A short article in the New Yorker on my favorite topic – business models for antibiotic use and innovation.
A short article in the New Yorker on my favorite topic – business models for antibiotic use and innovation.
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.
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.
Amidst news from Spain that a 75-year-old Catholic priest has received the experimental treatment ZMapp for Ebola, Art Caplan critiques what he describes as the “bad science” behind choosing its recipients:
ZMapp is not the answer to the Ebola epidemic ravaging West Africa. There is no chance of getting a significant amount of this drug made for many months. Deploying more health care workers, face guards, moon suits, gloves and antiseptic, along with restrictions on travel and burying the dead, is the only way to get the epidemic under control. [...]
The fact that a 75-year-old has been given the scarce drug is especially disturbing, not because he is 75 but because 75-year-olds do not have strong immune systems — something very important in battling a virus like Ebola. Moreover 75-year-olds often have other medical problems that complicate the ability of scientists to figure out if the drug is safe and if it is really working.
In testing unapproved, highly risky drugs like ZMapp, it is crucial that recipients not be so sick that they may well die regardless of whether they get the drug or not. Indeed, the recipients ought not be very sick so that side-effects can be seen and efficacy determined. To do that, doctors need to be able to monitor experimental subjects for months to make sure the drug does not damage their livers or cause any other fatal side-effect. So not every person infected with Ebola makes for the best recipient — younger, those more recently infected and those who can be closely monitored are among the “best” candidates.
You can read more of Art Caplan’s perspective on NBC News Health here.
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?
As the WHO announced today that medical ethicists will convene next week in New York to discuss the use of experimental medicines in the West African Ebola outbreak, Art Caplan has a timely new opinion piece in the Washington Post asking why only white American victims of the Ebola outbreak have been treated with an experimental serum. Caplan argues that the decision was a question of economics:
The reasons for different treatment are partly about logistics, partly about economics and, partly about a lack of any standard policy for giving out untested drugs in emergencies. Before this outbreak, ZMapp had only been tested on monkeys. Mapp, the tiny, San Diego based pharmaceutical company that makes the drug stated two years ago: “When administered one hour after infection [with Ebola], all animals survived…Two-thirds of the animals were protected even when the treatment, known as Zmapp, was administered 48 hours after infection.”
But privileged humans were always going to be the first ones to try it. ZMapp requires a lot of refrigeration and careful handling, plus close monitoring by experienced doctors and scientists—better to try it at a big urban hospital than in rural West Africa, where no such infrastructure exists. [...]
But it’s about more than logistics. Drugs based on monoclonal antibodies usually cost a lot—at least tens of thousands of dollars. This is obviously far more than poor people in poor nations can afford to pay; and a tiny company won’t enthusiastically give away its small supply of drug for free. It is likely that if they were going to donate drugs, it would be to people who would command a lot of press attention and, thus, investors and government money for further research—which is to say, not to poor Liberians, Nigerians or Guineans. [...]
To get Caplan’s full perspective, read the full article.
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.
Three days ago I commented on a couple of legal issues raised in the recent Nature report “Phage therapy gets revitalized” by Sara Reardon. One challenge concerns the reluctance of pharma companies to broadly invest in the development of phage therapies. As pointed out in the report, this does of course very much (but not only) relate to the question of patentability. Various aspects might present obstacles to the patentability of technology relating to phage therapy. To not complicate the discussion and considering recent developments I decided to focus on some of aspects under US patent law.
Like in Europe, the first door to patentability that phage-related technology would need to pass concerns patent eligibility. In the last years the US Supreme Court has rendered an astonishing number of fundamental patent-decisions, including not less than four (!) landmark judgments on patent eligibility, i.e. Bilski v. Kappos (2010), Mayo v. Prometheus (2012) , AMP v. Myriad (2013) and Alice v. CLS (2014). Most relevant in this context are the decisions in Prometheus and Myriad.
Art Caplan has a new opinion piece on NBC News responding to the recent media coverage of Ebola. He makes the case that although this has been the worst recorded outbreak of the disease, citizens of developed countries have little reason to panic:
Ebola is not going to run amok in downtown Boston, Cape May or Myrtle Beach or anywhere else in the U.S. It is running amok in poor African nations because local authorities did not have the will or the resources to respond quickly, because no one confronted local funeral customs that expose people to Ebola, mainly because the world did not care much if hundreds died in poor, politically insignificant nations.
The harsh ethical truth is the Ebola epidemic happened because few people in the wealthy nations of the world cared enough to do anything about it.
Read the full article.
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.
By Deborah Cho
A recent data brief summarizing a national survey spanning from 2005-2012 on the perception of weight status in U.S. children and adolescents highlights one major finding — many children and adolescents who are overweight or obese don’t know it. Key findings were that about 81% of overweight (defined as having age- and sex-specific BMI greater than or equal to the 85th and less than the 95th percentile of the 2000 CDC growth chart) boys and 71% of overweight girls believe they are about the right weight. Additionally, nearly 48% of obese (defined as having age- and sex-specific BMI greater than or equal to the 95th percentile of the 2000 CDC growth chart) boys and 36% of obese girls consider themselves to be about the right weight.
As an article on the NPR blog noted, “Kids can be cruel, especially about weight. So you might think overweight or obese children know all too well that they’re heavy.” But it seems that this is not the case, at least according to the survey. Furthermore, not only do overweight or obese children generally seem to be unaware of their weight status, but the misperception rate appears to be higher in those children and adolescents whose families have a lower income-to-poverty ratio. Non-Hispanic black and Mexican American children and adolescents were also found to have higher rates of misperception than Non-Hispanic white children and adolescents.
by Donald W. Light
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.
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.
I have a new article in JAMA this week, “Reconsideration of the Lifetime Ban on Blood Donation by Men Who Have Sex With Men,” co-authored with my former student Jeremy Feigenbaum and my frequent co-author Dr. Eli Adashi (former Dean of Medicine at Brown). In the article we show that FDA’s current policy is morally, ethically, and legally problematic. We are out of step with our peer countries (including the UK, Canada, South Africa) who do delay when men who have sex with men can give blood but not for a lifetime, the way the U.S. does. It is remarkable that if you have sex with a female prostitute or a woman who is HIV+ you face only a 12-month deferral in the U.S. but if you have had sex with a man, just once, ever, no matter his HIV status you face a lifetime delay.
We are in a world where the Defense of Marriage Act was struck down as unconstitutional, where Don’t Ask Don’t Tell has been struck down so that gay men and lesbians can proudly serve their country and shed blood (their own, others) on the battlefield. It is time to change a 30-yr old policy prohibiting them giving blood. What’s more, given the the Windsor decision and the recent Ninth Circuit application of heightened scrutiny to the exclusion of gay jurors for jury duty, we think there are serious constitutional questions about FDA’s policy as well.
My preferred approach, and the one I think FDA should move towards, is the Italian “test and assess” which has no blanket classification of MSM but instead does individualized risk assessment. As we describe in our paper thus far has not increased the risk of HIV+ blood making its way into the blood supply.
The Williams Institute in 2010 estimated that 6% of men had at least once had sex with another man, meaning there are potentially 7.2 million men who could become blood donors but are excluded by FDA’s rule. We owe it not only to these men, but also to all those who could benefit from their blood donations to revisit this rule.
Check out the “hot off the press” New England Journal of Medicine Perspectives piece “When Religious Freedom Clashes with Access to Care” by Petrie-Flom Faculty Director I. Glenn Cohen, Executive Director Holly Fernandez Lynch, and NEJM Executive Editor (and PFC Faculty Affiliate), Gregory Curfman. We review the legal background for SCOTUS’ Hobby Lobby decision, summarize the majority and dissenting opinions, and clarify some key implications of the case, including further problematization of the employer-based health insurance system, reduced likelihood of future attempts to offer religious exemptions to health care mandates, and expanded religious challenges in the health care space. We close by noting that although the public’s ire and praise has been directed at the Justices, they were applying Congress’ statute – and Congress could (but is very unlikely to) amend the Religious Freedom Restoration Act to be less stringent, or otherwise intervene to ensure that women have affordable access to contraceptive services regardless of their employer’s beliefs.
Take a look and let us know what you think!
Interested candidates should apply at www.childrenshospital.jobs.
Temporary Clinical Ethicist
The Clinical Ethicist provides formal and informal ethics consultations and collaborates with clinical teams, patients and families, managers, and consultants to address ethical issues in pediatric health care and research. Documents ethics activities. May participate in clinical ethics rounds and other educational activities.
Requires working knowledge of theories, principles and concepts typically acquired through completion of a graduate degree in ethics, bioethics, or moral philosophy; a working knowledge of health care and hospitals or clinical degree in a health professional field; and extensive experience in clinical bioethics, preferably in hospital or health delivery systems. Work requires excellent interpersonal, organizational, oral and written communication skills in order to mediate moral disagreements or concerns and develop consensus, compromises, or other ethically acceptable resolutions. Work requires sensitivity in speaking with parents, patients, staff and others in stressful circumstances, in discussing ethical decisions regarding life support, dying and death, disclosure of bad news, participation in research, organ donation and transplantation, and other potential conflicts of interest and values. Work requires demonstrated ability in multidisciplinary collaboration and the ability to initiate, prioritize, and manage multiple projects, working across multiple departmental lines of authority and accountability and under pressure to meet deadlines.
Provides formal and informal ethics consultations. Organizes and participates in clinical ethics rounds, and collaborates with clinical teams, patients and families, to address ethical issues in pediatric health care and research. Develops ethics resources and education and serves as a facilitator for change directed toward strengthening the Hospital staff’s sense of moral responsibility and moral community.
Work requires at least 5 years clinical inpatient experience in a staff physician or nursing role with substantial prior ethics education and experience derived from completion of an ethics fellowship or other advanced ethics training and/or significant ethics consultation experience. Preference for a clinical degree in a health professional field and graduate level preparation in this discipline, clinical ethics fellowship completion, graduate degree in bioethics or related field, a strong understanding of acute care pediatric health care, and five or more years of experience in clinical bioethics, preferably in a pediatric hospital or health delivery system. Significant focus on inpatient pediatric ethics consultations with active collaboration with nursing, social work, medical staff, and other internal and external individuals and groups.
Fairbanks School of Public Health and McKinney School of Law, Indiana University, Indianapolis.
This has been a big year for outbreaks of Vaccine-Preventable Illnesses (VPIs) in the United States. While we are only halfway through 2014, there have been more measles cases this year than we have seen since before 2000, when the Federal government officially declared the United States “measles free” (in other words: there are no more domestically-generated measles cases; all of our outbreaks are imported). We’ve also seen large mumps and whooping cough outbreaks. You can follow all the disease outbreak action, both here and worldwide, via the Council on Foreign Relations’ very cool interactive map.
States use their police power authority under the Constitution to try to minimize our risk of exposure to VPIs. First, every state requires that children demonstrate proof of immunization against many VPIs as a condition of entry into schools, preschools and day cares. States also permit exemptions to these laws – every state allows a child who may be medically susceptible to injury from vaccines to receive an exemption (with proper documentation of vulnerability), and most states allow parents to apply for an exemption based on either religious or broader philosophical grounds. A combination of factors, including: a nearly two decade trend of increasing numbers of families obtaining exemptions and clustering in particular communities (or avoiding vaccine requirements by taking advantage of law loopholes, such as if a state’s vaccine law does not cover private schools); waning effectiveness of vaccination protections over time (as has been seen with whooping cough); increased international travel facilitating ready reimportation of VPIs from abroad; and many more immunocompromised individuals living in our communities; have slightly weakened our overall protection against VPI outbreaks. Continue reading
The First Amendment has been repurposed as a powerful deregulatory tool, especially in health care (NEJM on data privacy) and public health (NEJM on smoking). Amy Kapczynski at YLS has put together a timely and powerful conference, Public Health In The Shadow of the First Amendment. October 17-18 in New Haven. Register here.
Katherine L. Record, JD, MPH, MA
Shortly after criticizing Massachusetts for incarcerating innocent individuals with substance use disorder (SUD) when drug rehab facilities are full, I received an email from a woman who lost her son to a heroin overdose just four months ago.
“Is preventing an overdose by detaining the SUD sufferer not a better alternative than leaving them to languish?” she asked.
She had found her 24 year-old son cold and blue, just hours after kissing him goodnight. He had been evicted from his sober living home for testing positive for drugs, but his mother did not know he had relapsed when he arrived at her front door. He was, in hindsight, a clear danger to himself – so why did his step-down house let him wander away? Why didn’t anyone call the authorities? Is jail not better than death?
Harvard Law Today has posted a feature on Cass Sunstein’s keynote address at the 2014 Petrie-Flom Center Annual Conference, “Behavioral Economics, Law, and Health Policy.” Sunstein, who is the Robert Walmsley University Professor at Harvard Law School and the co-author of Nudge: Improving Decisions About Health, Wealth, and Happiness, addressed the opening day of the conference on May 2, 2014, on the subject of “Choosing Not to Choose.”