An analysis published in the journal Anesthesiology1 in August has demonstrated that certain particular attributes of a pain medication-such as whether its abuse potential is high and what type of pain it can address-influence the probability of successful development and duration of development. The authors make a case that a better understanding of success could inspire more investment into nonopioid medications for pain.
The study shows a decrease in the development of new medications with high abuse potential, including opioids, since the peak of the opioid epidemic around 2010.
"There has also been a concurrent increase in the number of development programs for low abuse potential pain medications, reflecting a societal need for such a paradigm shift in the management of pain,"1 the authors wrote.
"However, the overall probability of successful development is still highest for medications with high abuse potential and medications intended to treat nociceptive pain. There are many possible reasons for this, such as a greater familiarity with nociceptive pathology, relatively expedient readouts of the trial data, or more profound analgesia with opioid analgesics,"1 the authors wrote.
"Additionally, a poor understanding of neuropathic pain pathology, a lack of biomarkers, or a lack of effective targets may be limiting the successful development of these agents. The development of effective pain treatments without the potential for abuse should continue to be the pharmaceutical industry's goal in pain medication development,"1 they wrote.
"While pharmaceutical companies recognize this need, because of the subjective nature of pain-in addition to poorly defined phenotypes of pain response in human populations, a general lack of reliable biomarkers, and the high placebo response-the conduct of clinical trials for new drug approval in this space is a lengthy and costly proposition."1
The authors, led by Dermot P. Maher, MD, MS, MHS, of the Johns Hopkins University School of Medicine, demonstrated that, across all pain medications, the overall probability of successful development from phase 1 to approval is 10.4% (standard error, 1.5%).
Looking at different types of pain that a medication would address, the authors found that medications to treat nociceptive pain have a probability of successful development of 13.3% (standard error, 2.3%). They demonstrated that medications intended to treat neuropathic pain had a 7.1% (standard error, 1.9%) probability of successful development.
The team studied other factors, especially the abuse potential. The probability of successful development of medications with high potential of abuse is at 27.8% (standard error, 4.6%).
Development of drugs with a low potential of abuse had a 4.7% (standard error, 1.2%) probability of success.
The authors also wrote that the most common period for attrition is between phase 3 and approval. Development of pain medications that did make it to large phase 3 safety and efficacy trials took an average of 30 months.
To carry out the analysis, the authors used the Citeline database "to compute the probabilities of success, duration, and survivorship of pain medication development programs between January 1, 2000, and June 30, 2020, conditioned on the phase, type of pain (nociceptive vs. neuropathic), and the abuse potential of the medication," the authors wrote.
They examined outcomes and parameters of 469 pain medication development programs of 399 unique active pharmaceutical ingredients between 2000 and 2020.
A note from the editors of Anesthesiology accompanying the article, along with an accompanying editorial, asserts that despite the prevalence of pain and its societal cost, investment in new pain medicines is low because of a lack of understanding of the probability of success.
The underfinancing of new pain medications "has taken place for a variety of reasons, not least of which is the poor understanding of the probability of successful development of pain medications," the authors wrote. "A poor understanding of the probability of successful development prevents accurate modeling of the risks involved in pain pharmaceutical development and could lead investors and drug developers to instead pursue safer, more well-understood therapeutic areas."
If investors have a more accurate understanding of the probability of success, the authors propose, they might be more inclined to invest in better analgesic development and "lead to a more robust pipeline of new pain medications. Additionally, a knowledge of probabilities of successful development will help anesthesiologist and pain physicians, many of whom are very active in the drug development process, to better focus research and academic efforts."
The authors noted limitations of their study, including that analyzing historical trends cannot accurately predict the success of future drug development programs.
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