FDA considers a benefit-risk assessment for opioid analgesics

The FDA issued a draft guidance for the pharmaceutical industry when providing information in a new drug application (NDA) for opioid analgesic drugs. The FDA assesses risks and benefits of all drugs in the context of their labeled uses when reviewing NDAs. However, because of the widespread abuse of opioids the FDA will also consider the broader public health effect, including the risks related to misuse, abuse, opioid use disorders, accidental exposure, and overdoses for patients and others. The guidance details what data is required for the FDA to complete their benefit-risk analysis after receiving an NDA (Notice, 84 FR 29211, June 21, 2019).

Patient benefits. For the FDA to analyze patient benefits, pharmaceutical companies submitting opioid NDAs should show the efficacy and safety of the drug when used for its proposed indication. The NDA should provide a body of evidence supporting a finding of drug efficacy, what patient population was used and why, and a proposed duration of use for each proposed indication. In addition to efficacy, the companies should show the safety of the drug when used for its proposed use. The NDA should show drug safety by submitting supporting data of drug characteristics that mitigate adverse events associated with opioids, such as respiratory depression, sedation, and constipation. The FDA would also need data supporting any drug characteristics that mitigate risks of opioid use disorder.

Patient risks. In addition to the already known risks of opioids, the FDA will also consider questions about the risks to patients who are prescribed the drug and use it as labeled and directed by their physicians. The NDAs should provide data to support the answers to the following questions:

  • Does the drug have any risks not normally associated with opioid use? How serious are these risks, and can they be mitigated? Are the risks reversible?
  • Does the drug formulation cause any risks such as tablets that swell in the GI tract or stick to mucous membranes? For drugs formulated with abuse-deterrent properties, are there any risks associated with formulation?
  • Does the drug have characteristics that increase or decrease the risks of respiratory depression, sedation, or development of opioid dependence? Can packaging particulars or storage and disposal conditions mitigate the risks?
  • Is there evidence that typical adverse events associated with opioids occur at a higher rate?

Effectiveness and safety. The FDA considers the benefits and risks relative to other available treatment options for the prescribed condition. The comparative data of the drug to other treatment options is valuable, but the FDA notes, it is not required to be found superior to other options, to be approved for an ANDA. The FDA will consider the following questions when determining the effectiveness and safety of drugs in ANDAs:

  • Does efficacy data exist comparing the drug with other opioids or nonopioids for the condition? Does the drug have any advantages compared to other treatment options?
  • Does comparative safety data exist with other treatment options? Are there any safety advantages or disadvantages compared to other options?
  • What is the anticipated benefit-risk balance compared to other treatment options?
  • Does the drug have any other safety advantages over other treatment options?

Public health effects. The FDA proposed in the guidance that it would consider the greater public health effects of new opioids including patients and nonpatients. Nonpatients can be members of patient’s households, visitors to patient’s households and others. The risks are those related to misuse, abuse, opioid use disorder, accidental exposure, and overdose. The FDA will consider the following when analyzing public health effects:

  • Are there characteristics of the drug that increase or decrease risk of accidental exposure to children?
  • Are there characteristics of the drug that increase risk of misuse, abuse, and related adverse outcomes? Can the risks be mitigated?
  • Are there risks with the method of delivery?
  • Are there any potential unintended adverse consequences?
  • Safety of unintended routes of administration such as intravenous, intranasal, or inhalation
  • Discussion of anticipated use-specific subpopulations such as teens or patients with mental health disorders and how to mitigate such risks

Risk management. The FDA determined that there is a risk evaluation and mitigation strategy necessary for all opioid drugs intended for outpatient use to make sure the benefits outweigh the risks. The mitigation strategy requires training for all health care providers involved in the treatment of pain. To meet this requirement drug companies with approved opioid NDAs must provide grants to continuing education providers for development of these training courses. Any NDA must include any risk evaluation and mitigation strategies thought to be necessary to make sure the benefits outweigh the risks of the opioid drug.

Highlight on Wisconsin: As opioid overdose and deaths rise, state seeks $15.7 million in SAMHSA support

The rate of opioid overdose deaths in Wisconsin has risen approximately 81 percent from 2006 through 2015, according to a new Wisconsin Department of Health Services (DHS) report, titled “Select Opioid-Related Morbidity and Mortality Data for Wisconsin.” In response, the Wisconsin DHS has submitted an application for up to $15.7 million in federal funding to boost the state’s response to the growing misuse and abuse of opioids from the Substance Abuse and Mental Health Services Administration (SAMHSA). The amount of the grant is based on the unmet need for opioid-related treatment and the number of opioid-related deaths in the state. Wisconsin is eligible to receive up to $7,636,938 each year for the next two years under the 21st Century Cures Act.

The DHS report provides statewide and county-level data on opioid-related deaths and hospital visits, neonatal abstinence syndrome (NAS) (in which an infant is born with withdrawal symptoms from substances taken by the mother), and data on ambulance runs in which naloxone (a medication used to reverse opioid overdose) was administered. The report includes these data highlights:

  • The rate of opioid overdose deaths increased from 5.9 deaths/100,000 residents in 2006 to 10.7 deaths/100,000 in 2015.
  • Rates of drug overdose deaths involving opioids were higher among counties in the southeastern region of the state (Milwaukee area), and higher among men compared with women.
  • Drug overdose deaths involving opioids were highest among young men aged 25-34, and among women aged 35-54.
  • Hospital visits involving opioid acute poisoning (including overdose) increased from 25.3 to 52.0 per 100,000 between 2006 and 2014.
  • The rate of ambulance runs in which naloxone was administered rose from 51.2 to 67 per 100,000 from 2011 to 2015.
  • The rate of NAS increased from 2.0 to 8.7 per 1,000 live births from 2006 to 2014, a rate increase of 335 percent.

In 2016, DHS issued a Public Health Advisory due to the opioid epidemic. In 2017, Governor Scott Walker called for a special session of the legislature to consider recommendations presented by the Governor’s Task Force on Opioid Abuse. New legislative proposals will build on efforts already underway under the HOPE (Heroin, Opioid Prevention and Education) agenda, which includes 17 bills aimed at prevention and treatment of opioid addiction and overdose.

Pending approval from SAMHSA, the funds will be used to:

  • Support community coalitions focused on reducing the nonmedical use of opioids among people age 12 to 25.
  • Establish a hotline to provide information on treatment services and recovery supports.
  • Expand access to treatment for uninsured and underinsured individuals.
  • Establish new opioid-specific treatment programs to reduce the distance people have to travel for these services.
  • Establish a network of individuals in long-term recovery from the misuse and abuse of opioids trained to coach people through the treatment and recovery process.
  • Develop training for professionals on proven intervention and treatment strategies for opioid misuse and abuse.

 

Highlight on Hawaii: Lawmakers say aloha to stronger overdose measures

More people in Hawaii die from drug overdoses than car crashes—a reality that is driven by an excess of opioid abuse. However, recent efforts are directed at reducing the state of Hawaii’s opioid crisis. A key component of the state’s fight against drug abuse is a piece of legislation (S.B. 2392) which creates immunity for those who describe and dispense overdose reversal medication such as Naloxone. Additionally, the law authorizes a greater range of individuals to administer such medications to individuals experiencing an overdose.

Drug abuse

In 2015, Hawaii saw 158 deaths from drug poisonings/overdoses, adding to the total of 1,523 over the past 10 years. Drug overdoses are a greater problem in Hawaii than in other U.S. states. For example, drug overdose deaths increased by 83 percent between 2006 and 2014—an increase which more than doubled the 37 percent average rise nationwide. There is speculation that Hawaii may be particularly susceptible with respect to overdoses due to its isolation and the inconsistency in the quality of drugs brought to the islands.

Naloxone

The FDA approved Naloxone to prevent overdose by opioids such as heroin, morphine, and oxycodone. The drug reverses the toxicity of an overdose by blocking opioid receptor sites. The medication is administered when a patient is showing signs of an opioid overdose. The drug is an important life-saving medication, according to a community health outreach worker who has heard stories about “people trying to help friends overdosing on narcotics like opioids, injecting them with everything from saltwater to milk.”

Law

The law encourages the prescription, distribution, and administration of Naloxone through a variety of measures. A key provision of the law is immunity that it provides for health care professionals and pharmacists who prescribe, dispense, distribute or administer overdose medications like Naloxone. The legislation also authorizes several kinds of individuals—police, firefighters, lifeguards, all emergency medical technicians, family, and friends—to administer drugs like Naloxone to individuals experiencing opioid-related drug overdoses.

Bigger than Hawaii

The opioid crisis is a problem that stretches far beyond the island chain of Hawaii, with overdose deaths from prescription painkillers claiming 165,000 lives in the U.S. since 2000. Part of the problem is the widespread prescription and use of opioids. In 2015, 227 million opioid prescriptions were written, enough for 9 out of 10 American adults to receive a bottle of opioids.

Influence

An investigation by the Associated Press and the Center for Public Integrity discovered that the prevalence of opioid use and abuse may be, in no small part, related to the financial efforts of pharmaceutical manufacturers. For example, the investigation found that “drug companies and allied advocates spent more than $880 million on lobbying and political contributions at the state and federal level over the past decade.” The figure is staggering when juxtaposed with the $4 million spent by organizations advocating for limits on opioids and the fact that the pharmaceutical lobbying is eight times higher than spending by the gun lobby over the same period. Additionally, the pharmaceutical industry maintains an average of 1,350 lobbyists covering all 50 state capitals.

A step forward

However, despite these significant and growing challenges, states like Hawaii are taking steps to reduce the impact of opioids. Authorizing greater utilization of drugs like Naloxone is an important move in the journey towards eliminating opioid abuse, one that all states can benefit from.

HHS prescribes regulations for opioid addiction treatment reports

Medical practitioners who treat up to 275 patients in an office-based setting must provide various information to assist HHS in complying with newly established regulations regarding medication assisted treatment (MAT) of opioid use disorders. In an advance release of a Final rule set to publish in the Federal Register September 27, 2016, HHS requires information related to: (1) a practitioner’s annual caseload of patients to be reported monthly; (2) the number of patients provided behavioral health services and referred to behavioral health services; and (3) the features of the practitioner’s diversion control plan.

Background

Buprenorphine is used in MAT to help people reduce or quit their use of heroin or other opiates, such as pain relievers like morphine. Unlike methadone treatment, which must be performed in a highly structured clinic, buprenorphine is the first medication to treat opioid dependency that is permitted to be prescribed or dispensed in physician offices, significantly increasing treatment access.

HHS had increased access to MAT in an office-based setting by allowing eligible physicians to request approval to treat up to 275 patients if certain conditions are met in a previous Final rule titled “Medication Assisted Treatment for Opioid Use Disorders” (81 FR 44712, July 8, 2016) (MAT rule). The MAT rule had originally proposed requirements to ensure that patients received the full array of services that comprise evidence-based MAT and minimize the risk that the medications provided for treatment are misused or diverted (see Proposal could push up patient limit for opioid abuse treatment, Health Law Daily, March 29, 2016).

HHS also made changes to the original proposed reporting requirements based on earlier comments by adding a requirement proposing that practitioners provide reports to the Substance Abuse and Mental Health Services Administration (SAMHSA) to maintain their approval to treat up to 275 patients in a supplemental Notice of Proposed Rulemaking (SNPRM) (81 FR 44576, July 8, 2016). The purpose of the reporting requirements is to help HHS assess practitioner compliance with the additional responsibilities of practitioners who are authorized to treat up to the highest patient limit.

Reporting requirements

HHS recognized that asking practitioners to calculate and report average monthly caseload of patients receiving buprenorphine-based MAT each year could be could be burdensome and changed this reporting requirement in the Final rule. The revised text requires practitioners to report annual caseloads of patients by month. By seeking information on the annual caseload of patients by month, HHS noted that an appropriate balance between collecting valuable information needed to assess compliance with the rule and avoiding undue burden to practitioners would be struck.

In addition, the reporting requirement has been revised to request the practitioner report on the number of patients provided behavioral health services and referred to behavioral health services. By seeking information on the number of patients that were provided services and referred for behavioral health services will meet the needs of assessing compliance of the MAT rule.

HHS modified the third reporting requirement, which required that the practitioner report on the features of their diversion control plan, by striking requirements related to reporting the number of patients who: (1) completed a buprenorphine course of treatment; (2) were referred to a less intensive level of care; (3) no longer wished to take buprenorphine; or (4) no longer taking buprenorphine for reasons not listed.

Beyond scope

HHS declined to address comments requesting higher patient limits, access to buprenorphine, or SAMHSA audit practitioners to ensure compliance with the MAT rule because the comments did not relate directly to the reporting requirements of the SNPRM.