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ETHICAL CONSIDERATIONS FOR ZIKA VIRUS HUMAN CHALLENGE TRIALS
REPORT & RECOMMENDATIONS
February 2017 :: 43 pages
The National Institute of Allergy and Infectious Diseases (NIAID) and the Walter Reed Army Institute of Research (WRAIR)
WRITING GROUP AUTHORS
Seema K. Shah, J.D., Committee chair
Associate Professor, Treuman Katz Center for Pediatric Bioethics, University of Washington &
Seattle Children’s Research Institute, Seattle, Washington, U.S.A.
Jonathan Kimmelman, Ph.D.
Associate Professor, Interim Director, Department of Biomedical Ethics, McGill University,
Anne Drapkin Lyerly, M.D., M.A.
Professor, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, U.S.A.
Holly Fernandez Lynch, J.D., M.Bioethics.
Executive Director, Petrie-Flom Center; Faculty, Harvard Medical School Center for Bioethics,
Cambridge, Massachusetts, U.S.A.
Francine McCutchan, Ph.D.
Director, CHIM Consortium Project, Center for Vaccine Innovation and Access, PATH,
Washington, D.C., U.S.A.
Franklin G. Miller, Ph.D.
Professor, Weil Cornell Medical College, New York, New York, U.S.A.
Ricardo Palacios, M.D., Ph.D.
Clinical R&D Manager, Instituto Butantan, São Paulo, Brazil
Carlos Pardo-Villamizar, M.D.
Director, Neurovirus Emerging in the Americas Study (NEAS), Johns Hopkins University,
Baltimore, Maryland, U.S.A.
Carmen Zorrilla, M.D.
Professor, University of Puerto Rico School of Medicine, San Juan, Puerto Rico, U.S.A.
[Excerpts; Editor’s text-bolding]
1. The National Institute of Allergy and Infectious Diseases (NIAID) and the Walter Reed Army Institute of Research (WRAIR) convened a planning committee with members from relevant federal agencies, researchers, and ethicists to determine how best to address the ethical issues raised by a possible Zika virus human challenge study. This group planned an expert consultation meeting in Rockville, Maryland, on December 12, 2016 and formed an independent writing committee with cross-disciplinary expertise to develop recommendations. The writing committee was charged with answering the following questions:
:: Can a Zika virus human challenge trial be ethically justified?
:: If so, under what conditions?
2. Given the potentially devastating effects of Zika infection during pregnancy, the insidious nature of the disease, and the promise of what can be learned from human challenge trials, the writing committee concluded that a Zika virus human challenge trial could be ethically justified if certain conditions were met. However, at this point in time, based on what was heard at the consultation meeting and on our review of the latest scientific and ethics research, the writing committee has determined that these conditions preclude the conduct of a Zika virus human challenge trial, as detailed in the body of this report.
3. At some point in the future, if circumstances change or if a protocol is designed to address the recommendations in this report, members of this writing committee (or a similar body) should apply these recommendations to determine if a specific proposal for a Zika virus human challenge study is ethically sound…
Part 4: Summary of Recommendations and Answers to the Charge of the Consultation
The Zika virus human challenge research writing committee has the following findings and recommendations regarding the charge of the consultation:
1A: There is substantial uncertainty about the risks to potential volunteers in a Zika virus human challenge study. Although the known risks of a Zika virus human challenge trial appear comparable to the risks of phase I research with healthy volunteers, without greater knowledge about outcomes from Zika exposure, these risks would require high social benefit to be justified. Strategies to minimize risks include careful selection of inclusion and exclusion criteria, close medical monitoring, relatively long periods of confinement, and prompt medical attention for volunteers who become ill.
1B: The committee was particularly concerned about possible risks to third parties, i.e., that Zika virus might be transmitted from study volunteers to others, such as fetuses and members of the community. Because these third parties generally cannot know about, protect themselves from, or consent to risks, risks to them are only reasonable if they can be reduced to near-zero. However, the mechanisms of transmission of Zika virus and how long individuals with Zika virus can infect others are not fully understood. Before proceeding with a Zika virus challenge study, researchers should therefore demonstrate that the risks to third parties are not likely to be realized. This could be done through developing risk management strategies and obtaining relevant data. Approaches to minimizing risk would rely upon either relatively long periods of isolation, the use of effective long-acting reversible contraception, careful inclusion and exclusion criteria (including potentially enrolling only women), and/or individual participants’ self-report about their own sexual practices as well as the practices of their partners, though the committee was not certain to what extent these strategies would be compatible with appropriate scientific design. Additional information could be gathered through modeling based on rates of transmission and pregnancy in similar studies and research to characterize the modes of infection and transmissibility of Zika virus. More research using virus culture, which detects infectious virus rather than virus genetic material, could clarify the period of infectiousness and the relative risk of exposure to different body fluids, and is an important priority for the development of a Zika virus human challenge study.
2: Whether a Zika virus human challenge trial has sufficient social value to proceed depends on the reasons for doing it and whether there are alternative ways to obtain the information. The most compelling rationale for conducting a Zika virus human challenge trial, given the risks and uncertainty, would be if field trials were prohibitively difficult to conduct in light of a waning epidemic. This rationale is not currently met, but it could come to pass in the future. Another valuable reason to conduct a challenge trial would be to accelerate the development of a vaccine that could prevent congenital Zika infection. This rationale must be accompanied with strong evidence that results from a Zika virus human challenge trial would be used by stakeholders (e.g., indication from regulatory agencies that finding a correlate would speed up the licensing of a vaccine). The committee did not hear sufficient evidence that this rationale is currently met. Finally, using a challenge trial solely to learn about the pathogenesis and natural history of Zika infection is unlikely to justify the risk involved given the alternative ways to obtain similar information.
3: A Zika virus human challenge trial should only enroll individuals with capacity to provide their voluntary informed consent. Such a trial should also take steps to minimize the risks to fetuses to as close to zero as possible.
4: Researchers and sponsors of a Zika virus human challenge trial should use a robust informed consent process. For example, researchers and sponsors could require multiple voluntary steps for individuals to take to enroll, adequate time for discussion, and evaluation of and feedback given to enhance participant understanding about critical issues (e.g., the uncertainty involved, the risks to third parties and fetuses, precautions that should be taken, and restrictions on the right to withdraw).
5: Volunteers should be paid fairly for their time and inconvenience, but they should demonstrate understanding of the risks and uncertainties involved and be evaluated with objective evidence of their eligibility and compliance wherever possible.
6: The right to withdraw should be respected in challenge trials by halting the collection of data for volunteers who want to withdraw even if they will have to remain confined to protect themselves or others.
7: Contemporaneous external evaluation of risk by relevant experts is advisable before a Zika virus human challenge trial proceeds.
8: In the event a Zika virus CHIM trial proceeds, study sponsors should ensure that sites are adequately insured to cover the costs of care and compensation for research-related injury, to both study participants and third parties, and that insurance policies that are purchased have adequate processes in place to efficiently and fairly evaluate and resolve claims.
9: Community engagement with the geographical community surrounding the site(s) of a Zika virus human challenge trial should be conducted in advance of the research to show respect for the community and its values, obtain community buy-in to the goals of the research, and proceed with transparency.
WHO publishes list of bacteria for which new antibiotics are urgently needed
27 February 2017 | GENEVA – WHO today published its first ever list of antibiotic-resistant “priority pathogens” – a catalogue of 12 families of bacteria that pose the greatest threat to human health.
The list was drawn up in a bid to guide and promote research and development (R&D) of new antibiotics, as part of WHO’s efforts to address growing global resistance to antimicrobial medicines.
The list highlights in particular the threat of gram-negative bacteria that are resistant to multiple antibiotics. These bacteria have built-in abilities to find new ways to resist treatment and can pass along genetic material that allows other bacteria to become drug-resistant as well.
“This list is a new tool to ensure R&D responds to urgent public health needs,” says Dr Marie-Paule Kieny, WHO’s Assistant Director-General for Health Systems and Innovation. “Antibiotic resistance is growing, and we are fast running out of treatment options. If we leave it to market forces alone, the new antibiotics we most urgently need are not going to be developed in time.”
The WHO list is divided into three categories according to the urgency of need for new antibiotics: critical, high and medium priority.
The most critical group of all includes multidrug resistant bacteria that pose a particular threat in hospitals, nursing homes, and among patients whose care requires devices such as ventilators and blood catheters. They include Acinetobacter, Pseudomonas and various Enterobacteriaceae (including Klebsiella, E. coli, Serratia, and Proteus). They can cause severe and often deadly infections such as bloodstream infections and pneumonia.
These bacteria have become resistant to a large number of antibiotics, including carbapenems and third generation cephalosporins – the best available antibiotics for treating multi-drug resistant bacteria.
The second and third tiers in the list – the high and medium priority categories – contain other increasingly drug-resistant bacteria that cause more common diseases such as gonorrhoea and food poisoning caused by salmonella.
G20 health experts will meet this week in Berlin. Mr Hermann Gröhe, Federal Minister of Health, Germany says “We need effective antibiotics for our health systems. We have to take joint action today for a healthier tomorrow. Therefore, we will discuss and bring the attention of the G20 to the fight against antimicrobial resistance. WHO’s first global priority pathogen list is an important new tool to secure and guide research and development related to new antibiotics.”
The list is intended to spur governments to put in place policies that incentivize basic science and advanced R&D by both publicly funded agencies and the private sector investing in new antibiotic discovery. It will provide guidance to new R&D initiatives such as the WHO/Drugs for Neglected Diseases initiative (DNDi) Global Antibiotic R&D Partnership that is engaging in not-for-profit development of new antibiotics.
Tuberculosis – whose resistance to traditional treatment has been growing in recent years – was not included in the list because it is targeted by other, dedicated programmes. Other bacteria that were not included, such as streptococcus A and B and chlamydia, have low levels of resistance to existing treatments and do not currently pose a significant public health threat.
The list was developed in collaboration with the Division of Infectious Diseases at the University of Tübingen, Germany, using a multi-criteria decision analysis technique vetted by a group of international experts. The criteria for selecting pathogens on the list were: how deadly the infections they cause are; whether their treatment requires long hospital stays; how frequently they are resistant to existing antibiotics when people in communities catch them; how easily they spread between animals, from animals to humans, and from person to person; whether they can be prevented (e.g. through good hygiene and vaccination); how many treatment options remain; and whether new antibiotics to treat them are already in the R&D pipeline.
“New antibiotics targeting this priority list of pathogens will help to reduce deaths due to resistant infections around the world,” says Prof Evelina Tacconelli, Head of the Division of Infectious Diseases at the University of Tübingen and a major contributor to the development of the list. “Waiting any longer will cause further public health problems and dramatically impact on patient care.”
While more R&D is vital, alone, it cannot solve the problem. To address resistance, there must also be better prevention of infections and appropriate use of existing antibiotics in humans and animals, as well as rational use of any new antibiotics that are developed in future.
WHO priority pathogens list for R&D of new antibiotics
Priority 1: CRITICAL
Acinetobacter baumannii, carbapenem-resistant
Pseudomonas aeruginosa, carbapenem-resistant
Enterobacteriaceae, carbapenem-resistant, ESBL-producing
Priority 2: HIGH
Enterococcus faecium, vancomycin-resistant
Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant
Helicobacter pylori, clarithromycin-resistant
Campylobacter spp., fluoroquinolone-resistant
Neisseria gonorrhoeae, cephalosporin-resistant, fluoroquinolone-resistant
Priority 3: MEDIUM
Streptococcus pneumoniae, penicillin-non-susceptible
Haemophilus influenzae, ampicillin-resistant
Shigella spp., fluoroquinolone-resistant
WHO stresses urgent need for R&D for drug-resistant TB alongside newly-prioritized antibiotic-resistant pathogens
28 February 2017 | GENEVA – WHO reaffirms the critical need for research and development (R&D) of new antibiotics to tackle the threat of drug-resistant tuberculosis (TB).
“Addressing drug-resistant TB research is a top priority for WHO and for the world,” said Dr Margaret Chan, WHO Director-General. “More than US$ 800 million per year is currently necessary to fund badly needed research into new antibiotics to treat TB.”
The MDR-TB public health crisis continues: there were an estimated 580 000 cases and 250 000 related deaths in 2015. Only 125 000 were started on treatment, and just half of those people were cured.
Only two new antibiotics to address MDR-TB have completed Phase IIB trials in the past 50 years. Both are still in Phase III trials, and more funding will be required to complete the process and to develop other effective treatment regimens.
On 27 February, WHO published a list of antibiotic-resistant pathogens that have recently been prioritized as posing great risk to human health.
“Mycobacterium tuberculosis, the bacterium responsible for human TB, was not included in the scope of the prioritization exercise as the intention was to identify previously unrecognised health threats due to increasing antibiotic resistance. There is already consensus that TB is a top priority for R&D for new antibiotics,” said Dr Marie-Paule Kieny, Assistant Director-General at WHO.
A series of high-level global meetings on TB have been scheduled in 2017-2018. Drug-resistant TB and research will be major themes at the WHO Ministerial Conference on TB planned in Moscow in November 2017. It will also be a key agenda item at the UN General Assembly high-level meeting on TB in 2018. MDR-TB and research needs are also under discussion in wider fora such as those focusing on antimicrobial resistance and health security.
Bulletin of the World Health Organization
Article ID: BLT.16.175166
This online first version has been peer-reviewed, accepted and edited, but not formatted and finalized with corrections from authors and proofreaders.
Lessons learnt from 12 oral cholera vaccine campaigns in resource-poor settings
A Hsiao, SN Desai, V Mogasale, JL Excler, L Digilio
[Free full-text from title link above]
Improving water and sanitation is the preferred choice for cholera control in the long-term. Nevertheless, vaccination is an available tool that has been shown to be a cost‒effective option for cholera prevention in endemic countries or during outbreaks. In 2011 the first low-cost oral cholera vaccine for international use was given prequalification by the World Health Organization (WHO). To increase and prioritize use of the vaccine, WHO created a global stockpile in 2013 from which countries may request oral cholera vaccine for reactive campaigns. WHO has issued specific guidelines for applying for the vaccine, which was previously in short supply (despite prequalification for a second oral vaccine in 2015). The addition of a third WHO-prequalified oral cholera vaccine in 2016 is expected to increase the global stockpile considerably and alleviate supply issues. However, prioritization and best use of the vaccine
(e.g. how, when and where to use) will remain challenges. We describe 12 past oral cholera vaccine campaigns, conducted in settings with varying burdens of cholera. These case studies illustrate three key challenges faced in the use of the oral cholera vaccines: regulatory hurdles, cold chain logistics and vaccine coverage and uptake. To pave the way for the introduction of
current and future oral cholera vaccines, we discuss operational challenges and make recommendations for future research with respect to each of these challenges.