INTERNATIONAL REGULATORY CASE STUDY: THE COMPLEXITIES OF PRODUCT REGISTRATION

Abizer BookwalaDirector, Regulatory Affairs, GRACS BD&LGlobal Regulatory Affairs and Clinical Safety

Nov 2017

Video

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Merck-At-A-Glance

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• We are a global health and animal care leader with a 125-year history of working to make a difference.

• Our company is known as Merck in the United States and Canada. Everywhere else, we are known as MSD. We are approximately 69,000 employees in more than 140 countries

• We have a long history of devoting time and energy to increasing access to medicines and vaccines through far-reaching programs that donate and deliver our products to the people who need them.

• At Merck, we're applying our global reach, financial strength and scientific excellence to do more of what we're passionate about: improving health and improving lives.

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Every day, 800 women die

from complications of pregnancy and

childbirth

Nearly all of these deaths are preventable

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Maternal Mortality in the US

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“To the world, you might be just one person, but to one person, you might be the world.”– Unknown

“Women are not dying because of diseases we cannot treat…

They are dying because societies have yet to make the decision that their lives are worth saving.”

--Dr. Mahmoud Fathalla

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http://merckformothers.com/

Merck for Mothers is a 10-year, $500 million initiative focused on a world where no woman has to die from complications of pregnancy or childbirth

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There are more than 50 projects in more than 30 countries around the world including India, Senegal, Uganda, the U.S., and Zambia. The concept is to test innovative models that expand women's access to affordable, quality care with the potential to be scaled and sustained.

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Prevention of Postpartum Haemorrhage (PPH)

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• Postpartum haemorrhage (PPH) is the leading cause of maternal mortalityand a significant contributor to severe maternal morbidity and long termdisability worldwide*

• PPH contributes to more than 479K of maternal deaths in the developingregions from 2002-2009; 19.7% of all maternal mortality**

• The use of uterotonic drugs to prevent and treat PPH is recommended bythe World Health Organization (WHO) and national guidelines worldwide

• Oxytocin is the uterotonic drug of choice for the prevention of PPH

Background for PPH

* Alkema L, Chou D, Hogan D, et al. Global, regional, and national levels and trends in maternal mortality between 1990 and 2015, with scenario-based projections to 2030: a systematic analysis by the UN Maternal Mortality Estimation Inter-Agency Group. Lancet 2016; 387: 462—74. ** Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Global Health 2014; 2: e323—e333.

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Limitations of Oxytocin: Current landscape

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• Has pervasive inconsistencies in its quality of manufacture

• Requires a consistent cold chain to maintain effectiveness

• Loses potency as it is exposed to heat

• Adds burden and complication to already fragile cold-chain infrastructure

Oxytocin is life-saving and the gold standard for preventing PPH, but it…

WHO recommends that oxytocin be refrigerated at 2-8°C to preserve its integrity. Temporary storage outside a refrigerator at a maximum of 30°C is acceptable for no more than three months.*

* USAID (2007). Prevention of Postpartum Hemorrhage: Implementing Active Management of the Third Stage of Labor (AMTSL). http://www.path.org/publications/files/MCHN_popphi_amtsl_ref_man_2of3.pdf

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Alternative to Oxytocin - Target Product Profile

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1. Non-inferior efficacy, equivalent safety to oxytocin2. Heat stable long duration3. All delivery pathways (C-section & vaginal)4. IM administration5. Affordable6. Limited re-training7. Broader reach

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Carbetocin (refrigerated) in the market since 1997 Safety profile similar to oxytocin Primarily C-section indication Comparative effectiveness data suggests carbetocin may be more

efficacious than oxytocin Despite various trials & history of use, comparative effectiveness data not

yet conclusive Different study populations (CS) and route of administration (IV) Limited studies in vaginal delivery

Heat Stable version was first approved in 2015

Carbetocin

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Maternal Mortality (2015 WHO) MfM Markets

1-19

20-99

100-299

300-499

500-999

≥1000

Population <100.000 not included in the assessment

Data not available

Not applicable

MfM Target Countries

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Merck for Mothers, Ferring Pharmaceuticals and the WHO are collaborating to develop and make accessible heat-stable Carbetocin

MSD for Mothers

Catalyst, Trial

funding

Scientific, Technical & Regulatory Expertise

Conduct, analyze phase III

trial

Update PPH treatment guidelines; EML & PQ inclusion

Country-level advocacy

Product expertise & clinical trial

supplies

Register inidentifiedcountries

Support introduction

& uptake efforts

Manufacture & access;

affordable, sustainable

price

Partnering for Success

World Health Organization

FerringPharmaceuticals

Tri-party Agreement between Merck-for-Mothers, WHO and Ferring signed in 2014

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Attributes of the partnership

Partnering for Success

Speed to market Development of new product would not be ideal

Product cost Comparable to Oxytocin (current gold standard)

Focus on countries with greatest need Registration and availability of product in Low & Middle Income markets

Protection of partner private market revenue Partner revenue protection

Apply Merck Regulatory and Marketing expertise to support launch preparation Market access

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Carbetocin Filing Strategy

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1997 - Cold chainformulation

2015 approval –Heat stable formulation

Post-Study submission - vaginal delivery

Solution for intravenous and intramuscular injection

”Name”

MAGHP

Solution for intravenous and intramuscular injection

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WHO TRIAL(A65870)

A. Metin Gülmezoglu, Mariana Widmer, Maternal and Perinatal Health and Preventing Unsafe Abortion

A phase III, randomized, double-blind, active controlled, multinational, multicentric, non-inferiority trial using Carbetocin room temperature stable (RTS), intramuscular (IM), for the prevention of postpartum haemorrhage

during the third stage of labour in women delivering vaginally

Australian New Zealand Clinical Trials Registry ACTRN12614000870651

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WHO Trial

WHO sites (23)Argentina (3)Egypt (1)India (6)Kenya (1)Nigeria (2)Singapore (1)South Africa (3)Thailand (4)United Kingdom (1)Uganda (1)

10 countries – 23 centres (hospitals)30,000 women

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Regulatory Strategy

Tri-party agreement states that Ferring should obtain registration in UK

Evaluated alternatives that may be more suitable in order to achieve the goals of the project in the target countries

Six different pathways evaluated: 1. PABAL line extension2. Duplicate Application (UK clone)3. EMA Article 584. SwissMedic Marketing Authorisation for Global Health Products (MAGHP)5. WHO route only6. Generic application

No “perfect” pathway; two most suitable are considered to be the Swiss MAGHP and the EMA article 58, both intended for supporting registrations in developing countries

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Regulatory Strategy

MAGHP procedure is the preferred option over Article 58 procedure for the following reasons: Pros:

– MA is granted – not just an opinion like for the Article 58 procedure– CPPs and registration samples can be issued confirming launch of product

i.e. fulfil country registration requirements– Expected eligibility for WHO Pre-Qualification Collaborative Registration

Procedure (PQ CRP), which will give faster approval in 25 of the 91 Annex 2 countries, many of which are the high burden countries

Cons:– Procedure is still in the pilot phase– Slightly longer approval time than e.g. Art 58, but with access to WHO PQ

CRP, the product will get faster approval in 25 of the 91 Annex 2 countries

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Why MAGHP?

Marketing Authorisation Global Health Products (MAGHP) is built on Swissmedic MAA procedures

– Swissmedic was collaborative during agency consultation

Collaboration between Swissmedic, WHO PQ Team and National Medicinal Regulatory Authority (NMRAs) of EAC countries (Burundi, Kenya, Rwanda, Uganda, Tanzania, South Sudan)

– Approval within 90 days of dossier submission in EAC countries.

WHO and other NMRAs may participate actively or as observer– Product is expected to be eligible for WHO PQ collaboration registration procedure (CRP),

if WHO PQT is involved in the assessment and co-listed

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Next Steps

Once the trial ends (currently ~95% complete); 28,500 subjects are currently enrolled. LPLV expected January 2018 Assess, review and generate documents for filing, publication Update dossier/prepare filing Submit via MAGHP

– First Approval (approx 18 months post-submission)

Registration Expansion– Filing in >90 low and middle income countries, countries with highest

maternal mortality rates

Lives Saved!

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Thank you