FDA approved concept. Rubber stamp with FDA and pills on craft paper. 3d illustration.

Book Review: ‘Drugs and the FDA: Safety, Efficacy, and the Public’s Trust’ by Mikkael A. Sekeres

By Matthew Chun

In Drugs and the FDA: Safety, Efficacy, and the Public’s Trust, oncologist Mikkael A. Sekeres tells a captivating story of how the U.S. Food and Drug Administration became the agency it is today and how it makes some of its toughest decisions regarding the regulation of potent drugs.

Sekeres centers his narrative on the controversial 2011 Avastin hearings, in which the FDA reconsidered and ultimately withdrew the breast cancer indication for Genentech’s Avastin drug. Having served on the Oncologic Drugs Advisory Committee (ODAC) tasked with making a recommendation to the FDA based on the hearings and clinical data, Sekeres provides a relatable personal account of the emotion-filled proceedings and the agonizing decision to withdraw approval of a beloved treatment option that never lived up to its promising initial results.

As he recounts his experience as an ODAC member, Sekeres skillfully weaves in historical references to various regulatory failures, including poisoned vaccines, opioid deaths, thalidomide-induced birth defects, and the woefully inadequate response to HIV/AIDS, which shaped the role of the FDA since its inception in 1930. Upon describing how the FDA developed its modern system of checks and balances to ensure drug safety, efficacy, and accessibility, Sekeres then illustrates how the Avastin hearings put all of these processes and values to the test. Among other things, Drugs and the FDA encourages readers to grapple with several important themes that pervade the agency’s decision-making process, including (1) the tension between drug safety and accessibility, (2) the relative weight of expert opinion versus patient autonomy, and (3) the role of democracy and transparency in drug regulation.

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Bill of Health - Poll worker Counts ballots in a mask, election during the pandemic

Election Litigation in the Era of COVID-19

By Dessie Otachliska

The 2020 Presidential election promises to be unlike any in history. The country is still in the midst of a global pandemic, which has already claimed the lives of more than 220,000 people nationwide and created the worst economic recession in recent history. As of October 25, 2020, forty-six states still have some COVID-related restrictions in place. Despite that, COVID infections are rising in thirty-two states, and a potential vaccine remains months away from viability. But this election is unique for other reasons. A week before November 3, it had already become the most litigated election in American history. In the last six months alone, over 414 COVID-related election law cases have been filed in forty-four states. With a substantial number of cases filed in swing states like Florida, Pennsylvania, and Wisconsin, courts have been called to decide contested and timely questions surrounding polling place procedures, deadlines for absentee ballots, and witness and notarization requirements for absentee ballots, to name just a few. The question that will likely remain unresolved for months, if not years, after the election is to what extent such litigation will shape the results of the 2020 presidential election.

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Live Blogging FDA in the 21st Century Conference, Panel 9 – Addressing the Challenges of and Harnessing New Technologies

Last but not least!  Our final conference panel focused on “Addressing the Challenges of and Harnessing New Technologies,” and was moderated by Fran Miller.

We heard first from Margaret Riley on “Twenty-First Century Technology with Twentieth Century Baggage: FDA Regulation of Regenerative Medicine.”  Riley explained that regenerative medicine (i.e., the use of pluripotent stem cells) has the potential to cure disease, injury, and even remedy organ shortages.  Of course, it is a hugely political issue and the debate is emotional, value-laden, and not necessarily logical.  As a result, the legislation/regulation that results in this area may be far from ideal.

Focusing on FDA specifically, Riley explained that the agency’s approach to stem cell regulation is rooted in its regulation of gene therapy and tissue products, as initiated in the 1990s.  FDA’s regulation of autologous stem cell therapies – in which a person’s own cells are removed, manipulated, and reintroduced – as a drug was recently upheld by the District Court of DC (US v. Regenerative Sciences, 878 F. Supp. 2d 248 (DDC 2012)), but is now on appeal to the DC Circuit. Riley is not sure what the outcome will be on appeal, but noted that getting BLA’s approved on a doctor-by-doctor basis will be very difficult and likely impossible.  One possible outcome of FDA regulation is likely to be off-shoring and stem cell tourism; ironically, strict regulation may end up not protecting patients, who will end up going abroad.

Next up was Nathan Cortez, who asked “Is the FDA Equipped to Regulate Mobile Health Devices?”

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Live Blogging from FDA in the 21st Century Conference, Panel 8: Food, Supplement, and Tobacco Regulation

[Live blogging off-the-cuff, so apologies in advance for any errors in summarizing, typos, etc]

Moderated by Emily Broad Leib, Harvard Law School

Robin Craig, Leslie Francis, and Erika George, University of Utah The FDA’s Authority Over Labeling: Current Ironies and Future Improvements:

Goal is to look at FDA authority over safety and labeling of Genetically Modified (GM) foods argue that FDA should do more, and argue for human right to food approach.

By GM we mean rDNA modification not husbandry and not careful selection.

FDA has moved to use guidance and policy. In particular two are relevant here. First, in food additives there is GRAS – Generally Recognized as Safe. E.g., Cinnamon was treated as GRAS. Manufacturers can self-determine a product is GRAS without notifying FDA, or, if in doubt, request a GRAS notice letter from FDA. This was proposed in 1997 and final review never issued, but this is how they do it. Has increased frequency of GRAS review request from FDA. But the process is voluntary and relies entirely on info from producer not scientific separate work by FDA.

In 1992, FDA issued a policy document related to GM foods. Stated no scientific evidence that GM foods have more safety concerns than existing husbandry techniques, so GM technology is NOT material information. This was NOT a conclusion that GM foods were GRAS.

In 1996, FDA issued a guidance for GM foods. Consultation process to determine whether there are material differences between GM version and non, voluntary process, encouraged to get consumer trust. Like GRAS totally voluntary, totally reliant on FDA data. 95 reported consultations between 1996 and 2012.

Alliance for Biointegrity v. Shalala, challenged in 2000 in D.D.C., court deferred to agency on safety questions and whether the info on GM was “material” and therefore needs to be disclosed.

Where would FDA get authority to regulate GM foods? May pose allergy risks? May be relevant to nutrition or quality. Maybe an additive not GRAS. But each of these arguments apply to specific GM food not GM foods as a whole.

Their argument: Consumers have a right to know so they can make their own consumption risks, and consumer or religious views are not merely preferences but a ground for the information that is material to consumers.

On why this is best understood as Human Right to Food. Adequate right to food is an HR right framed after WWII about enough food that is not adulterated and not against your faith or ethics (kosher, halal, vegan) and respectful of environment. U.S. is not part to Socioeconomic rights convention, which is most explicit protection of this right, but are signatories to other treaties that protect the right more indirectly.

Whole Foods has moved ahead on this as have others. Even if not a worry as GRAS, consumption may be inappropriate. We need a national strategy. More of a precautionary take that understands material to matter to consumers.

Jennifer Pomeranz, Yale, A Comprehensive Strategy to Overhaul FDA Authority for Misleading Food Labels:

Obesity and diabetes is the big problem in public health. And also people showing nutritional deficiencies because too much processed food. Current labeling is misleading makes people think food is healthier than they are. This is a unique public health problem. FDA has very weak authority and power here.

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Live Blogging FDA in the 21st Century Conference, Plenary 3: Susan Winckler, President and CEO of FDLI

[Posted on behalf of Holly Fernandez Lynch, Executive Director, Petrie-Flom Center (with the same disclaimer about the off-the-cuff nature of live blogging)]

For the last plenary session of the conference, we heard from Susan Winckler, President and CEO of the Food and Drug Law Institute, who discussed “Other Influencers of Food and Drug Law” – namely the media and Congress.

Susan began by contrasting media past and present – from newspapers, radios, and TV news, today the agency has to contend with the range of issues and challenges associated with social media.  There has been a shift from dealing with a defined press corps focused (and expert) on FDA to a “media of the masses,” which requires some level of training and background on the agency’s mission and intricacies.  The agency can now also speak directly to the public, and be more proactive, without the filter of reporters and news media editors.

Associated with this media shift, Susan identified several new realities and challenges:

  • How to explain complex scientific and legal issues in 140 character tweets?
  • How to speak with “one voice” despite the fact that every agency employee now has a media outlet?
  • How to address the expectation that FDA make declarations in real time, giving immediate responses to new developments? 
Susan then moved on to discuss the various ways in which congress engages with and influences the agency, beyond amending the FDCA:

Live Blogging from FDA in the 21st Century Conference, Panel 7: Major Issues in Device Regulation

[Posted on behalf of Jeffrey SkopekAcademic 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

Live Blogging from FDA in the 21st Century Conference, Panel 6: Regulatory Exclusivities and the Regulation of Generic Drugs and Biosimilars

[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.

Live Blogging from FDA in the 21st Century Conference, Plenary 2: Alta Charo on Integrating Speed and Safety

By Michelle Meyer

[This is off-the-cuff live blogging, so apologies for any errors, typos, etc]

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.) Read More

Live Blogging from FDA in the 21st Century Conference, Panel 5: Major Issues in Drug Regulation

 [Live-blogging off-the-cuff, all errors, typos, etc, are my fault]

Geoffrey Levitt, Pfizer, Drug Safety Communication: The Evolving Environment

A drug by itself is just an object. Because of that fact it creates turf, governance. You must have effective processes for communicating accurate info.

Pharmacovigilance is the accuracy part. Spontaneous adverse event reports are flooding to companies. 600,000 of such reports go to Pfizer a year, with 2000 a day on avg. Each has to be classified, reported, and followed-up. If you mess up you get a warning letter. But it has limits: passive, haphazard, poor signal to noise value. Main value is generating safety signals to follow up on. But studies of that kind for follow-up are very expensive and competing with other possible safety studies and new drug development for funding.

For this reason there has been interest in active real-time drug safety monitoring, like Sentinel.

Once you have accurate and up to date info, how do you communicate it to the audiences that need it. It is not static info, dynamic and constantly changing, and often not fully baked. Timing is everything. That leads to governance. Who owns it? Which stakeholders get to drive it. In Wyeth v. Levine, S. Ct says drug sponsor owns the label, and is responsible at all times for content of the label, including safety info. In reality not that simple. Today there is a number of players outside health authority and drug sponsor who have emerged as powerful forces. Academic researchers, drug payers, detailers, and many others.  This is not by accident. One reason is emergence of vocal critics who have critiqued the sponsors ability to directly communicate. Claim that this is a form of collusion  of which Levitt does not agree.

Vioxx sparked a few important developments. IOM produced one of the most important recommendations that led to FDAAA especially as to post-market surveillance and power over the safety label. Balance of authority shifted from that authority towards FDA. FDA also began to be more proactive about communicating, even before fully confirmed and without participation of sponsor. Also put into place obligations to post clinical trial results on public website, so clinicaltrials.gov is born. In retrospect, that was the opening shot in a full barrage of FDA on clinical trial transparency. In Europe this had led to a drastic new policy of affirmatively publishing clinical study reports full-scale not just trial results.

Critics of the current model want to tear down the gate, and reinterpret data themselves by own standards. That may lead to different results and different conclusions. Will the erosion of the primacy of the sponsor and FDA lead to more truth or more confusion?

W. Nicholson Price II, Petrie-Flom Center, The Role of Innovation Policy in Pharmaceutical Manufacturing

M & M manufacturing is more precise than drug manufacturing. Poor innovation in drugs. 200 to 300 billion dollars a year are spent on drug manufacturing. This is very expensive and inefficient, contrary to the typical story that drug manufacturing is cheap. Drugs are way behind computers and electronics. Uses same processes as decades ago. A 20% reduction in manufacturing costs would lead to a gain annually 50 billion for consumers if paid back directly, or even more if invested in R & D. Connected also to drug shortages.

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Live Blogging from FDA in the 21st Century Conference, Panel 4: Timing Is Everything

Another great conference session this afternoon: “Timing Is Everything: Balancing Access and Uncertainty.”  This one was moderated by Jeff Skopek, with presentations by Shannon Gibson, Trudo Lemmens, and Efthimios Parasidis.

First, we heard from Gibson and Lemmens on “Overcoming ‘Premarket Syndrome,’” AKA the various problems associated with relying solely on premarket data for safety and efficacy determinations.  These problems include the fact that industry studies have been shown to be more likely to be biased in favor of demonstrating a positive result, and premarket studies also cannot really demonstrate how a product will be used in clinical practice.  Moreover, for niche market drugs (e.g., those for orphan indications or pharmacogenomics), which are becoming more and more popular, there are fewer patients available to serve as clinical trial subjects, thereby inherently limiting the data that may be generated prior to approval and increasing uncertainty around safety and effectiveness.

So what should we do? Develop an improved post-market research agenda, say Gibson and Lemmens, and explore “adaptive licensing,” by which they mean rendering regulatory decisions based on the entire body of evidence collected throughout a product’s life cycle.   They argue that drug access decisions should not be binary, but instead, should be incremental and continually reassessed based on new data, including data that becomes available after a drug has been initially made available to patients. They closed by pointing out the importance of data transparency at all points in drug regulation.

Next, we heard from Efthimios Parasidis on “Innovative Regulating as a Public Health Imperative.”  Parasidis focused on the ways in which FDA can leverage its existing post-market regulatory authorities granted under the Food and Drug Administration Amendments Act of 2007, including requiring post-market studies and imposing Risk Evaluation and Mitigation Strategy requirements (REMS).

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