- Email: [email protected]
Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs
DRUDIS-2564; No of Pages 4 Drug Discovery Today Volume 00, Number 00 October 2019
PERSPECTIVE
feature Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs The advanced therapy medicinal products (ATMPs) landscape is entirely different from classical drug development. Academia has been the major source of ATMP development, and academic hospitals act as trial sites for the clinical testing of ATMPs, including early academic-led trials as well as industry-sponsored trials that pursue the full developmental pathway to market authorization. The recent breakthrough developments in some ATMPs, such as genetically engineered immune cells, have confronted academic hospitals with a substantial amount of public demand, competitive pressure, and costs. At the same time, risks, toxicities, and necessary countermeasures demand an appropriate infrastructure, expertise and training which have not yet been fully standardized. How can Ethics Committees consider trial sites and investigators in clinical trials with ATMPs as appropriately qualified?
Introduction: what is so special about ATMPs? ATMPs are medicinal products based on gene therapy, somatic cell therapy, or tissue engineering. Regulation (EU) 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 [1]. Given that ATMPs pose specific challenges to developers, manufacturers, regulators, and clinicians, Articles 4 and 5 of Regulation 1394/2007 have asked the European Commission (EC) to establish distinct sets of rules for these innovative E-mail address: [email protected]. 1359-6446/ã 2019 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.drudis.2019.10.003
and complex cell-based medicinal products. Issues related to the manufacture of ATMPs have been addressed in a Guideline on Good Manufacturing Practice (GMP) for Advanced Therapy Medicinal Products, adding a separate Part IV to EudraLex Volume 4 [2]. With regard to good clinical practice (GCP), a stakeholder consultation has been performed for this purpose [3]. Surprisingly, this consultation did not address the qualification of clinical trial sites and investigators. That said, the following questions demand consideration: (i) how can clinical trial sites and investigators using ATMPs give documented evidence of their specific qualification?; (ii) how can Ethics Committees, charged with the task of approving clinical trial sites and investigators as appropriately qualified, find ways to consider the qualification of trial sites and investigators in view
of the specific risks inherent in ATMPs?; and (iii) how can Ethics Committees draw on specific and independent expertise needed to assess this special group of innovative medicines?*
What are the risks in ATMPs? CAR-T cells as an example Genetically engineered cells, such as chimeric antigen receptor-transduced (CAR-T) cells, have received a considerable amount of attention over the past few years [4]. Here, they serve as
* The evaluation of advanced therapy medicinal products often requires specific expertise, which goes beyond the traditional pharmaceutical field and covers areas bordering on other sectors, such as biotechnology and medical devices [Regulation (EC) 1394/2007 [1]].
www.drugdiscoverytoday.com 1 Please cite this article in press as: Hildebrandt, M. Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs, Drug Discov Today (2019), https:// doi.org/10.1016/j.drudis.2019.10.003
Features PERSPECTIVE
Martin Hildebrandt1,2
DRUDIS-2564; No of Pages 4 PERSPECTIVE
Features PERSPECTIVE
prominent examples of ATMPs, because they carry a distinct efficacy and toxicity, and attract high clinical attention and desire for pharmaceutical exploitation [5,6], with impacts on the qualification of trial sites and investigators. With two CAR-T cell products already authorized for marketing in the EU, >40 other CAR-T cell products are in clinical development [7] and almost 400 trials using CAR-T cells are currently recruiting [8]. The impressive clinical response rates have raised public attention and suggest that CAR-T cells could act as a spearhead for a spectrum of indications beyond the current ones (i.e., acute lymphatic leukemias and certain types of lymphoid neoplasm). With patients in desperate need, clinicians have put growing pressure on regulators and politicians to render these promising therapies more rapidly available, irrespective of gaps in infrastructure, clinical expertise, and concepts for the coverage of costs. The growing clinical use of CAR-T cells has helped to recognize a distinct toxicity pattern of CAR-T cell therapies, most prominently: (i) a cytokine release syndrome characterized by high fever, hypotension, hypoxia, and/or multiorgan toxicity; and (ii) a CAR-T-cell-related encephalopathy syndrome (CRES), typically characterized by toxic encephalopathy with symptoms of confusion and delirium, occasionally seizures and cerebral edema. Similarly serious, albeit less frequent, are cases of fulminant hemophagocytic lymphohistiocytosis (HLH) or macrophage-activation syndrome (MAS), characterized by severe immune activation, lymphohistiocytic tissue infiltration, and immune-mediated multiorgan failure (reviewed in Refs [6,7]). Although attempts have been taken to reduce the therapy-associated risks and to ultimately allow for CAR-T cell therapy to be performed in an outpatient setting [9], CAR-T cells with novel targets show a common pattern of toxicity that depends mainly on on-target, offtumor effects, because CAR-T cells exert their cytotoxic effect upon antigen recognition and binding. Furthermore, sequential and simultaneous combination with other innovative therapies, such as checkpoint inhibitors [10], will bring not only higher and broader efficacy, but also hitherto unknown toxic effects, apart from another dimension in costs.
Qualification of trial sites and investigators: who is in charge? ATMPs are on a playing field that is entirely different from traditional pharmacopoeia and off-the-shelf products [9,11], and studies brought in front of Ethics Committees challenge 2
Drug Discovery Today Volume 00, Number 00 October 2019
our knowledge of these innovative medicines as they may challenge the applicants themselves. The safety and well-being of participants is dependent on the availability of an expertise and infrastructure that can cope with the potential risks inherent in the exposure of patients to these innovative products. Who is in charge of selecting such qualified centers and investigators? The ICH harmonized tripartite Guideline for Good Clinical Practice E6 (R2) states that the responsibility for selecting appropriately qualified investigator(s)/ institution(s) lies with the sponsor: ‘Each investigator should be qualified by training and experience and should have adequate resources to properly conduct the trial for which the investigator is selected ( . . . )’, furthermore that: ‘If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multicentre trials, their organization and/or selection are the sponsor’s responsibility.’ [12]. The US Food and Drug Administration (FDA) stipulates that the qualification of trial sites and investigators be judged upon ‘the adequacy of the facility’s staff and equipment, including the availability of emergency or specialized care’, and based ‘upon the nature and risks of the proposed research’ [13]. Thus, it is the responsibility of the sponsor to ascertain the qualifications of clinical sites and investigators, and the qualifications of trial sites and investigators should be considered based on the risks inherent in the investigational medicinal product.
Are there standards to consider a site as appropriately qualified? First attempts to define standards for the treatment environment and patient surveillance before, during, and following CAR-T therapy have been developed [14] and commended for lending their expertise to others. Standardized treatment algorithms and rules for toxicity management in patients treated with CAR-T cells and similar ATMPs are essential, especially in clinical trials: they give evidence of a quality and risk management infrastructure and of the professional expertise needed to ensure the safety of trial participants, as a criterion of qualification. Major pharmaceutical companies that explore the clinical use of CAR-T cells have decided to build on existing accreditation schemes, such as the FACT-JACIE standards [15], for centers with hematopoietic stem cell and bone marrow transplantation programs. In its 7th edition, the accreditation scheme includes a chapter on minimum standards for ‘the administration of
immune effector cell products, such as chimeric antigen receptor T cells (CAR-T cells), natural killer cells, virus-specific T cells, therapeutic cellular vaccines, and others’ [16]. In another FACT guideline, standards for cellular therapy have been published, representing ‘basic fundamentals that can be applied to any cell source or therapeutic application, and are intended to be used throughout product development and clinical trials.’ [17]. A trial site that adheres to such standards, and explicitly adopts those sections that address cell-based immunotherapy, should be assumed to have the capacities, training, and infrastructure needed to handle cell-based medicinal products, whereas details specific to the investigational product and the trial in question might require additional qualifications. Caution will be needed in the GCP arena because the ATMP under investigation will bring new toxicities and adverse events that might not be attributed to the novel therapy because of the lack of knowledge specific to this type of products.
ATMPs: the hospital as an exemption or a gap? Academic hospitals have been at the forefront of the research and development leading to the clinical use of ATMPs [11]. The fact that traditional industry now pursues clinical trials and marketing authorization with genetically engineered immune cells should take into account that academic ‘participating’ trial sites have often made huge investments in GCP and GMP infrastructure, without which the performance of the trials simply would not be feasible, rendering the trial site not acceptably qualified from the perspective of an Ethics Committee. In this highly pressurized field in terms of costs, public awareness, and patients’ despair, the commercial facet will make it difficult to ensure due diligence in the selection and qualification of trial sites. The notion that hospitals should be offered specific standards for the preparation of ATMPs on a nonroutine basis according to specific quality standards in a still ill-defined way, the socalled ‘Hospital Exemption’ [cf. [1], Article 28(2)] should let us bear in mind that hospitals occupy a special place in the ATMP arena, at the crossroads of research, development, earlyphase, and noncommercial clinical use, especially when a marketing authorization might not be either desired or possible. For autologous products, they often also provide cell apheresis products and similar products as starting materials vital for the ATMPs. Therefore, a revision of the ‘Hospital Exemption’ [1] should take
www.drugdiscoverytoday.com Please cite this article in press as: Hildebrandt, M. Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs, Drug Discov Today (2019), https:// doi.org/10.1016/j.drudis.2019.10.003
DRUDIS-2564; No of Pages 4 Drug Discovery Today Volume 00, Number 00 October 2019
Are adverse effects collected and communicated? The role of Registries Registries for the documentation of adverse events observed in CAR-T cells and similar ATMPs have been called for and are currently being established. As an example, the European Society for Blood & Marrow Transplantation (EBMT) registry has been expanded to accommodate the use of immune effector cells. Recently, the European Medicine Association (EMA) qualified ‘the cellular therapy module of the EBMT registry as an appropriate data source for post-authorisation studies to support regulatory decision-making concerning CAR-T cell therapy for haematological malignancies’ [18]. However, the documentation within clinical trials is not foreseen to be reported (and potentially unblinded) to registries outside clinical trials, also for obvious economic reasons, and the resulting delays and gaps in reporting adverse effects are difficult to appreciate. A solution could be in: (i) a mandatory opening of the data safety update reports (DSURs) or parts thereof to the registries; and (ii) a rapid alert system to communicate unpublished, but crucial incidences to the registries and (accredited) clinical trial sites, preferably again via the registries. Beyond ATMPs, the Clinical Trials Registry, at the core of Clinical Trial Regulation, will hopefully bring a transparency to clinical trials that has not been encountered before [19]. A section dedicated to ATMPs in this registry would be helpful.
Networks In ATMPs, the experience needed in drug handling, application, adverse effects, and their management differ substantially from traditional pharmacopoeia [6]. Centers that move into this field should be encouraged to collaborate with more experienced centers to let future investigators acquire the knowledge needed, because this goes beyond clinical experience and traditional GCP training. Given the embryonic nature of consensus guidelines for treatment and follow-up even among experienced clinicians [20], the support of less experienced investigators within networks should be seen as a criterion of qualification. ‘Active involvement in clinical trials’, a criterion of qualification demanded by Ethics Committees in Germany [21], should be defined as documented evidence of interaction and training by colleagues in more experienced
centers. Given that academic centers will be expected more than others to handle clinical trials with ATMPs, networks and training opportunities should be established primarily in academia.
Concluding remarks: shared responsibilities Cell-based immunotherapies, a prominent example of ATMPs, are here to stay. The ATMP field has evolved from academia as the major source of ATMP development into a somewhat paradoxical situation, where few academic centers have remained in Europe that retain compliance with the European GMP ATMP and GCP legislations, because many of them have not been endowed sufficiently with the capacities and infrastructure to carry this development further in parallel to (or cooperation with) industry. Industry has benefitted from this development, because a substantial part of the burden of infrastructure still rests with academia. Of note, EU Regulation 536/2014 offers the option to researchers to act as co-sponsors of clinical trials, strengthening their role in clinical development.y The selection of trial sites and investigators is the responsibility of the sponsor, and the decision about the site(s) as being sufficiently qualified lies with the Ethics Committee. As such, Ethics Committees demand oversight in a highly competitive field at the edge of commercialization. Leaving the responsibility to the sponsor alone is not enough to ensure the safety of patients treated with cell-based high-risk medicinal products. From the perspective of an Ethics Committee, documented evidence of the qualification of trial sites and investigators using CAR-T cells and similar ATMPs should include: (i) a qualified trial site in possession of the infrastructure needed to handle these toxicities; (ii) a risk–benefit analysis that addresses the characteristics of the respective ATMP specifically and appropriately; (iii) the capacity to recognize, monitor, grade, manage, and document the acute toxicity inherent in this approach;
y In practice, there might be loose, informal networks of researchers or research institutions that jointly conduct a clinical trial. Those networks should be able to be co-sponsors of a clinical trial. To not weaken the concept of responsibility in a clinical trial, where a clinical trial has several sponsors, they should all be subject to the obligations of a sponsor under this Regulation. However, the cosponsors should be able to split up the responsibilities of the sponsor by contractual agreement.
(iv) transparency [i.e., a commitment by the sponsor (especially by Industry) to communicate crucial incidences and observations in a rapid alert system that allows other trials to benefit from these details of critical information); (v) documented evidence of active involvement of investigators in previous trials, for instance by training in a recognizable network of collaborating centers (i.e., qualified trial sites) that exchange knowledge, share training, and help each other, primarily as an academic initiative. Industry could contribute funding to such a network, which would be of immediate benefit to industry-sponsored trials; and (vi) the Hospital Exemption, a hitherto unfortunate attempt to address the role of specialized medical centers in the use of ATMPs, should be reconsidered and reshaped to include concepts for the use of ATMPs explicitly in the GCP arena. Ethics committees will depend on independent experts in ATMPs to provide guidance in assessing clinical centers and investigators as qualified for these special medicines. As suggested in the ATMP Regulation 1394/2007, Ethics Committees might have to revert to the regulators in the decisions on clinical trials with ATMPs to judge appropriately on the qualification of clinical sites and investigators, or find ways to address this special group of drugs together. Together with professional societies, they could establish an expert registry for ATMPs with full disclosure of financial interests, providing expertise both for Ethics Committees and clinical centers. Ideally, these experts would have insight into both GMP and GCP to judge the risks inherent in the proposed trial appropriately. Ultimately it will always come down to humans lending trust to others, when the Ethics Committee, on behalf of the patients participating in the trial, will consider the applicant as trustworthy or not. The quantum of trust cannot be replaced by legal and regulatory requirements, but has to emerge from structured evidence of risk awareness, preparedness, training, and communication with other centers. This will not suffice to guarantee a benefit to the participants and patients, but might help to make the development and clinical use of ATMPs safer, providing better science and better care.
References 1 Anon (2007) Regulation (EC) 1394/2007 of the European Parliament and of the Council on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. Off. J. Eur. Union 324, 121–137
www.drugdiscoverytoday.com 3 Please cite this article in press as: Hildebrandt, M. Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs, Drug Discov Today (2019), https:// doi.org/10.1016/j.drudis.2019.10.003
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the GCP arena into account, in a different way than explicitly excluding clinical testing, as is the case now.
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2 EudraLex (2007) The Rules Governing Medicinal Products in the European Union Volume 4: Good Manufacturing Practice. Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products. EC 3 Anon (2018) Targeted Stakeholder Consultation on the Draft Guidelines on Good Clinical Practice for Advanced Therapy Medicinal Products. EC 4 Subklewe, M. et al. (2019) Chimeric antigen receptor T cells: a race to revolutionize cancer therapy. Transfus. Med. Hemother. 46, 15–24 5 Capstone Headwaters and Argus Research (2018) Outsourcing Trends in Biopharmaceuticals and Cell/Gene Therapy. Institutional Industry Report. Capstone Headwaters and Argus Research 6 Neelapu, S.S. et al. (2018) Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit ‘ALL’. Nat. Rev. Clin. Oncol. 15, 218 7 ICER (2018)ChimericAntigen ReceptorT-Cell Therapy forB-Cell Cancers: Effectiveness and Value. Final Evidence Report. ICER 8 https://clinicaltrials.gov/ct2/results?recrs=ab&cond= &term=CART&cntry=&state=&city=ist= [Accessd 3 October 2019]. 9 Stein, A.M. et al. (2019) Tisagenlecleucel model-based cellular kinetic analysis of chimeric antigen receptor-T cells. CPT Pharmacometrics Syst. Pharmacol. 8, 285–295 10 Khalil, D.N. et al. (2016) The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat. Rev. Clin. Oncol. 13, 273–290
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11 Pearce, K.F. et al. (2014) Regulation of advanced therapy medicinal products in Europe and the role of academia. Cytotherapy 16, 289–297 12 ICH (2016) Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). ICH 13 Anon (2013) Guidance for IRBs, Clinical Investigators, and Sponsors: IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed. Biotechnol. Law Rep. 2013 . http://dx.doi.org/10.1089/blr.2013.9999 Published online April 4 14 Lee, D.W. et al. (2018) ASBMT consensus grading for cytokine release syndrome and neurological toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 25, 625–638 15 EBMT (2018) FACT-JACIE International Standards for Hematopoietic Cellular Therapy. Product Collection, Processing, and Administration (7th edn), EBMT 16 FACT (2018) FACT Standards for Immune Effector Cells. FACT 17 FACT (2019) FACT Common Standards for Cellular Therapies (2nd edn), FACT 18 EMA (2019) Qualification Opinion on Cellular Therapy Module of the European Society for Blood & Marrow Transplantation (EBMT) Registry. EMA 19 EU (2014) Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical
Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC. EU 21 Anon (2019) Empfehlungen zur Bewertung der Qualifikation von Prüfern und Stellvertretern sowie zur Bewertung der Auswahlkriterien von ärztlichen Mitgliedern einer Prüfgruppe (gemäb Arzneimittelgesetz, Verordnung (EU) Nr. 536/2014, Medizinproduktegesetz) durch Ethik-Kommissionen. Dtsch Arztebl 116 A-176/B-152/C-152 20 Hayden, P.J. et al. (2019) An international survey on the management of patients receiving CAR T-cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT. Curr. Res. Transl. Med. 67, 79–88
Martin Hildebrandt1,2 1
Ethics Committee of the State of Berlin, Berlin, Germany 2 TUMCells Interdisciplinary Center for Cellular Therapies, TUM School of Medicine, Munich, Germany
Features PERSPECTIVE 4
www.drugdiscoverytoday.com Please cite this article in press as: Hildebrandt, M. Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs, Drug Discov Today (2019), https:// doi.org/10.1016/j.drudis.2019.10.003
PERSPECTIVE
feature Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs The advanced therapy medicinal products (ATMPs) landscape is entirely different from classical drug development. Academia has been the major source of ATMP development, and academic hospitals act as trial sites for the clinical testing of ATMPs, including early academic-led trials as well as industry-sponsored trials that pursue the full developmental pathway to market authorization. The recent breakthrough developments in some ATMPs, such as genetically engineered immune cells, have confronted academic hospitals with a substantial amount of public demand, competitive pressure, and costs. At the same time, risks, toxicities, and necessary countermeasures demand an appropriate infrastructure, expertise and training which have not yet been fully standardized. How can Ethics Committees consider trial sites and investigators in clinical trials with ATMPs as appropriately qualified?
Introduction: what is so special about ATMPs? ATMPs are medicinal products based on gene therapy, somatic cell therapy, or tissue engineering. Regulation (EU) 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 [1]. Given that ATMPs pose specific challenges to developers, manufacturers, regulators, and clinicians, Articles 4 and 5 of Regulation 1394/2007 have asked the European Commission (EC) to establish distinct sets of rules for these innovative E-mail address: [email protected]. 1359-6446/ã 2019 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.drudis.2019.10.003
and complex cell-based medicinal products. Issues related to the manufacture of ATMPs have been addressed in a Guideline on Good Manufacturing Practice (GMP) for Advanced Therapy Medicinal Products, adding a separate Part IV to EudraLex Volume 4 [2]. With regard to good clinical practice (GCP), a stakeholder consultation has been performed for this purpose [3]. Surprisingly, this consultation did not address the qualification of clinical trial sites and investigators. That said, the following questions demand consideration: (i) how can clinical trial sites and investigators using ATMPs give documented evidence of their specific qualification?; (ii) how can Ethics Committees, charged with the task of approving clinical trial sites and investigators as appropriately qualified, find ways to consider the qualification of trial sites and investigators in view
of the specific risks inherent in ATMPs?; and (iii) how can Ethics Committees draw on specific and independent expertise needed to assess this special group of innovative medicines?*
What are the risks in ATMPs? CAR-T cells as an example Genetically engineered cells, such as chimeric antigen receptor-transduced (CAR-T) cells, have received a considerable amount of attention over the past few years [4]. Here, they serve as
* The evaluation of advanced therapy medicinal products often requires specific expertise, which goes beyond the traditional pharmaceutical field and covers areas bordering on other sectors, such as biotechnology and medical devices [Regulation (EC) 1394/2007 [1]].
www.drugdiscoverytoday.com 1 Please cite this article in press as: Hildebrandt, M. Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs, Drug Discov Today (2019), https:// doi.org/10.1016/j.drudis.2019.10.003
Features PERSPECTIVE
Martin Hildebrandt1,2
DRUDIS-2564; No of Pages 4 PERSPECTIVE
Features PERSPECTIVE
prominent examples of ATMPs, because they carry a distinct efficacy and toxicity, and attract high clinical attention and desire for pharmaceutical exploitation [5,6], with impacts on the qualification of trial sites and investigators. With two CAR-T cell products already authorized for marketing in the EU, >40 other CAR-T cell products are in clinical development [7] and almost 400 trials using CAR-T cells are currently recruiting [8]. The impressive clinical response rates have raised public attention and suggest that CAR-T cells could act as a spearhead for a spectrum of indications beyond the current ones (i.e., acute lymphatic leukemias and certain types of lymphoid neoplasm). With patients in desperate need, clinicians have put growing pressure on regulators and politicians to render these promising therapies more rapidly available, irrespective of gaps in infrastructure, clinical expertise, and concepts for the coverage of costs. The growing clinical use of CAR-T cells has helped to recognize a distinct toxicity pattern of CAR-T cell therapies, most prominently: (i) a cytokine release syndrome characterized by high fever, hypotension, hypoxia, and/or multiorgan toxicity; and (ii) a CAR-T-cell-related encephalopathy syndrome (CRES), typically characterized by toxic encephalopathy with symptoms of confusion and delirium, occasionally seizures and cerebral edema. Similarly serious, albeit less frequent, are cases of fulminant hemophagocytic lymphohistiocytosis (HLH) or macrophage-activation syndrome (MAS), characterized by severe immune activation, lymphohistiocytic tissue infiltration, and immune-mediated multiorgan failure (reviewed in Refs [6,7]). Although attempts have been taken to reduce the therapy-associated risks and to ultimately allow for CAR-T cell therapy to be performed in an outpatient setting [9], CAR-T cells with novel targets show a common pattern of toxicity that depends mainly on on-target, offtumor effects, because CAR-T cells exert their cytotoxic effect upon antigen recognition and binding. Furthermore, sequential and simultaneous combination with other innovative therapies, such as checkpoint inhibitors [10], will bring not only higher and broader efficacy, but also hitherto unknown toxic effects, apart from another dimension in costs.
Qualification of trial sites and investigators: who is in charge? ATMPs are on a playing field that is entirely different from traditional pharmacopoeia and off-the-shelf products [9,11], and studies brought in front of Ethics Committees challenge 2
Drug Discovery Today Volume 00, Number 00 October 2019
our knowledge of these innovative medicines as they may challenge the applicants themselves. The safety and well-being of participants is dependent on the availability of an expertise and infrastructure that can cope with the potential risks inherent in the exposure of patients to these innovative products. Who is in charge of selecting such qualified centers and investigators? The ICH harmonized tripartite Guideline for Good Clinical Practice E6 (R2) states that the responsibility for selecting appropriately qualified investigator(s)/ institution(s) lies with the sponsor: ‘Each investigator should be qualified by training and experience and should have adequate resources to properly conduct the trial for which the investigator is selected ( . . . )’, furthermore that: ‘If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multicentre trials, their organization and/or selection are the sponsor’s responsibility.’ [12]. The US Food and Drug Administration (FDA) stipulates that the qualification of trial sites and investigators be judged upon ‘the adequacy of the facility’s staff and equipment, including the availability of emergency or specialized care’, and based ‘upon the nature and risks of the proposed research’ [13]. Thus, it is the responsibility of the sponsor to ascertain the qualifications of clinical sites and investigators, and the qualifications of trial sites and investigators should be considered based on the risks inherent in the investigational medicinal product.
Are there standards to consider a site as appropriately qualified? First attempts to define standards for the treatment environment and patient surveillance before, during, and following CAR-T therapy have been developed [14] and commended for lending their expertise to others. Standardized treatment algorithms and rules for toxicity management in patients treated with CAR-T cells and similar ATMPs are essential, especially in clinical trials: they give evidence of a quality and risk management infrastructure and of the professional expertise needed to ensure the safety of trial participants, as a criterion of qualification. Major pharmaceutical companies that explore the clinical use of CAR-T cells have decided to build on existing accreditation schemes, such as the FACT-JACIE standards [15], for centers with hematopoietic stem cell and bone marrow transplantation programs. In its 7th edition, the accreditation scheme includes a chapter on minimum standards for ‘the administration of
immune effector cell products, such as chimeric antigen receptor T cells (CAR-T cells), natural killer cells, virus-specific T cells, therapeutic cellular vaccines, and others’ [16]. In another FACT guideline, standards for cellular therapy have been published, representing ‘basic fundamentals that can be applied to any cell source or therapeutic application, and are intended to be used throughout product development and clinical trials.’ [17]. A trial site that adheres to such standards, and explicitly adopts those sections that address cell-based immunotherapy, should be assumed to have the capacities, training, and infrastructure needed to handle cell-based medicinal products, whereas details specific to the investigational product and the trial in question might require additional qualifications. Caution will be needed in the GCP arena because the ATMP under investigation will bring new toxicities and adverse events that might not be attributed to the novel therapy because of the lack of knowledge specific to this type of products.
ATMPs: the hospital as an exemption or a gap? Academic hospitals have been at the forefront of the research and development leading to the clinical use of ATMPs [11]. The fact that traditional industry now pursues clinical trials and marketing authorization with genetically engineered immune cells should take into account that academic ‘participating’ trial sites have often made huge investments in GCP and GMP infrastructure, without which the performance of the trials simply would not be feasible, rendering the trial site not acceptably qualified from the perspective of an Ethics Committee. In this highly pressurized field in terms of costs, public awareness, and patients’ despair, the commercial facet will make it difficult to ensure due diligence in the selection and qualification of trial sites. The notion that hospitals should be offered specific standards for the preparation of ATMPs on a nonroutine basis according to specific quality standards in a still ill-defined way, the socalled ‘Hospital Exemption’ [cf. [1], Article 28(2)] should let us bear in mind that hospitals occupy a special place in the ATMP arena, at the crossroads of research, development, earlyphase, and noncommercial clinical use, especially when a marketing authorization might not be either desired or possible. For autologous products, they often also provide cell apheresis products and similar products as starting materials vital for the ATMPs. Therefore, a revision of the ‘Hospital Exemption’ [1] should take
www.drugdiscoverytoday.com Please cite this article in press as: Hildebrandt, M. Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs, Drug Discov Today (2019), https:// doi.org/10.1016/j.drudis.2019.10.003
DRUDIS-2564; No of Pages 4 Drug Discovery Today Volume 00, Number 00 October 2019
Are adverse effects collected and communicated? The role of Registries Registries for the documentation of adverse events observed in CAR-T cells and similar ATMPs have been called for and are currently being established. As an example, the European Society for Blood & Marrow Transplantation (EBMT) registry has been expanded to accommodate the use of immune effector cells. Recently, the European Medicine Association (EMA) qualified ‘the cellular therapy module of the EBMT registry as an appropriate data source for post-authorisation studies to support regulatory decision-making concerning CAR-T cell therapy for haematological malignancies’ [18]. However, the documentation within clinical trials is not foreseen to be reported (and potentially unblinded) to registries outside clinical trials, also for obvious economic reasons, and the resulting delays and gaps in reporting adverse effects are difficult to appreciate. A solution could be in: (i) a mandatory opening of the data safety update reports (DSURs) or parts thereof to the registries; and (ii) a rapid alert system to communicate unpublished, but crucial incidences to the registries and (accredited) clinical trial sites, preferably again via the registries. Beyond ATMPs, the Clinical Trials Registry, at the core of Clinical Trial Regulation, will hopefully bring a transparency to clinical trials that has not been encountered before [19]. A section dedicated to ATMPs in this registry would be helpful.
Networks In ATMPs, the experience needed in drug handling, application, adverse effects, and their management differ substantially from traditional pharmacopoeia [6]. Centers that move into this field should be encouraged to collaborate with more experienced centers to let future investigators acquire the knowledge needed, because this goes beyond clinical experience and traditional GCP training. Given the embryonic nature of consensus guidelines for treatment and follow-up even among experienced clinicians [20], the support of less experienced investigators within networks should be seen as a criterion of qualification. ‘Active involvement in clinical trials’, a criterion of qualification demanded by Ethics Committees in Germany [21], should be defined as documented evidence of interaction and training by colleagues in more experienced
centers. Given that academic centers will be expected more than others to handle clinical trials with ATMPs, networks and training opportunities should be established primarily in academia.
Concluding remarks: shared responsibilities Cell-based immunotherapies, a prominent example of ATMPs, are here to stay. The ATMP field has evolved from academia as the major source of ATMP development into a somewhat paradoxical situation, where few academic centers have remained in Europe that retain compliance with the European GMP ATMP and GCP legislations, because many of them have not been endowed sufficiently with the capacities and infrastructure to carry this development further in parallel to (or cooperation with) industry. Industry has benefitted from this development, because a substantial part of the burden of infrastructure still rests with academia. Of note, EU Regulation 536/2014 offers the option to researchers to act as co-sponsors of clinical trials, strengthening their role in clinical development.y The selection of trial sites and investigators is the responsibility of the sponsor, and the decision about the site(s) as being sufficiently qualified lies with the Ethics Committee. As such, Ethics Committees demand oversight in a highly competitive field at the edge of commercialization. Leaving the responsibility to the sponsor alone is not enough to ensure the safety of patients treated with cell-based high-risk medicinal products. From the perspective of an Ethics Committee, documented evidence of the qualification of trial sites and investigators using CAR-T cells and similar ATMPs should include: (i) a qualified trial site in possession of the infrastructure needed to handle these toxicities; (ii) a risk–benefit analysis that addresses the characteristics of the respective ATMP specifically and appropriately; (iii) the capacity to recognize, monitor, grade, manage, and document the acute toxicity inherent in this approach;
y In practice, there might be loose, informal networks of researchers or research institutions that jointly conduct a clinical trial. Those networks should be able to be co-sponsors of a clinical trial. To not weaken the concept of responsibility in a clinical trial, where a clinical trial has several sponsors, they should all be subject to the obligations of a sponsor under this Regulation. However, the cosponsors should be able to split up the responsibilities of the sponsor by contractual agreement.
(iv) transparency [i.e., a commitment by the sponsor (especially by Industry) to communicate crucial incidences and observations in a rapid alert system that allows other trials to benefit from these details of critical information); (v) documented evidence of active involvement of investigators in previous trials, for instance by training in a recognizable network of collaborating centers (i.e., qualified trial sites) that exchange knowledge, share training, and help each other, primarily as an academic initiative. Industry could contribute funding to such a network, which would be of immediate benefit to industry-sponsored trials; and (vi) the Hospital Exemption, a hitherto unfortunate attempt to address the role of specialized medical centers in the use of ATMPs, should be reconsidered and reshaped to include concepts for the use of ATMPs explicitly in the GCP arena. Ethics committees will depend on independent experts in ATMPs to provide guidance in assessing clinical centers and investigators as qualified for these special medicines. As suggested in the ATMP Regulation 1394/2007, Ethics Committees might have to revert to the regulators in the decisions on clinical trials with ATMPs to judge appropriately on the qualification of clinical sites and investigators, or find ways to address this special group of drugs together. Together with professional societies, they could establish an expert registry for ATMPs with full disclosure of financial interests, providing expertise both for Ethics Committees and clinical centers. Ideally, these experts would have insight into both GMP and GCP to judge the risks inherent in the proposed trial appropriately. Ultimately it will always come down to humans lending trust to others, when the Ethics Committee, on behalf of the patients participating in the trial, will consider the applicant as trustworthy or not. The quantum of trust cannot be replaced by legal and regulatory requirements, but has to emerge from structured evidence of risk awareness, preparedness, training, and communication with other centers. This will not suffice to guarantee a benefit to the participants and patients, but might help to make the development and clinical use of ATMPs safer, providing better science and better care.
References 1 Anon (2007) Regulation (EC) 1394/2007 of the European Parliament and of the Council on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. Off. J. Eur. Union 324, 121–137
www.drugdiscoverytoday.com 3 Please cite this article in press as: Hildebrandt, M. Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs, Drug Discov Today (2019), https:// doi.org/10.1016/j.drudis.2019.10.003
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the GCP arena into account, in a different way than explicitly excluding clinical testing, as is the case now.
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2 EudraLex (2007) The Rules Governing Medicinal Products in the European Union Volume 4: Good Manufacturing Practice. Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products. EC 3 Anon (2018) Targeted Stakeholder Consultation on the Draft Guidelines on Good Clinical Practice for Advanced Therapy Medicinal Products. EC 4 Subklewe, M. et al. (2019) Chimeric antigen receptor T cells: a race to revolutionize cancer therapy. Transfus. Med. Hemother. 46, 15–24 5 Capstone Headwaters and Argus Research (2018) Outsourcing Trends in Biopharmaceuticals and Cell/Gene Therapy. Institutional Industry Report. Capstone Headwaters and Argus Research 6 Neelapu, S.S. et al. (2018) Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit ‘ALL’. Nat. Rev. Clin. Oncol. 15, 218 7 ICER (2018)ChimericAntigen ReceptorT-Cell Therapy forB-Cell Cancers: Effectiveness and Value. Final Evidence Report. ICER 8 https://clinicaltrials.gov/ct2/results?recrs=ab&cond= &term=CART&cntry=&state=&city=ist= [Accessd 3 October 2019]. 9 Stein, A.M. et al. (2019) Tisagenlecleucel model-based cellular kinetic analysis of chimeric antigen receptor-T cells. CPT Pharmacometrics Syst. Pharmacol. 8, 285–295 10 Khalil, D.N. et al. (2016) The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat. Rev. Clin. Oncol. 13, 273–290
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11 Pearce, K.F. et al. (2014) Regulation of advanced therapy medicinal products in Europe and the role of academia. Cytotherapy 16, 289–297 12 ICH (2016) Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). ICH 13 Anon (2013) Guidance for IRBs, Clinical Investigators, and Sponsors: IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed. Biotechnol. Law Rep. 2013 . http://dx.doi.org/10.1089/blr.2013.9999 Published online April 4 14 Lee, D.W. et al. (2018) ASBMT consensus grading for cytokine release syndrome and neurological toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 25, 625–638 15 EBMT (2018) FACT-JACIE International Standards for Hematopoietic Cellular Therapy. Product Collection, Processing, and Administration (7th edn), EBMT 16 FACT (2018) FACT Standards for Immune Effector Cells. FACT 17 FACT (2019) FACT Common Standards for Cellular Therapies (2nd edn), FACT 18 EMA (2019) Qualification Opinion on Cellular Therapy Module of the European Society for Blood & Marrow Transplantation (EBMT) Registry. EMA 19 EU (2014) Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on Clinical
Trials on Medicinal Products for Human Use, and Repealing Directive 2001/20/EC. EU 21 Anon (2019) Empfehlungen zur Bewertung der Qualifikation von Prüfern und Stellvertretern sowie zur Bewertung der Auswahlkriterien von ärztlichen Mitgliedern einer Prüfgruppe (gemäb Arzneimittelgesetz, Verordnung (EU) Nr. 536/2014, Medizinproduktegesetz) durch Ethik-Kommissionen. Dtsch Arztebl 116 A-176/B-152/C-152 20 Hayden, P.J. et al. (2019) An international survey on the management of patients receiving CAR T-cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT. Curr. Res. Transl. Med. 67, 79–88
Martin Hildebrandt1,2 1
Ethics Committee of the State of Berlin, Berlin, Germany 2 TUMCells Interdisciplinary Center for Cellular Therapies, TUM School of Medicine, Munich, Germany
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www.drugdiscoverytoday.com Please cite this article in press as: Hildebrandt, M. Horses for courses: an approach to the qualification of clinical trial sites and investigators in ATMPs, Drug Discov Today (2019), https:// doi.org/10.1016/j.drudis.2019.10.003