3037_FDAPost2-1Matt Furlow co-wrote this blog post with Pratap Khedkar.

Scott Gottlieb’s nearly two-year stint as commissioner of the FDA is coming to an end, and with the ink on his resignation letter barely dry, Norman Sharpless was appointed acting head. Gottlieb is a tough act for the former director of the National Cancer Institute to follow, even temporarily. Gottlieb brought welcome change to the agency and excelled across three ideal FDA leader focus areas—to protect, innovate and scale up—when historically, the agency’s focus had been heavily skewed to protect, was slow to innovate and was cautious to scale up.  

Before Gottlieb, things like social media guidelines for pharma companies took many years to wind through the hallways of the FDA and the backlog of new drug applications had become considerable. While leading the FDA, Gottlieb put his personal stamp on aspects of the business that many of his predecessors hadn’t. And for pharma, that meant encouraging companies to follow through with more attempts, and laying a foundation that enabled products to more smoothly reach the market. He also spent considerable time helping companies expose more consumers and stakeholders to their offerings. Gottlieb took the issues of patient access, affordability and choice, and expanded them. And his innate ability to be liked across the aisle helped push those policies forward.

Let’s take a closer look at how Gottlieb’s leadership style could influence what the next commissioner could—or should—do to maintain the FDA’s new momentum.

To Protect

Protecting and promoting public health is table stakes, of course, but that makes it no less important in the list of what makes an FDA commissioner successful. Public protection is deeply embedded in the agency’s genes and, in some ways, has become the default behavior because the commissioner is backed by a large bureaucracy that’s accustomed to regularly addressing public health policies. Regardless, the commissioner is tasked with setting high-priority initiatives and seeing to it that they’re reinforced with the right resources.

Gottlieb’s period of service was full of crowning achievements on the public health front: He took on the opioid epidemic, attempted to curb teen vaping, and implemented an ObamaCare rule requiring chain restaurants to reveal meals’ calorie counts, for example. But he also made his mark on the pharma industry by retooling the agency’s approach to encourage and prepare for future innovations.

Sharpless has been an enthusiastic supporter of Gottlieb’s e-cigarette campaign, so we give him full marks on his ability to protect the public. However, one side of the aisle believes that Gottlieb’s crackdown on e-cigarettes has gone too far. Despite the pushback, a firm stance on protection is needed. After all, innovation can’t be supported without a bedrock of trust, so only a good protection record will make more innovation possible.

To Innovate

Gottlieb showed that someone in his post can draft, pilot and enforce regulations in a way that enables pharma industry innovation. Will innovation now come to a screeching halt or can his successor drive the agenda forward? Or even better, will the new commissioner (and in the interim, the acting commissioner) encourage pharma companies to strive for a higher level of innovation than we’re seeing today?

Gottlieb demonstrated regulatory flexibility and a willingness to coordinate closely with manufacturers to bring new medicines to market more quickly. He issued draft guidance that advises sponsors on the design and conduct of first-in-human clinical trials for oncology drugs and biologics, including best practices for expanding and adapting expansion cohorts to expedite clinical development. And his approach paid dividends: The agency’s Center for Drug Evaluation and Research approved a record number (59) of novel drugs and biologics in 2018, 58% of which held orphan indications.

The FDA’s Real-Time Oncology Review program (RTOR) is another noteworthy achievement. The pilot program was established to make the review process of oncology therapeutics more efficient. Though the program is currently limited to applications for new indications on already approved products, RTOR may expand in the future to include new molecular entities. Novartis’s Kisqali was the first drug to be approved under RTOR with its population expansion to first-line treatment of pre- and peri-menopausal women with HR-positive, HER2-negative metastatic breast cancer. Just one month later, Merck’s Keytruda gained line extension into first-line treatment of metastatic non-squamous non-small cell lung cancer patients who have no EGFR or ALK mutations. Several other applications are currently under review, including AbbVie’s venetoclax in combination with obinutuzumab for previously-untreated CLL patients.

And we can’t talk about innovation without applauding Gottlieb’s tech-savvy approach. As I recently wrote in an op-ed for STAT News, “From gene therapies to mobile apps and wearable medical devices, healthcare has a different look than it did even a decade ago, and Gottlieb seemed to recognize the need to pivot in response to these external pressures.” For one, he’s leaving the agency in a strong position to face an expected uptick in gene therapy applications and approvals—which could reach 10 to 20 gene therapy approvals per year by 2025.

He also turned his support of companies developing digital and connected health therapeutics (like pills with sensors that communicate with wearables/apps) into a pre-certification program aimed at encouraging innovation and easing regulations. On the artificial intelligence front, Gottlieb had begun planting the seed for a new regulatory framework to promote innovation and provide support for companies developing AI-based healthcare solutions.

If Sharpless does, indeed, nab a permanent spot at the FDA’s helm, an NCI agenda that’s heavily focused on modernizing clinical trials and improving data sharing ought to serve him well. For example, NCI-MATCH, a precision medicine cancer treatment trial, aims to advance the practice of identifying mutations that are druggable across multiple tumor types like what Loxo Oncology did with larotrectinib. The NCI also recently collaborated on programs designed to use AI for diagnostic purposes, in this case using automated visual evaluation to improve cervical cancer screening.

It’s easy to lose momentum when it comes to encouraging innovation in healthcare, and tech novices face a steep learning curve. Another challenge is helping other career officials and politicians to think beyond the confines of safety and broad access. Innovation often is perceived as “new” and risky. It’s easy to take your foot off the pedal, and any losses in doing so will largely be felt by future generations. With unfinished business in many of these tech-related areas, the new commissioner will need to share Gottlieb’s passion and sense of urgency to carry already established programs across the finish line—and contribute a few ideas of his or her own.

To Scale Up

In addition to making ongoing investments in regulatory science designed to protect patients and consumers, it falls on the FDA to establish modern, risk-based regulatory standards to help reduce uncertainty for innovators—yet another area where Gottlieb excelled. In line with that, the agency has spent considerable effort encouraging competition for generics and biosimilars even if Gottlieb personally has a somewhat mixed record when it comes to those areas.

In addition to pushing through a number of other initiatives designed to bolster the sector, Gottlieb’s term will be noted for approving a record number of generics. Gottlieb attempted to remove the barriers to generic entry by doing away with some originators’ practice of using the agency’s Risk Evaluation and Mitigation Strategy requirements to set up roadblocks to generic drug development. Most recently, he turned his attention to advancing the development of complex generics and promoting competition—and curbing drug prices.

Running contrary to some commonly held beliefs, approving one or two generic alternatives often doesn’t spark competition and drive drug prices down. Instead, significant price drops occur when the pool is expanded to include numerous competitors. When a drug has one generic alternative, prices drop roughly 12%, but prices drop 85% when a drug has 9 alternative options. Gottlieb pushed a radical idea in vertical integration: encouraging PBMs and health plans to invest in generic manufacturing in these cases, much as Civica Rx is doing.

Biosimilars have been getting a strong leg up from various FDA initiatives including the Biosimilar Action Plan, which aims to reform the regulatory process for biosimilars, and to promote competition and improve patient access. And while we’re seeing more biosimilars approved by the FDA, the U.S. still lags the EU. Gottlieb always expected the biologic follow-ons to endure a slow ramp-up. In fact, he compared biosimilars’ uptake to that of generics during his keynote at the J.P. Morgan Healthcare Conference in January. In early March, he opined that the future of biosimilars is at a critical point but continues to stand behind their benefit to U.S. patients.

Although Gottlieb has said that he’s confident that the biosimilars market could overcome industry challenges, he also has acknowledged that certain regulatory steps need to be taken to improve the approval process. Despite his optimism, more companies may pull out if the path to market doesn’t match their expectations. And if enough players pull out, the balance will be restored for the others, but prices will not drop enough.

It’s certainly not all roses on the biosimilars front: Industry execs were left scratching their heads about Gottlieb’s introduction and subsequent removal of suffixes for nonproprietary names for originator biologics. The removal of the suffixes is being perceived as an anti-biosimilars move since it sets up biosimilars as “different” from the originators. 

Improving access to biosimilars is an example of an issue that wasn’t fully explored by current FDA leadership, creating an opportunity for the next commissioner. It’s likely that any appointees will have deep clinical and academic backgrounds (and Sharpless certainly fits the bill), which would lean toward accelerating generic/biosimilar access. Pressuring drug pricing down via generics/biosimilars is a hot-button and (somewhat) bipartisan issue.

Another opportunity for the next agency head to make significant progress is to integrate real-world evidence into regulatory submissions to accelerate approvals. Serono/Pfizer’s Bavencio was the first oncology product (for Merkel cell carcinoma) to gain a first-line approval based on EHR data. The other scenario to consider is what’s happening at CMS and HHS in conjunction with the FDA. For example, if Stark Law is soon substantially modified as CMS Administrator Seema Verma indicated, that will combine with a lot of the innovation ideas above to enable provider/pharma collaboration to try ideas sooner in an isolated mode rather than wait for national approval.

Looking specifically at how Sharpless’s background positions him to lead the FDA in the interim (and potentially long-term), he gets full marks on his ability to protect the public and ranks at or above average on the innovation front. Aside from founding two biotech companies, truly cutting-edge work doesn’t make too many appearances on his CV so we’ll have to wait and see whether that affects his ability to innovate. I suspect that he’ll toe the line on scale depending on what Azar and Verma come up with, but that’d likely be an issue for anyone serving as the FDA’s interim commissioner.

A permanent appointee who brings strengths in protection, innovation and scaling will serve the FDA well. So long as the commissioner’s main strengths aren’t solely focused on an overly cautious interpretation of protection at the expense of the other two focus areas, the FDA will benefit from a fresh perspective.


BLOG POST: Ramping Up Real-World Evidence: Assessing the FDA's New RWE Framework

BLOG POST: Even in a Favorable Regulatory Environment, Will Biosimilars Gain Traction in the US This Year?


Topics: generics, Pratap Khedkar, Biosimilars, pharma manufacturer, regulatory, Scott Gottlieb, FDA Commissioner, product approvals