Good Reprint Practices

Now it could be that you think I’ve gone mad.  What does Apocalypse Now, the legendary Francis Ford Coppola movie, have to do with Good Reprint Practices?  Does it have something to do with some theme about rebellion, surfing in war zones, madness itself, some parallel to the deterioration of Marlon Brando or to the turbulent journey of Captain Willard’s morality?  Truthfully, it has nothing to do with any of that, though there’s plenty of metaphorical fodder there.  Really, Apocalypse Now has nothing to do with Good Reprint Practices, except for this, and it’s a stretch….  

I was falling asleep the other night with the TV on and Apocalypse Now Redux was on.  Apocalypse Now Redux, if you didn’t know, is a re-cut of the original movie with lots of new footage that was cut out of the original to make the original version of the movie watchable.  Of course I did what you do when you watch the redux version, you tend to fall asleep.  Don’t get me wrong, I love the movie and the redux, but I’ve seen it too many times to count and it just becomes wallpaper after awhile.  So back to Good Reprint Practices.  I was thinking about my next post while I was falling asleep to the movie.  Two things that can put most of the American population to sleep:  the extra scenes in the movie redux and thinking about FDA’s regulation of reprints.  Nonetheless, at one point I woke up and a scene with Dennis Hopper was on.  Dennis Hopper played a crazed photojournalist in the movie who becomes a follower of the murderous Colonel Kurtz (played by Marlon Brando) deep in a remote Cambodian jungle.  As I emerged from my haze, I heard Dennis Hopper’s character ranting to Martin Sheen (Captain Willard):

“This is dialectics. It’s very simple dialectics. One through nine. No maybes, no supposes, no fractions. You can’t travel in space. You can’t go out in space, you know, without like, you know, with fractions. What are you gonna land on? One-quarter? Three-eighths? What are you gonna do when you go from here to Venus, or something? That’s dialectic physics, OK. Dialectic logic is, there’s only love and hate.”

First of all, I hadn’t really paid attention to the term “dialectic” since I was writing literary criticism papers in college (b-l-letch!).  I’m not even sure I’ve heard the term since then (except for I guess the 30 or so times I watched Apocalypse Now).  But “dialectic physics?”  That’s a term about an impenetrable concept I do not want to know about.  I’m not going to talk about it either.  What I was so interested in was the fact that “You can’t go out in space…with fractions.”  “No maybes, no supposes, no fractions.”  For goodness sakes, isn’t that our prison–fractions?  Could you imagine drug regulation without supposition and maybes and fractions?   

In order to even begin to understand FDA’s Good Reprint Practices guidance document you have to live with varying conditions, dependencies and uncertainty.  Start with the simple idea of what constitutes a new intended use.  FDA itself has struggled with this idea over time.  For example, when FDA issued regulations implementing section 401 of the FDA Modernization Act of 1997, it gave two different definitions of “new uses” in two separate Federal Register Notices.  The first notice accompanied FDA’s draft Part 99 regulation in June 1998.

FDA’s Evolving Definition of “New Use”

FDA’s interpretation of the definition of “new use” is critical because it determined the scope of information for which FDAMA 401 and Part 99 applied.  Because FDA’s 2009 final Good Reprint Practices guidance document does very little to define “new use,” these previous Federal Register notices are of central importance.  They are instructive as to the scope of information for which FDA’s present guidance document may apply.  Importantly, FDA’s 2009 guidance includes a footnote defining an unapproved use in the following way:

“The terms ‘unapproved new use’, ‘unapproved use’, and ‘off-label use’ are used interchangeably in this guidance to refer to a use of an approved or cleared medical product that is not included in the product’s approved labeling or statement of intended uses.”

OK.  That’s like traveling through space and landing on a fraction.  What is a use that needs approval to begin with?  What is a use?  You didn’t land on a fraction, you landed on a physics formula.  What if you have mortality or morbidity data for an approved use?  What if you have health related quality of life claims in a reprint?  What if you have a study in a pediatric or geriatric population?  Often outcomes are approved in sNDAs or sBLAs for drugs, like mortality benefits and functional improvements.  Does this mean these are unapproved new uses if they are outcomes related to the approved “use” of a product?  It depends.  Maybe, maybe not.

In its June 1998 Federal Register notice, FDA defined “new use” as “one that would require approval or clearance of a supplemental application in order for it to be included in the product labeling.”  This is a fairly problematic definition, because its often unknowable without asking FDA.  Sometimes you may get a clear answer, and sometimes you might get an answer like, “submit a package, protocol, or studies, and we’ll give you an opinion.”  At that point, you might as well just seek approval.  This may simply be the definition of a claim that needs substantiation or a claim that requires prior approval or a claim that constitutes an unapproved new use or two of the above or all of the above.  

However, FDA revised its interpretation in its subsequent notice in November 1998 implementing the final Part 99 regulation.  In its November 1998 Federal Register notice of the final rule, FDA explained the following:

“With respect to claims of efficacy in a new patient subgroup, including a new age group, claims that are more detailed than the approved labeling, and claims that relate to different intended outcomes…FDA’s prescription drug advertising regulations may permit companies to make such claims about prescription drugs in certain circumstances, without submitting a supplement, provided they have on file, the required evidence to support the claim.”  [italics added]

In FDA’s November 1998 Federal Register notice they seemed to lean toward a distinction between those data or claims that need substantiation but relate to an approved use and those claims that relate to a distinct new use (but which also require substantiation for approval).  Of course, this can be a maddening thought process, particularly for the former.  Also, FDA’s reference to patient sub-populations in its November 1998 notice should not be over-interpreted.  For example, one might come to the conclusion that a pediatric sub-population might not constitute an unapproved new use.  However, unlike perhaps an older or geriatric population that is often (at least partially) subsumed by a general indication in adults, pediatric populations constitute an age group that is excluded from adult studies in most, if not all, cases.  Therefore, pediatric use is an example of a use in a population that FDA would likely interpret to be an unapproved new use in nearly all circumstances.  There’s more to FDA’s explanation in this Federal Register notice and you can read the specific comment from which it comes here.  You should read the entire thing.

Let the Credits Roll

In the end, the answers to the most fundamental questions can be uncertain and fractional.  Keep in mind as well that while particular data or claims in a reprint may only require substantiation but not concern a new use, an FDA misbranding violation can result from the dissemination of information relating to new uses and from false or misleading advertising or labeling (resulting from unsubstantiated claims).  Most useful is a thorough knowledge of FDA’s record of approvals in the area of use and a thorough knowledge of your product’s own regulatory history as well.  Many answers will not be so easy and you never know where you will land…

“You can’t go out in space, you know, without like, you know, with fractions. What are you gonna land on? One-quarter? Three-eighths? What are you gonna do when you go from here to Venus, or something?”

Safe journey,

 

John

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