Radpid Response Regulatory Framework for COVID-19 vaccine development

sofa-2, 7ai aeo, eftofoaito naq@yen 91TerT eleple fdsnor site dleitf@rest aionee reft rs, or& fdeeft-110003 Block-2, 7th Floor, C.G.O. Complex Sta dhei forest fer»rror Lodhi Road, New Delhi-10003 GOVERNMENT OF INDIA Tele: 011-24365071 Fax: 011-24362884 MINISTRY OF SCIENCE & TECHNOLOGY ~~ Website : http://www.dbtindia.nic.in DEPARTMENT OF BIOTECHNOLOGY No. BT/03/27/2020-PID Dated: 26 May, 2020 OFFICE MEMORANDUM Sub: Rapid Response Regulatory Framework for COVID-19 Vaccine development -reg. In pursuance of the recommendation of Empowered Committee of RCGM and CDSCO constituted by this Department OM of even No. dated 20.03.2020 to deal with applications for development of vaccines, diagnostics, prophylactics and therapeutics under Rapid Response Regulatory Framework for COVID-19, the Rapid regulatory framework for fast track processing of applications relating to recombinant vaccines for COVID 19 has been developed, which is attached herewith for information and necessary action by all the stakeholders. Scien tist-F & Member Secretary, RCGM To: 1. All IBSCs 2. NIC to upload.on DBT website, IBKP Portal and CDSCO Portal.BT /03/27/2020-PID Date: 23.05.2020 Rapid Response Regulatory Framework to deal with applications for COVID 19 Vaccine Development To facilitate the COVID-19 vaccines development, the following guidance note is issued for the COVID-19 Vaccines Rapid Regulatory pathways. This guidance document is recommendatory and dynamic in nature without prejudice to statutory provisions. Individual application will be examined based on the type of vaccines candidate and their data requirement. Individual applications will be examined and considered depending on their completeness for approval under the Rapid Response Regulatory Framework. The applicants and regulators shall engage on regular basis to ensure the requisite progress in the development. Following guidance note is hereby issued: 1. The checklist for application to conduct pre-clinical toxicity (PCT) studies for recombinant vaccine development for COVID-19 as per appendix -I. 2. Consideration of preclinical data generated outside India: Considering the research collaboration of Indian enterprises with foreign research organizations the preclinical studies already done outside India may be considered in regulatory submission and individual application will be examined based on quality of data generated and conduct oflimited preclinical study may be asked for after examination, if required. 3. The applicant may submit parallel application for conducting appropriate phase of clinical trial to CDSCO for consideration at the time of conduct of PCT studies based on proof of concept. However, the application for clinical trial will be approved subject to NOC from RCGM after examination of data of pre-clinical studies. 4. Consideration of data on clinical studies: Data generated outside India will be considered and examined and an abbreviated pathway may be considered for COVID 19 vaccine based on scientific rational and level of completeness of data in human trials in addition to satisfactory preclinical data. Phase I/II or phase III multicentric study on statistically significant sample size may be considered based on, initial safety studies, proof of concept and dose finding data.BT /03/27 /2020-PI D Date:26.05.2020 Appendix-1 Checklist for application to conduct Pre-Clinical Toxicity (PCT) studies for recombinant vaccine for COVID-19. S. No. Parameters Remarks Provided Yes/No (Page no.) A General· - The Vaccine production platform (live viral vector, DNA, Yeast/ cell line expression,etc.) and the anticipated end product (DS) substantiated with published literature regarding its quality attributes, safety and immunogenicity. Substantiation can be with unpublished literature as well (inhouse research, patent needs, etc.). In such cases there should be substantial documentation like manuscripts, inhouse documents, etc. A1 The application to contain Table of contents, all pages serially Required numbered, and all cited annexure(s) included in the final application. A2 Approval(s) accorded so far for the product under Firm should apply for development by IBSC, RCGM, IAEC, etc. approved by the appropriate approvals. Rolling CPCSEA, etc. submission allowed. (approvals as per proforma and guidelines may be provided later when COVID-19 situation improves) A3 Describe source of material (isolate, lab, country) Required B Molecular Characterization B1 Describe origin of gene(s) coding the molecule under Required consideration (isolate, lab, organization country) B2 Provide Nucleotide and translated protein sequences Required B3 Information about the vector (Include restriction map, Required , Promoter and Terminator used for the expression of recombinant gene, method of transformation, selection agent used, etc.)/ B4 Description of host organism characteristics// Cell type to be Required used for expression and method of recombinant gene delivery85 Safety of the host organism (indicate Risk Group#). Required 86 Copy number and stability of plasmid in expressing host cell Can be submitted [for microbial fermentation before induction and at the time of later with toxicity harvest. report. 87 Provide information on the expression levels of protein Can be submitted later with toxicity report. 88 Provide brief note on containment level adopted and biosafety Required procedures followed during the study. 89 Describe waste disposal SOP Required C Standardization of fermentation/production procedures**,## C1 Detailed media composition for pre-inoculum, inoculum and production process (Indicate wherever commercial media Brief information used), feeding rate of media (in grams of nutrient/h/L of initial required fermentation broth) C2 Information on three batches of fermentation and batch size Three batches to (in terms of liters). Batches to be non-sequential, preferably establish consistency [48hrs-1 week apart. of the process required. C3 Consolidated trend of different parameters from three Three batches to representative batches (such as cell growth, product establish consistency formation, pl, temperature, dissolved oxygen, nutrient of the process consumption, agitation rate, aeration rate, required CO2supplementation) during fermentation. C4 Time dependent product profile: Key profiles of three 1 ). Concentration of product/L, yield and volumetric batches required productivity productivity (titre in case of recombinant virus). 2. Consistency of specific protein yield (amount of protein per unit cell mass at different cell concentration during fermentation). 3) In case of multiple antigenic targets- consistency for all the targets cs Describe waste disposal SOP Required D Downstream process for purification**,## D1 Purification process (flow chart detailing all major steps Required involved). D2 List of reagents, resins, membranes used in the purification Required in short process along with their properties. 2D3 Description of each unit of operation step (batch size) during Required in short purification. Chromatograms of three consistency batches. D4 Quality of the product at each step of purification Required SDS-PAGE, reducing and non-reducing gels (include suitable MW Marker, Mention loading of OS in µg (e.g., 1g, 3pg. 5pg etc.) Chromatographic analysis for each purification step (include an overlay of all batches). Batch consistency in terms (1) active component(s) (2) in case of multiple antigens or extracts or DNA or RNA constructs or VLPs or polysome/ liposomes/ microsomes or heat inactivated virus, etc., where multiple virus-associated antigens will be used for immunization. Batch consistency o1 product profile including different antigen ratios, wherever applicable, should be provided with supporting data in the form of silver stained gels or HPLCs profile, etc Data on downstream purification process shall include presence o1 any impurities such as host cell derived proteins/DNA/RNA, depending on the nature of the candidate vaccine and reagents/materials used in the downstream process. Biological activity for three batches should be compared to show they are within the permitted range. As above batches to be non-sequential. D5 Stepwise and Overall recovery of the product (for each batch) Required in a tabulated form D6 Summary table showing consistent recovery of drug Required substance (yield at each stage of purification, overall product yield, specific activity etc.) E Physico-chemical characterization,## E1 Intact mass analysis An overall plan of characterization be Confirming the identity of the expressed gene product. provided for PCT studies. E2 Peptide mapping (overlay results of all batches) and N [terminus amino acids sequencing data The basic CMC data should be submitted E3 Secondary structure data by CD spectroscopy/Near and far or RCGM approval of UV visible spectra (overlay results of all batches) PCT study protocol. Complete CMC data E4 Fluorescence spectroscopy to provide evidence for similarity should be submitted at high order structure (overlay results) along with PCT E5 Data on disulfide bond presence (when applicable) reports. E6 Charge heterogeneity (Data from Ion exchange Note; The data chromatography, lsoelectrofocusing, etc. ) requirement vary 3E7 Carbohydrate/glycan content analysis and details of depending on the type components, as applicable of vaccine. In case o DNA vaccine, E8 Presence of aggregates (using any suitable method e.g. Size sequence information Exclusion Chromatography (SEC), Dynamic Light Scattering of vector and targe1 (DLS) etc.) CARS Co\V-2 virus E9 Endotoxin/Pyrogen content (for each consistency batch) gene(s), host cell DNA contamination, E10 Host Cell Protein content (for each consistency batch) etc. will be important. In case of subuni vaccine, expressed E11 Host Cell DNA content (for each consistency batch) SARS CoV-2 virus protein(s), glycan analysis, CHO content, Ds purity, aggregates will be important Stability of the DP and its effective ( efficacy) dose is a primary requirement for PCT studies. F Immune response/ Biological activity F1 Specify Adjuvant and dose formulation. Specify laboratory Required. This is animal model used for assessing the immunogenicity critical for a vaccine (number, age, gender, strain), Vaccination protocol candidate (site/dosage) concentration of antigen used, the immune response profile, antibody titers, etc. describe method of measuring antibody profile, antibody titres, etc. Provide data on antibody profile, antibody titre. F2 Assessment of neutralizing antibodies, if any. Describe method for assessment of neutralization antibodies, provided data on neutralization efficiency/specificity, etc. F3 Report any adverse effect in animals Required F4 Polyclonal or monoclonal antibody product? If poly clonal, Required batch consistency data and if monoclonal, clone data and other sib clones availability G Formulation and Stability studies of Drug Substance (DS) and Drug Product (DP), proposed done GT Submit consolidated three batch data Required for three batches 4G2 SOS-PAGE analysis (preferably silver stained & in alignment Basic characterization with MW Marker) and confirming the identity by western for the Vaccine drug blotting product. G3 Overlay of Size Exclusion Chromatography analysis Detailed can be given with Tox. Report G4 Data on bioactivity/bioassays G5 Stability data on real time***, accelerated and stress studies Stability Program I of all batches of drug substance (DS) and drug product (DP) Protocol should be at defined time points for DS and depending on the proposed given in PCT shelf life for DP application and with [the proof of start of stability for DS and DP. [The stability data can be submitted in rolling submission for special COVID 19 situations as stability of the compound is a primary requirement for PCT studies) Storage temp. of DS and DP Required Stability studies results should be submitted along with C3b form. With Toxicity report Should include Real time, Accelerated stability and Stress stability Plan should be for all data. hree G6 Define the composition of DP. Specify the adjuvant, Required excipients/stabilizers used in the formulation. In the case of multiple antigenic targets in the DP indicate the ratio of the 'different targets H Acceptability criteria of the formulated material for preclinical safety studies(Acceptance limits should be set based on Indian pharmacopoeia for vaccines or equivalent regulation for general test parameters and in house criteria.) H1 Specifications for DS and DP should be established around Required critical quality attributes. I Proposed study plan for preclinical toxicity studies 511 Whether the representative toxicology batch of DP is one of Submit the batch size the RCGM approved consistency batch. which should be If not, generate complete comparative data of this batch with sufficient enough tc lthat of the consistency batch approved earlier by RCGM. conduct characterization and PCT studies. Submit the profile of batch and COA after he batch is taken for PCT within a week of he testing is completed. 12 List of preclinical toxicity and immunogenicity studies to be Required conducted. (including protocol/guidelines/standards to be followed) 13 Selection criteria for animals selected and numbers to be Required used in each group. Justification for the selection of animal model/numbers) 14 Submit detailed Pre-clinical toxicity & lmmunogenicity Required (sequence specific, non-specific to other proteins and with adjuvant, as applicable0) study protocols. Protocols should include route of administration, dosage to be tested (based on effective dose), basis of dose calculation, vehicle, mode of administration, volume of administration (single or multiple administration. 15 Required Provide address and accreditation status of the facility where studies are to be conducted. 16 Explain compliance of containment facility measures. Required 17 Specify decontamination and disposal mechanisms. Required 18 Explain plans in case of any Emergency. Required 19 Attach copies of IBSC approvals of the Sponsor and CRO(s) Required (Photocopy of /BSC/ minutes wherein proposed studies were (Online meetings are approved). allowed) oh Undertaking/ Declaration Letter Signatures Required ( all legal To be signed in original by hand (Electronic/ scanned signatures to be sianatures not acceptable) accepted) # Follow the link below to determine Risk Group of host cell/organism and containment level to be followed. (http://www.dbtindia.nic.in/wp-content/uploads/Regulations- 6Guidelines-for-Reocminant-DNA-Research-and-Biocontainment-2017.pdf). For SARS Co\V-2 follow the Interim Guidance Document on Laboratory Biosafety to Handle COVID-19 Specimens available at IBKP portal. The end product (OS) from the chosen production platform to be supported with appropriate documents (regulatory/ published reports/ Clinical trials) for its quality attributes and safety **Original Data (Tables, figures in colour wherever appropriate & graphs) with proper labelling and appropriate interpretation must be submitted. Figures with overlay data should be submitted for to facilitate direct comparison, if and applicable. Up to one month Real time stability data of OS and DP required at the time of submission (if not a plan and weekly report of studies result may be submitted after application ), applicant is required to submit a minimum one month data at the time of Form C3b submission, both with undertaking of commitment statement to continue studies for remaining period as per plan, and the remaining data at the time of toxicity report (Form C5) submission. # # Data: (i.e. batch size, date of initiation & completion of fermentation, purification, formulation and stability studies) and formulation details along with excipients. Number of samples analyzed at each data point should sufficient enough to reveal statistically significant differences among the batches and assay points. To be adhered if planned for multiple antigenic targets Gross pictures should be taken with sufficient shadow less white light and printed on photo quality, glossy , color ink jet paper and there should be a dimension marker (scale) included in the picture below the organ. Histopathology pictures (high resolution pictures showing magnification used) shall be submitted. In addition, the stain used and the magnification at which the picture was taken should also be given in the photograph. Historical data of haematology, clinical chemistry, histopathology should be mentioned in the report, including the normal range. Evaluation criteria should be in terms of both statistical significance and biological response of the test system Test system (animals) to be used for the toxicity/immune response studies should be characterized appropriately to generate reliable and reproducible data. 7