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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
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