FROM KAMPALA TO CAPE TOWN

FROM KAMPALA TO CAPE TOWN A JOURNEY ON THE HIV VACCINE NETWORKS HIGHWAY

ROGER TATOUD, PH.D .

SENIOR PROGRAMME MANAGER (TRANSLATIONAL RESEARCH, HIV)

UK HIV VACCINE CONSORTIUM

IMPERIAL COLLEGE L OND ON

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Presenter

Presentation Notes

Thank you Brief intro on the UK HVC and involvement with regulators Disclaimer Transition on highways

Adult HIV Prevalence 2013 (UNIADS 2013)

HIV Vaccine Trial Sites (IAVI Database)

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Presenter

Presentation Notes

Areas of high prevalence, areas where research take place, follow the Trans-African highways Though it reveals a concentration of research in high prevalence areas. Ignoring countries with still high prevalence of HIV – could be a historical as much as a scientific decision Corridor of HIV, corridor of research Not necessarily the best for Phase I, but illustrate the difficulty to do early stage research in research as many countries require products to be tested in the North.

AN IDEAL NETWORK FOR CONDUCTING HIV VACCINE STUDIES Good clinical infrastructure (clinics, health centres, pharmacy, bio-banking, archiving facilities)

GCP-certified laboratories for immunoassays

Data management facilities

Good communication infrastructure (road/internet)

Qualified staff (GCP, GLP): Clinicians, social scientists, pharmacists, nurses, lab staff

Community Advisory Board (CAB/CAG)

Relevant participants

Local and national support

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Presenter

Presentation Notes

Doing research is not just about a product, some volunteers and a clinic. Complex, multifaceted, requires resources I and expertise n many areas from infrastructure to qualified staff but also national and local support.

AFREVACC PARTNERSHIP Imperial College London

Medical Research Council Clinical Trials Unit (UK)

Fundació Clinic per la Recerca Biomédica (Spain)

University of Munich (Germany)

Amsterdam Institute for Global Health Development (Netherlands)

Wits Reproductive Health & HIV Institute (South Africa)

Africa Centre for Health and Population Studies (South Africa)

Centre Hospitalier Universitaire Lausanne (Switzerland)

Contract Laboratory Services (South Africa)

Universidade Catolica de Moçambique, Beira (Mozambique)

Manhica Health Centre (Mozambique)

Mbeya Medical Research Programme (Tanzania)

The network was established in 2008 to explore HIV vaccine development and build HIV vaccine trial capacity in South Africa, Tanzania & Mozambique. 4

Presenter

Presentation Notes

Example of a network Brief description of the network Explain why no study took place, and how the study was piggy-backed onto the TaMoVac network

MAJOR HIV VACCINE NETWORKS

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HVTN: Public and private sources, the National Institute of Allergy and Infectious Diseases (NIAID) is the main funder and another significant funding source is the Bill & Melinda Gates Foundation (BMGF).

IAVI: Government, Multilateral, Foundation, Corporate

EDCTP: EU and government co-funding

SAAVI

Presenter

Presentation Notes

Other networks, sometimes in the same place Mention how they also work together Following slide: where the studies took place

HIV VACCINE TRIALS IN AFRICA

Sources

IAVI Database

ClinicalTrials.gov

AVAC

Colleagues

Known status

Able to start

Prophylactic (37)

Therapeutic (3)

6

3

11

3

2

1

6

14

1

5

1

1

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Presenter

Presentation Notes

Only vaccines studies – not feasibility studies. Mostly prophylactic studies. About 40 studies – mention cost. Uganda, Kenya and South Africa as countries where most studies took place. Countries with a “success story” or with resources and infrastructure favouring research. West Africa?

ONGOING HIV VACCINE STUDIES

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Ph. Name Status Strategy Immunogens Ppts Countries

I RV262 Ongoing DNA Viral Vector - Pox

Pennvax-G (env-gag) MVA-CMDR 92 Kenya, Tanzania,

Uganda, USA

I IAVI S001 Ongoing Viral Vector – Replicating Viral Vector - Adeno

SeV-G (replicating) Ad35-GRIN 64 Kenya, United Kingdom,

Rwanda

I HVTN 086, SAAVI 103 Ongoing Viral Vector – Pox

DNA Protein

SAAVI MVA-C SAAVI DNA-C2

Oligomeric gp140/MF59 184 South Africa

I HVTN 097 Ongoing Viral Vector – Pox Protein

ALVAC-HIV vCP1521 AIDSVAX B/E 100 South Africa

I/II IAVI N004 HIV-CORE 004 Ongoing

Viral Vector – Adeno Viral Vector – Pox

DNA

Ad35-GRIN MVA.HIVconsv pSG2.HIVconsv

72 Kenya

I/II HVTN 084 Ongoing Viral Vector – Adeno Viral Vector - Adeno

VRC-HIVADV054-00-VP (gag-pol) VRC-HIVADV014-00-VP 100 Peru, Brazil,

USA, Swaziland

II TaMoVac II (AFV) Ongoing DNA

Viral Vector - Pox Protein

HIVIS-DNA MVA-CMDR GP140+GLA

198 Tanzania, Mozambique

Horizon 2020 and EDCTP 2 are coming…

Presenter

Presentation Notes

A variation on a theme Slide for regulators Prime Boost Reboost – selected insert but usually gag pol nef and env Different clades Different regimen Sometimes different route of administration (SeV-G nasal) or mode of administration (TaMoVaC, ID with or without electroporation)

REGULATORY APPROVALS

Straight Ahead!

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PRODUCT DEVELOPMENT PATH

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Basic research

Prototype Discovery &

Design

Pre-clinical Develop-

ment

Early clinical trials (I/II)

Late clinical trials (III/IV)

Regulatory approval Marketing

Post marketing compliance

Patient

32 years and counting

2-5 years

3-10 years

1-2 years Product

Manufacture

1-2 years Product

Manufacture

• R&D • Ethics

• Relevance • Design • Risk/Benefit • Patient information & consent • Investigator competence

• Clinical Trial Authorisation • Sponsorship • Investigator competence • Manufacture (IB/IMPD) • Safety • Protocol • IMP management (labelling/Stability) • Monitoring • Management (Trial, Product, Data)

Knowledge

Presenter

Presentation Notes

Regulatory approval is a complex process that takes place at several stages of the product development path. Audience will hear about clinical approval during the conference, for example about Truvada for PrEP in the UK In clinical research, it consists in a number of separate and distinct approvals The purpose of the Ethical review process is to assure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in a research study. Clinical Trial Authorisation is required to ensure high standards in terms of comprehensive documentation for the clinical protocol, record keeping, training, and facilities, including computers and software are in place for the purpose of conducting a clinical study. Extensive knowledge and understanding of clinical research but also of all steps leading to the proposed research and also of international guidelines.

GUIDES TO GOODNESS

Presenter

Presentation Notes

EMA, WHO, FDA National Guides South Africa has a its own GCP guideline since 200 revised in 2006. Sponsor countries wants to work to their standard.

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Presenter

Presentation Notes

Routemap to clinical studies Point to regulatory steps Note that the difference between UK and Africa is that there is more resources available and limited time to go through the process.

CASE STUDY 1 - SATVI TB VACCINE TRIAL

92 Applications for 16 TB vaccine trials (32/60) between 2004-2012

MCC & UCT Faculty of health Science HREC (S. Af.)

Median approval time for first submission to MCC was 122 days (IQR 112 - 168; range 71 - 350)

Approval time for amendment submissions to the MCC was 103 days (IQR 76 - 141, range 23 - 191)

Median approval time for first submission to HREC was 60 days (IQR 33 - 81; range 18 - 125).

For amendment submissions to HREC, median was 6 days; IQR 4 - 13; range 1 – 37)

No difference in approval time by clinical phase, year of submission, calendar month of submission, sponsor, PI, age of study participants, sample size, or use of a CRO for either MCC or HREC submission

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Geldenhuys, et al., S Afr Med J 2013;103(2):85-89.

Presenter

Presentation Notes

Hennie Geldenhuys from the South African Tuberculosis Vaccine Initiative (SATVI). Example. Not to put MCC under the spotlight Time delay is also caused by applicants responding slowly

CASE STUDY 2 – PRODUCT SHELF-LIFE EXTENSION

TaMoVac II: EDCTP funded Phase II placebo controlled study Led by Prof. Eligius Lyamuya (MUHAS) sponsored by SMI.

Site in Tanzania and Mozambique (Ilesh Jani)

6 arms study with multiple products and devices

0 4 12 24 40

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7 DNA Plasmids (KI/SMI) Env A,B,C Gag A,B RT B Rev B

MVA NIH/WRAIR

Env E, Gag A, Pol A

With or Without GP140+GLA (bedside mix)

UK HVC

Presenter

Presentation Notes

A Phase II trial to assess the safety and immunogenicity of DNA priming administered by the ID Zetajet® with or without ID Derma Vax™ electroporation followed by IM MVA boosting with or without CN54 rgp140/GLA-AF in healthy volunteers in Tanzania and Mozambique Go through complexity for the regulators.

Sponsor

Manufacturer 3

Distributor

Manufacturer 2

Manufacturer 1

Tanzanian sites

Mozambique Site

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Presenter

Presentation Notes

Describe the manufacturing of the UK HVC products and their journey GLA travelled 22,000 km Risk assessment could have shown that Seattle-Iowa City and back may not be a good idea Import licence - Custom process Delivery in country from Dar to Mbeya No question about the journey but request for shelf life extension was turned down

POTENTIAL REGULATORY CHALLENGES IN INTERNATIONAL CLINICAL TRIALS

Research priority

Limited expertise and capacity of local regulatory bodies

Conflicting ethos of funders, researchers and regulators

Multiple layers of reviews with inconsistent findings

Importation process

Variation in standard for participant compensation for trial-related injury

Increased scrutiny and restriction of bio-banking and repository research

Ownership of data, samples and publication rights

Post study drug provision and long term commitment to the provision of treatment

Civil society awareness and understanding of clinical research (public pressure)

Adapted from Ndebele et al., JAIDS 65(S1):S29, 2014

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IMPACT OF POORLY-RESOURCED REGULATORY SYSTEMS

Increase costs

Complicate operational planning by sponsors and researchers

Create further delay

Threaten successful completion of trial

Impact on scientific validity of clinical research

Lead to frustration and distrust in the system

Affect perception of clinical research by participants, the public and the international communities at large

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HOW TO MAKE IT WORK BETTER?

Understand the purpose of the regulatory requirements and processes

• STEP, Ebola • Multi-component trials • Manufacturing processes, product shelf-life, timelines

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Engaging with existing regulatory structures

• EDCTP: MARC (Mapping of the capacity to ethically review health research) • WHO: AVAREF (African Vaccine Regulatory Forum) • African Medicines Building local capacity • Regulatory Harmonisation Initiative

Mindfulness of what it means to conduct research in developing countries

African stakeholders to take leadership

Moving towards a single Pan-African regulatory body (similar to EU)

• EDCTP-funded Pan African Clinical Trials Registry (PACTR) Working together to strike the right balance

Presenter

Presentation Notes

Too slow with HIV, too fast with Ebola? Time will tell Striking the right balance, interpreting the guidelines not just following them Example of label (would it be approved by regulator?) Traceability matters Working together, African Ownership and Leadership Mindfulness from all about what it means to do clinical research in developing countries

AKNOWLEDGEMENTS

Sarah Joseph (MRC-CTU at UCL)

Phil Bergin (IAVI)

Merlin Robb (WRAIR)

Sheena McCormack (MRC-CTU at UCL)

Eligius Lyamuya and Muhammad Bakari (TaMoVac - Tanzania)

Bindiya Meggi (TaMoVac – Mozambique)

IAVI

AVAC

Sue Marlow

Kate Skinner (Holden-Dye)

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FROM KAMPALA TO CAPE TOWN

Health & Medicine

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