[Posted on behalf of Jeffrey Skopek, Academic Fellow, Petrie-Flom Center (with the same disclaimer about the off-the-cuff nature of live blogging)]
Jeffrey Shapiro (Hyman, Phelps, McNamara PC), Why the 510(k) Pathway is the Right Approach for Most Medical Devices
Jeff Shapiro began with an introduction to FDA approval processes for medical devices. He explained that all devices reach the marked based on a finding of reasonable assurance of safety and efficacy, whether it is through the PMA or 510(k) process.
His focus was on the 510(k) clearance process for Class I/II devices, which is based upon FDA’s finding of substantial equivalence to a “predicate device.” This predicate device is another Class I/II device that (1) has the same intended use and (2) has the same technological characteristic, or has difference characteristics but does not raise new questions of safety. He explained that this review process creates a chain of linked comparisons through which the FDA allows advances only far enough that likely clinical impact can be predicted. Novel devices are shifted to PMA process.
He argued that the 510(k) approach has many benefits. Like common law, it is precedent driven. It provides an open regulatory architecture. It allows leapfrogging within industry sectors, avoiding re-inventing the wheel. It is efficient, focusing on modifications, rather than complete evaluation. Each clearance adds richness to the body of potential baseline technology, allowing fine comparisons in a wide variety of device types. The PMA approval, by contrast, has closed regulatory architecture. Each iteration must re-invent the wheel, and thus is only practical for a small number of high risk devices.
He closed by suggesting that the 510(k) process can be improved in ways discussed in his paper, but that it works well for most medical devices and should thus be around for a long time.
Kayte Spector-Bagdady/Elizabeth Pike (Presidential Commission for the Study of Bioethical Issues), Device-ive Manuevers: FDA Regulation of the Bifurcation of Direct-to-Consumer Genomic Data and Information
[Posted on behalf of W. Nicholson Price II, Academic Fellow, The Petrie-Flom Center (with the disclaimer re: live blogging - see posts below)]
The first panel of today is on regulatory exclusivity and generic drugs, moderated by Ben Roin at the Petrie-Flom Center.
Leading off was Kate Greenwood, discussing orphan drug development and recycled molecules. She started off with Makena, known as 17-P, first approved in 1976 as Delalutin. In 1996 FDA withdrew its approval at the manufacturer’s request, as it hadn’t been marketing it. A few years later, a study showed that the molecule, 17-P, helped prevent premature birth. Compounding pharmacies started making it, and in 2006, CustoPharm filed a Citizen’s Petition asking whether the way was clear for a generic; FDA said yes, though the route might be challenging. But in May 2006, a different company filed for a NDA for this new use; it was approved as Makena in January 2007; the company (KV Pharmaceuticals) priced it at $30,000 for a course of treatment (vs. $300 for the compounded version, still available pre-approval). Responding to criticism, FDA stated that Makena’s reliance on government funding did not prevent Orphan Drug application. But a few months later, FDA stated that compounding pharmacies could still make 17-P for patients; KV declared bankruptcy and blamed FDA’s decision not to discretionarily enforce Orphan Drug exclusivity. KV has since sued FDA and HHS, and the case is pending.
Kate moved on to discuss ways to adjust the innovation/access balance, including shortening the exclusivity period, allowing limited competition, or capping or controlling drug prices. There are concerns, however, that after Makena payers won’t really allow any monopoly price period.
Next up was Kevin Outterson, talking about opacity of R&D information; all we see are the shadows of data. There are $250 billion of branded drug sales, with something like $200 billion in patent rents in the U.S. alone (twice that globally). Patent theory describes this as the engine behind development in drugs – but it’s not free; we pay in higher drug prices. We’re paying for R&D, not the pills themselves, which would be priced at the generics’ cost. There’s no industry that celebrates inefficiency the way drugs do, touting the $1.2 billion figure for drug development. Don’t blame patent law, though! They require up-front disclosure. But that doesn’t apply to clinical data, which is kept locked away, only accessible to FDA. This process, which society pays for, is anathema to the scientific process.
Day two of PFC’s FDA in the 21st Century conference begins with a morning plenary by the very fabulous Alta Charo, of the University of Wisconsin Law School, who is speaking on “Integrating Speed and Safety.”
Today Alta is presenting what she calls “more of an initial idea than an actual proposal,” and she notes that she’s very interested to hear responses to it, so comment away or contact her offline. She wants to integrate into the usual and longstanding “FDA speed versus safety” debate some concerns that should be of interest to industry. “In other words,” she said, “I’d like to be nice to the drug people.”
Alta begins with a brief history of the speed versus safety debate, which turns out to be quite cyclical. Before 1906, she asks us to recall, we had true snake oil: products with high toxicity and little or no efficacy. Often these products were nevertheless perceived as effective because they contained alcohol or other drugs, so made you feel better at least, but of course that’s part of what made these products so dangerous, especially for children.
And so with the Federal Food and Drugs Act of 1906, we get post-market remedies for misbranding, although they require proof of intent. And then in 1937 over 100 children die from elixir of sulfanilamide. And the following year we get the Food, Drug, and Cosmetic Act. But the FDCA targets only safety. (Although rightly Alta notes that it’s hard to see how regulators were truly only looking at safety and not also at some form of efficacy, since there is no such thing as safety in the abstract, only safety relative to purpose for which someone is taking the drug.) Continue reading
[This is off-the-cuff live blogging, so apologies for any errors, typos, etc]
First up is Mark Lange from Eli Lilly (who notes that he is here in his personal capacity only!), speaking about “Data Transparency and the Role of the FDA.”
He prefaces his talk by noting that when he refers to “data,” he means raw, patient-level data from clinical trials. Most calls for the transparency of such data, he says, reflect a common theme about lack of trust in the pharmaceutical industry. So we might wonder: why doesn’t the pharmaceutical industry simply accede to that request and make their data available?
Mark notes that industry has several concerns. One important one pertains to data exclusivity. In several (if not all) markets, data exclusivity rights are premised on keeping the relevant data confidential, and posting it publicly would be deemed a waiver of those rights. In addition, data exclusivity prevents generic competitors from free riding, and publishing data could allow them to circumvent the very point of data exclusivity.
Moving to privacy concerns, Mark notes that research subjects’ understanding is that their data will be used for particular purposes and shared with regulators, but not be publicly posted on the Internet for anyone to do with whatever they want. Relatedly, there is the potential for interpretation of public data to be biased; research results may be over-interpreted and analyses may be flawed or even erroneous. Competitors might look for fairly trivial flaws the the data and try to use them to their advantage rather than sincerely trying to advance scientific progress and transparency.
Mark suggests, however, the choice between privacy and transparency is a false one. A better alternative is available — namely, for objective, expert regulators such as the FDA to receive and vet data in ways that address both audiences and both sets of concerns. The FDA is in fact already experienced in doing this. For example, it determines whether research demonstrates that a drug is safe and effective for a particular use through its marketing application approval mechanism, and it determines the accuracy and adequacy of the portrayal of research results in product labeling and product advertisements. And late last year, it was given responsibility for overseeing clinicaltrials.gov, which includes results from all pre-specified primary and secondary outcomes measures from nearly all clinical trials either conducted in the U.S. or intended to be used in support of an application for marketing approval in the U.S. This new responsibility, Mark suggests, could be a powerful tool, depending on how the FDA uses it. For instance, the FDA could exercise authority to monitor and enforce the absence of required results and the inclusion of false or misleading results data.
In concluding, Mark stresses that, when faced with requests for public access to patient-level trial data, we should consider the important role of regulators as trusted intermediaries who can balance competing concerns. Continue reading
By Joanna Sax
Thank you for inviting me to blog. Later this week, I’ll be attending Harvard Law School’s Petrie-Flom Annual Conference on the FDA in the 21st Century. My paper/presentation addresses the role of the FDA in the regulation of dietary supplements. By way of preview, my paper compares similarities between the dietary supplement industry and tobacco. Both industries have successfully avoided heavy regulation by the FDA.
A tension exists between the personal choice/autonomy to use a variety of dietary supplements with the actual or potential health danger. With the current light-handed regulation, costs for dietary supplements are much lower than they would be if they had to be approved by the FDA prior to market. Some consumers believe that if a product says it is ‘natural’ then it must be safe. This, however, is not necessarily true. Would you eat any wild plant or mushroom just because it is natural? I hope not. In recent years, a number of adverse events, including death, have been shown to be correlated or caused by use of dietary supplements.
It seems that some of the tactics employed by the tobacco industry to avoid regulation are similar to tactics employed by the dietary supplement industry. My paper/presentation addresses what lessons we can learn from the tobacco industry to analyze if the FDA should be granted the authority to increase the regulation of the dietary supplement industry. I hope to see you all in Boston.
By Scott Burris
Last week, Northeastern University’s effort to convene a much-needed conference on the future of health policy was a casualty of the successful manhunt for the Boston Marathon bombers. One hardly wants to make too much of a stymied conference given all the human damage of the bombing and its aftermath, but all of us who had gathered for the meeting regretted that we would not hear from the panelists, and sympathized with organizers who had put so much into planning it. In recognition of that, I am summarizing here what I planned to say there. It is a tale of two polities that seem to compete for existence in our perceptions of the politics of public health.
One public health is incredibly popular with citizens and lawmakers alike – demonstrated by polling and passage of legislation. I’ve recently blogged on this here. The other public health is the despised nanny state, big government, the sequestered and slashed-to-the bone struggling provider of essential services that don’t get no respect and don’t deserve the meager tax dollars we still pay in. We see this in budget cuts, in hyperbolic allegations of “corruption,” and in disingenuous advocacy for a radical caveat emptor regime for all legal products.
What do we make of these two radically different views of where public health now stands in the public’s regard? My claim is that the former is largely the truth – public health is popular, not despised – but the latter view is what is driving budgets and a lot of policy. The action points follow: a sustained fight to mobilize public support and win more battles over budgets and laws. I see three main strands of work:
Working in private, the National Academy of Sciences’ panel on human-subjects regulations in social-behavioral sciences met this weekend to draft a final report. On Friday, the panel had wrapped up its public “Workshop on Proposed Revisions to the Common Rule in Relation to Behavioral and Social Sciences.” The workshop aimed to critique OHRP’s proposed revisions to federal human-subjects regulations (known as the Common Rule), rather to critique the regulations directly.
Here is what the National Academy panel members said they took to be a few take-points from the public workshop, which I attended:
- LOW-RISK: It’s essential to change regulations for lower-risk research, but the ANPRM does not currently set out a good way to do this. Few participants seemed keen on the new category of “excused,” nor did they like the current use of “exempt.” The key question to my mind is, How much autonomy, do the panelists think, should be handed over to scholar-investigators and taken away from IRBs? Speaker Lois Brako advocated requiring everyone to register their studies with their institutions. Other speakers (Brian Muskanski, Rena Lederman) suggested researchers should be given leeway to interpret abstract terms like “risk” and key moments such as when a study begins. Do panelists agree that scholar-investigators are trustworthy and knowledgeable enough to interpret regulations?
- INTERNATIONAL: The Common Rule gives little attention to research outside the USA, and OHRP’s proposed revisions do not address this dangerous and retrograde gap. Pearl O’Rouke of Partners Healthcare and Thomas Coates of UCLA usefully emphasized this important point and showed the stakes. To my mind, the question for many researchers will be, How should cross-national differences—in institutions’ resources, in study populations—be taken into account in the regulations? Medical anthropologists, for example, are in the midst of a raging debate over this issue. The traditional view has been that we should respect local differences, and this was the original point of requiring IRBs to account for “community attitudes,” which has morphed into a big problem for multisite studies in the present day. The avant garde in medical anthropology suggests that such “ethical variability” is not just inhumane, but it indulges a western insistence on treating some people as “others” rather than as us—whether in the USA or abroad—which happens to be very convenient for drug developers. In my own research, IRB members also faced the more routine question of whether “community” meant a study population, local residents of a region, or something else altogether. The panel may not have time to consider whether it makes sense to clarify what “community” means and, more broadly, who gets to speak on behalf of a “community” regarding its attitudes.
- PRIVACY: We have to come up with a system for reviewing social-behavioral research that is either more flexible or more refined. There is a wide range of appropriate protections, but they can quickly seem inappropriate if applied to some studies. Comparing a few of the presentations makes this point. George Alter explained the rigorous and necessary privacy protection plan for the big data sets and collaborative networks involved in University of Michigan’s ICPSR. On the flip side, Brian Mustanski and Rena Lederman explained the overweening attention to the so-called risks in their studies that involve first-hand interviews and observations.
- EVIDENCE: We need more data on IRB outcomes. It is apparent that the data exist—as talks such as Lois Brako’s showed, in which she documented her team’s impressive overhaul of the IRB at University of Michigan, dysfunctional only a few years ago. The data need to be expanded, analyzed and shared—and supported for the long term. Who will have the money or time for that? That remains to be seen, but either way I will be curious to see the effects of the workshop buzz word: “evidence-based” decision-making. Although panelists saw value in case studies, it would be easiest for them and for policymakers to prioritize problems that can be documented with statistics rather than stories. I wonder, How might this skew the problems that are identified the people included in discussions?
Today and tomorrow, the National Academy of Sciences is hosting a workshop on revisions to the human-subjects regulations (the “Common Rule”), especially for rules on social and behavioral research. The workshop is being simulcast, and viewers can send in questions. Join us!
The most provocative presentation this morning, from my perch in the front row, was from Brian Mustanski, who studies adolescent health and risk behaviors–especially same-sex experiences. It’s an important topic to study because of the risk of HIV/AIDS transmission, among other things. But it’s tough for investigators to conduct studies on sex because the topic worries Institutional Review Boards (or researchers believe the topic will worry their IRBs). Sociologist Janice Irvine makes a similar argument in her survey of sex researchers.
Do IRBs need to be so worried? Mustanski and his colleagues asked the adolescents that they studied how comfortable the kids felt answering their sex survey. Around 70 percent felt either “comfortable” or “very comfortable” answering the sex questions–the implication being that it was silly for IRBs to think the questions posed more of a minimal risk. But his data also showed that 3 percent of the respondents felt “very uncomfortable.” He did not point out this finding, and so I asked Dr. Richard Campbell, another presenter, to weigh in on whether he would consider 3 percent to constitute a “large” or “likely” risk. Earlier Dr. Campbell had given a conceptual talk arguing that IRBs conflate the magnitude of risk with the likelihood of risk to participants. In answer to my question, Campbell said that making 2-4 precent of adolescents “very uncomfortable” would not constitute a large or likely risk, and so the research should go forward.
I imagine that IRB members of a more conservative bent would disagree–and this is the crux of the problem. In considering how to revise the human-subjects regulations, would it be more helpful to make the regulations more specific, for example by setting quantitative thresholds and standards that everyone would have to follow? Or would it be best to make the regulations more flexible? The regulations already give IRBs more discretion than they use. IRBs don’t use the flexibility in the regulations because they are always concerned about institutional liability. For IRBs, conversations about protecting human subjects from harm is simultaneously a conversation about protecting the institution from legal harm. IRBs would read surveys like Mustanski’s by seeing the few people who are uncomfortable rather than the majority of people who were entirely comfortable. Why? Because it only takes one lawsuit.
Is this regulatory contradiction too big for NAS? The debate in Washington continues.
Petrie-Flom Center Annual Conference:
Friday and Saturday, May 3-4, 2013
Harvard Law School, Cambridge, MA
The Petrie-Flom Center invites you to attend our annual conference, this year entitled: “The Food and Drug Administration in the 21st Century.” Attendance is free and open to the public. Registration required; space is limited.
The Food and Drug Administration, the US government’s oldest comprehensive consumer protection agency, bears the monumental task of safeguarding the public health through regulation of food, drugs and biologics, devices, cosmetics, animal products, radiation-emitting products, and now, tobacco. The agency faces a number of perennial issues related to funding, relationships with industry, and striking the proper balance between consumer choice and consumer protection. It also faces several modern challenges related to globalization, novel technologies, newly added responsibilities, and changing threats to the public health.
How is the agency faring in the 21st century? What are the greatest challenges to the FDA’s success, and what does success look like? What lessons has it learned and how can it best meet the challenges of today? Should we keep the agency we have, pull it apart, or rebuild from scratch? This conference will gather leading experts from academia, government, and private industry to evaluate the FDA based on these and other questions, and to begin charting a course for the agency’s future.
* For the full conference agenda, including speakers, presentation titles, and specific times, please click here. *
DAY 1 – Friday, May 3, 2013, 9:00-5:00
- Welcome and Introduction
- PLENARY 1 - PETER BARTON HUTT (Covington & Burling)
- The FDA in a Changing World
- Preserving Public Trust and Demanding Accountability
- LUNCH AND KEYNOTE (TBD)
- Protecting the Public Within Constitutional Limits
- Timing Is Everything: Balancing Access and Uncertainty
- Major Issues in Drug Regulation
DAY 2 – Saturday, May 4, 2013, 9:00-4:00
- PLENARY 2 - ALTA CHARO (University of Wisconsin Law School)
- Regulatory Exclusivities and the Regulation of Generic Drugs and Biosimilars
- Major Issues in Device Regulation
- LUNCH AND PLENARY 3 - SUSAN WINCKLER (President and CEO, Food & Drug Law Institute)
- Major Issues in Food, Supplement, and Tobacco Regulation
- Addressing the Challenges of and Harnessing New Technologies
- Closing Remarks
Questions: petrie-flom at law.harvard.edu; 617.496.4662.
Issues and Case Studies in Clinical Trial Data Sharing: Lessons and Solutions
May 17, 2013, 8:00AM-5:00PM
Harvard Law School, Wasserstein Hall, Milstein West A (2nd Floor)
1585 Massachusetts Ave., Cambridge, MA
Our current agenda/objectives are below the fold, and will be updated with additional detail shortly. Please make sure to register as space is limited!
Join us for an important meeting:
Roundtable: Family, Privacy, Secrets & the Law March 7-8, 2013
March 7-8, 2013
University of Maryland
Francis King Carey School of Law
500 West Baltimore Street
Baltimore, MD 21201
March 7, 5 p.m. - Book Reading and signing by Jonathan Odell, author of The Healing
March 8, 9 a.m. – 4 p.m. – Roundtable discussions
Family, Privacy, Secrets & the Law roundtable engages the intersections of medicine, criminal law, family law, and constitutional law. The conference faculty will chart contemporary issues that span genetic privacy, disclosure of parental identity in assisted reproduction cases and DNA conscription to domestic violence and child sexual abuse.
There are times in which the law protects secrets, such as between a lawyer and client, doctor and patient, or clergy and congregant. Yet, there are times when the law demands that secret-keepers reveal their confidences such as the increasing demand on doctors to disclose confidential medical information on pregnant women to law enforcement. How should we understand the contours and boundaries of these dynamics within the law? On one hand, law tends to address secrets through the lens of legal duties to protect the vulnerable via its regulations governing abuse and neglect. On the other hand, this set of laws captures only a small percentage of secrets held by family members and other trusted “secret keepers” (doctors, clergy, extended family, neighbors) who, for a variety of reasons elect not to inform the state.
This roundtable interrogates states’ obligations to protect the vulnerable and at what cost. It considers the ways in which the law promises/owes protection and the success, failure or harms it brings about when endeavoring to intervene and offer protection. Against that backdrop, the law also has the obligation to honor individual and family autonomy and privacy.
From the Northeastern University School of Law Program on Health Policy and Law:
Join us for a day of informative discussion and exploration with some of the nation’s leading policymakers and researchers in health policy and law. Engage in conversations that examine the new directions for health policy and law, regionally, nationally and globally in the wake of the tumultuous events of 2012, including the Supreme Court’s ACA decision and the US Presidential Election.
April 19, 2013. Please see conference website for agenda and registration information.
Please save the date for this upcoming conference at Harvard Law School on May 17, 2013:
Issues and Case Studies in Clinical Trial Data Sharing:
What Have We Learned?
LOCATION: Wasserstein Hall, Milstein West A, Harvard Law School
1585 Massachusetts Avenue, Cambridge, MA
Speakers and registration information to be announced shortly
May 17, 2013 (8AM – 6PM)
To discuss opportunities for and implications of emerging clinical trial data disclosure standards
To review evidence from recent case studies in clinical trial data disclosure, especially related to disclosure of participant-level data
To review the rationale behind disclosure requirements of patient-level data and discuss whether the case studies demonstrate the goals have been met
To identify potential areas of collaboration among stakeholder groups, such as the formation of working groups to provide recommendations or standards in this area
To review variance in regulatory approaches and areas for possible harmonization
To identify other key areas of learning that may inform policy in this important area moving forward
To use conference findings as basis of a publication in a peer-reviewed journal that captures the case studies, provides insights into these issues and offers recommendations for moving forward