What FDA Giveth, It Also Taketh Away
FDA recently announced a “Guidance for Industry on Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices” (January 2009). The document outlines permissible journal articles and the Agency’s recommendations for distribution; thus, FDA appears to giveth.
FDA statements about authors’ financial interest in the product or manufacturer, the publications that meet FDA journal quality, and information that does not “pose a significant health risk, if relied upon,” raise the bar considerably. Authors now have to seek publication in journals with independent, expert editorial boards that are sensitive to conflicts-of-interest and have high-quality peer review.
This raises the conundrum of whether articles not meeting these requirements will in the future be acceptable to FDA to support 505(b)(2) NDA submissions or to support BLAs. What should a company do if a study shows excellent safety and effectiveness in an article previously published in a medical journal that does not meet these editorial standards? It appears that FDA is establishing surreptitiously a new standard for the publication of clinical studies of both off-label and label uses. Conversely, can publishers of scientific/clinical journals that meet the requirements now claim that they are in compliance with FDA publication standards in terms of the potential clinical utility of their published articles?
There is another implied FDA standard regarding the viability of off-label publications in terms of whether the protocol design and resultant clinical data is capable of showing that the use of the off-label product “…do[es] not pose a significant health risk, if relied upon,….” Many academic medicine studies may focus on a small aspect of the potential utility of an off-label drug as applied to a new disease area. Must editorial staff and peer reviewers now evaluate these FDA criteria when reviewing an article for publication? Alas, I can now see the disclaimer that journal publishers may now add to their front pages – “Publication of this article in our journal does not imply any expressed or implied endorsement of the alleged clinical benefit(s) from off-label use of this product, which this article discusses, Use At Your Own Risk.”
In February, two former sales officials of a device company pleaded guilty to a felony misbranding charge that they had promoted unauthorized or off-label use of a medical device; they now face up to three years in prison and a $250,000 fine; thus, FDA taketh.
FDA is also investigating whether the company knew the products were being promoted for off-label use. These guilty pleas should impact the way companies control distribution of publications on unapproved uses and how sales and marketing personnel follow up on distribution of such material. Companies are advised to develop standard operating procedures and training for sales personnel to make sure that they are complying with the new guidance.
These days, many start-up companies are focusing on a narrower clinical indication to expedite product development within tight financial constraints. The rationale is that the narrower clinical indication will be augmented in the marketplace by off-label use.
This practice is also popular with larger companies that are expanding their usually broad clinical indication. This strategy is now at risk with substantial liability exposure if the company fails to generate sufficiently broad preclinical and clinical safety data to demonstrate that the potential off-label use “…[does] not pose a significant health risk, if relied upon.” I am sure this higher FDA standard will not be lost on plaintiff product liability attorneys.