Abuse Potential for Narcolepsy Drugs? The FDA Wants to Know

For many drugs on the path to Food and Drug Administration (FDA) approval, the road to the prescription pad runs through "abuse potential assessment." Few people in the world know more about the topic than Jack E. Henningfield, PhD, professor adjunct of Behavioral Biology in the Department of Behavioral Sciences at the Johns Hopkins University school of Medicine.

For JZP-110, a medication designed to boost wakefulness in narcoleptics, Dublin, Ireland-based Jazz Pharmaceuticals called on Henningfield to gauge the drug's abuse potential. It's a crucial step in the FDA approval process, and Henningfield, also on staff at Pinney Associates, closely studied the question.

Henningfield was an advisor on a study on the abuse potential of JZP-110, and a co-author on a poster describing their findings which was on display at the recent American Professional Sleep Societies (APSS) meeting in Denver. The poster was entitled, A Randomized, Double-Blind, Placebo-Controlled, Crossover Study for Evaluation of Human Abuse Liability of JZP-110.

"What the FDA promotes is for developers to find drugs that work as well or better than amphetamines, but have a lower risk of abuse profile," explains Henningfield. Up until a decade ago, drugs for helping people stay alert and awake were mostly "schedule II" stimulant drugs.

"Amphetamines work for that [staying alert], but they are highly abusable drugs," he says. "What's really exciting about JZP-110 is that it looks like it has a substantially lower risk of abuse. For the FDA to be assured that a new drug really is of lower abuse potential, it requires a lot of questions to be answered by scientific studies.

"For example, FDA wants to know where it works in the brain and what it does," continues Henningfield. "Does it look like amphetamine? We want to know if it looks like an abusable drug in animals. Does it look less abusable by the many tests we rely upon?"

There are many studies and at this point, Henningfield says, "the signals suggest a new medicine with significantly less abuse potential than amphetamine."

Although all lines of evidence are important, the most important single study to evaluate the relative abuse potential of new drugs is the human abuse potential study. Thus, this human abuse liability study "is a big deal" in assessing JZP-110.

Troublesome findings can halt a drug's approval, and it's certainly a phenomenon that Henningfield has seen during his abuse liability work that started in the 1970s. High profile celebrity deaths have fueled a renewed focus on abuse potential by the public, but it's nothing new for the FDA that has been evaluating drugs for abuse potential for decades, or for scientist such as Henningfield, who has studied countless pharmaceuticals and non-prescribed substances. "I live and breathe abuse potential assessment," he says.

The American Sleep & Breathing Academy (ASBA) sat down with Henningfield to learn more about his specific work with JZP-110, as well as the overall topic of abuse potential assessment.

ASBA: What is the rationale behind abuse potential assessment?
Jack E. Henningfield, PhD, professor adjunct of Behavioral Biology in the Department of Behavioral Sciences at the Johns Hopkins University school of Medicine: Any time you are dealing with and developing a drug that is a new drug—a new molecular or chemical entity— that affects the central nervous system [CNS] you have to do what is called an abuse potential assessment for the FDA. In the same way that you have to look at the safety from the perspective of cardiovascular risk and liver disease and everything else, you have to thoroughly investigate its abuse potential risk.

ASBA: What is your definition of abuse potential?
Henningfield: Abuse potential is the risk that a drug will be used by people for inappropriate reasons like getting high, and that it might pose a risk for patients, and/or might be a target for people who are not patients. When the FDA knows that, they have to look at the data and base a recommendation as to how to restrict the drug, under what is called the Controlled Substance Act laws and regulations.

ASBA: What are some examples of schedule I drugs?
Henningfield: Drugs that have no medical use but carry a significant risk of addiction or abuse like heroin are placed in schedule I. Drugs that are highly addictive but have medical use and are approved are placed in schedule II—that would be like oxycodone or morphine or amphetamine.

ASBA: What types of wakefulness drugs have there been?
Henningfield: For helping people stay alert and awake, until a decades or so ago, the main drugs were the schedule II stimulus. An amphetamine works for that, but it's a highly abusable drug, and so what FDA promotes is for developers to find drugs that work as well or better than amphetamines, but have a lower risk of abuse profile. What's really exciting about JZP-110 is that it looks like it has a substantially lower risk of abuse.

ASBA: What types of conclusions were researchers developing decades ago?
Henningfield: What they found decades ago was that if you take people from the general population who do not abuse drugs and give them drugs of abuse, some people like them and others don't. But if you take people who have histories of drug abuse, they are kind of like the wine connoisseurs who know the good wine and can even tell you what type of wine it is by tasting it. In studies like this, you look for people who have histories of abusing the category of drug of interest because are expert in evaluating such drugs. That way, you have people who are sensitive. They know what they are looking for when they are looking for an abusable drug. They also represent a population of great concern for abuse of that category of drug.

ASBA: And what were the particulars of the JZP-110 study?
Henningfield: So in this case, there were 43 adults that ended up in the study. Thirty-seven completed all of the conditions, and they all had histories of recreational stimulant abuse. For abuse potential studies this is a large and adequately powered size to provide reliable findings. The volunteers must bepeople who were healthy; they weren't currently so heavily using that they could not safely and ethically participate, but they were all people who knew a good stimulant for abuse when they felt it. In other words, they've tried stimulants like cocaine and amphetamine and they like to use them.
Then, in a very careful laboratory environmentthat is designed to be safe and ethical, and provide valid results, they participate as in patients, on an in-patient research unit. And that way you can make sure that they are safe, not getting any other drugs and that you can get reliable and valid data. You give them what is called the positive control, and the positive control will be something that you know produced an affect—and you also are using it to compare the new drug.

ASBA: What comparisons can be made to other medications?
Henningfield: Abuse potential is always relative. In this case, the comparator drug was a weak stimulant called Phentermine. It is a stimulant that's placed in schedule IV of the controlled substances act. Remember I said amphetamine was schedule II, so Phentermine is down the road quite a ways. If caffeine is a stimulant, but it's not scheduled because it has been used for millennia in a generally safe manner and its use and even dependent use by some is accepted by society.

ASBA: If caffeine were introduced today, what would be its classification?
Henningfield: If caffeine was a new drug, I think the FDA might say, you know what, we're going to think about placing it in III, IV, or V. I'm not sure where they would put it, but from an abuse potential perspective it would seem to be well within the range of many Schedule IV drugs with respect to risk for compulsive use, physical dependence, and reinforcing effects.

In other words, Phentermine is closer to caffeine than it is to amphetamine, but it does have a documented abuse potential—and some people do abuse it, so that is the comparator. You look at how quickly does its effects onset, and what effects does it produce and how strong the effects are. The single most powerful measure is how much you like it right now. It seems so simple, but this measure of abuse potential does go back a half a century—liking at the moment.

ASBA: How did you account for dosage variations in the JZP-110 study?
Henningfield: Another characteristic of a valid study, is you push the dose…for the purpose of the study, it was assumed that it was around 300 milligrams. What's important is that on the street, people take higher doses than what are approved. What you do for a valid study is you push the dose, basically as high as you think you safely can, and in this case it went up to 1,200 milligrams. And that was considered, based on all of the preliminary data, an extremely high dose. A dose where, quite frankly, you start getting at least some side effects that people don't like. That is an important factor that makes this a powerful study. Depending on how you look at it, it went up to 3 or 4 times what is likely to be the highest clinical dose.

ASBA: What did you find when you did that?
Henningfield: What we found is that every dose of JZP-110, the liking score was lower than the high dose Phentermine. That doesn't necessarily mean that it is going to be scheduled less restrictively, but it fits with the other data that we are seeing, that conservatively, it looks no more abusable than Phentermine—and if anything, on the lower side. So for someone like me who is on the search for medicine with lower risk of abuse, lower risk of diversion, lower risk of addiction—to help people with medical needs, this is what we are looking for.

ASBA: What happens now? What will they do with these results?
Henningfield: The company will ultimately develop a new drug application to the FDA, and I don't know what their timeline is. At this point, on many aspects of the research program, FDA has input on the studies, like this abuse potential study. The NDA will have a section called the Integrated Safety Summary. That will look at all of the safety profile, from all the data that they have. It will look at how well it works – its efficacy. Everything that is related to safety, benefits, labeling will be carefully considered by FDA. One part of that package will be called the abuse potential assessment.

ASBA: What will the abuse potential document look like?
Henningfield: The abuse potential assessment will be a major document that will bring together everything that is potentially relevant to the abuse potential; where does it work, how does it act? What did the animal data look like? In animals, by the way JZP-110 it looks less abusable than amphetamine. The human abuse potential study, among all of the lines of evidence will be one of the single most important studies that FDA will consider, and that the company will consider in their recommendation. It's premature for me to say what the recommendation would be, because all lines of evidence, including the pivotal phase 3 efficacy and safety data need to be carefully assess in the abuse potential section that has yet to be developed.

ASBA: What is the profile of medicine at this point?
Henningfield: At this point, what we see from this study, is the profile of a medicine that looks more in the range of the schedule IV drugs than the schedule II drugs. I'm being very careful here, because there will be a single sentence at the end of the abuse potential assessment, it will be probably 100 or 200 pages with 1,000 or so pages of supplements, and there will be one sentence at the end recommending the schedule placement, a single number.

Whatever the number will be is to be determined, but now it's exciting because it looks like it's heading in the direction of something that will have a lower risk for abuse than strong stimulants like amphetamine. By law of the Controlled Substances Act, FDA develops its own recommendation, and they will look at what they call eight factors, and they will come up with their own scheduling placement number. Generally, when the companies are working with experts in this area, they try to come up with what they believe represents all of the scientific data and will be credible to the FDA.

We will all work together to make sure that we make a recommendation that will be credible and hopefully accepted by the FDA. By law, the National Institute on Drug Abuse (NIDA) will also have input and the input of FDA and NIDA will be the basis for the Assistant Secretary of the Department of Health and Human Services's recommendation to the US Department of Justice (DOJ). The DOJ's Drug Enforcement Administration, will take the DHHS's recommendation into consideration as it develops its proposed rule for scheduling.

This scheduling recommendation will be published in the Federal Register, allowing typically 60 days for public comment. After the comment period, DOJ/DEA will publish the final rule – the official schedule for the drug. Then the drug labeling can be completed and the drug can be marketed. In practice, FDA's recommendation is rarely deviated from by NIDA and DOJ/DEA.

About Jack E. Henningfield, PhD: Henningfield is one of the leading experts on addiction, and the behavioral, cognitive, and central nervous system effects of various drugs and drug formulations and the implications of such information for drug scheduling, and other labeling and risk management. He is professor adjunct of Behavioral Biology in the Department of Psychiatry and Behavioral Sciences at The Johns Hopkins University school of Medicine, and vice president for Research, Health Policy, and Abuse Liability at Pinney Associates.

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