Tanya Scharton-Kersten, PhD Senior Director, Regulatory Affairs and Quality Assurance

Rockville, Maryland June 12, 2015

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

• 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

State of the Field: May 2015

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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

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Current Framework for HIV Vaccine Development

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• From Bench to Clinic: A Researchers Guide to Move Candidate Vaccines into Trials, from Global HIV Vaccine Enterprise (2013).

• http://www.vaccineenterprise.org/benchtoclinic/index.html#!vaccine=dna&planning=optimistic • http://www.unaids.org/en/resources/campaigns/World-AIDS-Day-Report-2014/factsheet; 2013 statistics

Average - Protein Time: 45/50/61 months DNA-Vector-Protein 5-7 Mio USD investment

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

Scope

Time

Cost

Process Development

Preclinical

Regulatory

Clinical Trial Start

Manufacturing

From Bench to Clinic Model Global HIV Vaccine Enterprise Tool

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• 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.

Expediting Protein Development: Conventional Approach

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• 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

Expediting Protein Development: Conventional Approach

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• 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

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

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time scope

cost/resource

o What antigen(s) are required for inclusion in an HIV vaccine?

o How to elicit specific humoral and cellular responses?

scope

cost/resource

time

Changes to the Landscape: Recent Regulatory Evolution

2004: FDA Critical Path Initiative launched http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htm#get

2010: Advancing Regulatory Science Initiative launched

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)

Risk

Benefit

Industrialization

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Changes to the Landscape: External Environment

2009-2010: Swine Flu pandemic drives change in world wide approaches to rapid manufacturing

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2014: Ebola outbreak in West Africa fosters international response and worldwide innovation for rapid clinical trials

Era of personalized therapeutic vaccines for Cancer, allogeneic transplants for Diabetes

Era of Biosimilars: Launch of ‘The Purple Book’ and license of FIRST biosimilar in the US

Changes to the Landscape: HIV Science

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• 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

Research to Clinic in 12 months for HIV: Opportunities for Change

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Science

Manufacturing

Preclinical / Toxicology

Regulatory

Clinical Trials

Research to Clinic in 12 months for HIV: The cycle is already active, including GMP, in other fields

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12 Months: Annual Influenza Vaccination, relicensure worldwide with new GMP manufacturing of 3 components, fill, finish and release EVERY year

http://www.cdc.gov/flu/protect/vaccine/vaccines.htm 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

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

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The 12 Month Concept: Possible framework changes in Preclinical and Toxicology

• Leverage vast experience with ENV protein / DNA- protein, 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

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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

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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”

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Types of Clinical Trials Envisaged: Changes to Objectives, Scale and Endpoints

Conventional Phase I Exploratory Clinical Research Trial (ECRT)

Trial objective

• Product development • Initial screening for safety • Dose level and schedule

• Scientific information (immunology; mechanisms; methodologies)

• Not designed for product development

Trial size

• 20 – 200 volunteer range • Control/ placebo group

• Smaller; 10 – 30 volunteer range • May not include a control/ placebo group

Volunteer population

• Low risk for HIV infection • Low risk for HIV infection

Trial duration • 1 – 1 ½ year range (or longer) • Typically, less than 1 year

Clinical trial material

• ‘Product’ focus - Established technologies - Scalable process - Single immunogen in trial - Early focus on product characterization and stability

• Component / immunogen focus - Use of new technologies - Process not necessarily scalable - Potential multiple immunogens - Leverage historical data (eg HIV Env)

Trial endpoints

• Safety • Initial (standard)

immunogenicity

• Safety • Deep and broad immunological analysis: eg

antibody repertoire; binding to germline, innate signatures, transcriptome analyses, single cell responses, etc.

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Impact of Proposed ECRT Initiative Increased probability of success

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Candidate Selected

Process Development & Manufacturing

Release and Non Clinical

Testing Phase I

Trial Start First Human

Data

even for 2nd & 3rd generations due to resource diversion

Current

Phase II, III, licensure

Low probability of

success

Longer cycles

Typical timelines detailed in “Bench to Clinic”, Global HIV Vaccine Enterprise white paper

Multiple candidates

selected

Manufacturing Clinical Data

Impact of Proposed ECRT Initiative Increased probability of success

Candidate Selected

Process Development & Manufacturing

Release and Non Clinical

Testing Phase I

Trial Start First Human

Data

Current

Proposed ECRT: Streamlining process through enabling technologies with only definitive candidates progressed to stable manufacturing development and Ph I, II, III pipeline

Definitive Candidate

Process Development & Manufacturing

Phase I, II, III, licensure

High Probability of

Success

Phase II, III, licensure

Low probability of

success

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“Insanity: doing the same thing over and over again and expecting different results”

-Albert Einstein

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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)

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We thank our donors

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