MHRA Telephone Ref: 1099/Flutcore Ms Nathalie Gilmore Direct line: (0)

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1 Ms Martina Tomcalova ELC Group s.r.o Karolinska 650/ Prague 8 Czech Republic Monday 11 th January 2016 MHRA 151 Buckingham Palace Road Victoria London SW1W 9SZ United Kingdom Telephone +44 (0) Ref: 1099/Flutcore Dear Ms Tomcalova On 23 November 2015 you met with staff from the MHRA: Dr Julian Bonnerjea - Unit Manager Dr Christiane Niederlaender Quality Assessor Dr James McBlane - Non-clinical Assessor Dr Lisa Campbell Medical Assessor to discuss quality, non-clinical, clinical and regulatory aspects of Flutcore for vaccination against influenza. The Company should note that any scientific advice given is not legally binding with regard to any future application for the product concerned, neither on the part of MHRA/Commission on Human Medicines (CHM) nor on the Company. Furthermore, advice cannot be taken as indicative of any future agreed position. The answers given by MHRA (attached as Annex 1) are based on the questions and documentation submitted and cannot account for future changes and developments in scientific knowledge or regulatory requirements. Companies should note that the advice provided is without prejudice to applicable legislation relating to the particulars and documents which should be submitted in support of any Marketing Authorisation (or other) Application; it is also without prejudice to any intellectual property rights of third parties. The Company is advised that there is a requirement under EU paediatric Regulation (EC) No 1901/2006 to obtain approval by the Paediatric Committee (PDCO) for either the development of a product still under patent protection for use in the paediatric population or alternatively approval for any proposed waiver(s) in either the entire paediatric population or subgroups. The requirement to submit the results of such Paediatric Investigation Plans (PIPs) applies to applications for new medicines and to certain line extensions or variations. It is the Company s responsibility to liaise with the PDCO secretariat at the European Medicines Agency on the need for a PIP and further information can be obtained from their website: 01ac b8d Yours sincerely Ms Nathalie Gilmore Direct line: (0) nathalie.gilmore@mhra.gsi.gov.uk

2 ANNEX 1 Questions from the Company and Answers from MHRA Q1: Does the Agency concur with the proposed testing of the Master and Working Cell Banks? The parameters selected for testing and the acceptance criteria appear acceptable. The Sponsor should also consider whether any animal-derived materials are used in the preparation of the plasmids and cell banks and therefore whether testing for additional adventitious agents is appropriate. Q2: Does the Agency concur with the In Process Controls (IPCs) and manufacturing process parameters (PPs) identified for the manufacturing process for the drug substance for a Phase 1 clinical trial? Does the Agency have any other comments on the manufacturing process for the drug substance? The manufacturing process appears satisfactory but the Sponsor will have to demonstrate in the IMP dossier that the process is robust and capable of producing drug substance batches of acceptable quality. Any hold times or re-processing steps should be validated. Comparability data will be required if there are any changes to the manufacturing process during future development. If there is any potential for contamination with animal-derived materials from raw materials or equipment (e.g. column resins) used in the manufacturing process, the Sponsor may need to include additional in-process testing and/or inactivation steps in the manufacturing process. Q3: Does the agency concur with the content and completeness of the specification and testing methodology for the drug substance for a Phase 1 clinical trial? The panel of characterisation tests selected should allow the Sponsor to determine the structure and activity of the virus-like particle (VLP), including characterisation of the product- and process-related impurities. The tests may also be used for comparability studies later in development. The drug substance specification tests and additional characterisation tests presented in the briefing document do appear to be adequate. The parameters selected for routine testing in the drug substance specification appear satisfactory but the Sponsor should consider including the characterisation test for VLP formation in the routine tests as far as possible. Limits should be set for all parameters: the term report results should be avoided. These limits should be based on batch analysis data accumulated to date and all impurity limits should be justified by non-clinical studies. The activity assay should have an upper and lower limit. Q4: For the planned Phase 1 study, the final drug product presentation is proposed to be composed of separate vials of VLPs, adjuvant and dilution buffer in order to provide flexibility in trial design where dose escalation and formulations both with and without adjuvant are required. The final dosage form will be assembled at the clinical site as soon as practical before administration. Does the Agency concur with this plan and can they advise on appropriate QC/QA procedures required at the clinical site?

3 In response to a request at the scientific advice meeting for further information on the proposed procedure, the Company has provided a draft assembly procedure document. The draft procedure describes: - The assembly of vaccine with and without alhydrogel and placebo with and without alhydrogel prior to QP certification and release. - Operator training against the procedure. The acceptability of the final procedure will be determined at the time of the review of the Clinical Trial Authorisation (CTA) Application. Provided that the Company makes all efforts to minimise the likelihood of errors being introduced into this procedure, and that full and detailed records will be kept of the assembly operations and that these will be subject to a contemporaneous second operator verification and QP review, the procedure may be considered acceptable for a Phase I study. Q5: Does the Agency concur on the IPCs identified for the manufacturing process for the DRUG PRODUCT for a Phase 1 clinical trial? Does the Agency have any other comments on the manufacturing process for the drug product? The IPCs selected should be sufficient to ensure that the manufacturing process is robust and produces product of adequate quality and it is the Sponsor s responsibility to demonstrate that this is the case in the IMP dossier. The IPCs selected do not appear to include filter integrity testing of the sterile filters and a prefiltration bioburden limit of NMT 10 cfu/100 ml before sterile filtration. These should be included. Media fill runs will be required to validate the sterile filtration process. Q6: Does the agency concur on the content and completeness of the specification and testing methodology for drug product final containers for a Phase 1 clinical trial? The parameters selected appear largely satisfactory but there are no specific tests or limits for product-related degradation products. Limits will be required for all parameters: the term report results should be avoided. An upper and lower limit will be required for potency. The MHRA supports the reduction of animal testing and would therefore support the introduction of an in vitro potency test, which could use a surrogate marker for activity provided that this is fully justified in the IMP dossier. The assay should be adequately validated and it may be necessary to test a few batches with several potency assays to determine which assay gives the most robust and reproducible results. Q7: Does the Agency concur with the proposed stability strategy to support the use of the Drug Substance and Drug Product for a Phase 1 clinical trial? The proposed strategy is largely satisfactory. Limits should be included in the stability specification for all parameters. The Sponsor should consider whether it is necessary to introduce limits for specific degradation products. There are no tests for sterility or particulates included in the drug product stability testing: these will be required.

4 Provided that analytical results are within specification and there are no trends, it will be acceptable to base a 6 month shelf-life on 3 months real-time and 3 months accelerated stability data. Q8: Does the agency accept the study design for toxicity study including chosen animal model? The study as proposed is acceptable. It will be necessary to demonstrate that rats show immune responses to vaccination but it is acceptable if this is done within the Good Laboratory Practice toxicity study. However, the MHRA does advise that there is no need to include recovery animal groups in the study as these data would be very unlikely to influence the clinical trial design and this approach is in line with principles to reduce animal use where feasible. Q9: a) Does the agency accept the overall study design for immunogenicity testing including chosen animal model and chosen strains to address breadth of protection? b) To encompass animal welfare in the proposed immunogenicity testing, a moderate to severe disease will be considered with a non-lethal dose for ferrets, in line with the guidance EMA/CHMP/VWP/457259/2014. On ethical grounds, and that with the lethal dose, animals deteriorate very quickly, non-lethal dose is justifiable for viral challenge in ferrets in order to have comprehensive assessment of all important immunogenicity endpoints. Is this acceptable to the agency? a) The MHRA notes that the data from challenge studies with mice should be included in future CTA applications. The MHRA agrees with the use of ferrets to demonstrate the expectation that the vaccine may have protective efficacy in humans. The intramuscular route of vaccination and dosing on days 0, 14 and 28 are agreed and should support planned clinical dosing. In respect of the viral challenge, the use of H1N1 and H3N2 viruses is agreed and considered sufficient, and the intranasal route is agreed, as is the timing of the challenge in relation to vaccination. The inclusion of group 4, those given adjuvant only, is questioned in the design. There can be no expectation of benefit and the adjuvant is not novel. The question to be addressed relating to the adjuvant is whether it results in a greater magnitude of immunogenic response and protection from disease-related changes and this will be determined by comparing results from groups 2 and 3. Therefore, the MHRA advises the Sponsor to reconsider whether this study needs to include the group given only the adjuvant. b) The use of a non-lethal challenge is supported: the dose of challenge virus will need to be such that unvaccinated ferrets show changes that can be quantified and the beneficial effect of the vaccine shown; ideally this would be in both in terms of the magnitude of effect induced and in the timecourse of recovery following the viral challenge. Q10: Does the agency concur with the proposed Phase I study design for the candidate vaccine, including study objective, eligibility criteria and study endpoints? The proposed Phase I study design is acceptable in relation to study objectives (safety and immunogenicity), eligibility criteria and study endpoints. Contraceptive advice must however be more clearly defined.

5 The study protocol should contain detailed information on the level of contraception, the frequency of pregnancy testing, and the duration of the need for contraceptive measures and pregnancy testing. The protocol suggests that abstinence is an acceptable method of contraception. Abstinence is only acceptable as True abstinence: When this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception. Contraception guidance is provided using the following link; About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf Q11: Does the agency have any other points (quality, non-clinical, clinical, regulatory) that the company should consider in the development of this novel vaccine. The MHRA has no further points.