Physician letter of support to FDA for eteplirsen

Posted by: Christine McSherry on December 23, 2013

Janet Woodcock, MD

Director, Center for Drug Evaluation and Research

U.S. Food and Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993


Dr. Woodcock,

I wrote about a month ago voicing my concerns related to FDA’s interpretation of ‘recent data’ related to eteplirsen.  Such had been referred to by FDA-DNP as being a part of your ‘premature to file NDA’and ‘need for placebo group for a Ph III study’ statements.   As you may remember, I felt your interpretation(s) failed to properly apply the data—as presented in McDonald’s, Henricson’s, and Mazzone’s 2013 publications—for the grouped natural history of DMD boys—at least as compared to eteplirsen’s data.  However, this letter is about other concerns in your process(es) for detecting possible clinical benefit of drug candidates for DMD.

Though the recent PPMD forum on December 12 was a high-profile event and included FDA’s presence and involvement, several statements attributed to FDA personnel raise significant concern that the basic FDA-DNP ‘old’ way of thinking is not in any way changed, or, even in process of changing. However, if new therapies such as for DMD are to receive a fair hearing, I’m convinced such thinking will have to change.

For example, a tweeted statement (attributed only to “FDA”): We are looking at the natural history data very carefully and we are really trying to understand it.’   What’s wrong with that, you ask?  It is this:  natural history in DMD (and similar conditions) is not only that definable bygroup stats, but also that natural history unique to each individual affected.   The former seems to me reasonably clear, but the latter is in fact crystal clear.  There is a pattern of decline in each boy which is not known to spontaneously reverse—this pattern is itself a definablenatural history—for that boy.   E.g., a boy who had declined to the point of requiring assistance to ambulate, then becomes ambulatory without assistance—or even begins to run again; or, another boy with severe toe-walking then resumes ability to walk almost ‘flat’ footed—then the clearly known natural history (for those individuals) has been altered!  If a boy who couldn’t lift his arms above his shoulders can now ‘reach for the ceiling’ then his natural history has been altered. Something had to have occurred for such previously unknown improvements to have happened.

Based on data (including recent), such dramatic changes are not adequately explainable by ‘chance’, steroids, or, effort/placebo effect. Whether such clinical effect is from ataluren, eteplirsen, or other agent; whether it is in a majority or just a minority of affected boys, it should be clear that ‘natural history’ has been altered–in at least those boys! I.e., clinical benefit has been demonstrated compared to ‘natural history’!

Another statement of concern is attributed to Dr. McDonald to the effect that: ‘If 6MWD is greater than 350M at baseline, will have to show improvement or do longer trials’.  This statement is another ‘group’ natural history statement—limited to trying to discern clinical benefit by alteration of natural history among GROUPS only.  Though his field is DMD natural history (for ‘groups’ at least), this demonstrates the same worrisome narrow view of “natural history”.  It is, in my opinion, the central weakness, if not failing, at the core of the FDA’s thinking.  You/he are still only looking for clinical benefit in GROUPS, and only then, if finding it, are willing to apply it toINDIVIDUALS in the group (e.g., by approving its use).  This shows an ‘old’ mindset which is inadequate for some of the diseases which 21stcentury medicine is beginning to attack.  It is especially a setup for missing otherwise clearly demonstrable clinical benefit in DMD.

As a physician, I understand the belief that double-blinded, placebo-controlled studies represent the ‘holy grail’ of proof—I actually agree with its applicability to many circumstances.  However, in a rare disease whose course is very predictable based on an individual’s natural history, yet which remains confusing (to you, at least) from a group standpoint, then perhaps it is because this particular ‘holy grail’ can’t actually solve this particular problem!?  Or, at least not ‘solve’ it without much unneeded loss/damage in the search for such a solution. This statement attributed to Dr. Unger is exactly on point to this whole concern: ‘We have seen a lot of variability in placebo groups from one trial to the next–it creates problems.’  Not so much a problem unless using an ‘old’ paradigm of natural history.  Not so much either if you (FDA) stop looking from the group to the individual for clinical benefit, and start looking from the individual to the group!

So what am I suggesting?  If an agent shows clear clinical benefit across a number of INDIVIDUALS, based on any of several areas never known to reverse spontaneously; and, if there is an adequate safety profile, then grant tentative approval for more general use—including boys not yet on the downward slope of previously irreversible decline (e.g., all >7yr old).   Then require detailed clinical analysis on all users and before long, the FDA will have a sufficiently large database to compare with prior GROUP natural history data.  This should allow you—starting from the clear-cut individual natural history alteration—to decide if that clinical benefit is also a GROUP characteristic.  If so, then general use would continue; if not then this does not invalidate the benefit for that subset of individuals who DO benefit, and limitations on labeling may be felt appropriate.

I know that such disease-modifying, positive clinical effects have been seen with eteplirsen; I’m not as certain with other agents, as much of the individual data for those studies isn’t available for general analysis.  However, I feel sure you either already have, or can obtain such clinical data for the other agents for such decisions on benefit/risk analyses.

In my previous letter I urged you not to turn this critical decision over to ‘number crunchers’ who wouldn’t know clinical benefit if staring them in the face.  If the isolated statements quoted above are typical of the FDA’s opinion, then I fear that appellation includes some of the speakers from December 12.  If representative, then the statements made seem to indicate a continuing fixation on one criterion, one technique for defining and thus finding ‘clinical benefit’.   Please don’t miss the vast and flourishing forest of clinical benefit all around by looking only at one tree for an answer!


%%% Taylor, MD

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