The regulatory landscape in South Africa and neighbouring countries: updates, challenges

and opportunities

9th International VPM Days, Hannover, 15 September 2016Victor Strugo, Paul Serebro, Elandré Kok, Eleen Fourie

• Established February 2000, HQ Johannesburg, SA• Full service, protocol co-development to CSR• 16-year record: > 265 studies Phase I – IV• N > 48,000, sites > 700, most therapeutic areas, 15 African countries• > 80% repeat business• Predominance of TM (PDPs, Biotechs, AROs)• Preferred Provider GHCC, DAIDS (regulatory Africa)• Site Audits & training conducted in Africa, Asia, Europe & USA• 69 vaccine trials:

TB, HIV, Measles, Influenza, Hepatitis,Polio, HPV, RSV, Polyvalent paeds

• Collaboration with VPM since 2010 and SII directly since 2015

TRICLINIUM INTRODUCTION

Phase Ib Open Label, Randomized, Controlled, Dose-Escalation Study to Evaluate Safety and Immunogenicity of VPM1002 in Comparison with BCG in Healthy Volunteers in South Africa (Apr – Dec 2010)

Phase II Open Label, Randomized, Controlled Study to Evaluate Safety and Immunogenicity of VPM1002 in Comparison with BCG in HIV-unexposed, BCG naive newborn infants in South Africa (Nov 2011 –Nov 2012)

Phase II double-blind, randomized, controlled study to evaluate the safety and immunogenicity of VPM1002 in comparison with BCG in HIV-exposed and HIV-unexposed, BCG-naive newborn infants (Jun2015 – Sep 2016)

COLLABORATIONS WITH VPM / SII

Search criteria COUNTRYwww.clinicaltrials.gov

2016 (2015)

TRICLINIUMProjects Database

2016 (2015)

‘vaccine + South Africa’

131 (121) 69 (64)

‘Phase 1, 2 & 3’ 94(86) 63 (60)

‘Tuberculosis’ 36 (31) 32 (30)

VACCINE TRIALS IN SA

The Start

2000Triclinium founded – Clinical Trial Regulatory &Monitoring Services

2008Add QA/Auditing services

2013Becomes full-service CRO

2013eClinical Solutions Company founded –focusing on technology in the developing world

2014Triclinium acquired by AcquiPharma

2015Rebranded as TCD Group:Triclinium Clinical Development

Hexor acquired into group: TCD-OR

1991First CRO founded in SA. Later acquired by Global CRO.

2005Health Economics and Outcomes Based Research company launched.

2011BMGF selects Triclinium as 1 of 6 preferred CROs

2012DAIDS selects Triclinium as RegServices provider in South Africa

2016Global growth:TCD India established (Data Mgmt Services)

TCD MENA (to launch December)

New domain:www.tcd-global.com

(to launch October)

OUR EVOLUTION

Intro & Products Overview Sept 2016• NUKLEUS: Novel EDC development for TCD• RHINNO: e-submission software for IRBs• EMelA: SA DoH: too to rationalise national

implmenentation of Essential Medicines List

© Copyright 2016 PharmaLTX (Pty) Ltd

NUKLEUS EDC

© Copyright 2016 PharmaLTX (Pty) Ltd

Product Overview

The EDC solution provides cleaner data more quickly by eliminating paper-based data

collection – reducing costs and time to market for pharmaceutical and medical device

companies.

The solution maintains the workflow of paper while allowing fast, secure transmission

of source data via an online interface.

The uniquely designed framework allows all the stakeholders within the product

development lifecycle to work on a central, cloud-hosted platform sharing the same

database.

The entire portal is governed using role-based access and has been implemented and

built with the FDA’s CFR Part 11 regulations and HIPAA privacy laws as foundation.

Unique Features include:

Mobile App (offline compatible) for Electronic Patient Reported Outcome

Graphical Wizard to setup Entire Study (including complex edit checks)

Pre-configured with CDISC standards (SDTM, CDASH & ADaM)

Global Data Centre Partner (Amazon Web Services)

Currently hosting EDC solutions in Frankfurt, Singapore & Virginia.

RHINNO ETHICS

© Copyright 2016 PharmaLTX (Pty) Ltd

Product Overview

The solution offers a cloud-based management of the research ethics review process. Its

basis is facilitating the management from protocol submission to review to approval to

follow-up.

Researchers will find it easy to upload their files, receive immediate feedback that

submission is complete, and can follow progress of the review.

Reviewers can access their file and respond from wherever they may be, even when on

travel.

Administrators can distribute, respond, re-send, and manage an overview of all

proposals in review. They can also invite external reviewers in case their committee

lacks specific expertise

Statistics

Deployed to 29 Ethics Committee across 9 African Countries

Goal to have it deployed to 100 Ethics Committees across EMEA by end of 2017.

Partnership (COHRED)

COHRED, the Council on Health Research

for Development, is a global, non-profit

organization whose goal is to maximize the potential of research and innovation to deliver

sustainable solutions to the health and development problems of people living in low and

middle-income countries.

© Copyright 2016 PharmaLTX (Pty) Ltd

Product Overview

The Essential Drugs Programme (EDP) of South Africa was established in terms of

the National Drug Policy (NDP). The EDP includes the development of the Essential

Medicines List (EML) and Standard Treatment Guidelines (STGs) and aims to

ensure the availability and accessibility of medicines to treat the most common

conditions and to promote the rational use of medicines and still achieve optimum

therapeutic outcome.

We were selected to develop a web‐based Essential Medicines List Tool (EMLT) for

the South African National Department of Health. The solution has been named

EMelA (Essential Medicines electronic Access)

Partnerships

Made possible by the generous support of the US Agency for International

Development (USAID), under the terms of cooperative agreement number AID-

OAA-A-11-00021

EMelA Tool (EML & STG Master Database)

In the regulation of clinical research, WHAT ARE opportunities and challenges?

vs

High scientific / ethical norms Opacity & variabilitySystematic efficiency Excessive regulations

Challenges vs Opportunities

The human mind may start focused on content ….… but too often falls in love with process

Danger: rigour becomes rigidity

Challenges vs Opportunities

Degrees of Challenge:

Local expertise to find solutions

RegionMedian

Patients / Site

% of Sites

0 pts 1 - 3 pts 4 - 9 pts 10+ pts

Latin America 4.0 21% 26% 30% 23%

North America 3.0 29% 29% 24% 18%

Eastern Europe 6.0 15% 31% 26% 27%

Western Europe 4.0 15% 22% 29% 34%

Asia Pacific 4.0 19% 30% 34% 18%

Africa 10.0 4% 17% 28% 51%

Site enrolment performance by region

Why bother with Africa?

Source: Quintiles South Africa, Presented: SACRA Conference 2009

START-UP TIMELINE: SSV TO SIV

0

5

10

15

20

25

30

35

40

45

Africa NorthAmerica

AsiaPacific

WesternEurope

EasternEurope

LatinAmerica

Source: Quintiles South Africa, SACRA Conference 2008

Wee

ks (a

vera

ge)

Why bother with Africa?

0

500

1000

1500

2000

2500

South Africa Kenya Malawi Tanzania Uganda Zambia

Registry data: African countries

2005

2010

2015

African Trend 2005 - 2015

Source: www.clinicaltrials.gov, 28-Aug-2015

CONCERN ABOUT PROTECTION OF RESEARCH PARTICIPANTS PRE-WW II

• 1780 UK Edward Jenner - obtained informed consent • 1833 USA Army Doctor William Beaumont - consent required• 1900 Prussia Consent, protection for vulnerable• 1931 Germany Consent, protection for vulnerable

Abolished after 1933• 1947 Nürnberg Tribunal: WW II crimes against humanity

McNeill PM. In Kuhse H, Singer P. A companion to bioethics, Oxford: Blackwell, 1998

Ethical context – a flashback

SOUTH AFRICA ALONGSIDE USA IN EVOLUTION OF IRBS

• 1953 NIH – Protection of Human Subjects Review Panel screens intramural clinical research to be screened by

• 1965 Mar – Henry Beecher (Harvard) talk on IRB need, publ 1966• 1966 Feb – US Public Health Service IRB system established; extends

screening to extramural research • 1966 Jun – Beecher article in NEJM – supporting use of IRBs• 1966 Oct – Wits University, Johannesburg establishes HREC (Medical)• 1974 National Research Act: requires IRB to screen all research & federal

agencies to develop human research regulations, e.g. 45 CFR 46• 1979 Belmont Report• 1981 Health & Human Services provided first framework for IRB function• 1991 45 CFR 46 (“Common Rule “) adopted by US government

agencies (latest update 2009)

IRB = Institutional Review Board = Research Ethics Committee

The article that ‘accelerated change’

Henry K Beecher MD(1904-1976)

Emeritus Professor of Anaesthesiology at Harvard University

‘Father’ of Modern Research Ethics Committees

John HansenMB ChB, DCHRCP, MRCP, MD, FRCP, DSc

(1920-2011)Professor of Paediatrics at Wits

‘Initiator’ of Wits HREC in October 1966Chair 1966-1984

• 1966 June – Beecher’s NEJM article• 1966 October - Wits University establishes Human Research Ethics Committee• 1977+ SA Universities, research institutions establish RECs• 1979 SA MRC issues research ethics guidelines (revised 1987, 1993,

2002-5)• 1992 SA Medical Association establishes REC• 1995 PharmaEthics REC (non-institutional) established• 1996 SA Constitution entrenches informed consent in research • 2000 Dept of Health issues clinical trial GCP guidelines (2nd ed 2006)• 2004 Dept of Health issues research ethics guidelines (2nd ed 2015)• 2005 National Health Act of 2003 makes REC approval compulsory• 2006 National Health Research Ethics Council established• 2008 Registration with NHREC – first step in REC accreditation• 2008 Dept of Health establishes public register of clinical trials (SANCTR)• 2012 NHREC national audit of 33 registered RECs took place

RESEARCH ETHICS IN SOUTH AFRICA: HISTORICAL CAPSULE

Current versions, Department of Health

Download at www.nhrec.org.za

South African Research Ethics Guidelines

UNIQUE ASPECTS OF HUMAN RESEARCH ETHICS IN SOUTH AFRICA

• The South African Constitution (1996) entrenches informed consent to participate in research. No

other country defines this as this a legal right!

• The National Health Act (2003) makes approval of research by a registered Human Research Ethics Committee prior to commencement a legal

requirement.

GLOBAL CONTEXT: FOUNDATION DECADES OF RECS (IRBS)

• Before 1961: Ireland, Netherlands, Switzerland, USA• 1961-1970: South Africa, United Kingdom• 1971-1980: Denmark, France, Germany• 1981-1990: Botswana, Kenya, Uganda, Australia, New Zealand, India,

Italy, Norway, Sweden, Canada, Argentina, Brazil• 1991-2000: Malawi, Zimbabwe, China, Spain• 2001 +: Ghana, Nigeria, Russia

Conclusion: Africa often maligned, but history indicates a congruent intention to developed countries.

Question: Has the execution matched the intention ?

SAHPRA

– 2008 announcement: MCC will be replaced by a new regulatory authority, The South African Health Products Regulatory Agency (SAHPRA)

– Concept: upgraded version of the MCC

– Model: Similar to FDA

– Autonomy: outside Department of Health, so greater independence than MCC

– Funding: partly funded by government, partly by fees for services rendered

– Implementation: expected 2012 20132015 2016 2017 … 01 April (!?)

SOUTH AFRICAN MCC UPDATE

CLINICAL TRIALS STAKEHOLDER WORKSHOP: PRETORIA, MAY 2016

• Initiated by Clinical Trials Committee (CTC) of the MCC in 2015 – held twice a year

• Goals of these workshops:

– Improve communication

– Alert applicants to changes

– Discuss mutual concerns openly

– Maintain a healthy clinical research environment with adequate participant conditions.

SOUTH AFRICAN MCC UPDATE

POLICY/GUIDELINE DEVELOPMENT

– MCC aligned to ICH revision, latest Declaration of Helsinki and SA Department of Health priorities

– Need to elucidate MCC policy on specific processes > SA GCP (3rd edition 2016 imminent release)

– Task Team established to develop guidelines

– Serves as clarification of CTC’s expected practical application of SA GCP, local law and other guidelines.

– Once published, seen as minimum standards

– Waivers will require reasonable justification

– 3 completed, 14 in preparation, 11 not started

SOUTH AFRICAN MCC UPDATE

LIST OF PLANNED MCC POLICIES & GUIDELINES

LIST OF PLANNED MCC POLICIES & GUIDELINES

Capacity building

– “Transformation” should include previously disadvantaged researchers and research staff

– Academic sites; if no CB sites, show attempts to enlist some and/or reasons why not included

– Ways in which capacity is being developed within these groups:

SOUTH AFRICAN MCC POLICIES

Clinical Trial Insurance– Recent cases in SA have revealed false perception of

true “No Fault” Insurance policies, leaving sponsors (and sites) vulnerable to justified no-fault claims.

– Compensation: Basic principles of ABPI Guidelines (2014) must be followed.

– Costs must be reasonable and do not include costs for, e.g., a loss of income, compensation for pain or emotional suffering.

– If insurer defaults, the sponsor remains liable to pay compensation

– i.e. moral/ethical imperative > legal obligation

– Claims must be heard in participant’s country (local broker)

– Explicitly cover risk, participant numbers, duration (annual) renewal

– Investigator indemnification - sites with Group Malpractice insurance warned to ensure all staff effectively covered

SOUTH AFRICAN MCC POLICIES

Post-Trial Access

– For studies that involve chronic diseases for which there is no readily available alternative treatment and/or benefit from medication and where withdrawal is likely to lead to deterioration of their health status, post-trial access is mandatory……. Until the drug becomes available in the public health sector.

– Rationale is that economically disadvantaged populations once they have “contributed to drug development” deserve to benefit, and not to be dumped.

– Policy Document on Post-Trial Access in development

– Suggested that a roll-over study protocol be developed and if possible submitted alongside the original CTF1, with its own ICF.

SOUTH AFRICAN MCC POLICIES

HIV

– CTC will challenge protocols that exclude HIV+ participants, since local population is not reflected -acknowledge up front in CTF1 and provide convincing motivations for exclusion

– “known or suspected HIV” as exclusion criteria:

• HIV testing necessary, especially in trials involving IP which affects participant’s immunity

• Long-term trials:

– will HIV testing be repeated during trial?

– what if participant test positive during trial?

• Necessary consent forms

• Trained personnel to give counselling

SOUTH AFRICAN MCC POLICIES

SITE & SAFETY MONITORING

– CTC concerned with some interpretations of Risk-Based Monitoring

– CTF1 requires customized Mon Plans, not boiler-plate text

– Re-iterated need to comply with applicable expedited SAE/SUSAR reporting timelines.

– Sponsors encouraged to engage with CTC in discussion of safety concerns.

– 6-Monthly SAE line listings should be supplemented with safety physician/DSMB analysis of safety findings to date

SOUTH AFRICAN MCC POLICIES

• REC – Ensure research involving human participants will promote health, protect participants’ rights and dignity, and meet ethical standards Approval 2 – 3 months

• BEC – REC sub-committee: justification for storing human biological material for extended periods Approval 1 – 3 months

• DOH – provincial or municipal Approval 1 – 3 months• DAFF: NATIONAL BIOSAFETY (GMO) – Limiting exposure of

GMOs to the environment Approval 5 – 8 months• IBC (GMO & rDNA) - Reduce exposure of people and the

environment to potentially hazardous agents Approval 6 - 8 weeks

• MTA - Contract governing transfer of biological materials between institutions (usage, regulatory compliance, IP rights, etc) Approval 2 - 4 weeks

SOUTH AFRICA: ADDITIONAL REVIEWS

MCC PRE-REG CONSULTATIONS(PRC)

• to address issues relating to the development of a product

• a forum for the MCC to provide guidance to facilitate compliance with regulations

• three types of meetings

SOUTH AFRICA: ADVISORY MEETINGS

– Conducted before finalisation of non-clinical tests

– Design of pre human studies in order to support further studies in humans

– Planning for Phase 1 studies• Facility design

– General product issues

PRC – TYPE A

– Describe to reviewers the general info to accompany registration applications

– Discuss preliminary results obtained– Identify plans to further assess safety/efficacy– Discuss submission of incomplete applications– Discuss major outstanding issues

PRC – TYPE B

End Ph I / pre-Ph II• Review Phase I data• Reach agreement on

Phase II design– End goal of Phase II to

provide sufficient data to support continued development

End Ph II / pre-Ph III• Review Phase II data• Evaluate strategies for

Phase III• Identify additional info

needed for registration

Meetings requested by applicant through CTCPre-circulate agenda & documentation packageTypically attended by Council and/or CTC members

PRC – TYPE C

• Limited 30-minute slots on CTC meeting days• (6 meetings per year, 2 days each)• Appeal against or seek clarification on CTC

rejections• Applicant presence mandatory, sponsor

optional• Remote dial-in accommodated ….

CTC F2F CONSULTATION

• Generally: divided scopes of review (RAs – RECs)• RA main concern: IP quality (CoAs, GMP certificates, etc)• RECs / Scientific Advisory Councils: protection of participants

(trial design, patient facing materials, reimbursement,)• Multi level EC review (also National Scientific Advisory

Committee as part of review)– Uganda – UNCST– Kenya – NACOSTI– Malawi – NCST

• Mostly sequential submission process = up to 1 year until final approval. Where sequential, RA usually last.

OTHER AFRICAN COUNTRIES

• Parallel• South Africa• Uganda• Tanzania• Liberia• Sierra Leone• Guinea

• Sequential• Kenya• Malawi• Ethiopia

RA/REC APPLICATION PROCESSES

Useful guidance: Puppalwar G et al: Conducting clinical trials in emerging markets of sub-Saharan Africa: review of guidelines and resources for foreign sponsors. Open Access Journal of Clinical Trials, 2015:7

AUDITORS

Duursema, L*

Moeken, CMM*

Strugo, JL*

CONTRACTORS

Britz, PM

Jacobs, LH

Theron, B

Organogram: 22-Aug-2016

Managing DirectorStrugo, V (EXCO)

FINANCIAL

SERVICES

INFORMATION

TECHNOLOGY

REGULATORY

AFFAIRS

QUALITY

ASSURANCE &

TRAINING

BUSINESS

DEVELOPMENT

PROJECT

MANAGMENT

SCIENTIFIC

AFFAIRS

CLINICAL OPERATIONS

ABBREVIATIONSAdmin: Administrative BD: Business Development

Biom: Biometric CRA: Clinical Research Associate

CTA: Clinical Trial Assistant EXCO: Member of Executive Committee

HR: Human Resources j: Junior

IT: Information Technology PM: Project Manager/Management

QA: Quality Assurance RA: Regulatory Affairs

ROC: Regional Office Co-ordinator S: Senior

SA: Scientific Affairs TRA: Training Research Associate

*: Staff with dual responsibilities

Note: All names within functional blocks are listed in alphabetical order of surname

BOARD OF DIRECTORSCorken, GMM; Greeff, OBW; Millard, FW; Rossouw, C; Strugo, V; Van Wyk, AA (EXCO)

HR & ADMIN

SERVICES

CTA / ROC

Pentikainen, MT

CONTRACT CRAs

Armstrong, JW

Malherbe, A

Groenewoud, G

Podmore, SH

Snyman, J

Viljoen, M

jCRA

Mudibu, N

TRA

Bruggeman, SB

Burger, TM

Mabotja, LK

Tshule, KP

Wordon, ML

CTA

Mareverwa, MM

CONTRACT CRAs

Lopes, T

Mwapasa, GD

CONTRACTOR

Research Physician

Roux, MM

CONTRACTOR

Biostatistician

Potgieter, MA

CONTRACTORS

Data Operations

Manager

Venter, C

Data Management

Assistant

Barnes, CL

Data Manager

Kumar, V

Senior Data

Manager

Raju, K

Biom

Programmer

Kumar, M

Senior Biom

Programmer

Paul, P

Safety Officer

Coetzee, M

Research

Physician

Theron, SM

CRA

Bakker, M

Kotzé, M

Nkosi, HS

O’Donoghue, CL

Smith, S-R

Venter, TL

Training

Associate

Serebro, PH

QA/Training

Officer

Muir. AR*

QA/Training

Assistant

Kunene, NP

Head of QADuursema, L*

Head of Scientific AffairsVan Tonder, JJ*

(EXCO)

Data Operations

Manager

Deb, B

Hanumanthappa, R

Rapson, M

Biostatistician

Van Tonder, JJ*

Head of ClinOpsVan den Berg, EM

(EXCO)

PM

Joffe, D

Hohl, B

Magopane, O

Peacock AL

Smith , S-A

Uys, A

COM

Neumann, KC

COM

Strugo, JL*

Senior PM

Steyn, N

Head of PMHerbst, LG

(EXCO)

SCRA

Abdol, R

J v Rensburg, I

Koopman, MS

Mountney, J

Nkoane, NP

SCRA

Kinyoki, AM

Monene, WM

Oenga, ER

Seameco, T

SCRA

Artruc, AE

Coumi, NJ

Koegelenberg, J

Magopane, T

Mathole, ME

Head of HR &

Admin ServicesButt, MB

Operations DirectorRossouw, C

Financial DirectorMillard, FW

Head of Financial

ServicesVandrau, K

Financial

Assistant

Pillay, S

Prinsloo, VS

Standing, K-L

Financial

Assistant

Muller, JJ

Admin Assistant

Hartzenberg, T

Phillips, C

Reception / Travel

Office Assistant

Thomas, SM

Driver

Phokwane, SJ

Cleaner

Badiseng, JL

Masango, R

IT Support: PharmaLTX (Pty) Ltd

Manager of IT Support Services

Du Plooy, CJA

Senior Support Engineer

Breedt, J

Junior Support Engineer

Hartzenberg, M

RA Assistant

Kok, E

Nyembe, NN

Stemmet, A

Z-Kirstein, Z

Head of BDSouthwood, T

(EXCO)

Head of RAFourie, HJ

Senior BD

Associate

Storer, F

BD Associate

Copans, DS

Seima, RR

RA Associate

Maoto, PP

Van Wyk, MC

QA Manager

Moeken, CMM*

REGULATORY EMPHASIS OF TCD

Largest RegULAffairs group in SA CROs & Pharma

Physician & Scientist

inputs

Regulatory Experts

Source: www.clinicaltrials.gov

Clinical trials registered across Africa

Total2010:2,514

Total2015:5,401

Africa = Communicable Diseases

Facts from www.clinicaltrials.gov (1997 FDA Modernization Act, 1997)

Historical % ID trials

Currently active ID trials

(Sep 2016)

Mali 81 of 106 (76.4%) 66.7%Kenya 208 of 339 (61.4%) 54.0%Egypt 111 of 1252 (8.8%) 6.1%South Africa 466 of 2213 (21.0%) 25.0%

Outdated perception

SUMMARY (AND SUM) OF PERCEPTIONS

• SA remains strong African leader in clinical research• Other countries growing in clinical trial volume• African sites are hungry for research and perform well• Increase in NCD trials with increasing affluence• Regulatory infrastructures and processes improving (funding and

expertise dependent)• Most African cultures favour discourse – formal consultation is

welcomed and increasingly accommodated• Multiple review processes augment applicant burden but also

increase global credibility of mature oversight• Local CRO knowledge value in reducing/avoiding bottlenecks