Global Regulatory Perspective Workshop ISCT meeting Singapore 25 May 2016 Dr Nicolas FERRY ANSM, France
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Study I The CAR-T cell non-responder population -- patients who have shown progressive disease -- are additively treated with a checkpoint inhibitor at 15 days post-car T-cell infusion. Dosing of the inhibitor follows the package insert instructions. Some response is seen with the checkpoint inhibitor; however, there is rapid disease progression. The sponsor adds a third agent to the treatment regimen - a proteosome inhibitor. 1. How does the clinical study design and observations need to change to evaluate the addition of the checkpoint inhibitor? Of the proteasome inhibitor? 2
Regulatory perspective: Is the modification considered as a substantial modification or a new clinical trial? Article 2: Definitions (13) Substantial modification means any change to any aspect of the clinical trial which is made after notification of a decision referred to in Articles 8, 14, 19, 20 or 23 and which is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial 3
Regulatory perspective: Will the addition of a second drug modify the CAR-T cells (i.e. the active substance of the product) and/or the target cells? Molecular Therapy in press 4
There are different types of CAR-T cells Michel Sadelain et al. Cancer Discovery 2013;3:388-398 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptor AH Long et al;, Nature Med (2015) vol 21, p:581 5
Regulatory perspective: Check-point inhibitors may act on the CAR-T cells to reduce exhaustion 6
Regulatory perspective: Proteasome inhibitors will modify presentation of the tumor antigen by HLA molecules 7
Regulatory perspective: Is the modification considered as a substantial modification or a new clinical trial? Will the addition of a second drug modifiy the CAR-T cells (i.e. the active substance of the product) and/or the target cells? Combination of the CAR-T cells with another drug may trigger a different safety and efficacy pattern. The pattern of combination of the two drugs will have to be clarified (e.g. fixed or not) Are 1 or 2 MA(s) eventually considered by the applicant? EMA Guideline on fixed combination of medicinal products CPMP/EWP/240/95 Rev. 1, 2008 A new clinical trial after thorough preclinical evaluation is the most reasonable option 8
French procedure for starting a clinical trial in the EU for ATMP containing GMOs Ethics Committee Opinion Sponsor 1. EudraCT Number 2. CTA dossier 90 days + 90 days Written authorization Start of CT National Competent Authority Authorisation Specific Committee
ATMP Assessment.. to consult with experts optional Validation 45+31d +50d 26d rms Assessment Sponsor response 12d max Optional request for information No response Withdrawn in all MS Input from Ethics Committee Assessment max. 12d 12d Coordinated review Draft AR Part I 7d Consolidation Final AR Notification 5d cms Sponsor 45+31d Optional request for information Part II 5d Sponsor response 12d max Assessment max. 19d No response Withdrawn in cms 10 10
Study I 2. What preclinical studies are needed prior to testing each combination (addition of check point inhibitor, addition of proteasome inhibitor) in humans? Two major issues should be considered: Determination of the Proof of Concept and Mode of Action in relevant animal models (primary pharmacodynamics) Document toxicity of association in animal models 11
Primary pharmacodynamics: The impact of check point inhibitor or proteasome inhibitor on the CAR-T cells or on the tumor cells should be evaluated. - Which animal model? Immunocompromised mice? - The potency of the combination should be evaluated for each type of CAR-T cells - The dose finding is difficult because CAR-T cells are proliferating in vivo - The best schedule of administration should be determined (at which time inhibitors should be given) 12
How to document toxicity? CAR-T cells toxicity is better known (Cytokine release syndrome, tumor lysis syndrome) Check point inhibitors are also a specific toxicity pattern as well as proteasome inhibitor What is the best model to evaluate combined toxicity? Toxicity should be evaluated with GMP products with the same specificities and with same dosing schedules as foreseen in the clinical trial. 13
Study 2 1. What types of additional in vitro and in vivo preclinical studies would be required The RNA electroporated cells can be envisioned as a new drug substance and new drug product. Therefore a full quality evaluation of the new product should be provided. (e.g. interference between CARs) Also, the preclinical evaluation of the new drug product should address (at least) pharmacology (proof of concept), and toxicology. Pharmacokinetics (including biodistribution) and drug interaction could be considered not modified by RNA electroporation. 14
Study 2 2. The mrna used for research can t be recreated exactly because the sponsor can t get a clinical license for the mrna cap region. How can the sponsor demonstrate equivalence between research mrna and clinical grade mrna with a different cap sequence? There are two different issues in the question. The first is the quality of the two mrnas. In Europe, clinical grade manufacturing for pre clinical studies is possible without a license. Therefore, biocomparability of tthe two mrnas can be perfomed with GMP products. At least three independent batches of the mrna should be compared. In specific situations, comparison between a research grade and GMP grade mrna is acceptable after discussion with the regulatory authorities. 15
Study 2 3. What types of different adverse events might be expected and how might they be managed The in vivo pre clinical studies are aimed at evaluating the potential adverse events. Therefore it is critical to select the most reliable animal model. The adverse events are mainly related to the second CAR target. Depending on the target (pattern of expression in tumor and normal cells, level of expression.) risk minimisation measures will have to be provided by the applicant. 16
Study 2 4. How should the clinical study be designed to test this «double CAR». It is not possible to answer this question without further information. The product will be considered as a new drug. Phase I/II studies will document the safety of the product with possible information on the dose. Phase III studies are compulsory to document the clinical benefit over the single CAR-T cells as well as the clinical efficiency of the double CAR-T cells in specific populations. 17
Conclusions: It is acknowledged that CAR-T cell based immunotherapy is a breakthrough for some diseases (ALL) Evaluation of the actual benefit in other clinical situations is still missing Improvement of CAR-T cells efficacy, including combination with other drugs, is ongoing in many labs Safety issues of this efficient, yet potentially harmful strategy is a major concern for regulators 18