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During a day-long workshop held early November at the National Academies of Sciences, Engineering and Medicine titled “Regulatory strategies to address prescription opioid-related harms,” Nathaniel Katz, MD, MS, put forth a set of recommendations to the FDA, which in his opinion, would help streamline the drug development process, and bring improved treatments for pain on the market.1
Among his previous appointments, Dr Katz held the position of chair of the Advisory Committee, Anesthesia, Critical Care, and Addiction Products Division at the Food and Drug Administration (FDA).
Dr Katz’ experience at the FDA, as a clinician, and as president of a company consulting on and conducting clinical trials, helped him pinpoint a number of critical issues in the way in which pre-clinical and clinical studies are conducted.
Based on these observations and his experience, Dr Katz formulated 10 recommendations for the FDA, 3 of which he detailed during his presentation titled “Accelerating the Development of Better Treatments for Pain: Notes From the Drug Development Battlefield.”
Recommendation #1: Check for Scientific Integrity
A prominent issue that has impeded the development of pain treatments lies in inadequate levels of scientific integrity, according to Dr Katz. Such doubts cast a shadow on the validity of data from preclinical studies.
To overcome this challenge, Dr Katz suggested the FDA should start reviewing preclinical efficacy data; in an initial phase, such an oversight may consist in audits by the FDA in order to assess the integrity of preclinical efficacy data through site inspections. Whenever ethical misconduct is observed, such reviews should be conducted on a routine basis.
In order to put such a review mechanism in place, both a major retooling of the agency and substantial capital infusion would be required.
Recommendation #2: Install an ex-FDA Oversight Mechanism
An excellent example that highlights the way in which the FDA’s regulatory process can impede the development of “new and potentially game-changing treatments for pain,” lies in a class of analgesics, the anti-Nerve Growth Factor (NGF) antibodies.
Anti-NGF antibodies represent a new class of analgesics, found to be more effective for chronic pain than any other class of analgesics– including opioids– according to a number of studies on over 15 000 patients.2,3
In addition, anti-NGF antibodies are safer than opioids, declared Dr Katz. Yet, the FDA placed them on clinical hold for 4 years, because of an uncommon but serious safety concern (rapid joint destruction and sympathetic nerve lesions), despite the fact that the incidence of this adverse effect is lower than that of opioid overdose in patients with chronic pain (0.5 % vs ~2%).
“In my opinion, this class has already been shown to be safer than opioids for chronic pain,” added Dr Katz. “During [that 4-year period of clinical hold], we had about 80 000 opioid-overdose related deaths in the US.”
Another consequence of this clinical hold was the dropping by Johnson & Johnson of their anti-NGF antibody, fulranumab. This decision meant that the world’s largest pharmaceutical company was entirely leaving the drug development space for pain – a very concerning development, according to Dr Katz, likely to be due to the onerous burden linked to demonstrating product safety.
Although the FDA is cognizant of the fact that new treatments for pain are greatly needed, the way in which the agency functions impedes the development of such drugs, creating a “disconnect.”
For Dr Katz, the reasons underlying this disconnect are not clear. He ventured several possibilities, including the hiding of safety data, failure by the FDA to adopt a societal perspective or to consult safety data in an unbiased manner. Or could this be due to an overemphasis on preclinical toxicology?
Despite his extensive experience consulting for drug development companies, Dr Katz could not figure out the reasons for this 4 year-long clinical hold. He emphasized that such decisions by the FDA have major societal consequences, and therefore should include other parties, so as to allow for public scrutiny.
Before putting new promising analgesics on clinical hold, Dr Katz strongly recommended an ex-FDA oversight take place. Implementation of such a measure would be complicated because of proprietary data and legal issues, but such a motion would help the public be assured that a broad range of considerations are taken into account when these very high-stake decisions are made.
Recommendation #3: Install a Mechanism for Limited Approval
A sharp divide currently separates phase III and phase IV in clinical trials. This is due to the massive body of information required for a drug to get onto the market.
“We cannot be aware of certain parameters [regarding the effects of a drug] until large populations have been exposed,” said Dr Katz. In his view, installing a mechanism that would grant limited drug approval– between phase III and the marketplace–with a highly restricted distribution, would allow to gather data from a larger and more diverse population.
Such a measure might help curb the desertification of the pain drug development field as safety measures escalate.
References
- Katz N. Accelerating the development of better treatments for pain: notes from the drug development battlefield. Presented at: Regulatory strategies to address prescription opioid-related harms. The National Academies of Sciences, Engineering and Medicine. Washington, DC; November 4, 2016.
- Kumar V, Mahal BA. NGF – the TrkA to successful pain treatment. J Pain Res. 2012;5:279-287.
- Schnitzer TJ, Ekman EF, Spierings EL, et al. Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain. Ann Rheum Dis. 2015;74(6):1202-1211.
