Tag: FDA

Add Hepatitis C to the List of Unintended Consequences of Abuse-Deterrent Opioids

One year ago Cato published my policy analysis, “Abuse-Deterrent Opioids and the Law of Unintended Consequences,” which provided strong evidence that reformulating opioids, so that they could not be crushed for snorting or dissolved for injecting by nonmedical users, only served to drive nonmedical users to more dangerous, readily available, and cheaper heroin provided by the efficient black market. 

The evidence included a RAND study that found “a substantial share of the dramatic increase in heroin deaths since 2010 can be attributed to the reformulation of OxyContin” which replaced regular OxyContin in 2010. It also included a study from researchers at Notre Dame and Boston Universities that found:

When we combine heroin and opioid deaths together, we find no evidence that total heroin and opioid deaths fell at all after the reformulation—there appears to have been one-for-one substitution of heroin deaths for opioid deaths.

Now comes a new RAND study that finds the abuse-deterrent reformulation of OxyContin led to an increase in cases of hepatitis C from IV drug use. As nonmedical users switched from OxyContin to injectable heroin, more became exposed to hepatitis C, transmitted by needle sharing.

The study compared states with above-median misuse rates of OxyContin to states with below-median misuse rates before and after the drug’s reformulation—from 2004 to 2015. Prior to the reformulation there was almost no difference in hepatitis C infection rates between the states. After the reformulation, states with above-median misuse rates saw a 222 percent increase in hepatitis C infections, while the below-median states saw a 75 percent increase during the same period. 

Add hepatitis C to the list of unintended consequences from abuse-deterrent reformulation of opioids.

Despite mounting evidence that abuse-deterrent reformulation of opioids has done nothing to reduce overdoses but may in fact be adding to them, the Food and Drug Administration continues to encourage pharmaceutical manufacturers to bring more abuse-deterrent formulations to market. As was the case with OxyContin, reformulation often results in extension of existing patents, reducing competition from generics and allowing patent holders to charge and profit more from their product. So opioid manufacturers are answering the FDA’s call for more abuse-deterrent reformulations.

Now that we have strong evidence that abuse-deterrent formulations spread disease as well as death, perhaps the FDA will reconsider this ill-advised policy.

Topics:

The FDA Bends Over Backwards To Get Drug Makers To Ask Them To Make Naloxone OTC

Press reports have created the impression that the opioid overdose antidote naloxone is now available over the counter. But in fact, the drug is still classified in the US as prescription only, so states have developed workarounds to make it easier for patients to obtain it without going to a doctor for a prescription. In most states, patients can get naloxone by going up to the counter and asking the pharmacist, who is legally authorized by the state to dispense it. 

But some states prohibit third parties from obtaining a prescription for another person, so people in those states who wish to have the antidote available because they have a friend or relative who uses opioids cannot obtain it. And experience shows that many pharmacists choose to not stock naloxone or participate in any distribution program. Furthermore, the stigma now attached to opioid use has deterred many patients from going up to the pharmacy counter and explaining to a pharmacist why they need naloxone.

To get around such obstacles, Australia and Italy have designated naloxone as a truly over-the-counter drug. People can discreetly buy it off the shelf and check out at the cash register.

The Food and Drug Administration is on record since at least 2016 as believing that it is probably appropriate for naloxone to be rescheduled as OTC and has encouraged manufacturers to petition the FDA to that end. Yesterday  FDA Commissioner Gottlieb announced the FDA has even gone to the trouble of designing Drug Facts Labels (DFL) required of manufactures for their products to be sold over the counter, and has even tested these labels for “consumer comprehension” in front of focus groups. The Commissioner stated in the announcement that this represents an unprecedented effort to facilitate and speed up the reclassification of naloxone from prescription-only to OTC.

This is commendable. But as I have written herehere, and here, the Commissioner does not have to wait for manufacturers, who may lack the incentive, to request the move to OTC. Under FDA regulations, the FDA can undertake reclassification review at the request of “any interested person,” or the Commissioner himself. States may petition the FDA for reclassification. Finally, if all else fails, Congress can order the reclassification.

The FDA should no longer wait for manufacturers to ask them to make this lifesaving drug more accessible to those in need.

Has Opioid Hysteria Risen to the Point Where Innovation Is Forbidden?

On November 2 the Food and Drug Administration announced the approval of Dsuvia, a sublingual tablet containing the powerful fentanyl analog, sufentanil. Sufentanil has been used for years in the hospital setting, primarily in intravenous form for anesthesia. It is roughly 5 to 10 times more potent than fentanyl, and thus has a significant overdose potential. The FDA reached this decision following a 10-3 vote in favor of the drug’s approval by the Anesthetic and Analgesia Drug Products Advisory Committee (AADPAC), based on data from multicenter trials. It was not approved for outpatient use, but for use only in medically supervised settings, and may be of particular benefit to military health care practitioners.

FDA Commissioner Gottlieb’s announcement stated:

Dsuvia, which was previously approved by the European Medicines Agency in July under the brand name Dzuveo, has some unique features in that the drug is delivered in a stable form that makes it ideally suited for certain special circumstances where patients may not be able to swallow oral medication, and where access to intravenous pain relief is not possible. This includes potential uses on the battlefield. For this reason, the Department of Defense (DoD) worked closely with the sponsor on the development of this new medicine. This opioid formulation, along with Dsuvia’s unique delivery device, was a priority medical product for the Pentagon because it fills a specific and important, but limited, unmet medical need in treating our nation’s soldiers on the battlefield. The involvement and needs of the DoD in treating soldiers on the battlefield were discussed by the advisory committee.

The announcement was met with criticism from numerous quarters, including Anesthesiology Professor Raeford Brown of the University of Kentucky, who chairs the AADPAC, Senator Edward Markey (D-MA), and the advocacy group Public Citizen. They questioned the need for the development of a new and potent opioid in the presence of the opioid overdose crisis, and raised concerns about the potential for the drug’s diversion to the black market for non-medical users. These objections were trumpeted by the media.

The concerns raised by critics are unfounded. According to the Drug Enforcement Administration, most fentanyl and fentanyl analogs found on the streets are in an illicit powdered form, made in labs overseas and smuggled into the US via the mail, Fedex, and UPS, or using Mexican drug cartel infrastructure. While much of it is mixed in with heroin or cocaine, many dealers own pill presses and press the powder into counterfeit oxycodone or hydrocodone pills that are sold to unsuspecting nonmedical users. That’s how the artist known as Prince died. He liked to use Vicodin (hydrocodone) recreationally. Records show he never obtained any prescriptions from doctors. His dealer sold him what was believed to be Vicodin but was actually counterfeit and made from fentanyl, which caused his overdose death.

Recrudescent opiophobia now evokes positions held at the zenith of President Nixon’s war on drugs. The fact remains that opioids can be highly effective in treating pain, especially in the acute setting. Hysteria-driven policy should not stifle innovations in this or other forms of pain management.

Commissioner Gottlieb also stated in the FDA announcement:

We owe an answer to patients with medical pain, and the innovators who take risks to develop products to help address their needs. We owe it to Americans who want the FDA to do our part to help end one of the biggest addiction crises of modern times, while we carefully balance these grave risks against patient needs.

Commissioner Gottlieb made the right call here.

New FDA Initiative Implies CDC Opioid Guidelines Are Not Evidence-Based

On August 22, Food and Drug Commissioner Scott Gottlieb issued a press release announcing the FDA plans to contract with the National Academies of Sciences, Engineering, and Medicine (NASEM) to develop evidence-based guidelines for the appropriate prescribing of opioids for acute and post-surgical pain. The press release stated:

The primary scope of this work is to understand what evidence is needed to ensure that all current and future clinical practice guidelines for opioid analgesic prescribing are sufficient, and what research is needed to generate that evidence in a practical and feasible manner.

The FDA will ask NASEM to consult a “broad range of stakeholders” to contribute expert knowledge and opinions regarding existing guidelines and point out emerging evidence and public policy concerns related to the prescribing of opioids, utilizing the expertise within the various medical specialties. 

Recognizing the work of the Centers for Disease Control and Prevention for having “taken an initial step in developing federal guidelines,” Commissioner Gottlieb diplomatically stated the FDA initiative intends to “build on that work by generating evidence-based guidelines where needed” that would differ from the CDC’s endeavor because it would be “indication-specific” and based on “prospectively gathered evidence drawn from evaluations of clinical practice and the treatment of pain.”

The CDC guidelines for prescribing opioids, released in early 2016 and updated in 2017, have been criticized by addiction and pain medicine specialists for not being evidence-based. Unfortunately, these guidelines have been used as the basis for many new prescribing regulations instituted at the state-level and proposed on the federal level. The American Medical Association and other medical specialty organizations have spoken out against proposed federal prescription limits that are based upon an inaccurate interpretation of the flawed CDC guidelines. 

In May, Commissioner Gottlieb, in a blog post, mentioned he was aware of criticisms as well as complaints by patient and patient-advocacy groups and was interested in developing more “evidence-based information” on the matter of opioids and pain management. 

Now it appears he is taking the next step. While the press release language was diplomatic and avoided any notion of disrespect for the CDC’s efforts, it is difficult not to infer that the Commissioner agrees with many who have been criticizing the CDC guidelines over the past couple of years.

 

FDA Commissioner Gottlieb’s Sunday “Tweetorial” Is Both Encouraging and Frustrating

A fair reading of Food and Drug Administration Commissioner Scott Gottlieb’s “Sunday Tweetorial” on the opioid overdose crisis leaves one simultaneously encouraged and frustrated. 

First the encouraging news. The Commissioner admits that the so-called epidemic of opioid overdoses has “evolved” from one “mostly involving [diverted] prescription drugs to one that’s increasingly fueled by illicit substances being purchased online or off the street.” Most encouraging was this passage:

Even as lawful prescribing of opioids is declining, we’re seeing large increases in deaths from accidental drug overdoses as people turn to dangerous street drugs like heroin and synthetic opioids like fentanyl. Illegal online pharmacies, drug dealers and other bad actors are increasingly using the Internet to further their illicit distribution of opioids, where their risk of detection and the likelihood of repercussions are seen by criminals as significantly reduced.

As I have written here and here, the overdose crisis has always been primarily caused by non-medical users accessing drugs in a dangerous black market fueled by drug prohibition. As government interventions have made it more expensive and difficult to obtain diverted prescription opioids for non-medical use, the black market responds efficiently by filling the void with heroin, illicit fentanyl (there is a difference) and fentanyl analogs. So policies aimed at curtailing doctors’ prescriptions of opioids to patients only serve to drive up deaths from these more dangerous substitutes, while causing patients to suffer needlessly, sometimes desperately, in pain. Gottlieb validates my argument in his “tweetorial,” providing data from the Centers for Disease Control and Prevention and the Drug Enforcement Administration.

Now for the frustrating news. Gottlieb next reminds us, “No controlled substances, including opioids, can be lawfully sold or offered to be sold online. There is no gray area here.” He provides evidence of rampant illegal internet marketing of prescription opioids, with 95 percent of internet pharmacy websites selling opioids without a prescription, often conducting transactions with cryptocurrencies, and shipping these orders “virtually anywhere in the US.” This is also the way illicit fentanyl is flooding the market.

A Right To Try — But for How Many? And For How Long?

President Trump has signed legislation restoring the right of some terminally ill patients to determine the course of their medical treatment. This “right to try” law builds on legislation enacted by dozens of states. The federal right-to-try law is an important victory for patients and individual liberty. But I worry these gains will not last. Here’s why.

Patients have a fundamental human right to choose their course of medical treatment. But how are patients to know which treatments work and which are just snake oil? The U.S. Congress attempts to solve this problem by empowering the U.S. Food and Drug Administration (FDA) to block drugs from the market until the manufacturers demonstrate, to the FDA’s satisfaction, that the drug is safe and effective for its intended use. At a glance, this seems a reasonable approach to keeping patients safe. In practice, it has been a disaster. 

There are lots of problems with this model of certifying drug safety and efficacy. First, it routinely violates the fundamental human right of all patients to choose the course of their medical treatment. If the FDA blocks the drug you want from the market, or requires so much testing that you cannot afford it, or erects such high regulatory barriers that no one develops the drug you need, the government has violated your fundamental human right to choose your medical treatment.

Second, the FDA faces information asymmetries that make that first problem even worse, as well as result in unnecessary morbidity and mortality. Any government agency charged with keeping drugs off the market until it is convinced they are safe and effective will get a flood of information about its Type I errorsi.e., the harms it causes by approving drugs that end up harming patients. But it will receive far less information about its Type II errorsthe harms it causes by delaying the approval or blocking the development of helpful drugs. This is only natural: it is far easier to identify patients who were harmed by a drug they did use than patients who were not helped by a drug they didn’t use. The latter patients might not even know a beneficial drug exists because it hasn’t been approved yet. Indeed, the drug might not exist, because the FDA made its development uneconomical.

As a result, the FDA focuses almost exclusively on minimizing Type I errors. It does so by requiring manufacturers to conduct expensive and time-consuming clinical trials, so it can more often prevent harmful drugs from going to market. The agency requires more safety and efficacy testing before approving a drug than it would if it had complete information about both types of error. It requires all that additional testing even though doing so results in more harm from Type II errors than the additional testing prevents by eliminating Type I errors. The result is that the FDA’s approval process becomes costlier and longer, and violates the rights of more and more patients.

This next part is crucial. The public, media, and policymakers also receive far more information about the FDA’s Type I errors than its Type II errors, and therefore complain about the former far more than the latter. What this means is: the political forces that determine how the FDA operates reinforce the agency’s bias toward demanding more testing and more-often violating patients’ rights. We can think of the FDA’s standard operating procedure of minimizing Type I errors at the expense of more (and more costly) Type II errors as a kind of political equilibrium created by the information asymmetry the agency and those who control it face with respect to these two types of error. 

So while it is wonderful that President Trump has restored the right of some terminally ill patients to access drugs the FDA has not yet approved, I worry these gains will not last. This legislation does nothing to correct the information asymmetry faced by those who determine whether and when new therapies can reach patients. Inevitably, some drug accessed through this legislation will hurt some patients. When that happens, the same cast of charactersthe FDA, Congress, the media, and the publicwill all focus on those easily identifiable Type I errors. They will demand reforms that prevent further Type I errors. But because they cannot see the even greater Type II errors those reforms will cause, patients will end up both less safe and less free. The pendulum will swing back to the current political equilibrium. 

The only way to protect patient rights and to strike an appropriate balance between Type I and Type II errors is through fundamentaland I mean fundamentalreform of safety and efficacy certification for medical technologies. Read more here.

Is FDA Commissioner Realizing That America’s War on Opioids Has Become a War on Patients?

In a May 14 blog post, Food and Drug Commissioner Scott Gottlieb expressed concern about the effect the nation’s restrictive policy towards the manufacture and prescription of opioids is having on patients with chronic pain conditions. This is one of the first signs that someone in the administration has taken note of the unintended consequences of this misguided policy—a policy that is based upon the false narrative that the overdose crisis is primarily the result of doctors prescribing opioids to patients in pain.

In response to a wide range of public input solicited by the FDA beginning in September 2017, Commissioner Gottlieb stated:

We’ve heard the concerns expressed by these individuals about having continued access to necessary pain medication, the fear of being stigmatized as an addict, challenges in finding health care professionals willing to work with or even prescribe opioids, and sadly, for some patients, increased thoughts of or actual suicide because crushing pain was resulting in a loss of quality of life.

Pointing out that, “In some medical circumstances, opioids are the only drugs that work for some patients,” Dr. Gottlieb announced that a public meeting will be held on July 9 on “Patient-Focused Drug Development for Chronic Pain,” and invited pain patients to offer their perspectives.

Hinting at his dissatisfaction with the 2016 one-size-fits-all opioid prescription guidelines published by the Centers for Disease Control and Prevention that have greatly influenced state and federal opioid policymakers, he signaled that the FDA is considering proposing its own set of guidelines. Unlike the CDC guidelines, which are not evidence-based and were never intended to be prescriptive, Gottlieb stated:

In short, having sound, evidence-based information to inform prescribing can help ensure that patients aren’t over prescribed these drugs; while at the same time also making sure that patients with appropriate needs for short and, in some cases, longer-term use of these medicines are not denied access to necessary treatments. We will take the first steps toward developing this framework in the coming months, with the goal of providing standards that could inform the development of evidence based guidelines.

Opioid prescriptions peaked in 2010, and high-dose opioid prescriptions are down more than 41 percent since then. Yet the overdose rate continues to climb year after year, with fentanyl and heroin being the major culprits while overdoses from prescription type opioids have stabilized and have even slightly receded. The overdose problem was never really primarily caused by doctors treating patients in pain. It has always been principally due to nonmedical users accessing opioids in the illegal market. And as prescription opioids have become less accessible to them, they are migrating over to more dangerous drugs. The present policy towards the problem is making patients suffer while, at the same time, driving up the death rate. 

This is the first indication that a significant member of the Administration might be coming to that realization.