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.
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.
I have a long article in Slate (with Chris Chabris) on the importance of replicating science. We use a recent (and especially bitter) dispute over the failure to replicate a social psychology experiment as an occasion for discussing several things of much broader import, including:
By now, most of you have probably heard—perhaps via your Facebook feed itself—that for one week in January of 2012, Facebook altered the algorithms it uses to determine which status updates appeared in the News Feed of 689,003 randomly-selected users (about 1 of every 2500 Facebook users). The results of this study—conducted by Adam Kramer of Facebook, Jamie Guillory of the University of California, San Francisco, and Jeffrey Hancock of Cornell—were just published in the Proceedings of the National Academy of Sciences (PNAS).
Although some have defended the study, most have criticized it as unethical, primarily because the closest that these 689,003 users came to giving voluntary, informed consent to participate was when they—and the rest of us—created a Facebook account and thereby agreed to Facebook’s Data Use Policy, which in its current iteration warns users that Facebook “may use the information we receive about you . . . for internal operations, including troubleshooting, data analysis, testing, research and service improvement.”
Some of the discussion has reflected quite a bit of misunderstanding about the applicability of federal research regulations and IRB review to various kinds of actors, about when informed consent is and isn’t required under those regulations, and about what the study itself entailed. In this post, after going over the details of the study, I explain (more or less in order):
Nadia N. Sawicki
Earlier this month, the Drug Enforcement Administration issued notice that it would be increasing the 2014 production quota for marijuana from 21 kilograms to 650 kilograms – an almost 3000% increase. In the words of DEA spokeswoman Barbara Carreno, “That’s a lot of marijuana.” This step, according to the National Institute on Drug Abuse (NIDA), was a necessary response to a dramatic increase in current and proposed marijuana research. Continue reading
Following the approval of the European Parliament (EP) earlier last month, the Council of the European Union (the Council) adopted on 14 April 2014 a “Regulation on clinical trials on medicinal products for human use” repealing Directive 2001/20/EC. As described in a press-release, the new law:
“aims to remedy the shortcomings of the existing Clinical Trials Directive by setting up a uniform framework for the authorization of clinical trials by all the member states concerned with a given single assessment outcome. Simplified reporting procedures, and the possibility for the Commission to do checks, are among the law’s key innovations.”
Moreover, and very importantly, the Regulation seeks to improve transparency by requiring pharmaceutical companies and academic researchers to publish the results of all their European clinical trials in a publicly-accessible EU database. In contrast to earlier stipulations which only obliged sponsor to publish the end-results of their clinical trials, the new law requires full clinical study reports to be published after a decision on – or withdrawal of – marketing authorization applications. Sponsors who do not comply with these requirements will face fines.
These groundbreaking changes will enter into force 20 days after publication in the Official Journal of the EU. However, it will first apply six months after a new EU portal for the submission of data on clinical trials and the above mentioned EU database have become fully functional. Since this is expected to take at least two years, the Regulation will apply in 2016 at the earliest (with an opt-out choice available until 2018).
Please find attached a ppt presentation on “New regulatory pathways and incentives for sustainable antibiotics: Recent European & US Initiatives” given on March 7, 2014 at the Broad Institute of MIT and Harvard. The presentation was followed by a discussion moderated by US patent attorney Melissa Hunter-Ensor, Partner at Saul Ewing, Boston.
I started out by emphasizing increasing problems of antimicrobial resistance (AMR) on a global level, providing new statistics and facts. This was followed by a discussion of main reasons for these alarming developments, such as inappropriate use in agriculture and medicine, insufficient precautions, lack of education, climate change, travel behavior, insufficient collaboration and funding of R&D, scientific complexities, and the problem that incentives provided by the traditional innovation system model often fail in the case of antibiotics.
Next the presentation focused on a variety of solution models that could be discussed to fight AMR. These include both conservational and preventive approaches comprising use limitations, increased public awareness, and better hygiene, but also reactive push & pull strategies, such as increased investments, new collaborative models for R&D in antibiotics, prizes, “sui generis” IP-related incentives, regulatory responses and new pathways for approval.
By Kate Greenwood
Cross-Posted at Heath Reform Watch
Lately it seems that each passing day brings another article about the cost of orphan drugs. Earlier this week at FiercePharma, Tracy Staton reported that the United Kingdom’s National Institute for Health and Clinical Excellence (NICE) has asked Alexion Pharmaceuticals to justify the price of its drug Soliris which is, per Staton, “the most expensive drug in the world” at around $569,000 a year. Specifically, NICE seeks “‘clarification from the company on aspects of the manufacturing, research and development costs’” of the drug. According to Staton, this latest development in a review process characterized by “halting progress” is “a departure from NICE’s usual calculations, which typically focus on quality-of-life years and the like.”
Pushback by NICE and other payers notwithstanding, the orphan drug market is growing. As I blogged about here, in 2013 EvaluatePharma estimated that “the worldwide orphan drug market is set to grow to $127 [billion], a compound annual growth rate of +7.4% per year between 2012 and 2018[,]” which “is double that of the overall prescription drug market, excluding generics, which is set to grow at +3.7% per year.” In a recent article in the New England Journal of Medicine, venture-capital investors Robert Kocher and Bryan Roberts note that “more than half of the 139 drugs approved by the FDA since 2009 are for orphan diseases” and suggest that there is a risk of “systematically underinvesting in other important areas of medicine.”
Kocher and Roberts’ explain that one reason that orphan drugs attract investment is that their development costs are low. The problem or potential problem of underinvestment in diseases like depression and diabetes could therefore be addressed, they contend, by bringing the cost of developing treatments for these common conditions in line with the cost of developing treatments for rare diseases. And, they argue, one promising approach to doing so is to reduce clinical trial costs by reducing the size of clinical trials. Continue reading
On the misuse of antibiotics
“We should think of this as a global resource that needs to be conserved and taken care of. So antibiotics should never be used inappropriately. In the country right now, we have something on the order of 23 million people who are getting antibiotics for ear aches. Most of those situations would resolve on their own in a couple of days. We also give antibiotics many times for people just because they have some sort of a common cold — it’s estimated 18 million prescriptions a year — doesn’t help anyone who has the common cold. It’s a complete waste.”
On the rise of antibiotic-resistant bacteria
“It’s frightened people for more than a decade. You mentioned at the top the 23,000 Americans who are dying from resistant infections. The CDC said on top of that, there’s another 14,000 dying from a horrible disease, intestinal disease, called Clostridium difficile [C-diff] in the United States. Together, that’s larger than the number of people who die in this country each year from AIDS. And we’re not — as bad as things are now, the more troubling aspects, or what might happen in five or 10 years if some sort of a pathogen was resistant to everything we had got out to the population. It sounds like a Hollywood movie.”
You can listen to the full interview here.
Three weeks ago I blogged about my recent review of “Pharmaceutical Innovation, Competition and Patent Law – a Trilateral Perspective” (Edward Elgar 2013). The full review, which is forthcoming in a spring issue of European Competition Law Review (Sweet Maxwell), is now available at SSRN: http://ssrn.com/abstract=2396804.
Today, there are two big stories that relate to the “institutional corruption” of medicine (aka conflicts of interests). For those who have been working long and hard on these issues, they are cause for hope. The needle does move.
First, one of the biggest pharmaceutical companies, GlaxoSmithKline, has decided that it will stop paying doctors to promote their drugs. My prior work has shown that such payments are quite common (e.g., 61% of urologists and 57% of gastroenterologists taking money), and that they likely influence the prescribing decisions of the doctors who take such money. In recent months, Glaxo has made several such moves towards greater transparency and integrity, often as a result of threatened or actual criminal prosecutions. (See their newfound commitment to opening up their clinical trial data too.)
The NYT story quotes an industry consultant suggesting that the move to stop paying physicians is a result of the Affordable Care Act’s “sunshine” requirement that such payments will be disclosed, and that several other drugmakers are considering similar moves. I am a bit skeptical that the disclosure mandate had such an effect, since the disclosures were already required by Massachusetts and other states, and as part of the “corporate integrity agreements” that came of several federal prosecutions. My sense is that such disclosures are not likely to reach patients in a useable way, so its hard to understand how the transparency could really impose much of a disincentive on the companies. Yet, something has caused Glaxo to change course.
Second, the National Football League has decided to give the National Institute of Health $30 million to study brain injuries. The counterfactual is that the NFL could have kept the money, of course. But the more interesting alternative is that the NFL could have just spent the money itself, hand-picking the researchers and carefully specifying how the research should be performed, in order to buy the scientific conclusions that it preferred. This has been the classic strategy of industries facing litigation risk, from tobacco, to asbestos, and now the paper industry, whose law firm actually commissions scientific studies on its behalf. The NFL’s move instead proves that it is possible for a self-interested party to nonetheless fund independent, credible, gold-standard research, by using an intermediary, such as the NIH.
This is exactly the sort of reform that I have called for, as an alternative to the false dichotomy between public funding and private interest. For companies that have a bona fide interest in discovering and publicizing the scientific truth, a credible intermediary like the NIH can reassure consumers of scientific information that it is valid. Now, if only we can get big pharmaceutical companies to make the same move for their clinical trials and other scientific research studies. Perhaps the first-movers will be the most innovative companies who have bona fide products and are tired of them being lost in the cheap talk? If physicians making prescribing decisions continue to give greater credence towards NIH-funded research, such integrity could be rewarded.
EDIT: Corrected link to NFL story on NYT, and corrected amount from $100M to $30M. Also, disclaimer: I am not involved in this Petrie Flom Center collaboration with the NFL, and the views expressed here are entirely my own.
Aaron Kesselheim is a physician and an Assistant Professor of Medicine at the Harvard Medical School. He will be speaking at the Petrie-Flom Health Law Workshop on Monday, November 18, at 5:00pm, on “Do March-In Rights Protect Public Interests in Medical Products Arising from Federally-Funded Research?”
For more details on the workshop, including information on how to obtain a copy of the paper, please visit the Petrie-Flom Center’s website.
Looking for a great, informative session about bioethics grants?
Bioethics Funding at the National Institutes of Health
Thursday Nov. 7, 10:30 – 11:45 a.m.
|Liza Dawson, PhD
NIH/NIAID Division of AIDS
|Joe Millum, PhD
|Ann Hardy, DrPH
|Sam Garner, MBE
|Holly Taylor, PhD, MPH
JHU Berman Bioethics Institute
Please contact Liza Dawson, firstname.lastname@example.org, with questions.
The Economist has a long, detailed, and readable piece about the difficulties of inferring anything from the published findings of biomedical science. There are all sorts of problems that fall short of scientific fraud, including the the biases caused by industry-funding of biomedical science, the biases of unblinded raters who see what they want to see, and the biases of journal editors towards only publishing “positive” findings. (I am particularly enamored with this graphic, which shows the fundamental problem of inference.) It is rare for researchers to even bother to attempt to replicate prior findings, but when replications are attempted, they often fail.
The Economist piece can be read as something close to an outright assault on empiricism, at least as we now know it. In practical terms, it is prudent for physicians, patients, and payors to be wary of the findings presented in even the top journals.
One of the beauties of our scientific system is that it is wildly decentralized. Scientists (and their funders) can test any hypothesis that they find interesting, and they can use whatever methods they prefer. Likewise, journal editors can publish whatever they want. While such academic and market freedom is attractive, it results in quite a hodgepodge of science, with replication studies and publication of null results being afterthoughts. The NIH and NSF have in the past functioned to set an agenda and demand rigor, but as their funding wanes, the chaos waxes.
The problems are scientific, but any solution will be institutional (and thus legal). I have argued for a partial solution to industry bias in my short article, called “The Money Blind: How to Stop Industry Influence in Biomedical Science Without Violating the First Amendment.” Independent scientific testing could be conducted by a neutral intermediary, which would pool funds. In a similar vein, there is also a new project of the Science Exchange, called “The Reproducibility Initiative.” This program offers to be the independent scientific agency, which attempts to validate known results. But there is not yet a large-scale funding model in place. If biomedical journal editors would at least put disclosures in their structured abstracts (an intervention we have tested), over the long run that may also nudge industry to use such gold-standard independent testing, when they have something that is truly provable. And, at least in the domain of the products regulated by the FDA, the agency should consider using its current statutory authority to push companies towards independent, robust, and replicated science.
Enjoying the fall foliage in Mt. Auburn Cemetery yesterday, I came across this marker for Benjamin Waterhouse. In the overwrought language that is appropriate on a grave marker: “In 1800 he introduced to the new world the blessing of vaccination. Overcame popular prejudice and distrust by testing it on his own children and thus established a title to the gratitude of future generations.”
No less today, there seems to be plenty of popular distrust of elite science. (And it doesn’t help that so much of contemporary science is infected by conflicts of interest.) Self-experimentation does have a long venerable history, which has recently become more prominent in the quantified self movement. (I’m not sure about experimenting on my kid though.)
Tomorrow, I’m heading to NYC to make a pitch to the Robert Wood Johnson Foundation’s Pioneer Fund, for major funding to launch a new project that would create a platform for robust, randomized experiments of lifestyle interventions (think: migraine management, diets, exercise regimens, nutritional supplements) for which there is virtually no FDA oversight and thus no regulatory imperative for rigorous scientific investigations. Nonetheless, these lifestyle factors are the primary drivers of health and healthcare costs. By crowdsourcing these sorts of experiments in an sound ethical framework robust against institutional corruption, I hope to develop gold-standard scientific knowledge with huge samples, but also build public engagement, public understanding, and public trust of health science.
The crowd uses Wikipedia to organize knowledge, and Indiegogo to invest in new health devices. The crowd needs a platform to create knowledge too, especially through randomized interventions, which have the potential to actually change behaviors for the better and eliminate the confounding factors that undermine observational studies.
So, wish me luck in NYC tomorrow: http://bit.ly/pioneerpitch
Much attention has been paid to the government shutdown that started last week. Many of us heard heart-tugging stories on public radio about the NIH closing down new subject enrollment at its “House of Hope,” the clinical trial hospital on the NIH main campus. These stories gave many people the impression that clinical research halted around the country when the federal government failed to approve a Continuing Resolution.
The reality is both less dramatic in the short term and more concerning for the long term. For the most part, federally-funded projects at university campuses and hospitals are continuing as usual (or, the new “usual,” as reduced by sequestration), because the grants already awarded are like I.O.U.s from the government. By and large, university researchers will keep spending on their funded grants, with the knowledge that reimbursement will come once the government re-opens for business. The universities and hospitals are, in a sense, acting like banks that loan the government money while waiting for these expenses to be reimbursed.
Also, many clinical trials are funded by the pharmaceutical industry. So it is not the case that hospitals are closing their doors to research en masse. But the long-term effects of a shutdown will have lasting and compounding effects on our science pipeline. The U.S. federal government is the single largest funder of scientific research at American universities. Each month, thousands of grant proposals are sent to the various federal funding agencies for consideration. These in turn are filtered and assigned to peer review committees. The whole process of review, scoring, and funding approval typically takes months, sometimes more than a year.
Under the terms of the shutdown, the staff who normally receive and triage these grant proposals are considered non-essential. All but one of the federal grant on-line submission portals have been taken off-line. So thousands of researchers who had been working for months to write grant proposals for funds needed to conduct the next generation of studies are now left wondering when it will be possible to submit for agency review. Those studies hold the keys to future discoveries that could bring needed cures to the bedside, important products to the marketplace, and new jobs into the economy. Continue reading
If you were watching television this week you may have seen this clip of a taste test for hamburger meat grown in a “test tube” in London discussed here. The meat was grown from stem cells from existing cows used to grow 20,000 strands of tissue. Costing more than $330,000 to make, with funding by google Co-Founder Sergey Brin, the day where this will be available at your grocery store or served at your fast food franchise is far away. But it may come sooner if we conclude that there may be a moral duty to develop and eat this kind of meat rather than animal-grown meat and press our governments to start funding this work. What is the morality of test tube meat consumption?
Sometimes narrative can be a way into ethics so consider this bit from one of my favorite novelists (and Canadian public intellectuals) Margaret Atwood from her novel Oryx and Crake. She imagines a dystopian future that includes the the consumption of “Chickie Knobs” in one scene:
“This is the latest,” said Crake.
What they were looking at was a large bulblike object that seemed to be covered with stippled whitish-yellow skin. Out of it came twenty thick fleshy tubes, and at the end of each tube another bulb was growing.
“What the hell is it?” said Jimmy.
“Those are chickens,” said Crake. “Chicken parts. Just the breasts, on this one. They’ve got ones that specialize in drumsticks too, twelve to a growth unit.
“But there aren’t any heads…”
“That’s the head in the middle,” said the woman. “There’s a mouth opening at the top, they dump nutrients in there. No eyes or beak or anything, they don’t need those.”
To be clear the test tube meat unveiled earlier this week is not a Chickie Nob, it is grown from stem cells rather than being a cow with extra parts and brains missing (Atwood is silent on some characteristics of the Chickie Nob that may matter ethically such as whether it feels pain or is sentient), but I think many will react to the test tube meat the same way: disgust. Some in bioethics, like Leon Kass, think there can be a “Wisdom of Repugnance.” In my own work I have been a persistent skeptic on this theme. For me repugnance and disgust are good and should be cultivated as reactions for that which we deem immoral, but should be broken down and overcome for those things which we conclude are morally worth pursuing. Thus repugnance is a tool whose proper deployment depends on prior moral conclusions. In the case of test tube meat, whatever repugnance we feel is one we should get over and media, government, etc, should help us do so.
By Scott Burris
A couple weeks ago, I was in a conference room at a global health organization, all ready to give my talk on monitoring and evaluating legal health interventions. The chief of the organization’s formidable M&E operation was my host, and after briefly going through my bio he wound up his introduction by describing me as “the guy who will be telling us how to measure the un-measurable.”
In that one flourish, he captured the biggest barrier to more and better research on the impact of laws and legal practices on health: the cultural belief that law is different from other forms of individual and institutionalized human behavior and belief, so that it, alone, must perforce remain an evidence-free zone. This is certainly a tragedy of low expectations if ever there was one. Uncertainty is part of any hard decision, but if people in the organization I was visiting were talking about defining the optimum treatment regimen for a particular disease, they would take for granted that the deliberations of the decision-makers would be guided by a substantial evidence base. Yet when the question is what package of laws and legal practices create the best environment for preventing the same disease, or encouraging people to seek treatment, they see nothing strange about proceeding entirely on intuition and experience.
As Evan Anderson and I have recently written, the importance of law to health, and the overall success in properly evaluating its impact, belie this continued cultural prejudice. Law can be hard to evaluate, but so are most other influences on our behavior and environment. In a number of areas of legal intervention, researchers have found ways to measure the hard-to-measure and produce credible findings that have shaped policy. They have done so in ways that respect the prosaic realities of practical science work: developing reliable measures and data and deploying them within robust designs is not the work of individuals, it’s not cheap, and it is not quick. Where legal evaluation has thrived, it has done so because enough money was available for long enough to support multiple lines of inquiry by multiple teams of researchers. Careers, or stands of careers, could be built, and competition and disagreement could drive rigor and relevance.
This week, PHLR is celebrating one very tangible result of investment in the field: the publication of Public Health Law Research: Theory and Methods, which was conceived by the PHLR Methods Core and edited by Alex Wagenaar and me. The book, which was written both as a methods class text book and a general reference work, is an important piece of field-building, in that it tries to define the basic good practices of PHLR. But I think it does more: Alex, whose work on crash law exemplifies all that legal monitoring and evaluation can be, has led the production of a book that we can drop on the desk of every person in every funding and health services organization who thinks that measuring law is measuring the un-measurable.
By Joanna Sax
On April 29, Scott Burris blogged about a new bill that would allow Congress to set the scientific agenda, which would replace the traditional peer review process. I echo his expressed concerns, but want to add more. The idea that politicians, and not scientists, could determine the advancement of science is, frankly, a disaster. In the past we have seen political leaders spar with scientists over many things – such as whether the earth is round, whether the earth is the center of the universe, etc. If scientists did not or could not answer those questions, we might think we are walking on a flat earth.
Even now, there is a strong interaction between politics and science. Evolution, a scientific theory with unequivocal consensus among the scientific community, still faces political opposition. Recently, I’ve been thinking and writing in this area, that is, the interaction of politics and science. Questions for scientific inquiry should be determined by scientists. How we allocate and manage our resources requires, as others have argued, experts in many areas, including economics, management, and public policy.
To look at the interaction of science and politics, I conducted an empirical analysis comparing the type of information communicated to the public versus the consensus in the scientific community to determine whether politics is playing a role in scientific inquiry. The study centers on the debate regarding the funding of embryonic stem cell research. If you are interested in this area, please check out a recent draft here. It’s an early draft and I welcome comments – you can email comments to me at email@example.com