1) This document discusses the challenges and opportunities for conducting HIV vaccine clinical trials across Africa. It outlines several networks that conduct such trials, including ongoing studies in South Africa, Tanzania, Kenya, and other countries. 2) Regulatory approval for clinical trials can often be a lengthy process, taking over 100 days on average for some studies. Harmonization of regulatory systems and increasing local expertise could help address challenges. 3) International collaboration and engagement with local stakeholders is important for ensuring trials are conducted effectively and ethically. Capacity building aims to strike the right balance between scientific goals and respecting local contexts.

1. 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 LONDON 1

2. Adult HIV Prevalence 2013
(UNIADS 2013)
HIV Vaccine Trial Sites (IAVI Database) 2

3. 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
3

4. 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

5. MAJOR HIV VACCINE NETWORKS 5
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

6. 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
14

7. ONGOING HIV VACCINE STUDIES 7
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…

8. REGULATORY APPROVALS
Straight Ahead! 8

9. PRODUCT DEVELOPMENT PATH 9
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

10. GUIDES TO GOODNESS

11. 11

12. 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 12
Geldenhuys, et al., S Afr Med J 2013;103(2):85-89.

13. 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
13
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

14. Sponsor
Manufacturer 3
Distributor
Manufacturer 2
Manufacturer 1
Tanzanian sites
Mozambique Site 14

15. 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
15

16. 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 16

17. 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 17
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

18. 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)
18