On Monday, a group of over 50 members of Congress sent a letter urging the Department of Health and Human Services (HHS) and the National Institutes of Health (NIH) to use a little-known statutory provision to take action against high drug prices. Their goal is laudable, and HHS and the NIH should certainly offer guidance in this area – but the existing law offers only a partial solution to the problem as the legislators describe it.
The members of Congress wrote to remind HHS and the NIH of a provision in the 1980 Bayh-Dole Act giving the government “march-in rights” to patents resulting from government-funded research. More specifically, the statute spells out a range of conditions under which the government may require a patentholder to grant licenses on reasonable terms to others to practice the patent. The government may require such a license where “action is necessary to alleviate health or safety needs which are not reasonably satisfied,” 35 U.S.C. § 203(a)(2), or where the benefits of the invention are not being made “available to the public on reasonable terms,” 35 U.S.C. § 201(f). The legislators argue that many drugs today violate these conditions, as even many insured Americans cannot access prescription drugs without incurring significant financial harm.
Although the “march-in rights” provision has existed in the statute since 1980, it has never been exercised by the federal government, even when it has been specifically asked. And some of these cases have been paradigmatic examples where “health or safety needs” are not being satisfied. A December 2015 study notes that in Bayh-Dole’s history, there have only been five petitions requesting that the NIH exercise its march-in rights. Three of those requests were based on high prices for drugs for HIV/AIDS and glaucoma, and one was based on a persistent drug shortage which may have caused the deaths of people with Fabry disease, a rare condition. (The fifth petition involved a medical device under patent litigation at the time.) The NIH denied each request. Some scholars argued that if the NIH denied the Fabry disease petition, where Genzyme’s drug shortages lasted for multiple years and caused great suffering, possibly including death, there may be no circumstances under which the NIH would grant such a petition.
Here is HHS’s own summary of what has changed and what it thinks is most important:
The U.S. Department of Health and Human Services and fifteen other Federal Departments and Agencies have announced proposed revisions to modernize, strengthen, and make more effective the Federal Policy for the Protection of Human Subjects that was promulgated as a Common Rule in 1991. A Notice of Proposed Rulemaking (NPRM) was put on public display on September 2, 2015 by the Office of the Federal Register. The NPRM seeks comment on proposals to better protect human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators. It is expected that the NPRM will be published in the Federal Register on September 8, 2015. There are plans to release several webinars that will explain the changes proposed in the NPRM, and a town hall meeting is planned to be held in Washington, D.C. in October.Continue reading →
Republican candidates convened last night for the first debates of the 2016 campaign. The presidential hopefuls disagreed on every topic they faced — immigration, health care, foreign policy, gay rights, the economy — all but one, that is. Their differences of opinion disappeared each time they were asked about the controversy over the recent release of an undercover video with Planned Parenthood. On the issue raised by that edited film clip, the candidates came together in a rare consensus.
All 17 — from Ted Cruz to Carly Fiorina — staunchly opposed research that uses tissue cells from aborted or miscarried fetuses. The candidates unanimously called for Congress to end its support of Planned Parenthood over its contribution to that research, with some like Louisiana Gov. Bobby Jindal joining party leaders who would force a government shutdown over that issue. This, after Senate Republicans earlier this week failed to clear a procedural vote to defund. […]
This morning, the House of Representatives passed the 21st Century Cures Act by a vote of 344-77, achieving a truly bipartisan result in a difficult political environment. (I’ve blogged about the Act severaltimesnow, and the House Energy & Commerce Committee has a clear section-by-section summary here.) There is much to like in the bill (such as the increased NIH funding), much to be concerned about (such as some of the provisions abbreviating FDA review of drugs and devices), and much whose value will depend on implementation. It’s also not certain that any of these provisions will ultimately become law – the Senate has yet to even introduce its own draft bill, let alone vote on it or achieve a consensus with the House. But I wanted to use this post to draw attention to a new amendment to the Act that was introduced a few days ago and approved by the House this morning prior to the vote on the full bill.
Representatives Todd Young (R-IN) and Andy Harris (R-MD) introduced an amendment creating an Innovation Prize Program within the NIH. As the text stood on Wednesday (speakers on the floor of the House today suggested that some of this language is likely to change, if it has not already changed), it instructed the Director of the NIH to create the fund in service of one or both of these two goals: 1) “Identifying and funding areas of biomedical science that could realize significant advancements through the creation of a prize competition” and 2) “Improving health outcomes, particularly with respect to human diseases and conditions for which public and private investment in research is disproportionately small relative to Federal Government expenditures on prevention and treatment activities, thereby reducing Federal expenditures on health programs.” The Director is also given wide discretion to design prize competitions, including whether they involve a lump-sum award at the end or are parceled out in milestone payments along the way.
The nature of today’s most vital challenges and funding policies are driving more and more researchers towards interdisciplinary work. But what are the essential tools for those breaking the silos and leaving the comfort zones of their own disciplines?
Cross-disciplinary collaborations have become an increasingly important part of science. They are seen as a key factor for finding solutions to pressing societal challenges on a global scale including green technologies, sustainable food production and drug development. This has also been realized by regulators and policy-makers, as it is reflected in the 80 billion Euro “Horizon 2020″ EU Framework Programme for Research and Innovation. This programme puts special emphasis at breaking down barriers between fields to create a path breaking environment for knowledge, research and innovation.
However, igniting and successfully maintaining cross-disciplinary collaborations can be a delicate task. In this article we focus on the specific challenges associated with cross-disciplinary research in particular from the perspective of the theoretician. As research fellows of the 2020 Science project and collaboration partners, we bring broad experience of developing interdisciplinary collaborations [2–12]. We intend this guide for early career computational researchers as well as more senior scientists who are entering a cross disciplinary setting for the first time. We describe the key benefits, as well as some possible pitfalls, arising from collaborations between scientists with backgrounds in very different fields.
Knapp B, Bardenet R, Bernabeu MO, Bordas R, Bruna M, Minssen T, et al. (2015) Ten Simple Rules for a Successful Cross-Disciplinary Collaboration. PLoS Comput Biol 11(4): e1004214. doi:10.1371/journal.pcbi.1004214
Earlier today, the House Energy and Commerce Committee released the most recent draft of the 21st Century Cures Act, in time for it to be marked up by the Health Subcommittee tomorrow. At 300 pages, the new draft adds back in a number of provisions that were excised from the previous, 200-page iteration of the draft. I haven’t had time to uncover all of the new additions just yet, but given that this is my third blog post on the subject, I wanted to highlight some of the ways in which this version differs (and doesn’t differ) from the last draft.
Yesterday, a new discussion draft of the 21st Century Cures Act was released, just in time for today’s hearing on the draft before the House Energy and Commerce Committee. At just 200 pages (although with some sections still “to be supplied”), this version is just half the size of the previous draft. As such, it is perhaps more notable for what it took out of the original draft than for what it added in. I haven’t had time to digest fully all of the cuts just yet, but in advance of the hearing this morning I wanted to highlight two significant deletions from the first draft and one potentially significant addition.
First, when I blogged in February about the first draft of the Act, I expressed excitement over the idea of a Medical Product Innovation Advisory Commission. The Commission would have had the ability to oversee the way in which agencies like the NIH, FDA, and CMS all interact with each other to affect the development and dissemination of medical products. A significant portion of my scholarship focuses on precisely these ideas, and I was hopeful that the Commission would make it into the second draft. Alas, it did not.
Second, the first draft of the Act contained a series of very controversial exclusivity provisions. Chief among them may have been the draft provision giving “dormant therapies” (essentially, new drugs for unmet medical needs) the option of 15 years of exclusivity. Alexander Gaffney’s Regulatory Explainer on the first draft provides a helpful overview, for those who are interested in learning more about this provision. But interestingly, this and other provisions relating to increased exclusivity are gone from the new draft. Now, it is possible that some of this language will reappear later, especially as the section of the draft relating to “Repurposing Drugs for Serious and Life-Threatening Diseases and Conditions” has yet to be supplied. But in the first draft of the document, the sections for “Repurposing Drugs” and “Dormant Therapies” were separate, so it is not clear that this is likely to happen.
A new Google Chrome extension puts the spotlight on conflicts of interest. The browser app, available for free download here, was created at the Hacking iCorruption hackathon event held March 27-29 in Cambridge, MA. The event, co-sponsored by the Edmond J. Safra Center for Ethics at Harvard University and the MIT Center for Civic Media (hosted at the MIT Media Lab) brought together individuals with a variety of backgrounds and skills to work toward the common mission of fighting institutional corruption, in this case by creating practical tools. This project was one of several exciting tools created at the hackathon (information about other projects available here), and it won first prize among the projects.
The Chrome extension, called Unearth, puts funding and conflict of interest information on the abstract page of PubMed research articles. Christopher Robertson, Associate Professor of Law at the University of Arizona James E. Rodgers College of Law and Edmond J. Safra Center Fellow who was a member of the Unearth team, explains the rationale for the browser extension in this Youtube video. In short, conflict of interest and funding disclosures are often placed at the end of a research article and are generally unavailable on the abstract page. This makes it impractical for physicians and other research scientists to pay appropriate attention to this important information. Research from the Cochrane Collaboration has demonstrated that research studies funded by industry generally describe “greater benefits and fewer harmful side effects” than their non-industry funded counterparts. Thus, taking the source of research funding into account when reading a new research study is critical. Although the extension currently only works for open access articles from PubMed Central, this includes several million research articles for which funding and conflict of interest information was previously much more difficult to obtain. Additionally, the developers plan on expanding the breadth of coverage in the coming weeks. Continue reading →
Biogen, a Cambridge, Massachusetts biotech company, announced last week that early tests of their new drug aducanumab, a monoclonal antibody, had shown impressive results in treating those with early stage Alzheimer’s disease. The drug significantly reduced the amyloid plaque buildup in the brain that is associated with Alzheimer’s.
In a very early stage safety test aducanumab slowed the cognitive decline and dementia associated with Alzheimer’s in people. On the Mini Mental Status Exam, a widely used measure of cognitive function, people at risk of Alzheimer’s who got a placebo lost around 3 points over a year. But those who got the lowest dose of aducanumab worsened by just two points and those who got a higher dose lost less than a point.
Biogen was so excited by the early results in 166 volunteers that it is going to try to go directly to a much bigger clinical trial of the drug. Wall Street was very excited too—Biogen’s stock price shot up 10 percent. […]
Senator Elizabeth Warren (D-MA) recently introduced a new bill, the Medical Innovation Act, which would require pharmaceutical companies who settle with the government after committing certain illegal activities to reinvest additional money into the NIH. Senator Warren views the bill as a “swear jar” for drug companies, seeking to target those who commit certain types of wrongdoing, including violating the anti-kickback statutes or defrauding Medicare and Medicaid, in order to increase government support for research at a time when the NIH’s budget has been falling. Scholars and researchers who have lamented the shrinking of the NIH’s budget will find much to love in the bill, and they may even wish it had gone farther.
The Medical Innovation Act would be triggered under the following set of circumstances: drug companies (1) who sell at least one drug whose annual net sales exceed $1 billion, (2) where that drug can be traced at least in part to federally funded research (the Act refers to such products as “covered blockbuster drug[s]”), and (3) who enter into a settlement agreement of at least $1 million with the government after committing certain types of wrongdoing, would pay an additional penalty. As a threshold matter, the Act will not affect companies unless they appear to have broken the law. But even where companies have committed various forms of wrongdoing, the Act would not affect smaller drug companies, those who developed their drugs without the aid of the federal government, those who engaged in minor wrongdoing (and therefore only have small settlements), or those who take the government to trial rather than settling.
Affected companies would be required to pay an additional fine on top of the value of their settlement, paying 1% of the company’s profits multiplied by the number of covered blockbuster drugs sold by that company each year for five years. Because the annual profits attributable to these companies are typically very high, even with the Act’s various carve-outs, Senator Warren estimates that if the Act had existed for the past five years, it would’ve provided an additional $6 billion every year to the NIH, a full 20% increase in its budget. Going forward, this number might be smaller, if some companies respond to the Act’s incentives by committing less wrongdoing (a positive development in itself) or taking the government to trial (a relatively unlikely outcome, but possible in some cases), but the total amount is still likely to be substantial.
At the end of January, the House Energy & Commerce Committee released a discussion draft of the 21st Century Cures Act. This document marks the beginning of the legislative phase of the 21st Century Cures Initiative, during which the Committee has held numerous roundtables and hearings and issued several white papers. The first discussion draft of the Act, clocking in at nearly 400 pages (even with several sections “to be supplied”), is incredibly wide-ranging, including proposals that could affect every stage of the innovation process.
The discussion draft should be of interest to everyone in the health policy field. One series of proposals is targeted at the NIH, including more support for the National Center for Advancing Translational Sciences and for the NIH’s BRAIN initiative. Another set would act on the FDA, including one provision giving new drugs for unmet medical needs the option of 15 years of exclusivity. This provision, based on the MODDERN Cures Act, is particularly likely to inspire a great deal of controversy and opposition. The draft also contains a series of proposals designed to promote the development of new antibiotics, in keeping with President Obama’s recent focus on this issue. Its attention to the use of social media by drug companies and to the FDA’s regulation of health-related software will be of interest to many, as well.
The proposed draft is much too long to catalog fully in this brief blog post, although those who are interested in a broader summary might enjoy the 13-page summary of the Act put out by the Committee, the Sciencesummary by Kelly Servick and Jocelyn Kaiser, or Alexander Gaffney’s comprehensive Regulatory Explainer. But I do want to highlight one section of the draft which deserves more attention than it has gotten: section 2021, which would create a national Medical Product Innovation Advisory Commission.
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:
The facts that replication, despite being a cornerstone of the scientific method, is rarely practiced (and even less frequently published) not only in psychology but across science, and that when such studies are conducted, they frequently fail to replicate the original findings (let this be a warning to those of you who, like me, cite empirical literature in your scholarship);
Why replications are so rarely conducted and published, relative to their importance (tl;dr: it’s the incentives, stupid);
Why it’s critical that this aspect of the academic research culture change (because academic science doesn’t only affect academic scientists; the rest of us have a stake in science, too, including those who fund it, those who help researchers produce it (i.e., human subjects), those who consume and build on it (other scholars and policy-makers), and all of us who are subject to myriad laws and policies informed by it); and
Some better and worse ways of facilitating that cultural change (among other things, we disagree with Daniel Kahneman’s most recent proposal for conducting replications).
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):
How the federal regulations define “human subjects research” (HSR)
Why HSR conducted and funded solely by an entity like Facebook is not subject to the federal regulations
Why HSR conducted by academics at some institutions (like Cornell and UCSF) may be subject to IRB review, even when that research is not federally funded
Why involvement in the Facebook study by two academics nevertheless probably did not trigger Cornell’s and UCSF’s requirements of IRB review
Why an IRB—had one reviewed the study—might plausibly have approved the study with reduced (though not waived) informed consent requirements
And why we should think twice before holding academics to a higher standard than corporations
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 →
“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.
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 →