legislations specifically in the academic and hospitals sector.
After data had been gathered by performing a survey of key actors in this sector, the data have been compared, and supplemented with, interpreted in the light of and contextualised with other data elements that have been procured by the leader and participants of the WP. In addition, a selection of academic GMP facilities from each Member State was contacted for in-depth semi-structured telephone interviews by University College, London (UCL) - the result of which complemented the statistical analysis. A contextual analysis was completed by UCL of the data arising from the telephone interviews.
WP3: As outlined in Annex I to our grant proposal, the consortium has performed a series of GMP workshops, a public conference and a special session on the occasion of the 39th Annual Meeting of the EBMT (European Blood and Marrow Transplantation Group).
Workshop 1 ("Academia meets Industry") was held on March 4, 2011. At the kick-off meeting in Belgirate, we had agreed upon performing the workshop in Newcastle upon Tyne, i.e. at the center of one of our members, Prof Anne M Dickinson. The idea behind this was to visit different centers of the beneficiaries and to learn about their GMP facility, their work and their specific environment.
Workshop 2 was held in Vienna, Austria, on September 23, 2011. The focus on ethical issues was brought forward by speakers, participants and by members of the consortium, with discussions circling around critical questions prepared by Prof. Hildegard Greinix and Prof. Nina Worel who hosted the workshop.
Workshop 3 took place in Frankfurt am Main in March 2012; the conference on ATMPs was held in Brussels in October 2012, and the last workshop, organized in conjunction with the 39th annual EBMT meeting, took place in London in April 2013.
During the work of this project, the need to give more space to a broader political exchange had become more evident. For this reason, the scheduled working conference was shifted from the original venue in Hannover, Germany, to Brussels, Belgium. Furthermore, the event was performed as a joint conference, together with a consortium that addressed a topic closely related to ACADEMIC GMP (“CONTRACT”, Consent in a Trial & Care Environment, FP7 project No. 261412). The conference hosted members of the European Parliament who were asked to carry the critical issues emerging from the consortia’s work forward.
WP4: The Lund University team was assigned the task to efficiently implement a comprehensive web-based project platform and to maintain and update the website on a regular basis. The subcontractor that had been selected by the consortium to perform these tasks was also in charge of controlling and verifying data entry and, together with members of WP2, performing data extraction and data reporting.
WP5: After initially introducing the project to regulatory authorities, scientific organizations and the scientific community, with detailed information about activities of the consortium, the project objectives for this work package were the following:
- Presenting outreach activities at the conference
- Describing outreach activities in the proceedings volume of the conference and in the final report
- Organising the joint session with the EBMT at the 2013 Annual Meeting of the EBMT in London
2 Work Package 2: Data gathering
This study focused on European Academic Good Manufacturing Practice (GMP) facilities involved in the manufacture of Advanced Therapy Medicinal Products (ATMPs). The aim of the study has been to investigate, through survey analysis, how these facilities are operating, how they differ (within and between countries) and establish which factors appear to be influencing ‘success’. Work Package 2 has been concerned with respondent identification, data gathering, construction of survey questionnaires, analysis and interpretation of data.
Distribution of a short questionnaire to members of professional societies, regulatory bodies, coordinating scientists of all identified FP-funded projects related to cell therapy, stem cells, regenerative medicine and/or gene therapy, members of the Stem Cell Users Group (SCUG) and personal acquaintances enabled us to approach more than 700 contacts, of whom 85 respondents declared their willingness to participate in a detailed on-line questionnaire comprised of 71 facility and regulatory questions. In addition, 83 respondents said that they would be interested in “establishing a network, developed over the next 2 years, of non-industrial GMP institutions in Europe – giving Academic GMP a voice”.
In the second, more detailed questionnaire, respondents were asked about ATMP production/development, collaboration, facility size, consultation with regulatory bodies and opinion on implementation of current directives. After a six week period, 50 complete surveys had been received in total from 11 European countries.
The statistical data analysis of the GMP questionnaire was completed in December 2011 - thereafter the report was circulated to the Co-ordinator to and University College, London (UCL) for comment. Further ideas and suggestions were subsequently incorporated.
Selected recipients from each Member State were contacted for in-depth semi-structured telephone interviews by University College, London (UCL) - the result of which complemented the statistical analysis.
Additionally, a contextual analysis was completed by UCL of the data arising from the telephone interviews. In brief, the conclusion was that the EU Regulation of ATMPs is broadly recognised as essential for the future development of the field and there is, as yet, no evidence that this regulation is putting EU scientists and clinicians at a disadvantage to colleagues in the US and other developed countries. However, the additional cost and complexity of ATMP manufacture to GMP compliance does add very significant costs and is thus an indirect negative factor on development of novel therapies in the EU. Furthermore, the lack of consistency in the interpretation of Regulation (EC) 1394/2007 across EU Member States is a barrier to cross-border collaboration in the development, manufacture and clinical application of ATMPs, be it among academic institutions, within “conventional” clinical trials or within the so-called Hospital exemption clause (Art. 28(2)) or for industry if commercialisation is being considered.
The work has been disseminated to a wide audience. Currently a paper has been accepted by Cytotherapy subject to minor revision. Additionally, the results of the study have been discussed at the joint conference in Brussels (October 2012): “The Impact of EU legislation on Therapeutic Advance” and at two workshops at the 39th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT) in London (April 2013). Over 250 delegates attended each of the two sessions at EBMT and the feedback was very favourable.
2.1 Data entry and analysis
A short questionnaire was distributed to 747 relevant European contacts asking if their facilities currently produced ATMPs and/or intended to produce ATMPs in the future. In addition, potential respondents were asked if they would be interested in establishing a network, over the next 2 years, of non-industrial GMP institutions in Europe – giving academic GMP a voice. This questionnaire was made available through email and was accompanied by a covering letter explaining the purpose of the survey and data protection policy. University of Newcastle upon Tyne (UNEW) was responsible for the generation of the email questionnaire. E-mailed (short) questionnaires were entered into a database manually by a data manager based at UNEW.
A representative sample of 50 European facilities subsequently replied to a detailed questionnaire which asked about ATMP production/development, collaboration, facility size, consultation with regulatory bodies and opinion on implementation of current directives. Respondents were from the following countries: Germany (15), UK (10), Spain (7), Italy (4), Netherlands (4), Belgium (3), Austria (2), France (2), Republic of Ireland (1), Romania (1) and Turkey (1).
The analysis investigated how the facilities are operating, how they differed (within and between countries), and established which factors appear to be influencing ‘success’.
The questionnaire responses provided clear evidence that:
1. Those centres which are involved in the initial development of new ATMPs are also those which successfully achieve GMP-grade production for clinical trial.
2. Centres which successfully translated to clinical trial were those which interact with appropriate regulatory authorities for advice.
3. Experienced facilities in ATMP development regularly pass inspections – these facilities understand how to be compliant with GMP standards and are comparable with (and potentially competitive with) industry.
4. Experienced facilities in ATMP development mostly have a pre-existing background in manufacturing non-medicinal, minimally manipulated cell therapies (e.g. haematopoietic stem cell transplant products and associated lymphocyte infusion).
5. It is difficult for new centres to enter the field under existing regulations because of the investment required in facilities and expertise.
6. There is a general paucity of and need for quality control programmes for qualification and standardisation of these products as they progress through development in an attempt to attain marketing authorisation in the EU and beyond.
2.2 Interviews
Following preliminary analysis of the questionnaires, specific questions or areas of anomaly were chosen to be explored in greater depth by telephone interviews with one or more experts in ATMP development in each Member State. The interviews were performed in English or the native language of the interviewee in a semi-structured fashion to address procedures implemented in their facility, regulatory problems encountered and general understanding of implementation of the relevant regulations in their Member State. Interviewees were approached in all Member States of the EU, irrespective of whether they had responded to any of the questionnaires. In the end 20 scientists from 16 member states agreed to participate in the telephone interviews.
After conducting the interviews, there was evidence of uncertainty about the regulatory process and it was clear that this impacted on ATMP development. The inconsistencies in the implementation of Regulation (EC) No 1394/2007 are a considerable barrier to development of ATMPs across the European Union but this is largely due to the myriad of differences in national drug laws which underpin the ATMP Regulation. It was also noted that definitions of a cell-based medicinal product, a gene transfer medicinal product or a tissue engineered product as an ATMP are not harmonized.
It was established that the majority of ATMPs in development are patient-directed or intended to be produced in very small batch sizes, but there is widespread concern that problems with regulation will lead to patients travelling out of their Member State for novel therapies.
As regards interaction with local regulatory authorities, some interviewees reported extreme difficulties in obtaining manufacture approval of specific products. A further problem – particularly for small academic manufacturers -was the immense amount of paperwork associated with GMP and Good Clinical Practice (GCP) compliance. Also, whilst all interviewees supported the concept of a high standard of GMP for ATMPs, there was a common belief that a risk-based approach to compliance with pharmaceutical standards is required in the development of ATMPs.
Three additional issues were of repeated concern:
(1) the use of very contrived animal models in the development of ATMPs,
(2) the lack of training of pharmacy Qualified Persons (QPs) in the manufacture of ATMPs,
(3) heterogeneous implementation of the Hospital Exemption Clause (HEC) in Regulation 1394/2007/EC across the Member States.
2.3 Other data
A comprehensive literature search showed that the EU lags behind the United States (US) with regard to cell therapies in clinical trials; both academic and industry-led. In contrast to the EU, US cGMP facilities licensed by the Food and Drug Administration (FDA) for manufacturing for phase I/II and phase II trials are not subject to regulatory inspection and the burden of compliance is lower. The most active countries in this field outside of EU/USA are South Korea and Brazil where the burden of GMP compliance is also lighter. For example, EU GMP requires all “open” manufacturing steps to be performed in a class 100 (grade A) environment within a class 100 laboratory (grade B) which is extremely expensive to attain, requires excessive gowning and is often incompatible with the use of the equipment routinely used in ATMP manufacture such as floor mounted centrifuges. In contrast, cGMP requirements applied in the US, South Korea and elsewhere stipulate that this type of production step need be performed in a class 100 environment within a class 10,000 laboratory (grade C) with associated cost savings and ease of process design. EU GMP manufacture of investigational ATMPs in clinical trial requires formal release by an accredited “Qualified Person” which is unique to the EU and an added expense and complication.
2.4 Dissemination
The results of the surveys and the interviews have been widely disseminated at national meetings in EU MS, international conferences and are now about to be published in the international scientific journal Cytotherapy. They have been part of a written submission to the UK House of Lords Committee on Regenerative Medicine and of a submission to the European Commission impact assessment of Regulation 1394/2007. A detailed list of dissemination activities is attached to this report.
3 Work package 3: Workshops & Conference
Work package 3 (WP 3) was devoted to the organization and performance of workshops and conferences as outlined in the project description. After the first two workshops I (“Academia meets Industry”, Newcastle/ UK, March 2011) and II (“Ethics involving Advanced Cellular Therapies”, Vienna/Austria, September 2011), workshop III was performed in March 2012 in Frankfurt/M., Germany, followed by the Joint Conference: “Impact of EU Legislation on Therapeutic Advance” in Brussels, October 2012, and the workshop and regulatory session co-hosted by the Academic GMP Consortium and the EBMT on the occasion of the 39th Annual Meeting of EBMT in London, April 2013.
3.1 Workshop I: “Academia meets Industry”, Newcastle, UK, March 4, 2011
Workshop I was performed in Newcastle upon Tyne, i.e. at the center of one of our members, Prof Anne M Dickinson. The idea behind this was to visit different centers of the beneficiaries and to learn about their GMP facility, their work and their specific environment.
Prof Dickinson and Dr Sethe, both in Newcastle, were of tremendous help in organizing the workshop. We were surprised about the interest and positive feedback that we received from well-known experts, especially from national regulatory authorities, GMP experts and Industry at all levels, ranging from small enterprises and university spin-offs to "big pharma".
A detailed report on the workshop has been uploaded. However, some impressions of special importance shall be given here:
− Academia is not unequivocally understood as a professional in terms of GMP. Concern was raised from the side of industry that people coming from academia should not be regarded as competitive or even as potential employees.
− „Exemptions“ were said to form most academic experience, rendering academic centres less risk averse. Costs and time in ATMP manufacture were dramatically underestimated, with „money going to research first“.
− Quality management structures were often rudimentary, and scientific curiosity was perceived as a poor structured counterpart to the planned exploitation cultivated in Industry. Academia were said to be focused to own ideas, refractory to counseling, and reclusive with regard to scientific and technical exchange.
− Academia and Industry were perceived as belonging to different cultures, with different languages, and different currencies: publications and "impact factors" vs. financial balance or even bargain.
Academia took some serious cuffs in the dialogue, albeit in a friendly atmosphere. The sometimes overt condescension was a first hint at the validity of our general hypothesis: Academia is rather seen as a stranger in the field of pharmaceutical production, also and especially with regard to ATMPs, and has not been taken into account when the idea of a harmonized structure for marketing authorisation was pursued, leading to the current legislation.
3.2 Workshop II: “Ethics involving Advanced Cellular Therapies”, Vienna/Austria, September 2011
The second Workshop was held in Vienna, Austria, on September 23, 2011. The focus on ethical issues was brought forward by speakers, participants and by members of the consortium, with discussions circling around critical questions prepared by Prof. Hildegard Greinix and Prof. Nina Worel who hosted the workshop. The relatively high number of representatives from regulatory bodies was greeted as a sign of growing awareness of problems in the field.
After an introduction to the spectrum of potential therapeutic applications for Advanced Therapy Medicinal Products, the issue of safety emerged as a central topic in most of the presentations and discussions. Some aspects of the workshop shall be presented briefly:
- Given that the history of GMP is a history of reactions to scandals from the very beginning of drug manufacture, it was to be expected that representatives from the regulatory bodies would translate the risks associated with ATMPs into regulatory requirements. Here, regulatory questions have proven value in unmasking critical weaknesses of drug development which often had fatal consequences for the patients. Unfortonately, these questions were addressed insufficiently in the development and before the application, as proven in several saddening cases that were presented.
- Notwithstanding the regulatory concern, some incidents were “adverse events” that need to be studied, also were studied, and that pave the way for new scientific information and improvements to drug development. This, by the way, extends beyond ATMPs and is also confronted with the risk of withholding therapy. Some of the cases presented were rather examples of the power of patients’ despair than of scientific soundness.
- Patients nowadays take information on ATMPs from publicly available sources, such as the internet. Unfortunately, most of the responses are miracle cures whereas there are very few scientific publications. Medical articles are also very hard to read for the public. There are also unrealistic fears associated with advanced therapies.
- It is true that clinical studies have to comply with a lot of regulations but they intend to protect the patients. It is not realistic to have 2 levels for clinical studies: a lower standard for academia and a higher standard for the industry because patients' safety cannot be underestimated. Academic investigators face certain challenges because most of the advanced therapies are classified as medicinal products and thus are bound to adhere to standards of GMP and other regulations. Today, not all academic centers are capable of fulfilling these standards; this, however, points at a political problem that cannot be addressed by the regulators.
- A risk-based approach as laid down in the Guideline on human cell-based medicinal products (EMEA/CHMP/410869/2006) is not only a translation of risks into the regulatory requirements: A preemptive assessment of risks on all levels is considered as the most appropriate way to include expert knowledge from basic science to clinical application in a truly scientific manner, to achieve a sound decision based on a risk-benefit assessment and on current schientific knowledge that will always be limited.
- In response to a comment on the disastrous standards of some university laboratories, it was acknowledged that there is insufficient financial support for the academic centers, lack of infrastructure and lack of coordination between laboratories. Furthermore, the regulators saw the difficulty associated with ATMPs in the switch from conducting a clinical trial with a licensed product to drug manufacturing. Standards apply to both of these different roles and investigators have to adhere to these standards.
Dr. Nikolaus Forgó, Chair of Legal Informatics and IT-Law, Institute of Legal Informatics at the Gottfried Wilhelm Leibniz University of Hannover in Germany, gave an assessment of the ATMP regulation from a legal point of view: An interpretation of law as defined by Niklas Luhman as a transformation of uncertainty to certainty by the usage of time appeared hard to be applied in the case of the Directive 1394/2007/EC which rather turned uncertainty into uncertainty at a higher level, as proven by taking the legal environment of this legislation under scrutiny. However, law is not only the transformation from uncertainty to certainty by usage of time but also by communication between parties.
This workshop was the starting point for a most fruitful cooperation between two similar projects funded within the 7th Framework Programme, Academic GMP and CONTRACT headed by N. Forgó, and resulted in a joint conference in Brussels to reach out to policy makers in the very political heart of Europe.
3.3 Workshop III: “Regulation of Advanced Cell Therapies”, Frankfurt/M., Germany, March 16, 2012
Workshop III differed from the previous workshops in that it was embedded in the joint Conference of the18th Annual Meeting of the German Society for Gene Therapy (DG-GT), a Perspective Conference of the Stiftung Hämotherapie-Forschung on the Role of Haemotherapy and Transfusion Medicine, and the 1st Symposium of the LOEWE Center for Cell and Gene Therapy Frankfurt (CGT)), and therefore received broad attention. A copy of the entire conference programme (Annex 1) and the Academic GMP Workshop (Annex 2) have been attached to this report.
With a focus on the regulation of ATMP manufacture, the all-day workshop was divided in three sessions including plenary talks, round-table discussions and pro-con debates that were as vivid and fruitful as they were controversial. Regulators from local, national and EU authorities joined the debate as well as clinician-scientists, stakeholders from Industry and basic scientists. A questionnaire on the topic was distributed at the end, and an extract of the responses to this questionnaire has replenished a report from this conference published recently.
In many aspects, the workshop brought forth more questions than answers. In spite of all the criticism and different points of view, panel discussions as performed in this workshop could make a significant milestone to improve the regulatory landscape. The close cooperation between local and national authorities as well as the physicians and researchers of academia in some member states, especially in Germany and in the UK, could be a role model to initiate the next steps to improve the legislation at EU level.
Consensus existed about the medical necessity to develop advanced therapy medicinal products. However, it remains to be defined how the EU wanted their citizens to provide innovative therapies which the pharmaceutical industry for reasons of profitability (currently) is not interested in, and therefore are provided only by academic institutions for many years to come. In the past, relatively few individual patients have drawn benefit from the medical and scientific progress represented by ATMPs, but the future development is uncertain, in the face of the immense investment needed for the production of ATMPs in academic institutions and, moreover, investigator-initiated clinical trials, a challenge that brings academia to the limits, both financially and administratively. In most academic institutions, appropriate structures do not exist. Small and careful steps will be the only way to establish networks among academic centers, to facilitate the application process for clinical trials for the academic centers, and to draft funding policies to sustainably promote drug development in academic centers, also in view of the Horizon 2020 programme. It was also discussed to what extent cell therapy for individual therapy might at all go through the same development as conventional bulk pharmaceuticals, only for the purpose of leading to an EU marketing authorization. ATMPs, especially when intended as an individualized patient treatment, cannot uniformly be subject to the procedure of an EU-wide approval which is unlikely to be feasible for academic institutions. In this way, the development of life-saving therapy would succumb to EU legislation. It is particularly painful to see patients in critical situations turning to obscure therapists or into poorly controlled situations abroad, although the technical and clinical expertise is available for experimental cell therapies.
3.4 Joint Conference, Brussels, Belgium, October 11, 2012
With a growing recognition of the political dimension of our project, the working conference was shifted from the original venue in Hannover, Germany, to Brussels, Belgium. Furthermore, the conference has been performed as a joint conference, together with a consortium that addresses a topic closely related to ACADEMIC GMP (“CONTRACT”, Consent in a Trial & Care Environment, FP7 project No. 261412). The conference hosted members of the European Parliament who have been asked to carry the critical issues emerging from the consortia’s work forward.
It is with deep gratitude and respect that we acknowledge the continuous, inspiring and most forthcoming support by Dr. Joana Namorado who endorsed the idea to hold this conference in the very political heart of Europe, Brussels, and in a manner that might encourage other FP7 consortia to seek the interaction with policy makers; to my knowledge, other consortia are planning to follow this example.
Reaching beyond the topics of both consortia, the „Joint Conference: The Impact of EU legislation on Therapeutic Advance“ became a broader forum for an exchange of thoughts on the effects of current practice of European Regulation on Clinical Research and Innovation. Among the discussants were MEP Maria da Graca Carvalho (European People’s Party, Portugal), MEP Dr. Eva Lichtenberger (European Free Alliance, Austria), MEP Dr. Peter Liese (European People’s Party, Germany), Dr. Joana Namorado, European Commission Horizontal Aspects Coordination – Ethics and Gender Issues, and Dr. Cornelius Schmaltz, DG Research and Innovation, Policy Officer and Coordinator of FP7 Operations.
The conference touched another point of importance: the fact that, apparently, more and more directives are being repealed by regulations which, as is the case with the Regulation on ATMPs, have been endowed with immediate effect upon introduction. Keynote speakers highlighted the current status in the field and exemplified how dramatically current legislation can impinge on clinical practice. Patient advocacy groups requested partnership in development of novel therapies, and recognition of the fact that even seemingly small effects of innovative therapies may have a substantial impact on the reduction of disease burden and associated morbidity. Issues of informed consent were discussed with a specific focus on pediatric oncology and implications of informed consent procedures on participation in clinical trials in this patient population.
Among the conclusions arising from this conference, it became evident that technology and knowledge must be and can be transferred across member states. Bringing Europe forward, the most distinguished task of the European institutions, requires them to foster a change in thinking: ATMPs are a brilliant example for the fact that reclusive behavior does not bring scientific excellence to Europe, nor does it lend a hand to European citizens in need. Instead, collaboration in networks and with Industry is the only efficient way to endorse Europe’s competitiveness and welfare in a time when other parts of the world move at a much faster stride. Most and above all, Academia should show more self-confidence as being the only one minding the gap and responding to the just demand for therapeutic innovation in rare and complex diseases where industry is not present, making this a structural and political issue where political discourse, interaction and also lobbying for a just cause should not be a field left to Industrial stakeholders alone.
The results of this Conference have been made publicly available in a report, and the list of participants in this event is available for download at the homepage of the consortium.
3.5 “Cell Processing Day” in conjunction with the 39th annual EBMT meeting, London, United Kingdom, April 8, 2013
Together with the conference held in Brussels, this event marks the other of two definite highlights of our work within this consortium. The European Blood and Marrow Transplantation Group (EBMT) is one of the major key player organizations in all facets of current Stem Cell Transplantation and Cell Therapy. One of the participants of our consortium, Prof Jane Apperley (Imperial College London), is among the most distinguished Haematologists in Europe and beyond; she hosted this year’s Annual Meeting as Conference President, while other members of ‘Academic GMP’ contributed to the organizing committee. The meeting attracted about 6800 participants from all over the world.
As a part of the 2nd Cell Processing Day (April 8th, 2013), the sessions organized by our consortium attracted a surprisingly high number of attendees and provided an opportunity to elaborate on pathways to first-in man clinical trials with ATMPs. The consortium thus contributed and co-hosted an entire session and a workshop, thus covering 50% of the 2nd Cell Processing Day, a facet of EBMT’s Annual Meeting that was introduced only recently but has become an integral and widely appreciated part of the EBMT Annual Meetings. In another prominent session of the EBMT Annual Meeting, Academic GMP was offered to present the results of the consortium’s work to members of the Joint Accreditation Committee ISCT- EBMT (JACIE). All slides have been made publicly available on the homepage of our consortium. As a most distinguished way of going public, the consortium couldn’t have had a better conclusion of our work. A copy of the conference program can be found at: http://www.congrex.ch/fileadmin/files/2013/ebmt2013/ebook/ebmt2013-final-programme/flipviewerxpress.html.
4 Work package 4: IT Infrastructure
WP4 comprised a total of 3 tasks: Task 4.1 Requirement analysis and specification; Task 4.2 Design and implementation of IT platform, maintenance and updating of IT platform, and Task 4.3 Database updating, data extraction and reporting. All tasks were successfully completed.
The setup, maintenance and updating of the IT platform was conducted by our subcontractor as planned. The platform could be used without any problems and for all intended purposes. In addition to these tasks, the IT platform was amended by an open forum for questions and answers related to the focus of the Academic GMP project. Furthermore, a member restricted area for Academic GMP documents was established and as well as an interactive map of ATMP regulation in Europe.
With the project “Academic GMP” coming to an end, the website and all the information contained therein will continue to be available. As authorized by the Pharmaceutical Committee of the EC/ DG Health & Consumers, the interactive map of ATMP regulation in Europe was supplemented with data on the implementation of the Hospital Exemption Clause in the Member States. Please refer to the homepage at: http://www.academic-gmp.eu/map.html.
5 Work package 5: Outreach
Headed by the Medical University of Vienna, WP 5 was in charge of presenting the project to regulatory authorities, patient organizations, the scientific community, and the general public. A list of tasks was consequently defined to meet the objectives:
• Publication of a press release at the start of the project, introducing the Academic GMP Consortium and the aim of the project to the public.
• Communication with professional societies, patient organisations and regulatory authorities to inform them of our activities and invite them to the workshops.
• Creation of a list of GMP facilities in Europe, which might be interested in responding to the Academic GMP survey. A list of more than 800 relevant contacts has been compiled and has been used for the survey and other purposes along the project.
• Preparation of a brochure on the Consortium’s activities that would be produced and distributed at professional events. The brochure is publicly available on the homepage of the consortium.
5.1 Outreach to professional societies
The presidents of professional societies in the field, EBMT, ISCT and JACIE were informed about the research activities of our consortium. They were also sent the project survey along with invitations to our workshops and were asked to distribute this information to the members of their respective societies. These European and international societies were invited to participate in the conference and the Joint Session with EBMT at the 2013 Annual Meeting of the EBMT in London.
5.2 Contact details
A list with contact details of academic GMP facilities in Europe, their clinical partners and regulatory authorities was created in order to contribute to a closer communication between the partners in ATMP development and regulation. These contact details have already been used to invite respective institutions to the Academic GMP workshops and to encourage them to participate in our survey. Contact details of national and regional regulatory authorities were used for inviting them to the conference and the Joint Session with EBMT at the 2013 Annual Meeting of the EBMT in London.
5.3 Communication with the European regulatory authorities
The consortium was registered at the CAT office and was accepted as an interested party as of March 2011. Information about the research activities including workshops, surveys and the conference were also sent to the CAT. We sent additional information about the conference and the Joint Session with EBMT at the 2013 Annual Meeting of the EBMT in London to the CAT office. The information sent included the program agenda, venue and main objectives of the conference and joint session. Unfortunately, EMA could not allow members of the agency to participate in the joint session with EBMT as originally intended, for reasons of internal reorganization. However, members of the British Authorities (MHRA) were so kind as to substitute for their EMA colleagues.
5.4 Communication with patient organizations
Contact details of patients organizations that operate on a national and European level were collected in a list. Communication with these organizations was established and they were sent information about our research consortium including invitations to workshops and the conference. After providing a list with contact details of patients’ organizations that operate on a national and European level and informing them during the first reporting period about our research consortium, these patients’ organizations were invited to the workshops and the conference. Among these, several national umbrella organizations (ACHSE e.V. in Germany, Genetic Alliance, UK, and others) participated actively in the workshops, in the Joint Conference in Brussels and in the joint session with the EBMT.
5.5 Joint session on ATMP regulation, EBMT annual meeting, 2013
The president of the 39th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT), Prof. Jane Apperley, agreed to have a Joint EBMT session with our consortium. Two sessions with internationally renowned chairs and speakers were organized by our consortium.
The two EBMT – Academic GMP sessions were announced on the official homepage of the EBMT, as part of the 2nd Cell Processing Day, inviting all members including physicians, nurses, data manager, associated researchers, patients and patients’ advocacy groups and the public to the Annual Meeting and thus, also to the consortium’s workshops.
The two sessions (Workshop and plenary session) took place during the 39th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT) and were a Joint EBMT session with our consortium on April 8, 2013 at the ICC ExCel London. The first workshop was entitled “EBMT – Academic GMP Workshop: ATMP clinical trials” and was located within the Cell Processing Day and thus, had an ideal target audience consisting of clinicians and preclinical scientists performing research not only in the field of hematopoietic stem cell transplantation but also in areas of regenerative medicine and regulatory issues. Our consortium organized four presentations consisting of the following:
- Introduction of ATMP, ATIMP and CTD regulations: Prof. Mark Lowdell, London, UK
- How to produce an IMPD for regulatory submission: Dr. Pauline Meij, Leiden, NL
- First in patient: regulatory options, gaps and suggestions (Academic GMP):
Prof. Martin Hildebrandt, Munich, DE
- A regulator’s perspective of an ATMP specification file: Dr. Ian Rees, London, UK
During the workshop an actively participating audience of approximately 100 participants challenged definitions of ATMPs, discussed regulatory issues limiting progress in the clinical application of ATMPs and the role of academic facilities performing research in this very innovative field of advanced cellular therapies. The Chairs of the Joint EBMT session, Prof. Martin Hildebrandt and Prof. Gunnar Kvalheim from our research consortium entertained numerous questions and finally summarized the most important aspects of the discussion for incorporation into the position paper of the consortium.
The second workshop during the Cell Processing Day of the 39th Annual Meeting of EBMT on April 8, 2013 was chaired by Prof. Ulrike Köhl, Frankfurt, Germany from our research consortium, and was entitled “Quality control of ATMPs”. It was also supported by Academic GMP as clearly stated in the program booklet and during the scientific session. Our consortium organized three presentations consisting of the following:
- Enumeration and characterization of circulating cells (in vivo), viability of cell products, residual cell enumeration: Dr. Johannes Fischer, Düsseldorf, DE
- QC on ATMPs (GMP) and non-ATMPs with examples: Dr. Ineke Slaper-Cortenbach, Utrecht, NL
- Standardisation of cell counting, single versus dual platform approach, expanded cells (ex vivo); advantage in ATMPs: Dr. Albert Donnenberg, Pittsburgh, US
During this workshop, important issues on quality control of ATMPs were discussed including:
a. attempts to standardize the characterization of different cellular subpopulations for clinical use,
b. enumeration of different cellular fractions in the circulation and
c. options for ex vivo expansion of cellular subpopulations for clinical use.
The audience of approximately 130 participants from the fields of cell collection, processing, preclinical and clinical cellular research interacted lively with the Chairs and speakers of this workshop and finally agreed on important definitions and standardisation.
6 Dissemination of project results
The knowledge generated within the project has been monitored and managed with diligence and care. The gained knowledge was made available to the project partners on a regular basis through electronic emails, telephone calls and project meetings. It has also been shared with the public, the GMP/ATMP community and other stakeholders through publications, workshops and participation of consortium members to professional meetings. Please refer to WP5 for main activities performed in this area. A list of dissemination activities can be retrieved at the end of this report.
7 Communication with other consortia
Within the FP7 programme, several projects showed similarities or offered opportunities for a collaboration in several ways. For this reason, we explored these opportunities and used them for a better achievement of common goals as extensively as possible.
The CONTRACT Consortium (grant agreement no. 261412) investigated the impact of EU legislation on informed consent (Clinical Trials Directive, Data Protection Directive) on translational research with a view to informing future policy-making in this area. For complex medicines such as ATMPs, this was seen as of utmost interest to the development and application of ATMPs in clinical trials, exemplifying the close proximity of GMP (Good Manufacturing Practice) and GCP (Good Clinical Practice) in the challenging area of cellular therapies. In several meetings, mutual participation in workshops and, most importantly, in the Joint conference on the Impact of EU Legislation on Therapeutic Advance, this collaboration resulted in a most fruitful and recognizable joint effort. To a lesser extent, this held true for other projects that addressed other EU Regulations and directives, including the Tissues and Cells Directive (2004/23/EC), with the TISS.EU project (grant agreement no. 202204) coordinated by Dr. Christian Lenk and Prof. Dr. Claudia Wiesemann (Dept. for Ethics and History of Medicine, University of Göttingen) in cooperation with Dr. Nils Hoppe (Centre for Ethics and Law in the Life Sciences, University of Hannover). Other projects addressing the impact of EU legislation on health research were approached but declined to participate.
The expertise gathered in Academic GMP was welcomed by other projects funded within the FP7 framework programme who asked the consortium as a whole or members thereof to help in terms of investigational medicinal products, regulatory issues and manufacture. This includes the projects: BIOHYBRID (grant agreement no. 278612), T-CONTROL (grant agreement no. 601722), CellEurope (grant agreement no. 315963), AGORA (grant agreement no. 602366), and others.
8 Publications
As planned in the beginning, the results of our work are being published in a major scientific journal (Pearce et al, Cytotherapy 2013, in press). Other publications will be published soon or have been published already. The results communicated haven’t been easy to adopt to a classical format of publication, but were taken up by the peer reviewers and editors with profound interest. Some have been cited already to serve as proof for the challenges inherent in the field and the critical role of academia.
1. K.F. Pearce, M. Hildebrandt, H. Greinix, S. Scheding , U. Koehl, N. Worel, J. Apperley, M. Edinger , A. Hauser , E. Mischak-Weissinger , A.M.Dickinson M.W.Lowdell. The Regulation of Advanced Therapy Medicinal Products in Europe and the Role of Academia. Cytotherapy 2013, in press.
2. M. Hildebrandt, N. Forgó. Short Report: Joint conference on the Impact of EU Legislation on Therapeutic Advance. Cytotherapy 2013, in press.
3. U. Köhl, A. Hauser, M. Hildebrandt. Einfluß der EU-Verordnung 1394/2007 auf Arzneimittel für neuartige Therapien. Dt. Zeitschr. f. Klin. Forschung: 3/2013; 17(2): 57-62.
4. S. Sethe, M. Hildebrandt. Caught in the Gap: ATMP Manufacture in Academia. ISCT Telegraft 19(1), 2012.
5. S. Sethe, A. Dickinson, C. Batkai, M. Hildebrandt. Manufacture of Advanced Therapies: Academia meets Industry. Reg Rapp 8(7/8), 9-11, 2011.
In addition, Insight Publishers are currently preparing a report on the work of the Academic GMP consortium which is expected to appear in autumn 2013. This report will be made publicly available, as all publications emerging from our work.
9 Acknowledgement
In the performance of the management and coordination tasks, the value of the assistance by Ms. Carole Batkai cannot be overestimated. With her friendly and forthcoming attitude as well as with a high degree of professionalism, her continuous support to the tasks of coordination and management are acknowledged most gratefully.
We are gratefully indebted to our external advisors, Stefan Miltenyi, Volker Huppert, Murat Aktas and Marc Barthold, who participated actively in the events organized by our consortium, showing their interest, contributing their view from an industry perspective with close associations with the academic world, and by all means endorsed the project on every opportunity.
We wish to thank the European Commission for entrusting us with the financial and logistic support to perform this project. It is gratefully acknowledged that this project has led us far beyond the original concept, and into a constellation at the interface of science and policy/ public decision making, where the presence of scientists is requested and expected, for good reason.
Most and above all, it is with deep gratitude and respect that we acknowledge the continuous, inspiring and most forthcoming support by the scientific officer, Dr. Joana Namorado, who endorsed our work in a most favourable way, putting this project into a broader perspective. Dr. Namorado ignited an apprehension of the political dimension and responsibility of science, especially in the field of Health research, where European politicians need scientists to develop, to communicate and to explain politics and decisions from a scientific perspective.
Dr. Namorado supported vigorously the idea to hold a conference in the very political heart of Europe, Brussels, and in a manner that might encourage other FP7 consortia to seek the interaction with policy makers. This conference would never have been conceivable if we, the participants of this consortium, hadn’t had the opportunity to be supported by, and to interact with, the political Europe as an integral part of this project. I haven’t been fully aware of the political dimension of our project before, and I cannot be grateful enough for this opportunity to give academia a voice in this complex and dynamic field.
Potential Impact:
The survey gave proof of the existence of Academic and Non-Industry facilities that develop and produce ATMPs successfully. Successful institutions share distinct features that are independent from the country of origin. There is still a lack of academic facilities capable of contributing to the field of translational research, and it is difficult for new facilities to enter the field. Interestingly, those facilities who manufacture ATMPs in a University/Medical School apparently would benefit from collaboration/co-operation with other centres. However, the degree of implementation of EU Regulation varies between member states, with evidence of substantial differences in the criteria used to define ATMPs and in the approved manufacturing environment. This regards genuine academic facilities versus third party contract manufacturers, but also a country-specific interpretation of GMP standards.
In the interviews, topics were addressed such as experiences with the Regulatory classification of products, national practices of licensing, GMP requirements, the availability of Qualified Persons required to release batches and products for clinical use, cost implications and competitiveness. A focus was set on the application of the Hospital Exemption Clause, a highly disputed section of Regulation 1394/2007/EC that might be regarded as an apprehension of the role of Academia, especially in the “niche” of rare diseases and small patient populations that is not in the focus of Industry. In fact, it is evident that, apart from the “conventional” chain of product development, there are ATMPs that never have been intended to reach marketing authorisation, never will do so, and never will be in the scope of Industry. If, however, a therapy is available and a valid option for patients with unmet clinical need, who will provide these patients with a medicine they have the right to accede? And: How does the current regulation cover this field of products which, inadvertently or not, are in the main focus of Clinical interests in Academia?
Member states are handling Regulation 1394/2007/EC in an irritating way. Although the regulation as such took immediate effect upon publication, the 2-year exemption rule for manufacturers had been used apparently by many member states as a lag period for the implementation of the entire regulation. Beyond ATMPs, 1 one member state has no process of allowing hospitals or academic institutions the manufacture of call-based products; indeed,Academia is sometimes claimed to be incapable of handling the manufacture of such complex products and simply should not be allowed to do so. However, a valid alternative is not being offered. Even more so, no industry branch has the experience that some academic partners have accumulated in manufacture of ATMPs so, in this field, academic facilities may even outcompete industry.
Costs are an issue, mostly related to GMP-grade starting materials, the personnel required to run a facility efficiently and in compliance with current regulation, and to the infrastructure needed for aseptic manufacture and proper quality control of medicinal products. Costs are beneficial when adequate standards of quality are assured; on the other hand, a risk-based and less costly approach could allow for the manufacture of a certain product even when GMP compliance is not entirely maintained as long as the safety of the product is not affected.
The workshops and conferences exposed a surprisingly high support for an open-minded, collaborative discourse on the development, manufacture, and regulation of ATMPs and the challenges related to this field. Among the many results, this was among the the most striking ones since it demonstrated the need for an exchange that is quite uncommon to Academia; for good reason, academic researchers have been blamed to accept a reclusive behaviour as a necessity for survival in the highly competitive field of health research. Consequently, the following characteristics of the academic world require attention when Academia decides to grow up to the expectations that accompany the obvious role of academic institutions as the main procurer of ATMPs:
1) With limited, short-time employment, scientific success being measured in publications, and a planning perspective of only few years, the timelines inherent in Academic life are far shorter than needed for the lifecycle of product development and clinical application;
2) The financial resources needed are different from ‚conventional‘ research grants in that much more investment is needed;
3) The infrastructure needed in Academia to develop ATMPs successfully is growing, but still not available in sufficient amounts;
4) The field of GMP has not been incorporated fully into Academia as an opportunity for teaching and career development, while specialists in the field are daringly sought (and hunted) by Industry.
5) Academia has an approach to the manufacture of ATMPs that is not necessarily inferior to the Industry perspective, but different: it is about embedding the GMP structure into an Academic Culture, rather than using the GMP structure for Business development and expoitation. Both approaches are justified, they have similar goals in terms of quality standards, but arise from a different culture.
We see a convergence of interests with the regulators in terms of consumer protection: there is only one standard of safety, which is assured by the Standards of Good Manufacturing Practice. Risk awareness may be different in Academia, especially when a clinical background is present and the lives of patients are at stake; but risk knowledge is the fundamental basis for a risk-based approach and a responsible management of the challenges inherent in these complex medicines and the high public attention.
In spite of dramatic adverse events and scandals that have accompanied the development of these drugs, and will continue to do so, cell-based therapies show a safety profile that is not entirely different from what we see in other pharmaceuticals. Rather, there seems to be a problem in efficacy than in safety.
Academia and Advanced Therapy Medicinal Products: Conclusions
In ATMP Development and Manufacture, academic Institutions fill an ill-defined gap especially where Industry’s interests are not at stake, such as small populations of patients. The current regulation has actually improved the situation; it is not seen as a disaster, it has forced every member state to deal somehow with the manufacture of ATMPs, and, as a consequence, GMP facilities can actually be found in hospitals and/or academic institutions of all member states. However, current regulation does not address Academia. Moreover, there is uncertainty about the regulatory process and little harmonisation at the level of delivery across the Member States which are stifling development and commercialisation of these promising therapies. Most disturbing appears to be the detrimental effect on translation to early phase trials which remain largely academic investigator-led.
Proposals
- On the level of legislation, the performance of phase I/II trials needs facilitation. Here, the European Medicines Agency has a growing sense for the specific characteristics of ATMPs and a strong interest in the interaction with stakeholders, including Academia, as interested parties in a constant dialogue. Beyond conventional early-phase clinical trials, first-in-man proof of principle studies which are not phase I/II trials should be facilitated, for instance by omitting a high workload required for documents such as a full-length IMPD (Investigational Medicinal Product Dossier) or a Common Technical Document (CTD) at this stage, and by adopting the pharmacovigilance requirements to the small-scale scenario.
- Academia has to be recognized as a major contributor and partner in ATMP development, given the fact that this field is currently >90% academic led. With Academia being the only one to fill the gap in this field, universities depend on reliable resources to invest in GMP and GCP infrastructures needed to provide a therapy that practically no one else will provide at this stage. Small facilities could be endorsed also by a more risk-based approach as fostered by the FDA and offered by Annex 2 of 1 the European GMP guide.
- The interaction between Academia and Industry needs a better definition in the manufacturing trajectory. It should be noted that a network of GMP-compliant academic/hospital units is being established across the EU that work to the same (and sometimes higher) standards as Industry.
- The regulation of ATMP development in the EU must address both pathways of development: commercially viable products and non-commercial products. Here, legislators, regulators, funding bodies, universities and commercial sector must work together to develop this field with patients.
Technology and knowledge must be and can be transferred across member states. Bringing Europe forward, the most distinguished task of the European institutions, requires them to foster a change in thinking: ATMPs are a brilliant example for the fact that reclusive behavior does not bring scientific excellence to Europe, nor does it lend a hand to European citizens in need. Instead, collaboration in networks and with Industry is the only efficient way to endorse Europe’s competitiveness and welfare in a time when other parts of the world move at a much faster stride. Academia should show more self-confidence as being the only one minding the gap and responding to the just demand for therapeutic innovation in rare and complex diseases where industry is not present, making this a structural and political issuewhere political discourse, interaction and also lobbying for a just cause should not be a field left to Industrial stakeholders alone.
List of Websites:
http://www.academic-gmp.eu
For Contact details, please refer to the website and to the brochure (attached to this report). Thank you!
