HIV ENV MANUFACTURING WORKSHOP A workshop sponsored by the Division of AIDS/NIAID/NIH and the Global HIV Vaccine Enterprise

Transcription

1 HIV ENV MANUFACTURING WORKSHOP A workshop sponsored by the Division of AIDS/NIAID/NIH and the Global HIV Vaccine Enterprise Strategies for Facilitating Regulatory Pathways Tanya Scharton-Kersten, PhD Senior Director, Regulatory Affairs and Quality Assurance Rockville, Maryland June 12, 2015

2 State of the Field: May 2015 Despite significant progress in the HIV field during the past five years, there is still a low probability that vaccine candidates currently in the clinical pipeline will be the solution. Intentional focus on key scientific problems impeding HIV vaccine development is needed: What antigen(s) are required for inclusion in an HIV vaccine? How to elicit specific humoral and cell mediated responses needed for protection? What are correlates of protection? How to elicit durable protective immunity? Innovation in HIV vaccine discovery is still required for success 2

3 Facilitating Regulatory Pathways: Objectives Review current accepted approach for Research to Clinic for HIV vaccine candidates, particularly proteins Highlight evolution in the regulatory landscape that has created NEW opportunities Discuss these opportunities: HOW can we stay in the GMP framework and push the envelope for protein development? Conventional approach Less conventional approaches; through the lens of other related fields 3

4 Current Framework for HIV Vaccine Development Scope Process Development Manufacturing Preclinical Average - Protein Time: 45/50/61 months DNA-Vector-Protein 5-7 Mio USD investment Regulatory Clinical Trial Start Time Cost AIDS impact worldwide, 2013 statistics 4 new infections 3 AIDS related deaths PER MINUTE 10 Mio new infections 7.5 Mio deaths WHILE we develop the vaccine From Bench to Clinic: A Researchers Guide to Move Candidate Vaccines into Trials, from Global HIV Vaccine Enterprise (2013) statistics 4

5 From Bench to Clinic Model Global HIV Vaccine Enterprise Tool What is it? From Bench to Clinic is a webtool to help researchers most efficiently move their candidate vaccines into first-in-human trials. The tool is intended to acquaint researchers, funders and advocates, with the processes, costs and timelines involved in the first phase of product development. Origin Roger Tatoud, Imperial College London Eddy Sayeed, International AIDS Vaccine Initiative Pervin Anklesaria, the Bill & Melinda Gates Foundation, Jim Ackland, Global BioSolutions/IAVI, Song Ding, EuroVacc Foundation, Debbie Douglas, Alliance Coordinating Office, Phil Gomez, PwC, Jane Halpern, DAIDS, National Institutes of Health, Greg Hammond, Canadian HIV Vaccine Initiative, Tom Hassell, IAVI, Dietmar Katinger, Polymun Scientific, Shan Lu, University of Massachusetts, Anita Ng, Canadian HIV Vaccine Initiative, Michael Pensiero, DAIDS, National Institutes of Health, Stuart Shapiro, DAIDS, National Institutes of Health, Dean Smith, Health Canada, Jim Tartaglia, Sanofi Pasteur, Carol Weiss, U.S. Food and Drug Administration. 5

6 Expediting Protein Development: Conventional Approach Discovery Be brilliant Document everything, train your staff to maintain slightly above reasonable documentation practices Development / Manufacturing Choose a platform and leverage knowledge and compliance (ie. qualified cell banks) wherever possible Start contracts with partners (Master Agreement, Task orders, MTA, QAG) earlier than you think is necessary Use RFP processes as often as possible; healthy competition is good, having options is ideal Preclinical Proof of Principle and Toxicology Studies Use RFP processes, when feasible Know the guidances / regulations and ask is it necessary, could it be redundant, what are we learning? Wherever possible, Leverage existing data sets When a study IS needed: focus on right first time, consider consultation with statistician and/or toxicologist 6

7 Expediting Protein Development: Conventional Approach Regulatory Use a science based approach Use FDA consultation processes when/where appropriate to derisk programs and identify opportunities for acceleration Early advice new discovery or manufacturing platforms, novel clinical designs preind overall manufacturing strategy, viral clearance, proposed product release criteria, preclinical study design, clinical study design, regulatory strategy for program Start early; finish on time Clinical Follow GCP practices; qualify new sites, monitor appropriately, establish and maintain robust sponsor, investigator, manufacturer relationships Consider use of adaptive clinical trial designs; particularly since there is now extensive guidance for drugs, biologics and devices 7

8 Pushing The Envelope: Modified Approach to HIV Vaccine Development Right size time/cost/scope (Project Management Triangle) to facilitate innovation and incremental scientific progress in the clinic scope time cost/resource scope time cost/resource o What antigen(s) are required for inclusion in an HIV vaccine? o How to elicit specific humoral and cellular responses? 8

9 Changes to the Landscape: Recent Regulatory Evolution 2004: FDA Critical Path Initiative launched Risk pics/criticalpathinitiative/criticalpathopportuniti esreports/ucm htm#get Benefit Industrialization 2006: ICH Q9 Quality Risk Management (2006) adopted 2008: Revised legislation (21 CFR 210.2) and new guidance on GMP and INDs intended for use in phase I clinical trials (Docket No. FDA 2005 N 0170) 2010: Advancing Regulatory Science Initiative launched 9

10 Changes to the Landscape: External Environment : Swine Flu pandemic drives change in world wide approaches to rapid manufacturing 2014: Ebola outbreak in West Africa fosters international response and worldwide innovation for rapid clinical trials Era of Biosimilars: Launch of The Purple Book and license of FIRST biosimilar in the US Era of personalized therapeutic vaccines for Cancer, allogeneic transplants for Diabetes 10

11 Changes to the Landscape: HIV Science Unexpected success / failure in recent clinical trials has led to Renaissance period for HIV vaccinology New analytical tools are available for discovery research HIV envelope explosion Trimers, monomers, SOSIP, soluble, membrane, cleaved, uncleaved, degree of glycosylation. New clinical analytical tools makes potential benefit of clinical research in small populations more valuable Collaborative research and development frameworks have formed and there is a renewed willingness of innovators and developers to share experiences 11

12 Research to Clinic in 12 months for HIV: Opportunities for Change Science Manufacturing Preclinical / Toxicology Regulatory Clinical Trials 12

13 Research to Clinic in 12 months for HIV: The cycle is already active, including GMP, in other fields 12 Months: Annual Influenza Vaccination, relicensure worldwide with new GMP manufacturing of 3 components, fill, finish and release EVERY year 13 approved vaccines in the US: Eggs, MDCK cells, Vero cell, Sf9 (insect cells) technologies. Note: antigen recoveries < 10%. 3 months: Individual therapeutic cancer vaccines 1 week: Allogeneic islet transplant 13

14 The 12 Month Concept: Possible framework changes in Manufacturing Leverage recent GMP experience in other fields where small scale, rapid manufacturing is the norm - patient specific therapies and imaging tools Leverage knowledge in other fields where cost containment is the norm Generics, Biosimilars, Consumer Health (eg. sterile eye care), and Influenza Relook at appropriate legacy technologies (production), new technologies for containment and single use, and rapid technologies for testing and release Distinguish early in the process, projects for Experimental Clinical Research Trials (discovery) and those intended for later stage development; ensure team is aligned 14

15 The 12 Month Concept: Possible framework changes in Preclinical and Toxicology Leverage vast experience with ENV protein / DNAprotein, recombinant vectors with past clinical trials to right size toxicology efforts; avoid redundancy Increase use of cross reference letters, taking advantage of Common Technical Document structure for clinical trial applications Ensure toxicology studies are in the public domain to avoid redundancy in the field 15

16 The 12 Month Concept: Possible framework changes in Regulatory Consider concept of Comparability Protocols, which are well established for licensed products, within INDs Consider involvement in FDA s Advancing Regulatory Science Initiative to identify further opportunities for acceleration Identify appropriate meeting frameworks for Exploratory Clinical Research Trials 16

17 The 12 Month Concept: Possible framework changes in Clinical Trial Field Leverage recent FDA guidance on Adaptive Clinical Trials for Drugs, Biologics and Devices Implement Exploratory Clinical Research Trial concept Testing prototypes..not products Asking specific questions- offers the potential to address the key problems impeding HIV vaccine development Baseline studies for future products 17

18 Types of Clinical Trials Envisaged: Changes to Objectives, Scale and Endpoints Trial objective Conventional Phase I Product development Initial screening for safety Dose level and schedule Exploratory Clinical Research Trial (ECRT) Scientific information (immunology; mechanisms; methodologies) Not designed for product development Trial size Volunteer population volunteer range Control/ placebo group Low risk for HIV infection Smaller; volunteer range May not include a control/ placebo group Low risk for HIV infection Trial duration 1 1 ½ year range (or longer) Typically, less than 1 year Clinical trial material Trial endpoints Product focus - Established technologies - Scalable process - Single immunogen in trial - Early focus on product characterization and stability Safety Initial (standard) immunogenicity Component / immunogen focus - Use of new technologies - Process not necessarily scalable - Potential multiple immunogens - Leverage historical data (eg HIV Env) Safety Deep and broad immunological analysis: eg antibody repertoire; binding to germline, innate signatures, transcriptome analyses, single cell responses, etc. 18

19 Impact of Proposed ECRT Initiative Increased probability of success Current Candidate Selected Process Development & Manufacturing Release and Non Clinical Testing Phase I Trial Start First Human Data Longer cycles even for 2 nd & 3 rd generations due to resource diversion Phase II, III, licensure Low probability of success Typical timelines detailed in Bench to Clinic, Global HIV Vaccine Enterprise white paper 19

20 Impact of Proposed ECRT Initiative Increased probability of success Current Candidate Selected Process Development & Manufacturing Release and Non Clinical Testing Phase I Trial Start First Human Data Phase II, III, licensure Low probability of success Proposed ECRT: Streamlining process through enabling technologies with only definitive candidates progressed to stable manufacturing development and Ph I, II, III pipeline Multiple candidates selected Definitive Candidate Process Development & Manufacturing Phase I, II, III, licensure Manufacturing Clinical Data High Probability of Success 20

21 Insanity: doing the same thing over and over again and expecting different results -Albert Einstein 21

22 Acknowledgements IAVI R&D team The Bill and Melinda Gates Foundation Global HIV Vaccine Enterprise NIAID, DAIDS The innovators and manufacturers for sustaining the passion around HIV research (YOU) 22

23 We thank our donors 23