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The opioid epidemic has hit the United States hard in the last 25 years, killing more than 70,000 in 2019 alone, according to the CDC. The COVID-19 pandemic has not helped matters: “Over 81,000 drug overdose deaths occurred in the United States in the 12 months ending in May 2020, the highest number of overdose deaths ever recorded in a 12-month period, according to recent provisional data,” the CDC said.
“Opioid misuse and abuse remain a serious public health crisis facing the country,” said Patrizia Cavazzoni, MD, Director of the Food and Drug Administration (FDA) Center for Drug Evaluation and Research, as she announced her agency’s new draft guidance on pain medicine without opioids. “Preventing new addiction through fostering the development of novel non-opioid analgesics is an important priority for the FDA.”
Unfortunately, after years of dragging their feet, the FDA’s guidelines feel like too little, too late, according to Camelia Thompson, Senior Director of Science and Regulatory Affairs at the Biotechnology Innovation Organization (BIO).
“We’re still in the middle of an opioid epidemic,” Thompson explained. “The FDA withdrew the first guidance on non-opioid analgesics in 2017 and it has been five years where there’s been no guidance to the industry on development of these types of medicines.”
Non-opioid analgesics include well-known drugs like acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs). They are generally not addictive.
“Opioid analgesics are an important part of acute pain management. However, even at prescribed doses, they pose a risk for addiction, misuse, abuse or overdose that may result in death,” FDA said. “A non-opioid analgesic for acute pain that completely eliminates or significantly reduces the need for an opioid could have a major public health impact by alleviating patient suffering from acute pain while mitigating the risks associated with using an opioid.”
What’s in the FDA draft guidance on non-opioid analgesics?
On February 9, the FDA issued its new draft guidance to provide recommendations to companies developing non-opioid analgesics. The guidance was drafted in connection with the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment for Patients and Communities Act (SUPPORT), which became law on October 24, 2018.
Yet, concerns from the industry are manifold, Thompson said:
- The five-year delay in the guidance has already put development of non-opioid alternatives on hold.
- The guidance sets a higher bar for the development of new drugs than it has in the past, without proper clarification on “its intent to use (Mechanism of Action) of the drug as the primary determinant of the evidentiary standard for efficacy.”
- The draft guidance published is not holistic in its approach; while it focused on the two goals of (1) fostering the development of novel analgesic drugs and (2) decreasing opioid analgesic exposure and preventing new addiction, the guidance was clear that it “does not address the management of chronic pain, which will be the focus of future guidance.”
No guidance on chronic pain yet
“Every day many individuals have the same injury, disease, surgery, or treatment. Many of them experience associated pain, and most of them experience a resolution of pain when the disease is cured, the injury heals, or the treatment stops,” the NIH said. “However, in a significant proportion of these individuals, pain does not resolve and becomes chronic.”
Indeed, chronic pain is a considerably more prevalent problem than acute pain in the general population for a variety of reasons, yet this was not addressed in the guidance at all.
“Acute pain was reported by 15% of women, chronic pain by 29%, and disabling chronic pain by 7%. The corresponding figures for men were 12, 24 and 5%,” a recent study of people aged 40-60 found.
Addressing chronic pain requires a number of therapies to be investigated and invested in, ranging from physical therapy to mindfulness, yet the exclusion of developing non-addictive pain-relieving alternatives perpetuates the dangerous cycle of opioid addiction.
“Indeed, establishing an unnecessarily high threshold for supporting a general acute pain indication could discourage the development of novel analgesic drugs for such uses, contrary to the goals of the SUPPORT Act and FDA’s draft guidance,” BIO said in comments sent last month in response to the draft.
Biotech pushes forward on non-opioid alternatives
Despite obstacles to developing non-opioid alternatives, biotech has been stepping up.
BIO member Vertex has made headway in the development of their non-opioid analgesic, VX-548, announcing in March 2202 “positive results from two Phase 2 proof-of-concept (POC) studies that investigated treatment.”
There have been similar efforts by companies like Biogen, Amgen, and Genentech, though they have run into hurdles in development.
“The lack of guidance creates hurdles in the sense that sponsors don’t know what to do,” explained Thompson. “You can’t develop a drug in a vacuum.”
Drug manufacturers need clarity as they pursue research and development, and they need to be able to communicate with regulatory agencies, she said. The FDA has not provided that–thus making the frailty of the recent guidelines, coupled with the heightened bar of development standards, all the more frustrating for drug developers.
Overcoming this challenge requires two things, according to BIO’s comments:
- More timely and flexible mechanisms for sponsors to engage with the right people in the review division to get clarity on the path forward.
- A culture within the review division that encourages thought leadership and collaboration with sponsors to advise on complex or nuanced issues that may not be addressed or discussed in sufficient detail in formal policy.
“What senior agency management says publicly about the value and urgency of regulatory innovation has yet to permeate through its review divisions,” said Peter Pitts, President of the Center for Medicine in the Public Interest and Visiting Professor at the University of Paris School of Medicine (highlighted by BIO).
“This disconnect is causing a lack of faith within the broader healthcare ecosystem that FDA can be a potent ally in advancing patient access to new and important medical technologies,” continued Pitts. “That is not a good thing. Faith must be restored and reinforced.”
