Live Blogging: Post-Trial Responsibilities Conference, Session I

Holly Fernandez Lynch

Today, the Multi-Regional Clinical Trials Center (MRCT) at Harvard University and the Petrie-Flom Center at Harvard Law School are co-hosting a daylong conference on “Post-Trial Responsibilities: Ethics and Implementation.”  We’ll be live blogging the conference here at Bill of Health, and video/slides from the conference will be available soon.

The conference was kicked off by Mark Barnes, co-director of MRCT, who pointed to two key statements of ethics that refer to post-trial responsibilities, the Declaration of Helsinki’s Paragraph 34 (DoH) – which Mark referred to as “mysterious,” as it could not in practice mean what it literally says – and the Council for International Organizations of Medical Sciences Guideline 10 (CIOMS).

Mark went on to describe the wide spectrum of issues that may be encapsulated in the simple phrase “post-trial access” – for example, over what period of time is access provided, is it provided for chronic diseases or only transient conditions, is it necessary only till a patient is stabilized or for longer, is it a lifetime commitment, does it apply only to research subjects themselves or broader research communities?  How much evidence should we demand of benefit before imposing post-trial responsibilities?  Exactly what should be provided – only the study drug, whatever was offered to the control group, other supportive care?  Must post-trial access be free of charge?  What about improved infrastructure, knowledge, and other benefits as components of post-trial access?  Our goal for the day will be to clarify the ways in which the Declaration of Helsinki, the CIOMS guidelines, and other ethical standards and regulatory requirements require additional guidance for practical application to the complex real-life circumstances of clinical trials.

The conference’s first panel – “Setting the Stage” – had the objective of introducing current ethical and regulatory approaches, as well as key controversies.  The panel was kicked off by Christine Grady (NIH), who gave a talk on the ethics of post-trial responsibilities, including history, models, agreements, and controversies.  Christine explained that compared to the very clear articulation of researchers’ responsibilities before and during a trial, they have very little guidance on what should happen when a trial is over.  Indeed, they had no guidance whatsoever until the 1990s, when there was both an upsurge in international collaborative research, and HIV research more specifically.  In that context, new efforts cropped up to minimize the possibility of exploitation in international research, including development of the concepts of responsiveness to local needs and reasonable availability of research benefits, as well as capacity building, collaboration, and community engagement.

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Gilead Announces Access Program for Hepatitis C Drug

For all those who are interested in issues of global health, access to medicines, and drug pricing, yesterday Gilead formally announced its access program for enabling many developing countries to purchase its new Hepatitis C drug, Sovaldi, at low prices. This announcement is particularly noteworthy because Sovaldi represents a significant improvement over the current standard of care for Hepatitis C, as it can cure a much greater percentage of sufferers than could standard therapies, and it does so with many fewer negative side effects. Gilead’s partnership-based program will permit seven Indian generic drug companies to produce and sell the drug in 91 developing countries. The discounts are significant: although Gilead formally charges $1,000 a pill (or $84,000 for a course of treatment) for Sovaldi in the United States, it will charge just 1% of that, or $10 a pill, in India (the total cost there is estimated at $1,800, given the difference in strain prevalence).

The global health community has reacted to the announcement with mixed reviews. The 91 countries in the program include more than half of the world’s Hepatitis C patients. But tens of millions of other patients in large nations like China, Brazil, Mexico, and Thailand are left out of the program. Going forward, some of the excluded nations may seek to issue compulsory licenses in an effort to expand access to Sovaldi.

Gilead has also drawn fire in the United States for Sovaldi’s $84,000 sticker price (which, for various reasons, very few if any will actually pay), to the degree that members of both houses of Congress have asked Gilead to justify the price of the drug. Those opposing Sovaldi’s price have generally not come out publicly against the high price of many orphan drugs, which can cost $250,000-$350,000 per year. But because Hepatitis C afflicts about 2.7 million people in the US, as compared to the few thousand people with one of the relevant orphan diseases, its impact on insurers (both public and private) is likely to be much larger (as this very blog has previously noted).  Continue reading

Harvard Effective Altruism: an event today, Michael Kremer on Sept. 10, and a fellowship opportunity

A message from Harvard Effective Altruism:

On Saturday, Sept. 6 at 3pm in Sever 111, we are holding a giving game / donation discussion and an information session for Harvard students interested in our organization. We’ll explain what effective altruism is and what HCEA does here on campus. If you’re new to HCEA, you should definitely check it out!

Wednesday, Sept. 10 at 4:30pm in Science Center Hall A: Prof. Michael Kremer – a development economist at Harvard – will give a talk entitled “How can individuals reduce global poverty?” He’ll discuss the ways that individuals can use both their money and their careers to contribute to poverty reduction and international development.

All semester long! HCEA is hosting its third Philanthropy Fellowship program for Harvard undergrads and graduate students. Fellows will attend talks from speakers like Harvard professor Steven Pinker, Rob Mather of the Against Malaria Foundation, and Center for Applied Rationality president Julia Galef; learn about effective altruism at weekly dinners with other fellows and speakers; get to know likeminded students at discussions and social events; and fundraise for effective charities! You can find more information and apply on our website before 11:59pm on Sunday, Sept. 14th.

We hope to see soon! Altruistically yours,
Ales and John

Ebola and the Return of Quarantine

[Ed. Note: Cross-posted from HealthLawProf Blog.]

Last month’s riots in an Ebola-infected slum in Monrovia, Liberia demonstrated anew the perils of relying on quarantine, and similar highly coercive public health laws, to contain highly contagious diseases.

At first blush, Ebola viral disease (EVD) is exactly the type of disease for which broad quarantines (more precisely, sanitary cordons) would seem appropriate. Transmitted through direct contact with the bodily fluids of an infected person, EVD can spread rapidly through a community, as it has done in several West African nations. Although experimental treatments and vaccines offer promise for the future, they have not yet been shown to be effective in humans; nor are they readily available. As a result, health officials are forced to rely on tried and true public health strategies, such as identifying cases, isolating and treating them with strict infection control measures, and monitoring their contacts. Needless to say, doing so is very challenging and very expensive, especially in highly urbanized areas, with weak health systems.

Given the challenges, health officials and government leaders are often tempted to call in the troops, and rely on more heavy-handed measures, such as imposing sanitary cordons around whole towns or neighborhoods, quarantining those who have had contact with patients, and restricting travel into and out of affected regions. Although the impetus for these measures is understandable given the magnitude of the EVD threat, history suggests that such highly coercive tactics frequently backfire. Like the military-style show of force employed by the police department in Ferguson, Missouri earlier this summer, highly coercive public health measures can undermine the public’s trust in authorities. Thus, rather than reduce travel, identify contacts, and come forward if they show symptoms, individuals are more apt to try to leave affected areas and avoid the health care system. Or they riot, as they did in Monrovia and China during the SARS outbreak. In any case, the problem is made worse not better. Continue reading

A Look at the ALS and Ebola Responses

By Deborah Cho

I’m a little late to this discussion, but I want to talk briefly about the ALS Ice Bucket Challenge and how we make our decisions on charitable giving.

I’m sure by now most readers understand the basic concept of the challenge: individuals can choose to either record a video of themselves pouring ice water over their heads or to donate money to the ALS Association (or both — the rules don’t seem to be particularly consistent in application).   After the challenge is undertaken, the video is shared on social media or a message is posted announcing that the individual has donated, and then the individual “nominates” others for the challenge.

This challenge has virtually taken over the web in the past couple weeks (perhaps, as one writer commented, because it lets participants “(a) exhibit his altruism publicly and (b) show off how good he looks soaking wet.”), raising over 88 million dollars as of August 26, 2014.  As expected, however, the challenge was not without its very vocal critics.  Many were opposed to the narcissistic nature of the challenge, while others, more relevantly, questioned donating so much money to a charity and to fight a disease based on an internet fad. Continue reading

Art Caplan: Is It Fair That Americans Received the Ebola Treatment?

Art Caplan has a new video on Medscape laying out the principles behind rationing limited supplies of experimental ebola treatments. As he explains:

I believe the answer to the question of who should receive the drug is: people we can both learn from and potentially help the most. I believe those are the 2 values we use when trying to ration access to an experimental drug. If we do not learn whether something is safe and effective, then we have missed an opportunity, even in the middle of an epidemic, to find out whether it is worth giving out drugs that are new, untested, and unapproved. People who should be included are those who can be observed and kept under surveillance — not for a day or a week but probably for months and years. That favors people who are not in rural villages. That favors people who will have access to hospital facilities. Those criteria will drive the selection of who receives a new, unapproved drug.

Click here to see the video and read more.

Ethics of experimental Ebola interventions

In “Ethical considerations of experimental interventions in the Ebola outbreak“, published yesterday by The Lancet, Zeke Emanuel and I discuss what we take to be the key ethical questions about the use of Zmapp and other investigational agents in the current Ebola epidemic. In essence, we argue that the national and international response to the epidemic should focus on containment and strengthening health systems, rather than experimental treatments and vaccines; that experimental interventions, if they are used, should be distributed fairly and only in the context of clinical trials; and that advance planning is needed for research in future Ebola and other epidemics, as well as for making any proven interventions against Ebola accessible in affected regions.

The full article is available open access. Be sure to check out the Lancet’s new Ebola Resource Centre as well, which includes many other interesting pieces and a podcast (access here podcast) covering—among other things—our paper.

DARPA Announces Disease Forecasting Prize

On Friday, the Defense Advanced Research Projects Agency (DARPA) announced a challenge to the public: provide the most accurate forecast of the spread of chikungunya virus in each of the countries in the Pan American Health Organization, win $150,000. Innovation prizes like DARPA’s are increasing in popularity, with public and private entities alike issuing challenges across a variety of subjects and methodologies. DARPA isn’t the first to announce a disease forecasting prize, either – the Centers for Disease Control (CDC) recently awarded a prize for predicting the timing and intensity of last winter’s flu season. But the choices both to focus on chikungunya and to do so using a prize fund are interesting ones that deserve further discussion.

Chikungunya is a viral disease spread by infected mosquitoes, much like the better-known malaria and dengue fever. Its symptoms often resemble those of dengue, whose other common name – breakbone fever – is telling. Chikungunya is rarely fatal, but it is often temporarily disabling, until the disease has run its course. And unfortunately, also like dengue, there is no specific treatment for chikungunya, although recent Phase I trials of a candidate vaccine appear to have been successful. But perhaps most importantly for DARPA’s purposes, chikungunya is also experiencing a resurgence in the Americas, including in the United States.

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Art Caplan: WHO Ethics Committee on Ebola Just a Start

Art Caplan has a series of new opinion pieces out on the WHO ethics advisory committee meeting that approved the use of experimental drugs to treat patients ill with Ebola.

He suggests deeper exploration of issues of informed consent, corporate responsibility, and resource allocation in this blog post for The Health Care Blog. As he writes in his piece in NBC News Health:

It is important that the WHO committee affirmed the morality of compassionate use. This addresses the concern that any use of unapproved drugs is inherently exploitative. But there are huge ethical issues that still remain unaddressed and unanswered regarding experimental interventions.

In the wake of the Canadian government’s offering 1,000 doses of an experimental Ebola vaccine to the stricken nations, he also extends the argument from allocation of treatment to allocation of prophylaxis in this opinion piece in NBC News Health:

It is ethically appropriate in the midst of a deadly contagious epidemic to try both untested treatments and experimental preventative vaccines that have shown some promise in animals and no safety issues. But with only 1,000 doses of vaccine available, who should get them? And what do they need to be told?

The most ethical way to distribute limited experimental vaccine, is, as the WHO ethics group noted, with an eye toward collecting information on safety and efficacy. Rather than just handing out vaccine to a small group of people in countries that have seen Ebola outbreaks, it is important to learn as much as possible about whether the vaccine has any efficacy in humans and is safe.

You can read more at the links above.

Ebola, Ethics, and the WHO Getting to Yes

Earlier this week, the World Health Organization, responding both to the international outcry over the rapidly rising number of Ebola cases and deaths across sub-Saharan Africa (and critiques of the speed of their action), and the news that western health care workers and ministry had found ways to get access to the untested-in-humans Ebola drug ZMapp, convened a panel of ethicists to offer recommendations on more widespread use of experimental Ebola treatments.

The issues considered by the ethicists included:

1) Whether it is ethical to use unregistered interventions with unknown adverse effects for possible treatment or prophylaxis. If it is, what criteria and conditions need to be satisfied before they can be used?

2) If it is ethical to use these unregistered interventions in the circumstances mentioned above, then what criteria should guide the choice of the intervention and who should receive priority for treatment or prevention?

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The Revival of Phage Therapy to Fight Antimicrobial Resistance (AMR) – Part III: What about patent protection and alternative incentives?

In Part II of this blog on legal issues relating to the revival of phage therapy I discussed the US Supreme Court’s decisions in Myriad and Prometheus, which might present major obstacles to the patentability of phage-related technology (a more detailed analysis of the Myriad and Prometheus decisions is available here).

Yet, all is not lost. As indicated in Part II, Myriad does not directly affect the patentability of synthetically modified biological compounds and Prometheus would still allow patents on inventive applications of natural processes and correlations that add new features to “natural laws”. Thus there still seems to be considerable leeway for patenting within the area of page therapy.

One example, mentioned in a recent Nature article, could be the skillful selection and precise combination of different phages in order to attack one specific type of bacteria. Such selections, however, would face a tough battle to overcome the “additional features that add significantly more” and “not identical” thresholds set by Prometheus and Myriad. Another example with even better prospects for patentability relates to genetically modified phages that are – due to human intervention – enabled to target only specific bacteria. This technology was recently presented by MIT researchers at the 2014 American Society for Microbiology Meeting. The researchers led by Timothy Lu had genetically engineered phages that use a DNA-editing system called CRISPR to target and kill only antibiotic-resistant bacteria while leaving other susceptible cells untouched. The significant engineering and alteration of natural products and processes involved in such inventions would most likely meet both the Myriad and Prometheus standards.

Yet, while the USPTO has recently issued new patent eligibility guidance and the CAFC has begun to directly apply Prometheus and Myriad to reject patent claims in biotech cases (e.g. In re Roslin), many questions remain unsolved. In particular, it is still not sufficiently clear exactly how much modification is required to render a molecule or method sufficiently distinct from naturally occurring product and processes. And even if the patent-eligibility threshold could be met in extraordinarily circumstances, the claimed invention would still have to fulfil other patentability requirements such as novelty, non-obviousness and the written description-requirements. The threshold for these requirements, however, have been heightened in recent years (see e.g. KSR v. Teleflex (2007) , Nautilus (2014) etc.). Considering that phage therapy is almost a century old with a substantial common general knowledge and a state of the art employing routine methods, these crucial requirements might still prevent the patentability of many useful applications.

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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.

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Serious Risks from New Prescription Drugs

by Donald W. Light

Based on http://www.ethics.harvard.edu/lab/blog/436-new-prescription-drugs-a-major-health-risk

Few people know that new prescription drugs have a 1 in 5 chance of causing serious reactions after they have been approved. That is why expert physicians recommend not taking new drugs for at least five years unless patients have first tried better-established options and need to. Faster reviews advocated by the industry-funded public regulators increase the risk of serious harm to 1 in 3. Yet most drugs they approve are found to have few offsetting clinical advantages over existing ones.

Systematic reviews of hospital charts by expert teams have found that even properly prescribed drugs (aside from misprescribing, overdosing, or self-prescribing) cause about 1.9 million hospitalizations a year. Another 840,000 hospitalized patients given drugs have serious adverse reactions for a total of 2.74 million. Further, the expert teams attributed as many deaths to the drugs as people who die from stroke. A policy review done at the Edmond J. Safra Center for Ethics at Harvard University concluded that prescription drugs are tied with stroke as the 4th leading cause of death in the United States. The European Commission estimates that adverse reactions from prescription drugs cause 200,000 deaths; so together, about 328,000 patients in the US and Europe die from prescription drugs each year. The FDA does not acknowledge these facts and instead gathers a small fraction of the cases.

Perhaps this is “the price of progress”? For example, about 170 million Americans take prescription drugs, and many benefit from them. For some, drugs keep them alive. If we suppose they all benefit, then 2.7 million people have a severe reactions, it’s only about 1.5 percent – the price of progress?

However, independent reviews over the past 35 years have found that only 11-15 percent of newly approved drugs have significant clinical advantages over existing, better-known drugs. While these contribute to the large medicine chest of effective drugs developed over the decades, the 85-89 percent with little or no clinical advantage flood the market. Of the additional $70 billion spent on drugs since 2000 in the U.S. (and another $70 billion abroad), about four-fifths has been spent on purchasing these minor new variations rather than on the really innovative drugs.

In a recent decade, independent reviewers concluded that only 8 percent of 946 new products were clinically superior, down from 11-15 percent in previous decades. (See Figure) Only 2 were breakthroughs and another 13 represented a real therapeutic advance.

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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.

New Medical Tourism Website with Info for Patients

My good friends and co-authors at Simon Fraser University have a nice new website aimed at Canadians (though useful for people from all countries) considering using medical tourism about what to think about, questions to ask, steps to take, etc (Full Disclosure: I participated in a feedback session on the website). Here is a story about the website in the National Post, and here is the website itself.

The Right to Health at the Public/Private Divide: A Global Comparative Study

In the U.S., the right to health is often held up as a utopian legal principle that other countries manage to embrace and that we shortsightedly spurn.  What I learned working on a new project is that the right to health does not always lend itself to admirable ends.  In some countries, a formal right to health is not used to advance equity but rather for the opposite.  In other words, having a right to health can lead to a less equitable distribution of health care resources because, for example, people who are better able to navigate the legal system can claim more resources for themselves.

This insight and others are featured in an excellent book that just came out from Cambridge Press, The Right to Health at the Public/Private Divide: A Global Comparative Study, edited by Colleen M. Flood, University of Toronto, Faculty of Law and Aeyal Gross, Tel-Aviv University, Faculty of Law.  This book is worth reading, in part, because it features chapters on countries that are not the usual suspects, including Hungary, Venezuela, Nigeria, New Zealand, and Taiwan.  Two of the chapters are by U.S. health care scholars: one I wrote on the U.S. system and the Affordable Care Act (A Vision of an Emerging Right to Health Care in the United States: Expanding Health Care Equity through Legislative Reform) and one Christina Ho wrote on China (Health Rights at the Juncture between State and Market: the People’s Republic of China).

In my chapter, I argue that while the U.S. does not have a formal right to health, the ACA could provide the vision and foundation for an evolving American conception of a right to health care.

DUE 6/3: Call for Abstracts: Emerging Issues and New Frontiers for FDA Regulation

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The Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School and the Food and Drug Law Institute are pleased to announce an upcoming collaborative academic symposium:

Emerging Issues and New Frontiers for FDA Regulation

Monday, October 20, 2014 

Washington, DC

We are currently seeking abstracts for academic presentations/papers on the following topics:  Continue reading

Boko Haram Kidnappings and the Victims’ Mental Health

In mid-April, Boko Haram, an extremist organization operating in the northern region of Nigeria, kidnapped nearly 300 girls from their boarding school in Borno.  Kidnappers threatened thatNigeria_Boko_Haram_Kidnapping the girls would be sold to sex trafficking rings in neighboring countries, causing international alarm.   In the weeks since that mass kidnapping, world leaders have issued collective demands for the return of the girls–and placed pressure on Nigeria’s president, Goodluck Jonathan to take aggressive action to achieve the girls’ return.  Some pundits believe hope may be around the corner, because in the last two days, Boko Haram leaders claimed that they will release some of the girls to safe houses.  Yet, it remains unclear whether this will happen. Continue reading

Call for Abstracts: Emerging Issues and New Frontiers for FDA Regulation

PFC_Logo_300x300FDLI_logo_pink

 

 

 

The Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School and the Food and Drug Law Institute are pleased to announce an upcoming collaborative academic symposium:

Emerging Issues and New Frontiers for FDA Regulation

Monday, October 20, 2014 

Washington, DC

We are currently seeking abstracts for academic presentations/papers on the following topics:

  • Stem cell therapies
  • Nanotechnologies
  • Genetic (and biomarker) tests
  • Gene therapies
  • Personalized medicine
  • Comparative efficacy research
  • Drug resistant pathogens
  • Globalized markets
  • Tobacco
  • GMO
  • Bioterrorism countermeasures
  • Mobile health technologies
  • Health IT
  • Drug shortages
  • Other related topics

Abstracts should be no longer than 1 page, and should be emailed to Davina Rosen Marano at dsr@fdli.org by Tuesday, June 3, 2014. Questions should also be directed to Davina Rosen Marano.

We will notify selected participants by the end of June.  Selected participants will present at the symposium, and will be expected to submit a completed article by December 15, 2014 (after the event) to be considered for publication in a 2015 issue of FDLI’s Food and Drug Law Journal (FDLJ).  Publication decisions will be made based on usual FDLJ standards.