Dr. Jean-Hervé Bradol Research Director MSF Center for Reflection on Humanitarian Action & Knowledge Why the representative of an association of physicians is today in front of you to talk about medical innovations? A rather scientific topic After all, we, humanitarian doctors, are supposed to be poor doctors working for poor patients We usually take credit for our ethics but not for our contribution to medical science I hope to answer the question during the presentation    At the end of the medical school, mid-eighties, After a thesis on 4 methyl pyrazole as a new treatment for ethylene glycol intoxication, a rather esoteric topic, I told my professors that I was not planning to life-sentenced myself to be locked into an hospital or a lab but I would rather to the field, they were rather disappointed. Then, after several years in ER, in 1989, I left to africa and soon discovered that malaria was much more difficult to treat than what I have taught at Univeristy Medical Innovation in Humanitarian Situations: The Work of Médecins Sans Frontières

1991, Thai-Burmese border, Tak Province Thailand Asia 1991, Thai-Burmese border, Tak Province Thailand Burmese refugees camps Malaria resistant to most of available drugs Young children and pregnant woman become untreatable Some epidemics occurred at the rainy season A former field coordinator, A Shoklo Malaria Research Unit / Mahidol and Oxford universities Documented the resistances and studied alternatives without finding a solution. Then some patients came to us with a Chinese drug smuggled into Thailand through Burma from China. The family of new drugs, Artemesinine derivatives, was poorly known outside China. In fact, during the Vietnam war, for both parties malaria was a real burden, keeping large numbers of soldiers out of combat. The Vietnamese asked their Chinese ally to provide them with better treatments. Chinese academics first screened the plants used by their traditional medicine. This how the Artemisinine derivatives were re-discovered. Meanwhile, Western laboratories, especially the US military research institutions, identified several new molecules, among them Mefloquine and Halofantrine. The Vietnam was over before this new generation of drugs had any impact on the military balance of forces. Later on, the parasite, Plasmodium Falciparum rapidly developed resistances against mefloquine and halofantrine. .

With Chinese drugs, several difficulties immediately emerged: they have not been studied accordingly to international scientific standards; they were not patentable by Western pharmaceutical companies and consequently profits were not guaranteed by a patent giving a monopoly for 20 years; Politically, even psychologically, it was difficult to recognize that Chinese medical institutions have won the medical battle and find an alternative to outdated malaria drugs. In 1992, I attended an international tropical medicine conference held in Thailand, at Pataya, almost fully dedicated to malaria. And it was more than clear that neither WHO nor most of academic institutions, with few exceptions (Greenwood and White), had any plan to study these Chinese drugs. The first step in order to find a way out to this deadlock situation, one of the most common and deadly disease becoming untreatable, was to carry out clinical trials to look for alternatives. Several ethical dilemmas immediately pops up. Studies were conducted among Burmese refugees living in camps. Clinical trials in humanitarian situations raise specific ethical dilemma: Is it truly possible for refugees to choose whether or not to participate in a trial when the study is carried out by the very same aid organisation they depend on for their survival? When the reference treatment is totally ineffective and patients are at risk of easily dying is it still acceptable to compare it to a new therapy? To build a good research team and local structure is rather complex and rare in such precarious settings and the temptation is high to overuse it when it already exists by repeating studies of new drugs within the same population.

Back to Africa The main challenge Africa Then looking at epidemiological data, it was also obvious that the need for a new generation of drugs was higher in Africa than in Asia because malaria mainly kills toddlers in Africa. End of the nineties, the situations was rapidly worsening in sub- Saharan Africa. Several epidemics occurred in Kenya (98), Burundi (2000), Sudan (2002) and Ethiopia (2OO4). Studies show that usual drugs (chloroquine, Fansidar) have become useless. Quinine has kept a good level of efficacy but wasn't an alternative because of the duration of the treatment, seven days, the fact that quinine need to be administrated three times by day and the necessity to preserve this drug for severe cases.

Of course Africa is a more difficult context Of course Africa is a more difficult context. For instance diagnostic tools are less available

We were able to use new drugs only in Southern Sudan where health public authorities were almost non existing. Otherwise, we never obtained green lights to start using the new drugs. But we were asked by national authorities to study and demonstrate their added value.

MSF Malaria Studies 1996-2004 More than 12,000 patients were enrolled in 43 efficacy studies in 18 countries of Asia and Africa between 1996 and 2004. This accounted for 1/4 of the overall research output in these countries during that period. The vast majority of the studies were published in peer-reviewed journals Guthmann J.-P., Checchi F. et al., 2008, « Assessing Antimalarial Efficacy in a time of Change to Artemisinine-Based Combination Therapies : The Role of Médecins Sans Frontières », Plos Medicine, 5 (8), p. 1191-1199. More than 12,000 patients were enrolled in 43 efficacy studies in 18 countries of Asia and Africa between 1996 and 2004, accounting for one fourth of the overall research output in these countries. The vast majority of the studies were published in peer- reviewed journals, which shows that research performed in difficult settings can be of a high enough standard to ensure publication and to be useful in policy change. This has provided extensive evidence on the efficacy of most drug regimens currently in use for uncomplicated malaria, which was often used for treatment policy changes by the concerned countries. The greatest contribution was in conflict-affected countries of sub-Saharan Africa, where studies represent the vast majority of available data and where “traditional” academic research institutions were not or barely represented.

BURUNDI Despite sound scientific evidence, the prescription of new malaria drug wasn't supported by neither the Ministry of Health nor the WHO. A public controversy emerged because of the negative answer to our request to prescribe Artemisinine based combined treatments. The President of the International Council of MSF gave a interview to the national TV channel. The Ministry of Health was furious. Our head of mission has been earlier thrown out of the country because we have dared prescribing the new drugs. Ironically those drugs were already available in private drug stores and reimburse by the public health insurance of public servant. But, in the middle of the epidemic it was still not authorised to use them in public health centres where we were working. Finally, the President of Burundi, Major Buyoya, asked the Ministry to calm down and to prepare the switch. From a Burundian official standpoint, the new drugs were more expensive and not yet covered by international grants. Off the record, it was also clear that that private interests of those still sending the old ineffective drugs to the Ministry were at stake.

The same year, 2002, the creation of the Global Fund unlocked the financial aspect of the situation.

But, it was still difficult to organize the supply But, it was still difficult to organize the supply. Even if orders are on the table, producers need some time to meet the requests, specially in the case of Artemisinine derivatives that are extracted from a plant that is not so easy to grow, Artemisia annua. Moreover, most of the drugs available on markets are not meeting the standards if they include any Artemisinine derivatives at all.

Requirements to be met: The treatment must be accepted by the WHO Reliable supply sources must be identified – they must be sustainable, of good quality and reasonably priced Economic conditions must be created to finance the new protocol Legal questions must be addressed (intellectual property) Administrative authorisations from national authorities must be obtained on import and use New treatment protocols must be written and staff trained The treatment must be accepted by the WHO Reliable supply sources must be identified – they must be sustainable, of good quality and reasonably priced Economic conditions must be created to finance the new protocol Legal questions must be addressed (intellectual property) Administrative authorisations from national authorities must be obtained on import and use New treatment protocols must be written and staff trained

Finally, ASAQ EU money DNDI Sanofi

A full R&D process to go from right hand to left hand

Poor medicine for poor people However our colleagues were initially reluctant when we first proposed the study on medical innovation in humanitarian settings. The term “innovation” was disconcerting to our early interlocutors at MSF. When we’d say innovation, they’d think invention – something along the lines of discovering a new vaccine, drug or diagnostic test – and be skeptical that MSF could take any credit for innovation. In people’s general perception, humanitarian medical activity is a charity medicine that uses outdated tools (vaccines, diagnostics, and drugs) developed in wealthy countries – tools on the verge of being abandoned for a new generation of medical products. They see humanitarian medicine as akin to cleverly recycling secondhand goods for use in poverty-stricken contexts, and think it presumptuous to claim that this could have any role in creating innovation – even less so of creating innovation that would be useful to resource-rich countries

Medical Innovation in Humanitarian Situations The Work of Médecins Sans Frontières Edited by Jean-Hervé Bradol and Claudine Vidal Cholera: diagnosis and treatment outside the hospital Jean François Corty Meningitis: from practitioner to prescriber Eugénie d’Alessandro Human African trypanosomiasis: moving beyond arsenic Malaria: resistances treated by south-south mediation Suna Balkan and Jean-François Corty AIDS: a new pandemic requiring new medical and political practices Jean-Hervé Bradol and Elizabeth Szumilin Innovations? Jean-Hervé Bradol and Marc Le Pape MSF “satellites”. A strategy underlying different medical practices Claudine Vidal and Jacques Pinel Measure, analyse, publish and innovate Emmanuel Baron Controversy policy Marc Le Pape and Isabelle Defourny Remarks Nicolas Dodier BOOK TABLLE OF CONTENT

New drugs developed from 1975-2004 Total: 1,556 Tropical diseases: 18 1.3% TB: 3 Tropical diseases and tuberculosis account for 12% of the global disease burden, but only 1.3% of new drugs developed. Source: Chirac P, Torreele E. Lancet. 2006 May 12; 1560-1561. 16

2000: A Deserted R&D Landscape Organizations Activities TDR Specific Unspecified GSK CHALLENGE 4 CHALLENGE 4 Launch & utilization Launch & utilization CHALLENGE 3 WRAIR CHALLENGE 3 Registration Phase 3 Phase 2 Phase 1 CHALLENGE 2 Regulatory toxicity & safety In vivo efficacy Red existed in 2000. TDR VL: PX6518 preclin, miltefosine phIII (Zentaris) HAT: oral eflornithine phI Chagas: posaconazole (SCH56592) Afterwards, here is now 2007. Sources 11 Jan 2007: mmv.org, gsk.com (2005 Corporate Report), TB Alliance 2006 report. Personal communication with P. Olliaro, 10 Jan 2007. Lead optimization CHALLENGE 1 Lead identification Screening Visceral Leishmaniasis Cutaneous Leishmaniasis HAT Chagas 17

2007 Drug R&D Landscape for NTDs Organizations Activities TDR Specific CDND Unspecified TB Alliance NITD – PC dengue, TB IOWH CHALLENGE 4 MMV GSK Launch & utilization DNDi DD@D CHALLENGE 3 Sandler Center WRAIR Registration Phase 3 Phase 2 Phase 1 HAT Chagas Visceral Leishmaniasis Cutaneous Leishmaniasis Dengue Malaria TB CHALLENGE 2 Regulatory toxicity & safety Sources 11 Jan 2007: mmv.org, gsk.com (2005 Corporate Report), TB Alliance 2006 report. Personal communication with P. Olliaro, 10 Jan 2007. In vivo efficacy Lead optimization CHALLENGE 1 Lead identification Screening 18

Combined PDP pipeline today includes 143 candidates 8 Combined PDP pipeline today includes 143 candidates 104 biopharmaceutical candidates in development... ... and 39 diagnostic & vector control candidates Diagnostics Pre Clinical 59 57% Feasibility 7 26% Phase I 15 14% Test Development 7 26% Evaluation 6 Phase II 12 22% 12% CD4 Demonstration 1 4% FIND Phase III 10% 10 Country Adoption 6 IDRI 22% Registration 2 Drugs 2% The importance of a critical review of medical research based on humanitarian motivations Vaccines Vector control Microbicides Launched 6% 6 Early Stage IVCC In Development # candidates # candidates Notes: Includes products not funded by Gates Foundation. Biopharmaceutical candidates in development Include: IAVI, IPM, IVI, GATB, Aeras, MMV, MVI, MVP, PVS, DNDi, iOWH, PDVI, HHVI. Source: PDPs

Product Development Partnerships (PDPs): Filling the Gaps in Translational Research and Product Development 20 20