GLOBAL REGULATORY APPROACHES TO IMPROVE · PDF fileGLOBAL REGULATORY APPROACHES TO IMPROVE HEALTH CARE COLLABORATION / STRATEGIES / SOLUTIONS Murray M. Lumpkin, M.D., M.Sc. Bill and

GLOBAL REGULATORY APPROACHES TO IMPROVE HEALTH CARE COLLABORATION / STRATEGIES / SOLUTIONS

Murray M. Lumpkin, M.D., M.Sc. Bill and Melinda Gates Foundation TOPRA Annual Symposium 2017 London, United Kingdom 02 October 2017

© Bill & Melinda Gates Foundation |

THE FOCUS OF OUR WORK IS THE PATIENT “THE PATIENT IS WAITING” – but which patients? All – or --

© Bill & Melinda Gates Foundation | 2

• Only patients who can pay for medical products?

• Only patients who live in a country for which there is a “business case” for medical products?

• Only patients with diseases for which there is a “business case” for medical products?

IMPROVE HEALTH CARE – DEVELOPING MEDICAL PRODUCTS


THINK GLOBALLY

ACT LOCALLY

There are some significant differences in disease burden and access to effective, safe, quality products in various parts of the world.

There are some significant similarities in disease burden and differences in access to effective, safe, quality products in various parts of the world.

What can we as regulatory professionals do to help address some of these disparities?

There’s a lot going on!

2 mil km2

THE DEMOCRATIC REPUBLIC OF CONGO IS ABOUT 2/3 THE SIZE OF WESTERN EUROPE

• Last formal census: 1984 • Estimated population is 70-80 M • 200 ethnic groups with major regional

linguistic variation • Life expectancy: 49.6 years • Infant mortality: 73.15/1,000 live births • 1400 miles of paved roads – ½ in

“good” condition

• TB causes more Disability Adjusted Life Years (DALYs) than Diabetes • Only one new product approved in 40 years for TB • In type II diabetes, 6 new products were approved in 2013 and 2014

© 2014 Bill & Melinda Gates Foundation

FACTS ABOUT THE GEOGRAPHIES Country Median Age

(2012) ¹ <5 mortality rate per 1000 births (2012) ¹

No of births per mother ² (2012)

Deaths from TB per 100,000 (2012) ¹

Deaths from cardiovascular disease per 100,000 (both sexes) [2012]³

% secondary school attendance Males (2008-2012) 4

% school attendance Females (2008-2012) 4

DRC 17 146 6.0 54 359.6 35.1 28.3 Kenya 19 124 4.5 22 205.0 39.5 41.6

Nigeria 18 73 6.0 16 266.5 54.2 54.3 UK 40 5 1.9 0.5 136 97.4 99.6 US 37 7 1.9 0.1 111.8 88.8 90.2

¹ WHO World Health Statistics 2014; ² WB country data 2014; ³ WHO NCD report 2014;4 UNICEF country statistics 2013

Population 2100 Population 2010

The changing shape of global population

http://www.viewsoftheworld.net/wp-content/uploads/2011/10/WorldPopulationAnimation.gif

Population 2080

The changing shape of global population

Source: http://www.worldmapper.org/

Disease burden…malaria deaths

http://www.worldmapper.org/�

Disease burden…HIV prevalence



Disease burden…TB cases



Disease burden…Diarrhea prevalence



Disease burden… early neonatal mortality




Mismatch with available medical care…

Physicians


…or biomedical research



The good, the bad, and the ugly


THE GOOD -- Regulation done well - facilitates access and impact by assuring that products available are quality products whose claims are backed by independent evaluation of good science. Reg done well is thus a positive force for access to quality products with resultant positive impact on both the public health and the economic health of communities. THE BAD -- Regulation done poorly - retards access to quality products and has a negative impact on both the public health and the economic health of communities. THE UGLY -- Regulation not done at all - creates chaos both in public health and in the market place where products are of questionable quality and are not backed by science. Patients are exploited in a “buyer beware” dynamic that is a “rush to the bottom” when it comes to product quality, efficacy, and safety. There is access to items that purport to be medicines, and the impact on public health is highly negative.

REGULATION OF MEDICAL PRODUCTS

REGULATORY AND HTA ACTIVITIES IN HIGH INCOME COUNTRIES

ARE KEY STEPS

IN HEALTH PRODUCT ACCESS AND IMPACT


Delivery of product

Safety, Efficacy, and Quality data NRA Registration

Treatment Recommendation data

Might be helpful (more to do with clinical practice)

HTA / Payers (local or sub-local)

Surveil-lance (strong)

A C C E S S

I M P A C T

(disease, product safety, supply chain Integrity)

A P P R O V A L

REGULATORY AND OTHER ACTIVITIES IN LOW AND VERY LOW INCOME COUNTRIES

ARE KEY STEPS

IN GLOBAL HEALTH PRODUCT ACCESS AND IMPACT


Delivery of product (physical, transport, storage, theft, diversion)

Safety, Efficacy, and Quality data

1st regi-stration

WHO PQ

NRA Regi- stration

Treatment Recommendation data

WHO and other Treatment Recommendations - mandatory

Procure-ment (UN, multi-nationals and local)

Surveil-lance (weak to non-existent)

A C C E S S

I M P A C T

(disease, product safety, supply chain Integrity)

A P P R O V A L


REGISTRATION VERSUS TREATMENT RECOMMENDATION

REGISTRATION / PQ LISTING

• Manufacturing Quality and Consistency • Safety (clinical / pre-clinical) • Efficacy in clinical trials settings • Clinical trials of a certain size, ability to

determine if an effect is due to the product • Known benefit (efficacy) / known risk profile • Risk of the unknown about the product vs

known risk of the disease being treated • Country suitability with respect to product

presentation (stability in climate/transport and utility in health care system) and labeling

TREATMENT RECOMMENDATION (WHO “policy” or “normative guidance”)

• Safety in population using product • Efficacy / Effectiveness in population using

product • Impact of product use on public health • Feasibility of product implementation • Sometimes health economic evaluations (cost

effectiveness) (also done by procurers) • Role of product in context of existing

interventions • Broader perspectives

• Equity • Community acceptability (custom,

acceptability)


MEDICINES AND VACCINES REGISTRATION DATA

1st RA approval time

PQ approval time

Spread in RA submissions

SSAfrica approval time Median (months)

Medicines

Vaccines 15 16 78

SRA 10 months 4 52 11

NRA ~12 27 ~24 ~18

16

~12 16 N/A N/A

SRA

NRA

A

B

D C

SRA: Stringent Regulatory Authority (e.g. US FDA, EMA); NRA: National Regulatory Authority (e.g. India CDSCO, China FDA) (WHO classifications)

Speeding Access to Vaccines and Medicines in Low- and Middle-Income Countries: A Case for Change and a Framework for Optimized Product Market Authorization Vincent Ahonkhai, Samuel F. Martins, Alexandre Portet, Murray Lumpkin, Dan Hartman. Integrated Development – Global Health, Bill & Melinda Gates Foundation, Seattle, Washington, United States of America

PLoS ONE 11(11): e0166515. doi:10.1371/journal.pone.0166515 16 Nov 2016

26

THE PROBLEM: EXAMPLE OF LONG SUBMISSION SPREADS Year 1 Year 2 Year 3 Year 4 Year 5 Year 6

SRA A SRA B NRA A NRA B NRA C NRA D NRA E NRA F NRA G NRA H NRA I NRA J NRA K NRA L NRA M NRA N NRA O NRA P NRA Q NRA R NRA S NRA T NRA U

Total time (yrs) Reg. Authority

0.5

0.7

1.8

4.9

1.7

2.6

2.6

1.0

0.6

0.5

4.3

>5.0

0.7

1.2

2.0

0.3

0.9

3.3

1.0

1.0

>2.0

>1.7

>1.7

Submission

Approval

Source: BMGF Regulatory Strategy study © Bill & Melinda Gates Foundation |


(1)RELIANCE

(2)RE-ENGINEERING

(3)REGIONALISATION

STRATEGIC APPROACH

WHO PQ

1 For Rx and Dx, previous regulatory approval is not required for PQ submission. This would include products that are manufactured at different sites or for other reasons are not the same version as that approved by an SRA. For Vx, previous regulatory approval by a “vaccine functional” NRA is required.

NRA1

(generally in manufacturing country; generally

established products)

Full PQ assessment

SRA (includes EU Art 58,

Swissmedic MAGHP, and US FDA tropical voucher)

(established or innovative

products)

Abridged PQ assessment

Medicines, meeting major public health need, but not in scope for PQ - Ad hoc WHO PQ support of local registration, including support for joint reviews

being undertaken by RECs and other groups

NRA / REC (marketing country/

- ies)

PQ Collaborative Procedure

Joint Review Procedure (as part of PQ assessment process)

(not as part of PQ assessment process)

EUAL ERP

Interim, time-limited tendering allowed,

while PQ or SRA assessment proceeds

OVERVIEW OF FACILITATED REGISTRATION PATHWAYS

1

Current activities Developing activities

STATISTICS ON PQ COLLABORATIVE PROCEDURE (MEDICINES)

Key facts

30 countries plus CARICOM enrolled in the collaborative procedure

54 medicines registered

185 registrations

74 days as a median time for local registration

Country # of registrations Manufacturer # of registrations Therapeutic area

25 16 16 15 14 13

11 10 10 10 9 9

5 5 4 4 4

2 2 1

Nigeria Tanzania

Zambia Zimbabwe

Ukraine Malawi Ghana

Botswana Ethiopia Namibia

Philippines Uganda

Armenia Kenya

DRC Madagascar Mozambique

Cameroon Kyrgyzstan

Burkina Faso

100

26

21

16

7

5

3

2

2

1

1

Macleods Ph.

Cipla

Hetero Labs

Jai Pharma

Strides

Mylan Lab.

Ajanta Ph.

Cadila Ph.

DNDi*

Dong-A ST Co

Eisai Co

*Cipla Ltd is the supplier and is responsible for the product

84

39

28

22

12

HIV

TB

Malaria

Rep. Health

NTD

© Bill & Melinda Gates Foundation | 30 End of 2016

31

32

THE AMRH VISION

54 countries 1 continent

African Medicines Agency

5 regions

IGAD / AMU / CEN-SAD

ECCAS OCEAC

ECOWAS UEMOA EAC

SADC COMESA


33

AMRH - IMPACT IN EAST AFRICA Full implementation on track

Launched the regional EAC product registration system in Jan 2015 Using Expression of Interest approach First joint regional review in Oct 2015 with technical support from WHO and Swissmedic Second review in May 2016 Ethiopia joined for third review in Aug 2016 and subsequent review sessions, also South

Sudan has now joined (technical support by WHO and Swissmedic) Regulatory harmonization Model Law adopted by African Union Heads of State in Jan 2016

32 products have been reviewed (none previously PQed), with 4 accepted (rest awaiting com respon) Manufacturers: Sandoz (13), Mylan (5), Hetero (3), Roche (4), Bayer (1), Janssen (1), Merck (1),

EAC-based (4) TAs: Cancer (7), Cardiovascular (10), Diuretic (2), Epilepsy (2), HIV (2), Antibiotics (2),

Antidepressants (1), Herpes (1), Diabetes (2), TB (1, bedaquiline), others (2)

Expanding to other product streams (Vaccines) and regulatory functions (Pharmacovigilance, clinical trials) and geographies (west Africa – ECOWAS, and southern Africa – SADC/ZaZiBoNa)


• Caribbean Regulatory System – PAHO – CARICOM countries • Joined Collaborative Process as first regional regulatory organization • 11 recommendations (joint assessments; reliance on PQ or PAHO

regional reference) – first one now with national authorization (less than 60 days from joint review) – countries using fast track approach

• China CFDA – WHO and CFDA efforts to make China an NRA on whose work products (inspections, scientific reviews) WHO can rely (ML4) – focus initially on vaccines (2019) and generic drugs thereafter

• New WHO guidances on “Good Reliance Practices” • Pharmacovigilance strategies oriented to new products being initially

introduced into LICs


OTHER REGULATORY SYSTEMS INITIATIVES

• WHO’s Coalition of Interested Technical Partners as approach to Regulatory Systems Strengthening in LICs – focused initially on local PV, local manufacturing oversight, generic drugs, and local supply chain integrity – using new WHO NRA global benchmarking tool

• Substandard and falsified products – WHO database and investigations • Rationalizing local CMC requirements • Rationalizing local vaccine variation processes • Regulatory processes in public health emergencies (CTAs, emergency

authorizations, emergency use PV)


OTHER REGULATORY SYSTEMS INITIATIVES

THANK YOU


Documents

GLOBAL REGULATORY APPROACHES TO IMPROVE · PDF fileGLOBAL REGULATORY APPROACHES TO IMPROVE HEALTH CARE COLLABORATION / STRATEGIES / SOLUTIONS Murray M. Lumpkin, M.D., M.Sc. Bill and