[Healthy volunteers' protection around the world]. / VolREthics - Une initiative internationale de l'Inserm pour définir la protection des volontaires sains.

Healthy volunteers participating in biomedical research benefit from varying levels of protection in different parts of the world since they are too rarely identified as a specific subset of study participants with specific vulnerabilities and risks. These differences in protection can lead to unfair and ethically unacceptable situations. Healthy volunteers are subject to a number of risks, not only regarding the respect of their rights and of their health but they are also at risk of being exploited because of their financial situation, educational level and motivations. In the end, the scientific validity of the studies may also be called into question. Through its work, the VolREthics (Volunteers in Research and Ethics) initiative, set up by the Inserm ethics committee, outlines the ethical issues raised by the involvement of healthy volunteers in biomedical research, and highlights the need to improve their protection worldwide. Healthy volunteers are essential to scientific progress and society, and their potential vulnerabilities must be recognized and taken into account.

Title: VolREthics - Une initiative internationale de l'Inserm pour définir la protection des volontaires sains. Abstract: Les volontaires sains qui participent aux recherches biomédicales sont très rarement identifiés comme un groupe spécifique. Pourtant, de par leur vulnérabilité et les risques potentiels auxquels ils sont exposés, ils ne bénéficient que d'un niveau de protection qui reste variable selon les régions du monde. Il en résulte différents risques, non seulement pour le respect de leurs droits, de leur santé, mais également pour la validité scientifique des recherches. L'initiative internationale VolREthics (pour volontaires sains en recherche et éthique, ou Volunteers in Research and Ethics), lancée par le comité d'éthique de l'Inserm, a mis en évidence les questions éthiques soulevées par la participation des volontaires sains dans la recherche biomédicale. Elle insiste également sur la nécessité d'améliorer la protection de ces volontaires lors des recherches menées à travers le monde.

Efficacy and safety of ravidasvir plus sofosbuvir in patients with chronic hepatitis C infection without cirrhosis or with compensated cirrhosis (STORM-C-1): interim analysis of a two-stage, open-label, multicentre, single arm, phase 2/3 trial.

BACKGROUND: In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV. METHODS: STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183. FINDINGS: Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment. INTERPRETATION: In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality. FUNDING: National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.

Ethical rationale for better coordination of clinical research on COVID-19.

Hundreds of clinical trials of potential treatments and vaccines for the "coronavirus 19 disease" (COVID-19) have been set up in record time. This is a remarkable reaction to the global pandemic, but the absence of a global coordination of clinical research efforts raises serious ethical concerns. Some COVID-19 patients might carry the burden of clinical trial involvement even though their trial cannot be completed as researchers are competing for patients. A shortage of medicines can occur when existing drugs are diverted for clinical trials. Research ethics committees are overburdened with multiple applications. A multitude of trials can also overstretch medical staff and risk neglecting non-COVID-19 patients. And finally, conflicting conclusions from a multitude of heterogeneous trials might lead to delays in public health decisions about life-saving issues. These challenges are made worse by the unpredictable evolution of epidemics, the active involvement of political decision-makers in scientific issues and the pressure of social media globally. While freedom to conduct research must be safeguarded, global health emergency situations would greatly benefit from effective international coordination mechanisms for clinical research.

The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data.

BACKGROUND: Artesunate-amodiaquine (AS-AQ) is one of the most widely used artemisinin-based combination therapies (ACTs) to treat uncomplicated Plasmodium falciparum malaria in Africa. We investigated the impact of different dosing strategies on the efficacy of this combination for the treatment of falciparum malaria. METHODS: Individual patient data from AS-AQ clinical trials were pooled using the WorldWide Antimalarial Resistance Network (WWARN) standardised methodology. Risk factors for treatment failure were identified using a Cox regression model with shared frailty across study sites. RESULTS: Forty-three studies representing 9,106 treatments from 1999-2012 were included in the analysis; 4,138 (45.4%) treatments were with a fixed dose combination with an AQ target dose of 30 mg/kg (FDC), 1,293 (14.2%) with a non-fixed dose combination with an AQ target dose of 25 mg/kg (loose NFDC-25), 2,418 (26.6%) with a non-fixed dose combination with an AQ target dose of 30 mg/kg (loose NFDC-30), and the remaining 1,257 (13.8%) with a co-blistered non-fixed dose combination with an AQ target dose of 30 mg/kg (co-blistered NFDC). The median dose of AQ administered was 32.1 mg/kg [IQR: 25.9-38.2], the highest dose being administered to patients treated with co-blistered NFDC (median = 35.3 mg/kg [IQR: 30.6-43.7]) and the lowest to those treated with loose NFDC-25 (median = 25.0 mg/kg [IQR: 22.7-25.0]). Patients treated with FDC received a median dose of 32.4 mg/kg [IQR: 27-39.0]. After adjusting for reinfections, the corrected antimalarial efficacy on day 28 after treatment was similar for co-blistered NFDC (97.9% [95% confidence interval (CI): 97.0-98.8%]) and FDC (98.1% [95% CI: 97.6%-98.5%]; P = 0.799), but significantly lower for the loose NFDC-25 (93.4% [95% CI: 91.9%-94.9%]), and loose NFDC-30 (95.0% [95% CI: 94.1%-95.9%]) (P < 0.001 for all comparisons). After controlling for age, AQ dose, baseline parasitemia and region; treatment with loose NFDC-25 was associated with a 3.5-fold greater risk of recrudescence by day 28 (adjusted hazard ratio, AHR = 3.51 [95% CI: 2.02-6.12], P < 0.001) compared to FDC, and treatment with loose NFDC-30 was associated with a higher risk of recrudescence at only three sites. CONCLUSIONS: There was substantial variation in the total dose of amodiaquine administered in different AS-AQ combination regimens. Fixed dose AS-AQ combinations ensure optimal dosing and provide higher antimalarial treatment efficacy than the loose individual tablets in all age categories.

Improving the Quality of Host Country Ethical Oversight of International Research: The Use of a Collaborative 'Pre-Review' Mechanism for a Study of Fexinidazole for Human African Trypanosomiasis.

Developing countries face numerous barriers to conducting effective and efficient ethics reviews of international collaborative research. In addition to potentially overlooking important scientific and ethical considerations, inadequate or insufficiently trained ethics committees may insist on unwarranted changes to protocols that can impair a study's scientific or ethical validity. Moreover, poorly functioning review systems can impose substantial delays on the commencement of research, which needlessly undermine the development of new interventions for urgent medical needs. In response to these concerns, the Drugs for Neglected Diseases Initiative (DNDi), an independent nonprofit organization founded by a coalition of public sector and international organizations, developed a mechanism to facilitate more effective and efficient host country ethics review for a study of the use of fexinidazole for the treatment of late stage African Trypanosomiasis (HAT). The project involved the implementation of a novel 'pre-review' process of ethical oversight, conducted by an ad hoc committee of ethics committee representatives from African and European countries, in collaboration with internationally recognized scientific experts. This article examines the process and outcomes of this collaborative process.

Innovative public-private partnerships to maximize the delivery of anti-malarial medicines: lessons learned from the ASAQ Winthrop experience.

BACKGROUND: This case study describes how a public-private partnership initiated to develop a new anti-malarial combination, ASAQ Winthrop, has evolved over time to address issues posed by its effective deployment in the field. CASE DESCRIPTION: In 2002, DNDi created the FACT project to develop two fixed-dose combinations, artesunate-amodiaquine and artesunate-mefloquine, to meet the WHO anti-malarial treatment recommendations and international regulatory agencies approval standards. In 2002, Sanofi-Aventis had started a development programme for a fixed-dose combination of artesunate and amodiaquine, to replace its co-blister combination. DNDi and Sanofi-Aventis joined forces in 2004, with the objective of developing within the shortest possible time frame a non-patented, affordable and easy to use fixed-dose combination of artesunate and amodiaquine adapted to the needs of patients, in particular, those of children. The partners developed Coarsucam®/Artesunate Amodiaquine Winthrop® ("ASAQ Winthrop") which was prequalified by the WHO in 2008. Additional partnerships have since been established by DNDi and Sanofi-Aventis to ensure: 1) the adoption of this new medicine by malaria-endemic countries, 2) its appropriate usage through a broad range of information tools, and 3) the monitoring of its safety and efficacy in the field through an innovative Risk Management Plan. DISCUSSION AND EVALUATION: The partnership between DNDi and Sanofi-Aventis has enabled the development and pre-qualification of ASAQ Winthrop in a short timeframe. As a result of the multiple collaborations established by the two partners, as of late 2010, ASAQ Winthrop was registered in 30 sub-Saharan African countries and in India, with over 80 million treatments distributed in 21 countries. To date, 10 clinical studies, involving 3432 patients with ASAQ Winthrop were completed to document efficacy and safety issues identified in the Risk Management Plan. CONCLUSIONS: The speed at which ASAQ Winthrop was adopted in the field shows that this drug fits the needs of patients and health authorities. It also demonstrates the power of partnerships that combine different sets of strengths and skills, and that evolve to include additional actors to meet new global health challenges for poverty-related diseases.

Good clinical practice in developing countries: applying recommendations.

The recommendations for clinical research in developing countries were published in 2007 and the present article deals with issues which were not initially raised or discussed in depth. In particular, we discuss specific questions linked to trials conducted in developing countries with regard to informed consent, research project review by two ethics committees, standards of care, management of biological samples, study follow-up committees, notification of Serious Adverse Events, paediatric trials, and Contract Research Organizations.

Guidelines for clinical research in developing countries.

On the basis of a review of current clinical research conditions in developing countries, guidelines have been formulated to ensure scientific validity as well as adherence to universal ethical principles. The main recommendation is that projects should be reviewed by two Institutional Review Boards, one in the country where the Study Sponsor is based, and another in the country where the study is being carried out. In addition, an independent Data Safety Monitoring Board should be set up and systems established to ensure the effective reporting of Serious Adverse Events and to specify the Sponsor's obligations after the end of the Study.

Guidelines for Clinical Research in Developing Countries.

On the basis of a review of current clinical research conditions in developing countries, guidelines have been formulated to ensure scientific validity as well as adherence to universal ethical principles. The main recommendation is that projects should be reviewed by two Institutional Review Boards, one in the country where the Study Sponsor is based, and another in the country where the study is being carried out. In addition, an independent Data Safety Monitoring Board should be set up and systems established to ensure the effective reporting of Serious Adverse Events and to specify the Sponsor's obligations after the end of the Study.

Vaccination strategies for the last stages of global polio eradication.

Launched in 1988, the Global Poliomyelitis Eradication Initiative has enjoyed remarkable success. The WHO anticipates isolation of the last wild polio virus during late 2004/early 2005, paving the way for certification of a world free of polio in 2008. However, the ultimate objective of this campaign, discontinuation of polio vaccination, has been jeopardised by two recent developments: the characterisation of vaccine-derived polio viruses (VDPV), and renewed concerns over the risk of bioterrorism. The threat posed by VDPV has led the WHO to recommend discontinuation of OPV usage as soon as possible after eradication certification. Cessation of vaccination with OPV needs to be carefully designed to avoid creating conditions where VDPV will develop. For the longer term, strategies must be designed to guard against the risk of polio reemergence due to long-term VDPV excretors, accidental release of wild viruses or bioterrorism. The main strategies under consideration are a surveillance and response approach or a continuation of vaccination with IPV. Choosing between these strategies will pose a major dilemma for India and for many other countries.