Making products available for medical abortion and strategies for their introduction

1. Making products available for medical abortion and strategies for their introduction Peter Hall Acting CEO Concept Foundation Bangkok, Thailand

2. The mission of Concept Foundation To provide access to products for sexual and reproductive health of assured quality to the public sector of lower and middle income countries at the lowest possible cost. Concept Foundation was established as an international, charitable, not-for-profit organization in Thailand in 1989.

3. What is Concept Foundation? To achieve its mission, Concept Foundation designs and implements access-to-medicines programmes to make quality product available at an affordable cost. This involves: - the establishment and support of Public- Private Partnerships with pharmaceutical companies in developing countries; and - a systematic and coordinated approach to product introduction.

4. What does a PPP need to achieve? Private enterprises need to generate financial success Public sector needs access to low cost drugs of assured quality High Margin Preferential Price How to balance? ? • Financial support from donors: • Clinical research • Technology transfer • Quality assurance • Registration filing, etc. Cost benefit to public sector: • Affordable public sector pricing 4

5. Conditions of agreement between WHO and Concept Foundation • Price – Co-packaged product with preferential price to public sector, making it affordable to many more women. • Quality - Manufactured in USFDA/EMEA compliant facility, meeting international current Good Manufacturing Practice (cGMP). • Regulatory issues – Misoprostol used “off-label”, regulatory agencies welcome formal registration of misoprostol for use in medical abortion; clinical part of registration dossier based on WHO clinical trials. • Ease of use – co-packaged product easier for both provider and woman.

6. How does Concept Foundation achieve it? • Concept provides and manages key components for pharmaceutical manufacturing and marketing, such as: technology transfer, cGMP protocols, data from pivotal clinical studies, GCP-compliant clinical research, ICH-compliant regulatory documentation, regulatory dossier submissions, and identifying country-based importers and distributors. These activities save significant investments for the commercial partner and speed up time to market. • In return, the commercial partner agrees to serve under-developed and normally unprofitable markets with products of assured quality at the lowest possible cost. • Concept Foundation negotiates a transparent ex-factory supply price for public sector agencies and ensures that appropriate strategies have been developed for the introduction of a product.

7. What have Concept’s PPPs achieved? Some 150 million vials of the once-a-month injectable contraceptive, Cyclofem, have provided an additional choice to women in Asia and Latin America. Concept’s portfolio has also included a HIV diagnostic test and emergency contraception. Currently, Concept is making available a co-packaged mifepristone (1x200mg tablet) and misoprostol (4x200μg tablets) product, Medabon.

8. Regulatory issues Regulatory documentation generally comprises of 3 sections: • clinical evidence of safety and efficacy - requires data from pivotal GCP-compliant clinical research, also a key requirement for manufacturers of generic drugs is that they demonstrate that the products they produce are bioequivalent to the original, innovator product. • preclinical and toxicological evidence of safety; and • data on chemicals, manufacturing and control (CMC). The CMC component of an ICH-compliant regulatory dossier is difficult for many manufacturers to meet. It requires full information on the Active Pharmaceutical Ingredients (APIs); the manufacturing process; and all quality assurance procedures, including compliance with cGMP.

9. Regulatory issues Class 1:  ICH-compliant dossier. Full data from original safety and efficacy trials (NDA) or BE study (ANDA); full preclinical and toxicological data; full CMC data, evidence meet cGMP and a DMF for API; GMP inspection of factory • South Africa Class 2:  Abbreviated dossier; no original safety data but clinical review summarizing all clinical data and results of BE study; summary of preclinical/clinical data; BE study required; manufacturing process validation; DMF for API • Ethiopia, Algeria, Morocco, Tunisia, Egypt (may request additional data like Class 1 and manufacturer site visit); • The 14 countries of the South African Development Community (SADC) have formally adopted harmonized guidelines. But it will be some years before these countries meet similar standards to those required by South Africa.

10. Regulatory issues • 13 out of 14 SADC countries (14th is South Africa), Angola, Botswana, Democratic Republic of Congo, Lesotho, Madagascar, Malawi, Mauritius, Mozambique, Namibia, Seychelles, Swaziland, Tanzania, Zambia and Zimbabwe are at various stages between classes 2 and 3; • Ghana, Kenya and Uganda are also between classes 2 and 3. Class 3: Abbreviated dossier; overview and summary of preclinical/clinical data; no BE study; and no DMF required • WAHO is attempting to harmonize requirements in 15 countries, Benin, Burkina Faso, Cape Verde, Côte d’Ivoire, The Gambia, Ghana, Guinea, Guinea-Bissau, Liberia, Mali, Niger, Nigeria, Senegal, Sierra Leone, and Togo but is a lot further behind. Ghana is the furthest ahead. Class 4:  No formal regulatory dossier required. • The remaining 19 African countries fall under Class 3 and a few under Class 4.

11. Objectives of an introductory strategy • Provision of medical abortion in the context of CAC in all facilities meeting the requirements of the national guidelines. In the initial phase this will be undertaken in selected healthcare facilities. • Development of a training curriculum for the provision of comprehensive abortion care, in particular of MVA and medical abortion and including values clarification. • Development of IEC materials for professionals and users. • Development of an advocacy strategy for CAC. • Implementation of operations research to allow planning for scaling up to other health care facilities.

12. What has happened to date? Introduction of medical abortion into the public sector has suffered from either: • activities being undertaken by various national and international organizations in an ad hoc and uncoordinated manner; or • by undertaking a clinical trial or small OR study in lieu of a coordinated introductory strategy – neither addressing key service delivery needs nor guaranteeing the availability or affordability of product.

13. An optimal approach to product introduction To achieve the stated objectives, it is necessary to develop and implement an appropriately designed introductory process. This requires: • a systematic and incremental approach; and • coordination and collaboration between the public health system and all key stakeholders - synchronization of activities is the key to building an appropriate and supportive health system for the provision of medical abortion. This has begun in Nepal.

14. What is a supportive health system? • Drugs for medical abortion can be provided by trained mid-level providers but, in the few cases of incomplete abortion or excessive bleeding, there is need for access to referral services. • The health system must ensure access to a provider trained in the use of manual vacuum aspiration (MVA) and to blood transfusion services. • The health system must be prepared to provide training of all levels of health care providers and values clarification with providers. • Abortion remains a sensitive issue in many countries and there is a continuing need for advocacy with providers as well as the broader society.

15. Nepal Advocacy FHD/MOH TCIC/Ipas NESOG TCIC/Ipas NHTC/DHS Training curriculum development Policy FHD/MOH MSI FPAN PSI CREHPA NESOG Nursing Council Medical Council TCIC/Ipas Material development NHIECC TCIC/Ipas Service delivery Regional/district health authorities Project management TCIC NESOG Nursing Council Medical Council PSI All listed CAC service providers Public & private Training Operations Research NHTC/DHS CREHPA Product availability Sun Pharma NESOG Ipas partners Concept

16. Evidence now shows 24 hours is adequate Day 1 Day 2 Day 3 0800 2000 0800 2000 0800 24h 48h Evidence from WHO studies show the efficacy of the mifepristone-misoprostol regimen to be similar for intervals from 24-48 hours post-mifepristone, when misoprostol is given vaginally. Similar with sublingual administration.

17. The need for information - providers/policy makers WHO organized a meeting of experienced researchers and clinicians working on medical abortion. They responded to a list of the most frequently asked questions about medical abortion from health-care personnel providing abortion services. They reviewed those questions and compiled answers based on scientific literature and their own experience. Frequently asked clinical questions about medical abortion. World Health Organization, Geneva 2006 www.who.int/reproductive-health/publications/ medical_abortion/index.html

18. The need for information PATH, Ipas, Concept and WHO/HRP are finalizing materials for health care providers and programme managers who are working to introduce Medabon®. They are also intended to reach policy makers and the media and include: • Medical Abortion & Medabon®: Key Talking Points • Medabon®: Frequently Asked Questions (FAQ) • Medabon®: What You Need to Know (sample patient brochure) • Medabon®: Medical & Service Delivery Guidelines • Medabon®: Background for Providers of Emergency Care • Medabon®: A Framework for Introduction • Medical Abortion: Selected References Will be put on www.medabon.info in April 2009

19. Making medical abortion available - ideal Distributor/ importer selection Access to medicines Trademark Registration Introduction Introductory activities Scaling up Routine provision

20. Making medical abortion available - usual Distributor/ importer selection Access to medicines Trademark Registration Introduction Introductory activities Scaling up Routine provision

21. The need for product Concept, together with its commercial partner Sun Pharmaceuticals, is in the process of registering Medabon® in Ghana, Ethiopia, Mozambique, Zambia, Tunisia and will begin in 2009 in Benin, Burkina Faso and South Africa. Where else could it be registered and introduced? In any country with any indication for abortion, eg, rape, incest or the life of the woman, ie, in most countries in Africa. How can we get it done?