The fight against Antimicrobial Resistance: Important recent publications

One of my previous blogs discussed the growing threat of antimicrobial resistance (AMR). I concluded that antimicrobial resistance is a growing and complex threat involving multifaceted legal, socio-economic and scientific aspects. This requires sustained and coordinated action on both global and local levels.

A recent medical review on drug resistant tuberculosis supports these findings and provides further fodder to the debate. In their study, which was published in April 2014 in The Lancet – Respiratory Medicine, the authors analyzed the epidemiology, pathogenesis, diagnosis, management, implications for health-care workers, and ethical and medico-legal aspects of extensively drug-resistant tuberculosis and other resistant strains. In particular, the authors discussed the increasing threat of functionally untreatable tuberculosis, and the problems that it creates for public health and clinical practice. The paper concludes that the growth of highly resistant strains of tuberculosis make the development of new drugs and rapid diagnostics for tuberculosis—and increased funding to strengthen global control efforts, research, and advocacy—even more pressing.

This was also recognized in the recent WHO’s Global Surveillance Report on AMR, which was published this April. It is the first WHO report that studied the problem of AMR on a global level. Noting that resistance is occurring across many different infectious agents, the report concentrates on antibiotic resistance in seven different bacteria responsible for common, serious diseases such as bloodstream infections (sepsis), diarrhoea, pneumonia, urinary tract infections and gonorrhoea. The results demonstrate a wide-spread growth of resistance to antibiotics, especially “last resort” antibiotics. In particular the report reveals that this serious threat is no longer a mere forecast for the future. AMR is a contemporary problem in every region of the world and has the potential to affect anyone, of any age, in any country. Consequently the WHO report concludes that antibiotic resistance is now a major threat to public health that needs to be tackled on a global level.

Continue reading

Good news for many South African HIV patients—with a big glitch

On Wednesday, South African Health Minister Aaron Motsoaledi announced that, as of January 2015, HIV-positive patients in the country would start receiving free antiretroviral treatment once their CD4 count fell below 500, instead of current threshold of less than 350. Some patient groups would start receiving antiretrovirals immediately upon being diagnosed with HIV infection, regardless of their clinical stage.

Last month, Till Bärnighausen, Dan Wikler and I predicted in PLoS Medicine that sub-Saharan nations would move in the direction that South Africa is now moving, and pointed out a big complication. This policy change might make several gigantic trials of so-called treatment-as-prevention in sub-Saharan Africa impossible to complete successfully. As we explained, these trials remain important for assessing the potential of treatment-as-prevention to curb the spread of HIV in general populations (with many different relationship types and different levels of care delivery and support).

In treatment-as-prevention, antiretrovirals are offered to patients immediately upon their diagnosis with HIV. The hope is that very early treatment would be better for these patients and prevent them from infecting others. We also offered some ways out of this mess, but they involve untraditional approaches to research conduct and to policy. Our piece was featured in the June issue of UNAIDS’ HIV This Month.

Bumps on the Road Towards Clinical Trials Data Transparency- A recent U-Turn by the EMA?

By Timo Minssen

In a recent blog I discussed the benefits and potential draw-backs of a new “EU Regulation on clinical trials on medicinal products for human use,” which had been adopted by the European Parliament and Council in April 2014. Parallel to these legislative developments, the drug industry has responded with its own initiatives providing for varying degrees of transparency. But also medical authorities have been very active in developing their transparency policies.

In the US, the FDA proposed new rules which would require disclosure of masked and de-identified patient-level data. In the EU, the EMA organized during 2013 a series of meetings with its five advisory committees to devise a draft policy for proactive publication of and access to clinical-trial data. In June 2013 this process resulted in the publication, of a draft policy document titled “Publication and access to clinical-trial data” (EMA/240810/2013).

Following an invitation for public comments on this document, the EMA received more than 1,000 submissions from stakeholders. Based on these comments the EMA recently proposed “Terms of Use” (TOU) and “Redaction Principles” for clinical trial data disclosure.

In a letter to the EMA’s executive director Dr. Guido Rasi, dated 13 May 2014, the European Ombudsman, Emily O’Reilly, has now expressed concern about what seems to be a substantial shift of policy regarding clinical trial data transparency. Continue reading

Trials of HIV Treatment-as-Prevention: Ethics and Science. Friday, March 7

High hopes for overcoming the HIV epidemic rest to a large extent on HIV Treatment-as-Prevention (TasP). Large cluster-randomized controlled trials are currently under way to test the effectiveness of different TasP strategies in general populations in sub-Saharan Africa. At the same time, however, international antiretroviral treatment (ART) guidelines have already moved to definitions of ART eligibility including all – in the US guidelines – or nearly all – in the WHO guidelines – HIV-infected people. In this panel, we are bringing together the leaders of three TasP trials in sub-Saharan Africa, bioethicists, and public health researchers to debate the tension between the policy intentions expressed in these guidelines and the historic opportunity to learn whether TasP works or not. Please join us in considering different options to resolving this tension.

  • Till Bärnighausen, Harvard School of Public Health, and Wellcome Trust Africa Centre for Health and Population Science
  • Max Essex, Harvard School of Public Health
  • Deenan Pillay, Wellcome Trust Africa Centre for Health and Population Science, and University College London
  • Velephi Okello, Swaziland National AIDS Programme, Ministry of Health
  • Dan Wikler, Harvard School of Public Health
  • Nir Eyal, Harvard Medical School

 

Moderator: Megan Murray, Harvard School of Public Health and Harvard Medical School

 

Friday, March 7th, 10am-12pm

Kresge G3, Harvard School of Public Health

OHRP Revises Guidance on Remuneration for Human Research Subjects

by Suzanne M. Rivera, Ph.D.

The Office of Human Research Protections (OHRP) has issued revised guidance about research subject compensation.  And, although it has not attracted a great deal of fanfare, it deserves attention because the new guidance offers greater flexibility to investigators and to the Institutional Review Boards (IRBs) charged with reviewing proposed human research studies.   Under its list of Frequently Asked Questions (FAQ) related to informed consent, there is a question (7) which reads, “When does compensating subjects undermine informed consent or parental permission?”  (http://www.hhs.gov/ohrp/policy/consentfaqsmar2011.pdf).

Aside from the fact that it’s still a very leading question (asking “when does it?” implies that, in fact, it does…), the new answer provided by OHRP clarifies that compensation in and of itself is not necessarily coercive or a source of undue influence.  It says that remuneration to subjects may include compensation for risks associated with their participation in research and that compensation may be an acceptable motive for some individuals agreeing to participate in research.

That is a real paradigm shift. Continue reading

Academic Freedom and Responsibility

by Suzanne M. Rivera, Ph.D.

Earlier this month, the American Association of University Professors (AAUP) recommended that researchers should be trusted with the ability to decide whether individual studies involving human subjects should be exempt from regulation.  The AAUP’s report, which was prepared by a subcommittee of the Association’s Committee on Academic Freedom and Tenure, proposes that minimal risk research should be exempt from the human research protection regulations and that faculty ought to be given the ability to determine when such an exemption may apply to their own projects.

Specifically, the report states, “Research on autonomous adults should be exempt from IRB approval straightforwardly exempt, with no provisos and no requirement of IRB approval of the exemption) if its methodology either (a) imposes no more than minimal risk of harm on its subjects, or (b) consists entirely in speech or writing, freely engaged in, between subject and researcher.”

These recommendations, designed to address long-standing concerns by social scientists about bureaucratic intrusions into their work, are misguided and could result in real harm to research subjects. Continue reading

You Talkin’ to Me?

by Suzanne M. Rivera, Ph.D.

The principle of justice articulated in The Belmont Report requires equitable selection of human research subjects.  Equitable in this context means that the risks and benefits of the study are distributed fairly.  Fairness has two components: 1) avoiding exploitation of the vulnerable (e.g. preying upon a poor, uneducated population) and 2) avoiding the unjustified exclusion of any population ( whether out of bigotry, laziness or convenience).  

Recruitment strategies invariably shape the selection of research subjects and the extent to which a pool of participants really represents a cross-section of society.  Institutional Review Boards (IRBs) are charged with evaluating whether study recruitment plans and materials used to obtain informed consent are easily understood and free of misleading information.  This is relatively straightforward when researchers, IRB members, and study subjects all speak the same language.  But when studies are done in geographical areas that include numerous cultural and language communities, it can be quite tricky.

One of the barriers that prevents people from enrolling in (or even knowing about) studies is a lack of awareness and planning by researchers to address language differences.  The human research protection regulations at 45 CFR Part 46.116 require that informed consent information must be provided to research participants (or their representatives) in language understandable to them.  IRBs are supposed to be vigilant about this and require investigators to obtain translated Informed Consent Documents (ICDs) for use with non-English speaking research subjects.  But researchers commonly balk at this expectation, saying it’s unreasonable.   (A disproportionate number of objections have been raised to me thusly, “And what am I supposed to do if someone shows up speaking only Swahili?!”) Continue reading

Accentuate the Negative

by Suzanne M. Rivera, Ph.D.

While attending the annual Advancing Ethical Research Conference of Public Responsibility in Medicine and Research (PRIM&R) last month in San Diego, I had the opportunity to hear a talk by Dr. John Ioannidis, in which he debunked commonly accepted scientific “truths.”  Calling upon his own work, which is focused on looking critically at published studies to examine the strength of their claims (see his heavily downloaded 2005 paper “Why Most Published Research Findings Are False”), Ioannidis raised important questions for those of us who think about research ethics, and who oversee and manage the research conducted at universities and scientific institutes across the country.

Ioannidis persuasively argued that our system for publishing only studies with statistically significant positive findings has resulted in a bizarre kind of reality where virtually no studies are ever reported that found “negative” results.  Negative results are suppressed because nobody is interested in publishing them.  Editors and reviewers have a major role in this problem; they choose not to publish studies that are not “sexy.”  This artificially inflates the proportion of observed “positive” results and influences the likelihood a scientist will even write up a journal article because she knows what it takes to get published.

But isn’t there an ethical obligation to publish so-called negative results?  In human research, people give their time and undergo risks for the conduct of a study.  Their sacrifices are not meaningful if the results are never shared.  Furthermore, negative results tell us something important.  And if they are not published, some other research team somewhere else may unknowingly repeat a study, putting a new batch of subjects at risk, to investigate a question for which the answer is already known.  Finally, to the extent a study is conducted using taxpayer dollars, the data derived should be considered community property, and there are opportunity costs associated with unnecessarily repetitive work.  Continue reading

Film Review: How to Survive a Plague

By Suzanne M. Rivera

How to Survive a Plague is a moving chronicle of the onset of the AIDS epidemic as seen through the lens of the activists who mobilized to identify and make available the effective treatments we have today.  Beginning at the start of the epidemic, when little was known about the HIV virus and even hospitals were refusing to treat AIDS patients out of fear of contagion, the film follows a group of leaders in the groups ACT-UP and TAG.  Using existing footage interspersed with current-day interviews, it tells the story of how patients and concerned allies pushed the research community to find a way to treat what was then a lethal disease.

The film’s portrayal of the U.S. Government, specifically then-President George H. W. Bush and high ranking officials in the Food and Drug Administration, is damning.  As hundreds of thousands of people became infected with HIV and the death toll rose, prejudice against marginalized groups (especially gay men, IV drug users) contributed to a lack of urgency about the need to learn how stop the spread of the virus and how to treat the opportunistic infections that killed people with full-blown AIDS.  In contrast, footage of demonstrations, meetings, and conferences highlights the courage of the activists who risked and endured discrimination, beatings and arrests to bring attention to the need for more research.

But How to Survive a Plague is more than a documentary about the power people have to make change when they join together to demand action.  It also is a provocative commentary about unintended consequences.  I saw the film while attending the annual Advancing Ethical Research Conference of Public Responsibility in Medicine and Research (PRIM&R).  In that context, I was especially interested in the way How to Survive a Plague highlights an interesting ethical issue in clinical research. Namely, the problem of protecting people so much from research risks that the protection itself causes harm. Continue reading

Reporting Information about Clinical Trial Data: Passing the Torch from HHS to the FDA

By Leslie Francis

In 2007, motivated by concerns that pharmaceutical companies were not sharing negative data about what had been learned in clinical trials, Congress established enhanced reporting requirements.

A series of articles published in January 2012 in the British Medical Journal demonstrates that data reporting remains deeply problematic, especially for industry-sponsored trials. (The articles can be found here and are very much worth reading).

A posting Sept. 26 in the Federal Register indicates that the Secretary of HHS has delegated authority to to oversee the reporting process to the FDA.  Whether this signals improved monitoring of clinical trial data submissions remains to be seen.  One can only hope.