Good Reprint Practices

So…you may be sitting there trying to put together your thinking about FDA’s final guidance document.  You may be thinking about whether or not (or how) to put together a company policy or process in light of FDA’s guidance document.  One day you’re a college freshman sitting in the Thurston Howell III Memorial Library planning the best spring break ever, then one day you’re smack dab in the middle of interpreting an FDA guidance document…a document with an impenetrable regulatory, political, and constitutional law history.  ”And you may ask yourself, How did I get here?” as the Talking Heads would say. 

In most cases, you’re gonna end up with something that looks strikingly similar to FDA’s guidance, full of ultra-precise paraphrasing, with sprinkles of customization to retrofit into the company’s policy and process framework. Getting to an internal guidance document is one thing, but once you finalize your own policy, you now have to interpret it.  All of a sudden, you’ll get some proposals for reprints that your company is seeking to disseminate and you will be faced with your first big challenge…

Can this reprint comply with the guidance? 

Oh wait…does the guidance even apply to this reprint?

Nearly any research article published in medical journals or textbooks contains some efficacy or safety information that is not included in the FDA-approved labeling for the product(s) discussed.  A common, though in my opinion overly broad, interpretation of the term “off-label” is any information that is not contained in the labeling for a drug. Authors often make reference to comparative studies, outcomes, or clinical effects that are interpreted to be inconsistent with the FDA approved labeling, or at least, that are not supported by substantial evidence.  One could consider the term “off-label” to encompass “inconsistent” information, but the presence of supplemental or extraneous information that does not relate to unapproved uses does not independently cause an article to be off-label.

Let’s say you have a reprint that reports an adequate and well controlled clinical study for a your drug for its approved use, but the author also discusses outcomes or other studies that are not included in the label.  The author also engages in expert medical conjecture about the comparative safety or efficacy to products that are not part of the study.  It may be prudent to look at whether or not such a reprint must comply with FDA’s Good Reprint Practices guidance.  To make the determination, you need to follow the track of FDA’s language carefully.

In Section IV of FDA’s final guidance document, FDA outlines to which reprints “Good Reprint Practices” should be followed.  The final guidance states:

“Scientific and medical information that concerns the safety or effectiveness of an approved drug or approved or cleared medical device for an unapproved new use that is not included in the product’s approved labeling or statement of intended uses (including unapproved new uses of approved drugs and approved or cleared devices) is often published in journal articles or reference publications. These publications are often distributed by manufacturers to healthcare professionals or healthcare entities. When a manufacturer disseminates such medical and scientific information, FDA recommends that the following principles of “Good Reprint Practices” be followed.” [Emphasis added]

Consequently, a reasonable interpretation is that Good Reprint Practices applies to reprints that:

1. Concern the safety and effectiveness of approved drugs (or devices) for an unapproved new use

2. Are disseminated proactively by a manufacturer

Keep in mind, FDA’s final guidance is provided for the specific purpose of determining whether or not reprint dissemination will cause or result in new intended uses.  So a critical question in any determination is whether or not the the information in an article or reprint could be evidence of a new intended use and basis for a misbranding violation on that ground.  

Good.  That was easy.  So if it relates to efficacy and safety information that concerns an approved use (even if it is not contained in the labeling) then we’re in the clear.  Not really.  I mean “NO” not at all.  

FDA’s Final Guidance Does Not Directly Relate to Misbranding that Results from False or Misleading Labeling or Advertising

Good Reprint Practices provides guidance to distinguish how certain reprints, of a certain quality, can be disseminated by a company and for which FDA will not apply laws and regulations that apply to labeling, advertising and promotion.  However, for reprints for which this guidance does not apply, but for reprints that concern approved uses of products, FDA will likely apply its labeling and promotional regulations. These reprints still must not be false or misleading, must not contain claims or representations about the safety and effectiveness of drugs that are not supported by substantial evidence, and must present a fair balance between representations of effectiveness and information relating to side effects, contraindications, warnings and other precautionary information.  

In principle, one could argue that it may be appropriate to disseminate on-label reprints utilizing the Good Reprint Practices methodology for dissemination, selection, and disclosure in a way that should not be considered “promotional” and consequently, not subject to promotional requirements.  On the other hand, the plain language of FDA’s final guidance document is explicit as to which reprints fall under this guidance.  Beyond the plain language of the document, you’re on your own.  FDA has not articulated how it feels about dissemination of on-label reprints under its final guidance.  You’re left to interpret FDA’s intentions or your constitutional rights, or you can interpret 21 CFR sections 201 and 202  and the Food, Drug and Cosmetic Act as to how they apply to the on label reprint.

FDA’s final guidance relates to the dissemination of information and how FDA will apply its enforcement discretion relating to misbranding due to promotion of new intended uses.  Misbranding violations relating to the dissemination of false or misleading advertising or labeling are not the subject of this guidance document.

FDA’s Other Reprint Guidance

Another instructive, or at least educational, document is FDA’s ill-fated 1996 Guidance Document “Guidance to Industry on Dissemination of Reprints of Certain Published, Original Data.”  This guidance was one of the guidances that became the subject of the Washington Legal Foundation (WLF) case in which FDA’s reprint policies were successfully challenged in court.  FDA was enjoined by the court from enforcing this document at one time, but during the WLF case FDA argued that the document was superseded by Section 401 of the FDA Modernization Act (FDAMA 401).  

It’s important to understand that the court’s original injunction on this guidance document was based on the extent of restrictions that the guidance document contained.  What it allowed was not the subject of the case. Nonetheless, it is not in effect, either for FDA to enforce or for which manufacturers can glean an official FDA position.   The 1996 guidance document, in contrast to the Good Reprint Practices guidance, did not allow for the dissemination of articles that dealt primarily with unapproved uses.  The 1996 guidance did include provisions for disseminating pivotal trial reprints for approved uses that also contained off-label content.  The Washington Legal Foundation argued (in so many words, forgive me) that the 1996 guidance was unconstitutionally* too restrictive, because it prohibited proactive dissemination of truthful information that related primarily or significantly to unapproved uses.

FDA’s 1996 position on the dissemination of reprints can be summarized as follows:

Companies may [promotionally] disseminate unabridged, bona fide peer-reviewed published reprints of studies were relied on by the FDA in its approval of the drug (referred to as “original efficacy trials”). At the time, FDA intended to allow the dissemination of these reprints even if they contained “…effectiveness rates, data, analyses, uses, regimens, or other information that is different from the approved labeling….” The dissemination of reprints meeting the above criteria could be disseminated if they meet the following conditions:

• The principle subject of the reprint concerns the use(s) or indication(s) that has/have been approved by FDA and the publication reports the original study that was represented by the sponsor, submitted to FDA, and accepted by the FDA as one of the adequate and well-controlled studies providing evidence of effectiveness.
• The reprint is from a bona-fide, peer reviewed journal
• If the articles contains effectiveness rates, data, analyses, uses, regimens, or other information that is different from the approved labeling, the reprint should prominently state the difference(s), with specificity, on the face of the reprint.
• The reprint should disclose all material facts and should not be false or misleading.

So, I reiterate, this is educational and perhaps instructive for certain situations, but by no means does the 1996 guidance represent any official legal or FDA position.  The evaluation of any reprint is an exercise in analyzing the very specific facts and circumstances of the individual reprint and the product development and regulatory history, among other things.  I also want to reiterate that my perspectives are not bullet proof, and I welcome and encourage other thoughts on this topic.

If you are still reading, you have my deepest respect.  This was one long analysis of one narrow topic, and I still haven’t gotten into the meat of the Good Reprint Practices final guidance.  We’re getting there though.  

Yours Truly

John

 

*It’s possible that “unconstitutionally” is not a real word.  Maybe so, but it was an economical way to say what I was trying to say.  If it is a real word, it probably shouldn’t be.

Postscript: Leave A Comment // Subscribe (RSS Feed)

The Next Post: What is a New Intended Use? FDA Regulation, Apocalypse Now and Dialectic Physics
The Previous Post: Good Reprint Practices Adds Polls to Survey User Perspectives