Moving towards Regulatory Harmonization

of in-vitro Diagnostics

Rosanna W Peeling Professor and Chair, Diagnostic Research

London School of Hygiene & Tropical Medicine United Kingdom

• Landscape of regulatory oversight of IVDs

• Why harmonization and why now?

• Overall goals and priorities

• Inter-regional collaboration

• Moving forward

Regulatory Harmonization for IVDs

Diagnostics Bench to Bedside Pathway

Product Development

Product Evaluation

Marketing

Diagnostic Target Discovery

Platform development

Prototype & Proof of Principle

Pre-market Validation

Lab evaluation Analytical Performance

Policy & Implementation

Field evaluation Clinical Performance

Regulatory Approval

2-5 years 10-12 years 5-7 years

Lack of Regulatory Oversight for Diagnostics

In Vitro Diagnostic Devices

Regulated

No

52%

Yes

48%

Yes No

In Vitro Diagnostic Devices Regulation By

Region

No 11 9 5 2 2 15

Yes 4 9 4 14 3 7

AFRO AMRO EMRO EURO SEARO WPRO

TDR survey 2002

Quality Standards in Diagnostic Evaluations?

I. Diagnostics landscape

Regulation with Clinical Evaluation

68%

22%

10%

Yes

No

No Answer

Cost of clinical evaluations range from $2,000 to $2,000,000

Regulation of In-vitro Diagnostics: Top 10 Challenges

1. Regulatory landscape highly variable 2. Regulatory approval processes lengthy, especially for imported

tests 3. Most approval processes not transparent 4. Reviews often lack quality standards 5. Clinical performance studies often not required or lack rigour 6. Tests are sold and used in the developing world without

evidence of effectiveness 7. Cost of regulatory approval pass onto end-users 8. Companies with quality tests unable or unwilling to compete

in market flooded with low quality tests 9. Limited success with standardisation and harmonization 10. Companies often do not bother filing in countries with small

markets

• Landscape of regulatory oversight of IVDs

• Why harmonization and why now?

• Overall goals and priorities

• Inter-regional collaboration

• Moving forward

Regulatory Harmonization for IVDs

Global Harmonization Task Force (GHTF)

• GHTF was conceived in 1992 in response to the growing need for international

harmonization in the regulation of medical devices to ensure the safety,

effectiveness and quality of medical devices

• In 2006, GHTF included 3 Liaison Body members: the Asian Harmonization

Working Party (AHWP), International Organization for Standardization (ISO), and

International Electro-technical Commission (IEC)

• GHTF published and disseminated harmonized documents on basic regulatory

practices and served as an information exchange forum. GHTF documents are

developed by 5 Study Groups (SG):

– SG1 - Premarket Evaluation

– SG 2 - Post-Market Surveillance/Vigilance

– SG 3 - Quality Systems

– SG 4 - Auditing

– SG 5 - Clinical Safety/Performance

• In 2012, GHTF transitioned to a purely regulatory body called the International

Medical Devices Regulatory Forum (IMDRF) which will continue to promote the

principles of harmonization.

Asia Harmonization Working Party (AHWP)

Member Economies: (N=23) • Brunei, Cambodia, China, Hong Kong, India, Indonesia,

Korea, Laos, Malaysia, Myanmar, Pakistan, Philippines, Singapore, Taiwan, Thailand, Vietnam

• Abu Dhabi, Chile, Jordan, Kuwait, Saudi Arabia, South Africa, Yemen

• The Chair of AHWP for 2012-14 is Dr. Saleh S. Al-Tayyar

• Six working groups: – Work Group 1 (WG1) - Pre-Market Submission and CSDT

– Work Group 1a (WG1a) - IVDD

– Work Group 2 (WG2) - Post-Market Surveillance and Vigilance

– Work Group 3 (WG3) - Quality Management System

– Work Group 4 (WG4) - Quality System Audit

– Work Group 5 (WG5) - Clinical Safety/Performance

– Work Group 6 (WG6) - Capacity Building and Regulatory Training

– Special Task Group (STG - Nomenclature) - Medical Device Nomenclature

Countries AHWP (n=23) APEC (n=21) ASEAN (n=10)

Abu Dhabi ✓

Australia ✓

Brunei Darussalam ✓ ✓ ✓

Cambodia ✓ ✓ Canada ✓

Chile ✓ ✓

People’s Republic of China ✓ ✓

Chinese Taipei ✓ ✓

Hong Kong ✓ ✓

India ✓

Indonesia ✓ ✓ ✓

Japan ✓

Jordan ✓

Republic of Korea ✓ ✓

Kawait ✓

Laos ✓ ✓

Malaysia ✓ ✓ ✓

Mexico ✓

New Zealand ✓

Pakistan ✓

Peru ✓

Papua New Guinea ✓

The Philippines ✓ ✓ ✓

Russia ✓

Saudi Arabia ✓

Singapore ✓ ✓ ✓

South Africa ✓ Thailand ✓ ✓ ✓

The United States ✓

Vietnam ✓ ✓ ✓

ASEAN: ~600 million population and a combined GDP of ~ $2.9 trillion. • Medical Device Product Working Group (MDPWG) developed ASEAN Medical Device Directive (AMDD), with the goal of achieving a common dossier and PMS.

APEC: 40.5% of the world’s population, 54.2% of world’s GDP and 43.7% of world trade. • APEC Harmonization Center (AHC) and a Regulatory Harmonization Steering Committee (RHSC) • Priorities are good review practice; multi-regional clinical trials; supply chain integrity; biologics; combination products; advanced therapies

FY102 TFDA 推動新興市場國家之醫療器材法規科技研究及合作

AHWP IVD Guidances Development

Document Number Task Group Deadline

AHWP/WG1a/PD001

AHWP Regulatory Model for IVD

Albert Poon, Wen-Wei Tsai,

Jeffrey Chern

Jun 30 for endorsement in Nov 2013

AHWP/WG1a/PD002

IVD Essential Principles

Benny Ons, Shelley Tang,

Hsih-Te Yang

Jun 30 for endorsement in Nov 2013

AHWP/WG1a/PD003(Comparison)

Comparison between STED and

CSDT

Benny Ons, Wen-Wei Tsai,

Jeffrey Chern,

Mid Jul for endorsement in Nov 2013

AHWP/WG1a/PD001(AAIVD)

Strategies for Implementing

Regulatory Model for AAIVD

Albert Poon, Wen-Wei Tsai,

Jeffrey Chern

Jun 30 for agreement in Sep for next

stage development

AHWP/WG1a/PD003

IVD STED

Shelley Tang, Hsih-Te Yang,

Jeffrey Chern

Jun 30 for agreement in Sep for next

stage development

Pilot program for Common

Registration File

Shelley Tang, Albert Poon,

Hsih-Te Yang

To be discussed for agreement in Sep

for next stage development

HIV/AIDS Global Targets

• Place 15 million people on ART by 2015

• Eliminate new HIV infections in children

• Intensify HIV prevention

United Nations General Assembly High Level Meeting on AIDS, 2011

Investments of at least US$

22 billion are needed by 2015

As of 2012: 9 million HIV patients are on ART

Why pilot POC tests for CD4, Viral Load and Early Infant Diagnosis ?

• A CD4 test is used to determine eligibility to treatment (<500 CD4/ul of blood). It is estimated that millions of HIV infected patients do not have access to a CD4 test to determine whether they are eligible for life-saving treatments, e.g. in Malawi, <10% of HV service facilities offer CD4 tests

• for HIV patients already on treatment, less than 30% have access to a viral load assay to know if their treatment is still effective

• Most countries do not have access to tests that can diagnose HIV in babies born to HIV + mothers as babies carry their maternal antibodies up to 18 months of age. 53% of HIV+ babies are dead by 2 years of age, compared to a mortality rate of 7.6% for HIV- babies

HIV Viral Load Product Pipeline

2015 2013 2014 2016

Alere Q

Alere

LYNX Viral Load Platform

NWGHF

SAMBA VL

DDU/Cambridge

Liat™ Analyser

IQuum

EOSCAPE HIV™ Rapid RNA Assay System

Wave 80 Biosciences

Gene Xpert

Cepheid Cavidi AMP

Viral Load Assay with

BART Lumora

Truelab PCR

Molbio/bigTec Gene-RADAR

Nanobiosym

RT CPA HIV-1 Viral Load

Ustar

http://www.unitaid.eu/images/marketdynamics/publications/UNITAID-HIV_Diagnostic_Landscape-3rd_edition

UNITAID – LSHTM Project for POC CD4, viral load and Early Infant Diagnosis

• Lower barriers to market entry

– Define target product profiles, performance expectations, and methods of validation (standardise evaluation protocol)

– Prepare network of competent trial sites

– Joint review of trial data by national regulatory authorities

• Accelerate policy development and adoption

– Investing in POCTs to complement laboratory systems

– Use of models to estimate cost-effectiveness and potential impact

– sustainability

• Implement quality assurance systems to ensure ongoing quality of tests and testing

• Landscape of regulatory oversight of IVDs

• Why harmonization and why now?

• Overall goals and priorities

• Inter-regional collaboration

• Moving forward

Regulatory Harmonization for IVDs

Regulatory Harmonization Activities 2011:

Sept: South Africa IVD Directive Consultation

Nov: AHWP 16th Annual meeting

2012: Mar: East African Community (EAC) workshop Apr: Latin American Association for IVD workshop May: African Society for Laboratory Medicine & AHWP workshops July: EAC meeting to set up PAHWP Nov: Latin American Association for IVDs workshops Dec: AHWP 17th annual meeting & PAHWP launch at ASLM Conference

2013: May: AHWP WG1a workshop July: First African Regulatory Forum for Medical Diagnostics Sep: Inter-regional workshop convened by AHWP Oct: Latin American Association for IVDs Nov: ISO TC 212: ISO standard for IVD clinical performance studies Dec: AHWP 17th annual meeting

East African Community (EAC)

• A regional intergovernmental organisation:

Kenya Uganda Tanzania Rwanda Burundi

• EAC was established in 1999, with a treaty ratified by the original 3 Partner

States – Kenya, Uganda and Tanzania. Rwanda and Burundi became full

Members in 2007. Its headquarters: Arusha, Tanzania

• Vision: a prosperous, competitive, secure, stable and politically united East Africa

• Mission: to widen and deepen Economic, Political, Social and Culture integration

in order to improve the quality of life of the people of East Africa through

increased competitiveness, value added production, trade and investments

• Launched the EAC Medicines Registration Harmonization Project on 30 March 2012, Arusha, Tanzania with support from New Partnerships for African Development (NEPAD), WHO, Wold Bank, BMGF, Clinton Health Access Initiative, DFID, GIZ and others. EAC Secretariat has agreed to discuss harmonization of diagnostics at its next meeting in September

Regulation of in-vitro Diagnostics Burundi Kenya Rwanda Tanzania Tanzania

Zanzibar

Uganda Ethiopia Nigeria South

Africa

Legal Framework ✓ ✓ ✓ ✓ ✓ Not for

IVD

✓ ✓ ✓

IVD regulated? - ✓ - ✓ ✓ - ✓ ✓ SAHPRA

Premarket Controls

Risk Based

classification

- - - GHTF Not IVD

specific

- GHTF In process

GHTF

Registration - + - ✓ - - ✓ ✓ ✓

Clinical studies

Evaluation capacity

-

some

+

KEMRI

- Limited

Some ✓

- HIV

✓

Some

-

- ✓

✓

Manufacturing audit - + - - - - - - -

Marketing Controls

Advertising control ✓ + - ✓ - ✓ ✓ ✓ ✓

Market ing controls - + HIV, TB ✓ - ✓ ✓ ✓ ✓

Post-marketing Controls

Surveillance - + - ✓ - - - - ✓

Lab accreditation - ✓ - ✓ - ✓ ✓ - ✓

Device reporting - + - - - - - ✓

Corrections/Recall - + - - - - - ✓

Regulatory Harmonization for in-vitro Diagnostics

Goal: faster access to affordable POC diagnostics

Strategy: define a regulatory pathway that is “better, faster, safer and cheaper”

Technical Working Groups: 1. Risk Classification

2. Common Registration File

3. Quality management audits of manufacturing sites

4. Clinical evidence

5. Post-marketing surveillance

Pre-market

Controls

Pilot Implementation

Plan

Harmonization Activities

Impact

Training Registration

file

Quality

Assurance

Clinical

performance

studies

• Establish regional lab network to monitor POCTs

• Develop system for reporting product failures

• Mechanism for corrective action/recalls

Regulatory Oversight: Better, Safer, Faster & Cheaper

Marketing

Controls

Post-marketing

Surveillance

More public confidence in

diagnosis

Manufacturing

site audits

Consensus on essential data for review

Adoption of a common registration file Training on Good Review Practice

Development of common protocol

Establishment of trial ready sites Joint review of trial data

Convergence of standards

Mutual or 3rd party recognition of audit results

(MDSAP)

More country approvals for fewer trials

Reduce duplication of audits

A common submission template

Results

More affordable IVDs

Faster access of quality- assured diagnostics Better patient outcomes

Companies saves time, effort and money

Ongoing assurance of quality of POCTs

review of risk based classification systems

Adoption of a common classification system Create an AU-NEPAD classification panel

A common classification system

More streamlined regulatory process supports innovation

Regulatory Harmonization Activities 2011:

Sept: South Africa IVD Directive Consultation

Nov: AHWP 16th Annual meeting

2012: Mar: East African Community (EAC) Apr: Latin American Association for IVDs workshop May: African Society for Laboratory Medicine & AHWP workshop July: EAC meeting to set up PAHWP Nov: Latin American Association for IVDs workshop Dec: AHWP 17th annual meeting & PAHWP launch at ASLM Conference

2013: May: AHWP WG1a workshop July: First African Regulatory Forum for Medical Diagnostics Sep: Inter-regional workshop convened by AHWP Oct: Latin American Association for IVDs Nov: ISO TC 212: ISO standard for IVD clinical performance studies Dec: AHWP 17th annual meeting

24

Grand Challenges Canada: Progress towards IVD Regulatory Harmonization 2011-13

. .

Asia Harmonization Working Party (23 countries). IVD sub group

Latin America Diagnostic Association (ALADDIV) (12 countries)

Pan-African Harmonization Working Party (20 countries)

+

15 member states in SADC: Angola, Botswana, DRC, Lesotho, Malawi, Mauritius, Mozambique Namibia, Seychelles, South Africa Swaziland, Tanzania, Zambia Zimbabwe (Madagascar)

• Landscape of regulatory oversight of IVDs

• Why harmonization and why now?

• Overall goals and priorities

• Inter-regional collaboration

• Moving forward

Regulatory Harmonization for IVDs

Moving Forward: least burdensome approach to:

Reduce Costs

Faster Access

Save Lives

Support Innovation

Regulatory Issues

• In countries where NRAs do not exist or have no capacity to regulatory diagnostics, evaluation of the performance of diagnostics is often carried out by laboratories for their own procurement purposes or by the national reference laboratory at the request of disease control programmes

• there is growing tension between newly empowered NRAs and laboratories who have been conducting test evaluations.

• NRAs have the overall legal mandate to ensure safety, quality and effectiveness of in-vitro diagnostics

• Laboratories are technical bodies who can supply evidence of test effectiveness and post-marketing surveillance data on quality of tests

• Inter-regional collaboration on regulatory harmonization: Mar 2014: AHWP workshop Mar 2014: IMDRF on medical device single audit programme (MDSAP) Jul 2014: 3rd African Regulatory Forum on Medical Diagnostics

• Need to create new models of public-private collaboration to: support innovation create an enabling environment for accelerating market entry and patient access to quality-assured diagnostics

• Need to build regulatory capacity in countries within the context of harmonization and efficiency • Need to brainstorm on how regulatory science can keep pace with technological advances

Moving Forward

Thank you • LSHTM: Ruth McNerney, Kim Sollis, Rhosyn Tuta, Beth Downe • AU: Paul Tanui • EAC: Stanley Sonoiya, Jane Masingia, Louisa Kosimbei • WHO: Jean-Bosco Ndihokubwayo, Willie Urassa, Robyn Meurant • ASLM: Trevor Peter, Tsehaynesh Messele • GIZ: Wesley Ronoh, Thomas Walter • PAHWP: Issac Kadowa, Ilonze Chinyere, Sagie Pillay, Sarvashi Moodliar,

Patience Dabula, Agnes Kijo • AHWP: Liling Liu, Albert Poon, Jeffrey Chern, Jack Wong, Benny Ons • ALADDIV: Carlos Gouvea • National regulatory authority representatives • Consultants: Maurine Murtagh, Ben Cheng, Elliott Cowan, Albert

Poon, Simon Rugera, Skating Panda Ltd • Many companies who have given us advice • Funding:

- Grand Challenges Canada: Peter Singer, Ken Simiyu, Rebecca Lackman - Bill & Melinda Gates Foundation: Gene Walther, Christine Rousseau,

Vincent Ahonkhai, Samuel Martins - UNITAID: Brenda Waning