Gottlieb at One

An Assessment of the FDA Chief’s First Year

Jordan Reimschisel
Apr 30, 2018 · 14 min read
Source: Wikimedia Commons

On May 11, 2018, U.S. Food and Drug Administration (FDA) Commissioner Scott Gottlieb will celebrate the one year anniversary of his tenure. It has been a year full of exciting FDA approval firsts: the first gene therapy for cancer treatment, the first gene therapy for an inherited disease, the first medical device employing artificial intelligence, and the first direct-to-consumer genetic test for breast cancer risk.

Gottlieb adopted a rather “conventional approach” to his job, which has surprised almost everyone. Instead of burning the agency to the ground as some politicians and patient groups feared (and some libertarians hoped), he embraced its public health mission and worked to maximize the agency’s effectiveness. Instead of bowing to industry whims, Gottlieb reinforced what he consistently refers to as the FDA’s “gold standard” for safety and efficacy.

General Trends

For me, Gottlieb’s first year at the helm has been an overall success. Some experts will disagree, but at the very least, his actions have softened many critics.

Regulatory modernization and encouraging innovation were the themes for the FDA this year, reflecting trends extending throughout the Trump administration. These themes were also goals of the 21st Century Cures Act passed by Congress and signed by President Obama in the closing months of his administration. Gottlieb spent much of his first year issuing guidance documents to implement the programs established by the legislation, especially the Regenerative Medicine Advanced Therapy designation and the Breakthough Devices program.

These ideas ran throughout most of the actions the agency undertook this year. Agency officials, especially Gottlieb, frequently talked about these themes in speeches and press releases. They seemed to be the guiding principles that informed and influenced the agency’s priorities for the year.

Digital Health Innovation Action Plan

Perhaps the best illustration of this innovation-heavy philosophy that Gottlieb has emphasized is the FDA’s program to encourage innovation in digital health and software technologies, one of the most significant FDA actions this year.

Over the last several years, software has played an increasingly important role in medicine. From relatively simple health-related apps on a smartphone, to wearable fitness trackers, to artificial intelligence-powered tools to support clinical decision making, software is empowering patients and their doctors to make more informed decisions about their health.

As Adam Thierer and I explain in our essay “‘Build & Freeze’ Regulation Versus Iterative Innovation,” the FDA’s traditional model of regulation, built on long, costly clinical trials, simply does not work well with software development, since each new update to an app or AI algorithm would require a new review and approval from the FDA.

Recognizing that the traditional regulatory process would overburden the innovation in this field, Gottlieb announced the “Digital Health Innovation Action Plan” in late July 2017, via a blog post.

Gottlieb’s goal in the Action Plan is to balance the two competing priorities of encouraging innovation and ensuring safety and effectiveness. This has been the goal of the FDA throughout much of its existence, but it has been highlighted frequently during Gottlieb’s first year. Gottlieb and the agency intend to pursue this goal by:

  1. Issuing guidance documents to clarify the medical software sections of the 21st Century Cures Act.
  2. Launching a pilot program called FDA Pre-Cert for Software to develop a new approach to digital health regulation.
  3. Building the agency’s expertise in digital health technology through hiring and training.

The Pre-Cert program is the central, most exciting piece of the Action Plan and has generated the most interest and explanation.

The section on Pre-Cert in the Action Plan explains that the program is an attempt to create a “pragmatic” approach to fostering innovation and exercising oversight. It is intended to take the place of premarket submissions for certain products and reduce the necessary submission forms for other products.

The program focuses the FDA’s regulatory attention on the software developer, not the product, as is traditional. Historically, the agency has approved specific uses of a specific product. If a drug manufacturer, for example, wants to label a drug approved for use in treating lung cancer as a treatment for throat cancer, the manufacturer would have to go through the FDA process again even though it is the exact same drug. Under Pre-Cert the FDA uses a firm-based approach and not the product- and use-based approach, a noteworthy difference.

The program is currently in the pilot stage. The agency selected nine companies of various sizes to participate in the pilot, out of over 100 applications. The nine companies included Apple, Johnson & Johnson, genomics company Phosphorus, and Alphabet’s life-sciences company Verily. The FDA also hired three Entrepreneur-in-Residence fellows as part of the pilot. The agency intends to lean heavily on the input and experience of these initial participants to inform the eventual structure of the permanent Pre-Cert program.

Since the enactment of the Administrative Procedure Act in 1946, the FDA has been required to solicit public comment when promulgating new regulations, something it also does upon issuing draft guidance. But in the time since then, the FDA has increased its use of even more collaborative forms of oversight like public workshops and multi-stakeholder processes. The Pre-Cert pilot utilizes the collaborative style at, to my knowledge, an unprecedented level.

The FDA did include its high level vision for the permanent program in the Action Plan. It will be a voluntary program for which companies may, but are not required to, apply. The firms that do request the pre-certification will be measured against “objective criteria” that are intended to “demonstrate a culture of quality and organizational excellence.” If the agency finds that a firm meets or exceeds these criteria, then that firm will be subject to, and in some cases exempt from, a streamlined premarket approval process for new digital health technologies. Presumably, companies that do not volunteer for the program will be regulated under the traditional, product-based approach.

The Action Plan also notes that companies that are pre-certified could collect “real-world data” once their products are commercially available. This data can then be used to support the approval of “new and evolving product functions.” This reflects the FDA’s growing focus on incorporating “real-world data” and “real-world evidence” into regulatory decision making. Gottlieb inherited this trend from both the previous commissioner and the 21st Century Cures Act and continues to highlight it in speeches, guidance, and blog posts.

In January 2018, the FDA held the first public workshop to discuss the progress of the pilot program. This was only mildly successful. At a conference in March, Michelle Jump, the director of cybersecurity regulatory affairs at Carestream, said that there were “more questions than answers around the design of the precertification pilot.” She indicated that those questions still had not been answered several months later at the March conference.

Pre-Cert Working Model

Very recently, on April 26, Gottlieb delivered a speech at the Academy Health’s 2018 Health Datapalooza in D.C. announcing that the FDA was releasing the first draft of the Working Model of the pre-certification program. This Working Model fills in many of the details that were still unclear at the January conference.

The Working Model breaks down the program into four parts: the pre-certification decision, the review pathway decision, the actual premarket review, and the postmarket followup.

Pre-Certification

The primary challenge of the precertification decision is to determine the rubric by which applicants will be evaluated. The Working Model lists five “excellence principles” that companies must meet to be admitted to the program: product quality, patient safety, clinical responsibility, cybersecurity responsibility, and proactive culture. It also offers brief explanations of what each of those principles means. For example, it defines patient safety as, “Demonstration of a commitment to providing a safe patient experience, and emphasizing patient safety as a critical factor in all decision-making processes.”

The FDA asks for “objective indicators” to prove that an applicant demonstrates these principles. As admirable as objectivity is, I fear this will be a difficult task for the applicants. What data points objectively show that a firm has a commitment to patient safety? The meanings of these principles are subjective and open to wide interpretation. This means FDA officials will likely have some difficulty in making an objective decision on whether the data submitted by an applicant demonstrates an embodiment of the excellence principles. Perhaps the agency could publish a long-form rubric with the objective data they want to see from applicants. Until that happens, these pre-certification decisions will probably be subjective and open to possible abuse.

Review Pathway

The Working Model is much better at being objective in the review pathway portion of the program. This section contains several matrices and tables to determine exactly how different products will be treated under the program.

Each product is treated according to how risky it is. For example, one table classifies products into a type and subtype based on the seriousness of the condition it is intended to act upon and the significance of the information it provides (i.e. whether it is meant to treat or diagnose, or simply to inform a clinical decision). So a software product intended to treat or diagnose a critical condition would be classified as a type IV, subtype 9 software device, the highest classification possible. This classification determines whether the product must go through a streamlined review or can skip the review before it goes to market. The device in my example must go through a streamlined review for anything other than minor changes.

Review Itself

Many questions still remain in the actual review part of the program. This was the shortest section in the Working Model with more than a page of questions for public input. What information the agency will need beyond the intended use and classification data explained above is unclear. It is clear that the FDA wants this review process to be “interactive.”

The Working Model also notes that the review will be “supported by automated analysis” where possible and appropriate. This may signal the agency’s willingness to integrate AI or machine learning tools into regulatory decisions, but the Working Model did not elaborate at all on what was meant by the phrase.

Postmarket Followup

The postmarket followup section of the program was also left more vague than the first two parts. The Working Model admits most of these details “will be developed in a future version” of the program. It does say that the agency intends to use data on how the software product actually performs once it has been released “for monitoring and feedback at product, organizational, and program levels.”

While the Working Model clarifies several aspects of the Pre-Cert Program, plenty of details are left to be decided. It remains to be seen how attractive this program will appear to software developers and how much it will do to encourage innovation, though from what has been released this outcome seems likely. Whatever the result, it is encouraging to see Gottlieb’s willingness to reevaluate the FDA’s traditional approach to regulation and work with stakeholders to come up with a better system for software devices that will ultimately better serve American patients.

Generic Drugs

At the swearing-in ceremony of Health and Human Services Secretary Alex Azar, President Trump spoke extensively about the problem of high prescription drug prices. Immediately after introducing Azar, Trump beckoned him forward and commented that he would soon “get those prescription drug prices way down.” The President later mentioned that whenever he spoke to Azar, the price of drugs was always the first topic, reflecting how important this issue is to Trump.

Azar clearly understands that he will be judged based on how his department handles drug prices and the opioid crisis. These were the only two policy areas that Azar actually took the time to name during his very brief remarks at that swearing-in ceremony.

Azar’s focus on this topic has also trickled down to Gottlieb and the FDA, inspiring the Drug Competition Action Plan launched in late May 2017. While the FDA does not have the authority to regulate prices directly, Gottlieb believes the agency can influence drug prices by “facilitating increased competition in the market for prescription drugs.”

One part of the plan involves reducing the scientific and regulatory barriers that generic manufacturers face in producing their products. In pursuing this goal the agency published a list of off-patent, off-exclusivity branded drugs that did not have an approved generic equivalent in order to notify manufacturers of opportunities to create generic versions.

A second piece of the plan is to expedite the review of generic drug applications in situations where “competition is limited” in order to get those drugs to patients faster.

Another pillar of Gottlieb’s plan is to stop branded drug manufacturers who try to “game the system.” One example of this gaming that frequently comes up is branded manufacturers withholding samples of their drugs from generic manufacturers. In order to perform the studies necessary for proving that the generic drug works the same way as its branded counterpart, a necessary step to win FDA approval, the generic manufacturer needs a substantial amount of the branded drug. Ideally, the generic manufacturer should be able to purchase the branded drug at its fair market value, but branded manufacturers will sometimes use “regulatory strategies or commercial techniques” to prevent this from happening, thereby lengthening the de facto period of exclusivity and the profits that come with that.

Per capita, the U.S. spends more on healthcare than any other country, but has poorer health outcomes. Spending by the federal government accounts for a significant portion of that total. These levels are likely unsustainable, especially as programs like Medicare and Medicaid continue to grow.

Viewed in this light, Gottlieb’s attempts to help mitigate the problem are quite positive. The manner in which his is undertaking this task is also encouraging. Instead of seeking to expand the FDA’s authority on drug prices, Gottlieb has chosen to create an environment in which competition can thrive and trust supply and demand to do the rest.

Nicotine and Tobacco

Gottlieb has also made nicotine and tobacco regulation a signature issue of his tenure. In a July 2017 speech he compared the “epidemic of addiction to opioids” to the “addiction to nicotine,” and vowed to confront both problems “with the same vigor.” His experience treating cancer patients and his own battle with cancer also contribute to his strong desire to protect the public from the deleterious affects of nicotine and cigarettes.

In that speech, Gottlieb announced an aggressive, multi-year plan to implement the Family Smoking Prevention and Tobacco Control Act (Tobacco Act). This legislation, passed in 2009, gave the FDA the authority to regulate the “manufacture, distribution, and marketing of tobacco products” for the first time. A central part of the plan involves teaching the public that the way nicotine is consumed influences how harmful the product is. Combustible cigarettes are the most harmful and the FDA intends to regulate them most strictly.

The agency intends to regulate (by formal rulemaking) the amount of nicotine allowed in cigarettes, dropping it to minimally addictive levels. To begin this process, it will issue an Advance Notice of Proposed Rulemaking (ANPR) so that the public can comment on the potential benefits and any possible adverse effects of lowering nicotine in cigarettes.

Much of the new regulations will focus on ensuring that youth cannot access the most harmful nicotine products like cigarettes. According to Gottlieb, this will especially impact e-cigarettes and vapes. He is particularly concerned about products with “kid-appealing flavors” and directed the agency to issue an ANPR to address this issue.

Recently, the FDA issued a rarely used 904(b) letter (referring a section of the Tobacco Act) requesting company documents from e-cigarette brand Juul. The company’s products have become increasingly popular, especially among youth. Anticipating possible violations of the Tobacco Act, the FDA asked the company to turn over information related to the e-cigarette’s marketing and any research on whether any aspect of the product appeals to particular age groups. Not complying with these requests would be a violation of the Tobacco Act and would warrant enforcement action against Juul. The contents of the documents could also prompt enforcement letters. The FDA plans to take similar steps with other makers of e-cigarette products.

Concurrent with these actions, the agency has been conducting extensive under-cover operations to find and stop retailers from selling Juul products to minors, both in-store and online. So far the agency has issued about forty warning letters to retailers nationwide.

Even in his nicotine and tobacco action plan, Gottlieb continues to invoke the theme of encouraging innovation. He recognizes that innovation could lead to less harmful products that could help those addicted to cigarettes quit using them. This is partly why the agency moved to delay the effective date on a deeming rule for tobacco products. Gottlieb wanted the Center for Tobacco Products to review the implementation of the rule “with an eye towards fostering innovation where innovation could truly make a public health difference.”

Tobacco regulation presents an extremely difficult and unique tension between freedom and innovation on the one hand, and paternalism and public health on the other. Due to excellent, FDA-led public health education efforts like the “Real Cost Campaign,” the vast majority of consumers in the U.S. understand that smoking cigarettes harms their health. I do not think many individuals begin smoking without any idea of the health risks they are accepting. I also think that most smokers have adequate resources available to them should they choose to quit or use a less harmful nicotine-delivery system. Perhaps I am wrong. But if I am right that people do not participate in this behavior blind to the risks and have resources needed to quit if they so choose, then further regulation of the tobacco industry, especially aggressive regulation, is paternalistic and not innovation-friendly.

This is what makes Gottlieb’s aggressive actions to regulate nicotine and tobacco so surprising and, seemingly, out-of-character. On the two issues discussed above, the Commissioner has adopted strong, innovation-friendly stances. With tobacco, Gottlieb has emphatically stepped to the paternalistic side of the tension. To be fair, many other issues in health policy do not present the same stand-off between innovation and public health. Encouraging new cancer treatments likely contributes to better public health in the long run. Nevertheless, for me, Gottlieb’s actions represent a break with his usual mindset.

And, as I have written about previously, this could set a dangerous precedent. Perhaps such aggressive regulation will go no further than the tobacco industry under Gottlieb, but a future commissioner may expand into other industries that similarly present health concerns.

Conclusion

Gottlieb has been extraordinarily busy in his first year and not all of his activity has been covered here. I have presented the three issues that I think have gotten the most focus from Gottlieb and the broader agency this year. These issues will likely remain important for the next year and maybe beyond.

Other topics deserve attention and I have treated them elsewhere. Another essay of mine that would complement this assessment well is titled “Advanced Medical Technology: Four Burgeoning Issues From 2017.” Each of these four issues will involve the FDA in some way. Most of them did not receive a great amount of attention from the agency this year, but I believe they will be the star issues in the years to come.

Again, for me, Gottlieb’s first year at the FDA has been a positive one overall. I have supported most of the actions taken and initiatives started and I believe they will improve patient well-being in the long run.

And yet, I realize that there are still long term consequences even for actions with which I agree. Institutions and procedures matter. Gottlieb has continued the FDA’s push into soft law governance. One of his mottos this year has been “flexibility.” Soft law and flexibility are wonderful when they are being used to advance policies with which one agrees. But they can just as easily be used to stifle innovation and punish companies that go beyond the blessing of the FDA. The more the FDA cultivates its soft law powers, the less oversight it is subject to.

Despite these somewhat gloomy warnings, I think the near future of the FDA and the medical field which it oversees looks bright indeed.

Additional Reading

Advanced Medical Technology: Four Burgeoning Issues From 2017

When it comes to tobacco and cigarettes, people are smarter than you think

“Build & Freeze” Regulation Versus Iterative Innovation

Jordan Reimschisel

Written by

JD Candidate at Saint Louis University School of Law. I write about regenerative medicine, gene editing, and synthetic biology.

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