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Inadequate dissemination of phase I trials: Some alternate interpretations

Posted by plosmedicine on 31 Mar 2009 at 00:35 GMT

Author: Gary Novack
Position: President
Institution: PharmaLogic Development, Inc.
Submitted Date: March 05, 2009
Published Date: March 6, 2009
This comment was originally posted as a “Reader Response” on the publication date indicated above. All Reader Responses are now available as comments.

To the editor:
I found the article by Decullier et al1 on publication of Phase 1 trials to be of interest. My concern is with the interpretation and judgment of the findings. The use of the word “inadequate” suggests that the authors judged the rate of publication, 17% of sample, as being inadequate. In an area where there is little data, no agreed upon standards, I suggest that a less pejorative title might have excluded the term “Inadequate”.
There are several caveats on this analysis. First, it is from studies conducted in 1994 in France. While some period after the trial conductance is required to determine if publication occurred, nonetheless a myriad of changes in disclosure and publication policy have occurred in the ensuing 15 years. Next, the authors seem to equate numerical difference and statistical significance with clinical significance. While I concur that the overall rate of publication for Phase 1 studies vs. Phase 2-4 studies is clinically significant (17% vs. 43%, respectively), I do not think that some of the other comparisons are so clearly clinically significant (e.g., 95% vs. 88%, 95% vs. 81%).
Implied in this paper,1 as well as other recent publications in this journal,2;3 is that the reason for non-publication is a willful desire by the Sponsor to hide information. While some Sponsors have a long lead time to manuscript submission, I suggest that there is no difference between industrial and academic scientists in this regard.4 Among the reasons for non-publication or delayed publication are that early stage trials may be conducted before patents are issued, and thus confidentiality requirements dictate a delayed publication. If a project is stopped for any of a number of reasons, there is little interest in directing resources to manuscript preparation vs. other active projects. If is known that the next generation molecule is already in development, neither the authors, management, nor journal editors want to give journal space to the old molecule, and would rather wait for the new molecule. In my own field of ophthalmology, I have been able to published selected Phase 1 studies.5;6 However, the interest of journals in such studies is relatively low. More generally, as most Phase 1 studies are safety and/or pharmacokinetic studies, journals give higher priority to later stage studies which include efficacy data, and the ability to determine a benefit/safety ratio.
It seems that many of the clinical trial registration and presentation changes that the authors might purport are now not just a matter of practice,7 but as well a matter of law, at least in the U.S. since the September 2007 passage of the Food and Drug Administration Amendments Act of 2007 (

1. Decullier E, Chan AW, Chapuis F. Inadequate dissemination of phase I trials: a retrospective cohort study. PLoS Med 2009;6:e34.
2. Lee K, Bacchetti P, Sim I. Publication of Clinical Trials Supporting Successful New Drug Applications: A Literature Analysis. PLoS Medicine 2008;5:doi:10.1371/journal.pmed.0050191.
3. Rising K, Bacchetti P, Bero L. Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation. PLoS Med 2008;5:e217.
4. Novack GD. The Role of Pharmaceutical Companies in Sponsored Research. Ophthalmology 2007;114:1037-8.
5. Mundasad MV, Novack GD, Allgood VE, et al. Ocular Safety of INS365 Ophthalmic Solution: A P2Y2 Agonist, In Healthy Subjects. J Ocul Pharmacol Ther 2001;17:173-9.
6. Mundorf TK, Ogawa T, Inui N, et al. Timolol LA: a double-masked, active-controlled, randomized, crossover, comfort, ocular safety, and systemic bioavailability study in healthy volunteers. Curr Med Res Opin 2005;21:369-73.
7. Laine C, Horton R, DeAngelis CD, et al. Clinical Trial Registration: Looking Back and Moving Ahead. N Engl J Med 2007;356:2734-6.

Competing interests declared: The author owns stock in Inspire Pharmaceuticals, and consults with pharmaceutical and medical device firms in product development.