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The campaign against opioid abuse opens door to more innovative therapies.
One main goal of FDA’s Opioid Action Plan is to support the development of less dangerous pain medicines, including generic versions of therapies with anti-abuse features. With reports of thousands of opioid-related deaths a year, biopharmaceutical manufacturers are investing in promising non-opioid compounds and other innovations able to manage chronic and acute pain more safely.
These initiatives are supported by FDA’s Opioid Action Plan, released in February 2016 to assure Congress that FDA would do more to ensure the safe use of powerful opoid pain medications. The plan includes broader FDA consultation with advisory committees on the approval of new opioid formulations, stronger boxed warnings on drug labels, and easier access to treatments for opioid overdoses (1). FDA also supports expanded use of painkillers with abuse-deterrent formulations (ADFs) through the development of less costly generic versions of these advanced treatments.
The challenge for FDA, manufacturers, and the medical community is to meet the genuine demand from millions of individuals suffering from chronic and acute pain, while also doing more to prevent opioid overdose and misuse. So far, more informative drug labels, prescriber education, and pharmacy monitoring have done little to reduce abuse. Moreover, the new ADFs are expensive and not widely used. Approximately 90% of opioid prescribing is for some 175 immediate-release (IR) products, including more than 100 generics. FDA has approved approximately 35 extended-release/long-acting (ER/LA) therapies and five ER products with abuse-deterrent (AD) features, but these more expensive medications comprise only 10% of the market.
The public outcry for action to curb opioid-related addiction and deaths, however, is encouraging innovation and investment in the pain treatment area. The House and Senate have held numerous hearings on this lethal epidemic and are weighing a range of legislative actions to support more rigorous prescription monitoring and expanded treatment options for addicts. One proposal would levy fees on opioid manufacturers related to the strength of their medications to fund substance abuse treatment; another bill would provide added exclusivity and other incentives for industry investment in R&D on safer pain medicines.
The White House has requested an additional $1.1 billion to support local and state treatment programs, to better control opioid prescribing and dispensing, and to increase patient access to addiction treatments buprenorphine and naloxone. One consequence of cracking down on prescription drug abuse, unfortunately, has been a notable increase in the use of heroin and the even more dangerous illegal drug fentanyl.
The Centers for Disease Control and Prevention (CDC) recently issued new guidelines advising physicians to limit opioid prescriptions to three-day supplies for individuals with severe pain that can’t be managed with less dangerous analgesics. Some states are establishing prescribing limits on opioids, and a new Massachusetts law requires manufacturers to collect and dispose of unwanted controlled substances to prevent diversion. States also are filing suits against manufacturers for promoting pain medicines as safe and effective, as seen in a $200,000 fine paid by Endo Pharmaceuticals to New York for allegedly claiming greater safety for the AD features of its Opana ER. The Federal Trade Commission also recently issued a complaint against Endo for using pay-for-delay agreements to block generic competition to Opana (2).
More meetings, stiffer warnings
Meanwhile, FDA has filled its calendar with meetings with outside advisors to consider the regulation and approval of new analgesics, especially those for children. At a March 1, 2016 session of FDA’s Science Board, FDA Commissioner Robert Califf and agency officials sought advice on developing effective pain treatments, including ADFs. FDA’s pediatric advisory committee will discuss pediatric development plans for prescription opioids at a meeting in April 2016 and will explore the issue in greater depth at a two-day session in September 2016. In May 2016, advisors will review an application for an IR product that claims abuse-deterrent properties. Another meeting that month will examine the effectiveness of the agency’s current Risk Evaluation and Mitigation Strategy (REMS) for ER/LA opioids; one issue is whether to extend the program to the much greater number of IR products. And in June 2016, two expert panels will jointly weigh applications for two new ER painkillers featuring AD properties.
FDA also has proposed stronger warnings on the labels for all IR opioid products, similar to labeling changes made for ER opioid analgesics in 2013. The updated labeling guidance published in March 2016 will include boxed warnings to heighten prescriber awareness of the high risk of misuse, abuse, overdose, and death associated with these therapies (3). The revision also cautions women not to take these drugs chronically during pregnancy and calls for both IR and ER painkillers to carry safety information about the risk of drug interactions that can have serious adverse effects. Yet FDA stopped short of setting specific dosing recommendations or maximum doses, despite pressure for prescribing limits from some health authorities.
The development of more effective ADFs is considered key to curbing abuse of potent ER/LA products, and FDA encouraged brand manufacturers to take this route in guidance that was finalized in April 2015 (4). The agency has approved five ER opioids with AD features, is evaluating some 30 active investigational new drug applications (INDs) for ADFs and other new technologies, and at least three more products are being considered for approval this year, as noted previously.
But the higher cost of these products has drawn protests from pain patients and payers, prompting support for developing generic ADFs. FDA responded in March 2016 with draft guidance that outlines a “tier-based” approach for generics makers to conduct in-vitro studies and other manipulations to measure a product’s anti-abuse features (5–6). FDA maintains that generics should meet the same standards for abuse deterrence as innovators and plans to hold a public meeting on the proposal after considering comments that are due in late May 2016.
Despite these efforts, it may be years before generic ADFs come to market due to long patent protections for these relatively new brand products, and successful generic versions won’t be cheap. The testing and development of all pain medications is difficult, and ADFs are even more challenging. At the Science Board meeting, FDA staffers explained that just 2 out of 100 clinical trials for pain medications get past Phase II due to limited nonclinical models and challenges in pain measurement.
FDA looks to collaborate more with academics, advocacy groups, and industry to identify new AD technologies and drug-delivery systems that can slow penetration or bind to different receptors. A number of biotech manufacturers are exploring such strategies, including Baltimore-based Centrexion Therapeutics, which announced progress in developing non-opioid pain therapies (7). Headed by former Pfizer chairman Jeffrey Kindler and former Celgene chief Sol Barer, Centrexion made waves by acquiring three experimental pain compounds from Boehringer Ingelheim and announcing further clinical trials for an injectable, synthetic capsaicin to treat chronic osteoarthritis knee pain. Such efforts to create safer pain medications are likely to benefit from regulatory and financial support.
1. FDA, Fact Sheet–FDA Opioids Action Plan, FDA.gov.
2. Federal Trade Commission, “FTC Sues Endo Pharmaceuticals Inc. and Others for Illegally Blocking Lower-Cost Generic Versions of the Branded Drugs Opana ER and Lidoderm,” Press Release, March 31, 2016.
3. FDA, “FDA Announces Enhanced Warnings for Immediate-Release Opioid Pain Medications Related to Risks Of Misuse, Abuse, Addiction, Overdose and Death,” Press Release, March 22, 2016.
4. FDA, Abuse-Deterrent Opioids-Evaluation and Labeling, Guidance for Industry (CDER, Silver Spring, MD, April 2015).
5. FDA, “FDA Takes Important Step to Increase the Development of, and Access To, Abuse-Deterrent Opioids,” Press Release, March 24, 2016.
6. FDA, General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products, Draft Guidance (CDER, Silver Spring, MD, March 2016).
7. Centrexion Therapeutics, “Centrexion Therapeutics Expands Pain Pipeline with Acquisition of Three New Analgesic Candidates from Boehringer Ingelheim,” Press Release, March 30, 2016.