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A Ropes & Gray (RopesTalk) podcast series focused on current trends and developments related to controlled substances that affect the health care and life sciences industries.
Josh Oyster: Hi, I’m Josh Oyster, a partner in the life sciences regulatory and compliance practice group in Ropes & Gray’s Washington, D.C. office. Welcome to our latest episode of Controlling Opinions, a podcast series focused on current trends and developments related to controlled substances that affect the health care and life sciences industries. I’m joined today by my colleagues David Peloquin, a Boston-based partner from our health care practice, and Beth Weinman, a D.C.-based counsel from our life sciences regulatory and compliance practice. Today, we’re talking about current developments related to research with cannabis. We briefly covered the topic of cannabis in our last episode of Controlling Opinions. We talked about the potential rescheduling of marijuana at the federal level out of Schedule I. While we all await the next move in that process, there is a growing interest in clinical and public health research involving cannabis—it is important for stakeholders involved in that research to understand the current regulatory landscape.
David and Beth recently published a helpful article on this topic for AHLA Health Law Weekly entitled “Seeing Past the Smoke: Regulatory Considerations for Public Health Research on Commercially Available Cannabis.” David, why don’t you kick us off: What issues were you seeing that led you and Beth to write this article?
Writing About Cannabis Research
David Peloquin: Thanks, Josh. We observed an emerging public health research interest—specifically, researchers were wanting to understand how consumer-level cannabis use is impacting the overall health of individuals and their communities. Now, this is not a totally new area of interest for researchers, but it has taken on significantly more importance in recent years given the widespread availability of cannabis products, and the variety of ways they are obtainable legally in many states. Researchers have been looking and trying to better understand how cannabis products are being used by individuals (including the frequency, amount, dosage calculations, “indications,” and timing of their use), and what effect that use has on specific measurable indicators of physical health, as well as physical and mental functioning. Researchers also want to study the effect the availability of legal cannabis products has on other substance use. But, despite broader legalization trends for cannabis products, largely at the state level, research involving cannabis products is still subject to a complex patchwork of laws and regulations that are not necessarily readily apparent to public health researchers.
We wanted to peel apart the layers of this fragmented regulatory landscape to educate researchers and research institutions in two ways:
• First, we wanted to make clear who needs to be at the table to issue-spot, so that cannabis research won’t pose unanticipated legal risk to the researchers and their institutions.
• Second, in drilling down on some of the projects, we could not help but notice that some of the regulatory hurdles seemed potentially insurmountable—despite a lack of clear policy reasons for precluding the research. So, we thought it would be useful to expose some of the ways in which regulatory paradigms get in the way of conducting this important research—perhaps unintentionally. We also saw an opportunity for regulatory evolution and advocacy by researchers, which was really interesting.
Cannabis Is Different
Josh Oyster: So, Beth, why is research with cannabis different from research with other drugs, and even other controlled substances?
Beth Weinman: I think the answer to that is that cannabis is easily accessible and legal without a prescription under state and local law in many places—not everywhere, but in a lot of places. And this is the case despite the fact that it’s not been deregulated federally. The status of cannabis is confusing, and many people may not be thoughtful about the risks of conducting research with cannabis. But, in fact, there is a significant overlay of regulation that’s specific to the use of cannabis in the research context and hoops that the average consumer doesn’t have to jump through to use cannabis recreationally or even potentially for therapeutic purposes. So, that’s a real difference, I think, between research with cannabis and other drugs. I’ll note cannabis is regulated by a number of different regulatory bodies, and in some cases, regulators even have directly opposing policies. I can try and break that down.
Cannabis is, and has been for decades, classified as a Schedule I drug defined under the Control Substances Act (“CSA”), which is administered by the Drug Enforcement Administration (“DEA”) as “a drug with no currently accepted medical use and a high potential abuse.” Now, we know today that it’s not actually true that there’s no medically accepted use for synthetic and natural forms of THC, which is an ingredient in cannabis that’s responsible for the high that many people seek in recreational use. There are also medically accepted uses for CBD, another substance in the cannabis plant. Nevertheless, marijuana or cannabis remains a Schedule I drug, though, as Josh mentioned, there is an effort underway to have it rescheduled.
Over the past decade, many individual state controlled substances regulators and prosecutors who were once in total alignment with federal drug regulators have changed their stance, and state and local laws have been passed making marijuana legal, or at least decriminalized, as a medical or recreational consumer product. Now, again, that’s not everywhere, but it’s in a lot of places. In the process of legalization or decriminalization, some states have also set up control agencies for cannabis, like alcohol control boards, that put parameters around who can do what with the substance. Some states also have regulations governing research that’s conducted with federally controlled substances, regardless of the substance’s status at the state level.
On top of all this, there’s the Food and Drug Administration (“FDA”). The Food and Drug Administration regulates, as drugs, any “articles intended for the use in the…cure, mitigation, [or] treatment of disease in man or other animals” and articles other than food that are “intended to affect the structure or function of the body of man.” To be clear: medical marijuana and recreational cannabis consumed for any physical or psychoactive effects fit squarely within the definition of “drug” within the Federal Food, Drug, and Cosmetic Act (“FDCA”).
Types of Cannabis Research
Josh Oyster: Thanks, Beth. What kinds of research are you seeing from health care institutions and others in this sector?
David Peloquin: Happy to take that one, Josh. We see the research as falling in two primary buckets:
The first bucket includes the investigation of cannabis for specific therapeutic uses for the purpose of commercializing a medical treatment. Think about the development and research pathway for cannabis-related products that have already been approved for certain indications (for example, purified CBD for certain seizures or synthetic THC for the side effects of chemotherapy). While researchers in this camp might be curious about the possibility of using commercially available cannabis in such studies, this was not the main focus of our recent article. That’s because these kinds of studies need to be more controlled and have a consistent source of investigational product with specific parameters. Such products would not reliably be obtainable in the consumer marketplace. But, more importantly, researchers approaching cannabis from this angle, that is, seeking development and commercialization of a medical product, are likely thinking of it in the same vein as any other experimental, investigational substance. This is standard drug research where researchers, institutions, and companies conducting the research have staff who are used to considering all the angles of FDA, DEA, and related regulation.
The second bucket of research, and the primary audience for our article, were institutions and researchers that were much more focused on studying the real-world conditions of consumer cannabis use. In this type of research, there is no interest in a controlled supply or potentially any particular supply for that matter. These researchers are interested in understanding on a macro level what sorts of cannabis products are available in the community, how they are being used, and what sort of varying impacts (both objective and subjective) they are having on users and/or the community. We also imagined that this audience would be less familiar with the types of regulations that we’ve been discussing. But even a seemingly straightforward study that could involve a researcher going to a dispensary and buying up a stock of products for individuals to come and consume as they choose and be observed, is actually just as highly regulated as the therapeutic-type study of the first bucket. An interesting question arises when a study does not involve the researcher handling the cannabis product under study, that is, when the researcher isn’t actually involved in the provision of the investigational product and is only observing the use and potentially measuring impacts of the use of the product, whether through taking vital signs, blood draws, brain scans, or urine analysis. It was this type of study that was the focus of our article.
Regulatory Oversight of Cannabis Research
Josh Oyster: Thanks, David. And, Beth, how do regulators at the federal level—like FDA and DEA—and at the state level think about these different types of research activities?
Beth Weinman: That’s a good question, Josh. I think, of course, it depends on what research is presented to both of these agencies, but I’ll start with FDA. For FDA, many types of drug studies require an investigational new drug (“IND”) submission. Primarily, interventional research with investigational substances—either those that are wholly unapproved or protocols looking at approved drugs for unapproved uses—will need INDs. But FDA has also taken the position that INDs can be required—when not exempt—for any study design that provides any form of instruction or limitation of choice regarding the administration of the investigational drug products. I’ll note that the question of when drug studies are exempt from the need for an IND is a topic that would take much more time to explore than we have today.
But back to the idea of limitation of choice—for example, a protocol that says participants may consume as little or as much marijuana as they want in the delivery vehicle of their own choosing, but where the protocol says they can’t have any marijuana at all for 24 hours before the study starts, and they have to consume their marijuana of choice, for example, at 11:00 a.m. and 5:00 p.m. each day for five straight days. And this, of course, is a hypothetical and wholly fictional example, but that is a protocol that FDA would see as limiting choice, and FDA may consider that a research study that requires an IND. Whether this position is appropriate at all under the FDCA is a separate question—considering the purpose of this IND authority in the statute is to permit the interstate movement of a drug that couldn’t be shipped without the IND. So, you have to ask the question: does FDA really have the statutory authority to require an IND in a situation involving a study design where the researcher is not touching the drug at all, is not causing the shipment of the investigational product, and is not involved at all in the movement in interstate commerce? But this is a position FDA has taken publicly in warning letters involving other types of drug products, so I think it’s a position that researchers have to grapple with.
Researchers may not be thinking, or are likely not thinking, about the possible need for an IND in the context of public health research. We’ve seen this a lot and especially when a study is designed to look at real-world use where the researcher actually has no role at all in providing investigational product. I’ll note that FDA does offer avenues for agency consultation as to whether an IND is needed in a specific situation, and consultation around whether there might be an exemption from some of the requirements for an IND submission or waivers, if, for example, information in those sections can’t be provided or doesn’t make sense for one reason or another. And this can be useful, especially in some situations where the IND requirements are a very awkward fit for the kind of uncontrolled research that a public health researcher is looking at. For example, in the protocol I described: How do you provide manufacturing information, CMC (which is the chemistry, manufacturing, and controls section of an IND), when every participant is going to be using a different product? That’s absolutely impossible. But I’ll also note, FDA may be unwilling to approve the IND for these very specific reasons—the lack of certainty as to what, exactly, the subjects are going to be consuming. So, researchers really need to consider their outreach very thoughtfully.
There may also be issues with the uncontrolled nature of dosing, such as if study subjects are allowed to consume as much cannabis as they’d like to reach a subjective goal, without there being a clear measurement researchers can use to know how much cannabis was actually consumed. Additionally, while FDA does not require INDs for clinical investigations of dietary supplements where the intent of the investigation is to evaluate the supplement’s effect on the structure or function of the body, people should know that cannabis products are disqualified from the dietary supplement definition because of the presence of THC and CBD, because those ingredients do exist in approved drugs. So, researchers need to be aware that they don’t get out from under the IND analysis by trying to claim that the investigational substance is a “dietary supplement.”
Josh Oyster: Thanks so much, Beth. A lot of really interesting issues there on the FDA side. But what about the rules for research on the DEA side?
David Peloquin: Happy to speak to that, Josh. From a DEA perspective, DEA regulations come from the federal Controlled Substances Act, which is completely separate from any state laws about controlled substances. The DEA regulations are tied to the researcher’s direct level of interaction with the substance, such as researcher procurement, handling, storage, or dispensing of the product, for example. Since marijuana is currently still a Schedule I substance, a Schedule I researcher registration is required for investigations with marijuana in which the researcher handles the marijuana, and to the extent the researcher is touching the marijuana in the study, it must be sourced from a list of DEA-approved suppliers, which historically has been very limited. However, this requirement is directly opposed to any public health researchers that might want very intentionally not to study carefully cultivated crops and prefer instead to look at what kinds of products are available in the broader marketplace. One way potentially to avoid the sourcing requirement is ensuring the protocol prevents any researcher interaction with the cannabis and avoiding use of cannabis on the property of the research institution.
Josh Oyster: Thanks, David. In December 2022, so a little over a year ago, Congress passed the Medical Marijuana and Cannabidiol Research Expansion Act (“MMCREA”). How did that affect the DEA landscape for research involving cannabis?
David Peloquin: That’s a great question. For researchers themselves, the MMCREA (as I have abbreviated here) potentially streamlines and expedites the process by which registration applications are reviewed and approved by the attorney general. The attorney general under the Act “shall register a practitioner to conduct research with marijuana” if the applicant’s research protocol has been reviewed and allowed either i) under FDA’s IND regulations, ii) by the National Institutes of Health (“NIH”) or another agency funding scientific research, or iii) pursuant to DEA’s Schedule I research review process—so, you have to meet one of those three prongs of the statute—and the applicant also needs to demonstrate that there are effective procedures to adequately safeguard against diversion of the marijuana. MMCREA also gives an explicit timeline of 60 days on which such an application should be approved by the attorney general or more information should be requested from the applicant. MMCREA also allows for simplified research protocol changes in regard to quantity, type, source, and conditions of storage of marijuana, with changes automatically proceeding unless a researcher is explicitly notified otherwise by the attorney general. On the supply side, MMCREA included provisions to ease the ability for new cannabis cultivators to become DEA-approved. And it is additionally worth noting, I think, that even before MMCREA was enacted, the DEA was in the process of expanding the number of approved cultivators of research-grade marijuana. Through 2021, only one entity (the National Center for Development of Natural Products at the University of Mississippi) was permitted to cultivate research-grade marijuana. By August 2022, six additional such suppliers had been DEA-approved.
Josh Oyster: Thanks, David. So, we’ve talked about the federal level at the FDA and DEA—I’ll talk about state regulation for a moment. There are essentially 50+ distinct state regulatory regimes in play in the U.S., so it’s hard to say with any degree of certainty during this podcast what regulations a researcher in a given state will have to comply with. But the important thing to note is that analysis needs to be done before an investigator starts the research. Those who conduct a study without understanding the regulatory hurdles or pitfalls that may be in front of them—and then publish the results—they may be in for a surprise if regulators catch wind of the publication and then start asking questions. Some jurisdictions require certain kinds of cannabis research studies to have a state license before proceeding. For example, in New York, where the Office of Cannabis Management is charged with creating and administering cannabis regulations in the state, a special research license must be obtained in order to conduct much research with state-regulated cannabis products.
Beth Weinman: Josh, I’ll just note: it’s really important for researchers to make sure they fully understand the parameters of the legality of cannabis within their jurisdictions. The amount of cannabis that any individual can legally possess—as you’ve described, and as we’ve talked about in the article—can vary wildly, and it can depend on whether the cannabis is for “medical” or “recreational” use. Cultivation of marijuana can be subject to strict amount limitations, or even be entirely illegal if possession and use is illegal in certain circumstances or in certain places. Researchers need to be very thoughtful about where they’re conducting their research and what the local laws are, because they certainly don’t want to be involved with, or seen encouraging, illegal activity for reasons it’s obviously not hard to understand.
Potential for Regulatory Evolution
Josh Oyster: Thanks, Beth. I think that brings us back where I want to look more at the 10,000-foot level here and the way forward. What can researchers or other advocates do about the fact that the current regulatory landscape might, in certain respects, get in the way of useful research that people want to do? What’s the best way to move forward?
David Peloquin: I think there’s a few things one could think about here, Josh. First, the problem should be identified and recognized. Some regulatory structures, as they currently exist, simply did not contemplate the wide availability and legality of cannabis products—and they never thought about the question of public health research into use of legal substances with potentially significant public health impacts. And what you end up with is this perverse situation where a product—one that we know can have dramatic and immediate effects on physical and mental functioning—is widely available to a huge number of consumers, but researchers are limited in their ability to examine the impact of the product.
When you think about the types of institutions we had in mind while writing this piece—and that was universities and academic medical centers whose public health researchers may be trying to make sense of a sudden explosion of legal cannabis use in their surrounding community—it may not make sense to subject such research to all the same controls that are also applied to, let’s say, a biotech company looking to synthesize chemicals out of marijuana and study them for submission to FDA to support a new drug application. We’re really talking about apples and oranges here. Given the number of regulators operating in this space, it’s difficult to come up with a “simple” solution that solves all these problems, but dialogue with regulators is critical. We have found that many regulators—especially state regulators—are open to hearing about novel issues and questions from the regulated community, and ensuring regulations or interpretations of regulations are adapted to facilitate meaningful research. We’re not sure that federal regulators, like FDA, are there yet, but they may not be focusing on the issue, they may not see the research as worthy, or they may think these types of studies have significant enough risk that they need close monitoring. But whether FDA should be that monitor is another question when the research purpose is so far afield from FDA’s core mission. But there may be room here for education and advocacy with other federal agencies, like the Centers for Disease Control and Prevention (“CDC”) potentially, the Department of Health and Human Services (“HHS”) Office for Human Research Protection (“OHRP”), or the Substance Abuse and Mental Health Services Administration (“SAMHSA”).
For the Controlled Substances Act and the DEA, there have been recent efforts, such as the Medical Marijuana and Cannabidiol Research Expansion Act, that we spoke of earlier, to make it easier for researchers to obtain and work with DEA-approved cannabis products. But these don’t really help with the case of a research institution that’s looking specifically to study the cannabis products that are already in its own backyard. Recently, a memorandum was sent by HHS to DEA to recommend the rescheduling of marijuana from Schedule I to Schedule III, which would significantly ease the burdens on researchers (and others) looking to work with marijuana products. The issuance of this memo came in response to a call from President Biden to the HHS Secretary and U.S. Attorney General to review how marijuana is scheduled in the Controlled Substances Act, which, itself, was part of a broader slate of White House marijuana reforms. But, moving marijuana to Schedule III would not eliminate the broader issues regarding the study of cannabis that’s circulating out in the commercial marketplace that we’ve been focused on during today’s podcast. Manufacturers and distributors of all controlled substances are to be registered with the attorney general, and it seems unlikely that all cannabis cultivators operating to supply state-level marketplaces will immediately register with DEA upon rescheduling. This means that the CSA-compliant cannabis products that DEA-registered researchers could legally obtain would not accurately represent the commercial marketplace.
Josh Oyster: Thanks, David. Beth, how do you see the landscape evolving in the future?
Beth Weinman: For one, I definitely don’t see any reversal of the trend towards greater local legalization of cannabis in the future. Especially with recent rescheduling efforts at the federal level, it seems like we have crossed a tipping point in terms of broad legality. But we think it’s up to the research community to really understand the policy interests in the regulation that exists and the policy interests for the research that they want to conduct, and propose frameworks that make sense for this area and that are likely to be acceptable to regulators. Researchers who are working in this space need to have an appreciation for what is motivating the current regulatory structure and how that could apply to them. Then they need to start speaking up about the importance of their research, the unjustified difficulties that regulations pose—and sometimes, like we mentioned before, that potentially wholly preclude the research they want to do—and they should propose their ideas for what could be changed to ensure appropriate oversight without wholly precluding that research or making it simply too expensive to conduct. Researchers and their advocates should bring the right stakeholders together and grapple with these issues, so we don’t miss out on understanding the broader societal health impacts arising from use of these products and opportunities for optimizing safety and public health.
Josh Oyster: Thanks, Beth, and thanks, David. I think that’s all the time we have for today’s episode. Thanks also to our listeners for tuning in. If you have any questions regarding the cannabis topics we covered today, please don’t hesitate to contact one of us—we will continue to be monitoring this evolving landscape. And as a reminder, you can listen to Controlling Opinions and other RopesTalk podcasts through our ropesgray.com website, or you can subscribe wherever you listen to podcasts, including on Apple and Spotify. Thanks again for listening.