Last week, Food and Drug Administration Commissioner Scott Gottlieb delivered the keynote speech at the Food and Drug Law Institute’s annual conference. This event is the premier event for lawyers working in the food and drug industries to hear directly from most of the top officials at the FDA about the most pressing, cutting-edge issues in the field.
Gottlieb kicked off the conference with a wide-ranging keynote address that, I believe, contained several notable remarks and some important revelations.
Unsurprisingly, Gottlieb led off with the issue of high drug prices. This has been a major issue for the agency in the past year. President Trump has made drug prices a signature issue and that has influenced the officials in his administration that regulate the issue. Gottlieb reiterated the actions that he has been taking to promote the production of generic drugs and mentioned that Trump and Health and Human Services Secretary Alex Azar will have more on the topic soon. This is likely a reference to the much talked about speech from Trump that analysts have expected for some time now. Gottlieb also notably suggested that the federal government ought to “reexamine the current safe harbor for drug rebates under the Anti-Kickback Statute…” to deal with the system of rebates between payers and manufacturers.
The Anti-Kickback Statute is an anti-corruption law intended by Congress to protect patients and prevent overutilization, expanding costs, and poor quality care. The law prohibits “transactions intended to induce or reward referrals for items or services reimbursed by the federal health care programs.” Since the law is so broad Congress allowed for a number of exemptions and also granted the HHS Secretary power to promulgate regulations creating further “safe harbors” exempt from liability under the law. Gottlieb wants some of those safe harbors reexamined, thus opening up drug manufacturers and payers who participate in the “system of rebates” to possible criminal prosecution under the law.
Later on in his remarks on the issue of drug prices, Gottlieb got personal, calling out the lawyers in the room for trying to devise new ways to get around laws like the Hatch-Waxman Amendments that were designed to promote competition in the generics industry.
He pointedly told them,
To those who make a practice of advising clients on how to engage in this sort of regulatory arbitrage, my view is that your client is trading away the long run sustainability of the entire enterprise for very short run advantage and gains.
If this behavior were to continue, he warned,
If these tactics don’t abate, there’s a real risk that Congress and others will come to see our longstanding — and, on balance successful approach to balancing innovation, access, and competition — as a framework that’s no longer sustainable or worth supporting. That’s the risk that comes from an excessive focus on preserving incumbency rather than developing new innovations that’ll advance health, improve people’s lives, and also help grow the industry.
These only slightly veiled threats of increased regulation are significant because they are unusual for Gottlieb. Though when speaking on issues that are extremely important to him and his agency (drug prices, opioids, and tabacco) he has begun to employ threats like these with increasing frequency.
Gottlieb also mentioned the Digital Health Action Plan and the Pre-Cert Pilot program once again as an example of how the FDA was modernizing its regulatory approach to deal with new technologies.
The Action Plan and the Pilot Program is a radical re-thinking of the traditional, product-based regulatory system. It focuses on certifying that a digital health technology developer exemplifies a culture of safety and excellence and allowing that developer more freedom when putting a new product or update through the FDA’s review.
In the speech, Gottlieb stated that the agency was building on this approach and wanted to expand this firm-based mindset to other product fields in which innovation is rapid and iterative; namely, digital health technology that incorporates artificial intelligence. Gottlieb has mentioned AI in a couple other recent speeches and the agency just approved the first medical device that uses AI last month. This growing focus on the technology is exciting, especially considering the immense benefits that AI can offer to patients and doctors alike. Expanding the Pre-Cert program to AI-powered devices would likely mean more AI devices in clinical use much faster.
Gottlieb believes the field of medicine is at a “turning point” where gene therapy treatments will likely soon become a “backbone of modern medicine.”
To shepherd these new treatments along, Gottlieb announced the agency will build on the comprehensive oversight framework for regenerative medicine products debuted last year. This will include new guidance on the manufacturing and clinical stages of the treatments, as well as clarification about what endpoints the agency is looking for in the approval application.
Then, in the most significant portion of his gene therapy comments, Gottlieb stated that the most difficult regulatory questions did not have anything to do with efficacy. Most of the gene therapies look like they will end up being highly effective. Really, he said, “The critical questions don’t necessarily turn on the clinical portion of the review, but on the product related issues.” Specifically, those product related issues have to do with manufacturing and gene delivery. He gave two examples: “theoretical risks” from off target mutations, and the durability of the patient’s response.
This is somewhat unusual compared to many other treatments that the FDA regulates. Most products get mired down in the later clinical stages trying to prove efficacy. The regulatory decision for gene therapies may hinge instead on long-term safety and durability. Based on Gottlieb’s comments the agency seems likely to use an accelerated approval process, especially for treatments that target serious conditions, to quickly get the treatment’s benefits to patients while also ensuring strong post-market follow-up to continually assess those questions of long-term safety and durability. If problems are detected several years down the road (for example, the benefits of the therapy wear off) the FDA may pull the treatment off the market.
Similar to the Digital Health Action Plan, gene therapy is forcing the FDA to re-think its regulatory model, and that is both noteworthy and positive.
Genetically Altered Animals
For me, the portion of the speech in which Gottlieb discussed genetically altered animals to be used for food or medical purposes was the most significant and attention-grabbing.
Gottlieb announced that the FDA will soon release its comprehensive framework for regulating “genetically altered animals used for food as well as for medical purposes like the production of human drugs, organs and tissues for xenotransplantation, control of human disease transmission, or reducing human allergenicity.” He then specifically stated this would include “gene editing in animals.”
Practically anyone who followed science news heard about the scientist in Portland who last year became the first American scientist to genetically edit human embryos. This was a big deal and made headlines in almost every major news outlet. However, using gene editing tools in human embryos in the clinic on a regular basis is still likely some years in the future, maybe more. Gene editing with tools like CRISPR is having a much more immediate impact in agriculture. But using CRISPR to make corn resistant to certain diseases is not as flashy as modifying human embryos and piques the interest of a smaller audience.
Nevertheless, this is a huge deal to those farmers and scientists directly involved in agriculture science and those, like me, who are deeply interested in genetics. And it should be a big deal to more people because of the potential benefits using gene editing in agriculture can bring. These include increased yields, resistance to diseases, and making farming more sustainable. The regulation piece is important because of the immense costs that can be associated with regulation, especially FDA regulation.
Gottlieb’s announcement comes in the midst of an agency battle over jurisdiction. There are three agencies that are responsible for regulating food and agriculture: US Department of Agriculture, US Environmental Protection Agency, and FDA. The USDA oversees plant health and the commercial supply of meat, poultry, and egg products. The FDA has jurisdiction over food labeling and food products other than meat, poultry, and eggs. The FDA also regulates animal feed and drugs.
The USDA announced in March that it “does not regulate or have any plans to regulate plants that could otherwise have been developed through traditional breeding techniques as long as they are not plant pests or developed using plant pests.” Basically, farmers could use gene editing tools to modify farm products without increased regulation as long as they did not introduce foreign DNA into the product’s genome, as was the case with older methods of genetic modification.
The underlying argument the USDA used was that the changes being made using gene editing could be made by generations of cross-breeding, so new gene editing techniques like CRISPR are nothing more than a sped up version of traditional farming practices. Gene editing is just nature on steroids.
Many farmers and gene editing advocates wanted this reasoning applied to animals too, along with a similar refusal to add regulation.
It does not seem like Gottlieb shares this desire. He specifically attacks the argument the USDA relied upon:
One of the arguments being made by some is that single genetic changes happen all the time in nature, as part of common breeding techniques. So why would we regulate the deliberate alteration of single base pair changes using Cas9?
He points out that those making this argument are correct, both single nucleotide alteration and large changes like splicing and swapping entire genes happen in nature all the time. But, Gottlieb counters, does that mean we also should not regulate gene therapy in humans? For him, treating a very similar procedure very differently simply because one is done in livestock and the other is done in humans does not make sense because doing so will “inevitably undermine” the FDA’s regulation on the human side.
Never explicitly stated in the speech is the assumption that gene editing in animals qualifies as an “animal drug.” Gottlieb must assume this or his agency would not have the authority to regulate it. Yet, a number of experts have questioned whether this is a valid assumption. Is gene editing an animal drug in the same way that growth hormones or vaccines are? Should they be treated differently?
That aside, I think Gottlieb somewhat misses the point of the USDA’s argument. The agency has always considered cross-breeding to be “natural” and not demanding of additional regulation. They are extending the same attitude to a new technology that they view as closely akin to cross-breeding. The FDA also views cross-breeding as part of a continuum of technologies that accelerate the introduction of naturally occurring desirable traits into a group of animals. The USDA’s logic would dictate that gene editing should simply be added to this continuum and not treated as a separate category. Doing so would acknowledge the FDA’s long standing view that such technologies are not drugs but technological extensions of natural processes. Since the FDA has no comparable continuum on the human side (society has rightly emphatically denounced any attempt to selectively breed humans), it is appropriate to treat gene therapy differently than it treats gene editing in animals.
We will have to see if the FDA expands on its view in the guidance that Gottlieb stated would be coming.
I am somewhat surprised that this speech has not caused more waves in the interested communities. I have only read one or two stories that reported on the contents of the speech. To me, there were several newsworthy announcements. True, many were short on details, but they will likely be important when the full guidance documents are released. We will have to wait and see.