On March 12^th, the FDA’s Arthritis Advisory Committee will meet and discuss the anti-nerve growth factor (Anti-NGF), a drug class that is currently under clinical hold because of the threat of joint damage.  Clinical trials for Pfizer’s tanezumab were suspended in 2010, at the FDA’s request, when some patients’ arthritis worsened to the point of needing joint replacement – and a class-wide clinical hold followed.  (Similar treatments are in early stage development at Johnson & Johnson, Regeneron, Sanofi, Abbott, and AstraZeneca.

Anti-NGF therapies are being developed for the treatment of a variety of chronic painful conditions including osteoarthritis, chronic lower back pain, diabetic peripheral neuropathy, post-herpetic neuralgia, chronic pancreatitis, endometriosis, interstitial cystitis, vertebral fracture, thermal injury, and cancer pain.  And if the fact that, according to Professor Thomas Schnitzer of Northwestern University, “We’ve had over a hundred years without having a major new pain drug,” isn’t enough – Anti-NGF’s are non-opioids.

FDA has tasked the adcomm to determine whether reports of joint destruction represent a safety signal related to the Anti-NGF class of drugs and whether the risk/benefit balance for these drugs favors continued development as analgesics.

Why a clinical hold? While a Phase II, 450-patient proof-of-concept study showed that tanezumab relieved knee pain when compared to a placebo, a Phase III study (published in the New England Journal of Medicine) showed 16 patients experienced progressively worsening osteoarthritis associated with a form of bone damage known as necrosis, which required total joint replacements.

In an accompanying NEJM editorial, John Wood a researcher at University College, London and a visiting professor at Baylor College of Medicine (a post funded by Pfizer), wrote the joint failure “was most likely caused by excessive wear and tear in the absence of joint pain. Pain has an important role in the avoidance of self-harm, but chronic inflammatory pain has generally been considered to be wholly undesirable.” The tanezumab study “suggests that a complete quenching of pain in patients with osteoarthritis may not necessarily be a good thing.”

In other words, according to a report in the Wall Street Journal:

“Some researchers are suggesting that an experimental Pfizer drug may have liberated arthritis sufferers to such a degree that they became more physically active — and that the subsequent wear and tear on their joints led to joint replacement surgery.”

The drug made people feel “better than [they] ever felt before, and I have a feeling they just overused their joints,” Nancy Lane, a rheumatologist and bone-health specialist at UC Davis Health System in Sacramento. She suggests the drug could still play a role as long as doctors “counsel patients not to overuse their joints.”

What happens when a drug … works too well?  Lane says she has seen this pain-masking situation before, including with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin. “Because this is a new chapter in controlling pain, we didn’t realize we needed to counsel our patients in using their joints that were still diseased. Now we need to figure out how to use it so the risks don’t outweigh the benefits.”

And so the issue of patient education becomes crucial. What happens when a class of drugs is so effective, patients forget they have the underlying condition and behave contrary to their best medical interests? (In plain English – what happens when a therapy is so effective patients over do it and then suffer the consequences?) Hopefully the 3/12 adcomm will spend some quality time discussing this important social science question. Perhaps this issue should be taken up, um, jointly with the agency’s Risk Communications Advisory Committee? Anti-NGF drugs require not only a discussion of benefit/risk – but also the risk of benefit.

Those are, after all, precisely the kind of thorny scientific propositions FDA advisory committees are held to address.

Welcome to 21^st century medicine.

Ladies and Gentlemen, start your engines.