Aaron Kesselheim’s Presentation on FDA Regulation of Manufacturer Speech

On August 5, 2013, Dr. Scott Harkonen filed his petition for a writ of certiorari with the United States Supreme Court. As noted in some previous posts, Dr. Harkonen was acquitted of misbranding, but convicted of wire fraud, for his role in issuing a press release about the results of a clinical trial of interferon gamma 1b, in patients with idiopathic pulmonary fibrosis.  (See Multiplicity versus Duplicity – The Harkonen Conviction; The Matrixx Motion in U.S. v. Harkonen; The (Clinical) Trial by Franz Kafka).

Dr. Harkonen’s petition presents two questions:

“1. Whether a conclusion about the meaning of scientific data, one on which scientists may reasonably disagree, satisfies the element of a “false or fraudulent” statement under the wire fraud statute, 18 U.S.C. § 1343?

2. Whether applying 18 U.S.C. § 1343 to scientific conclusions drawn from accurate data violates the First Amendment’s proscription against viewpoint discrimination, or renders the statute, as applied , unconstitutionally vague.”

Both questions are important given that the government has conceded that Dr. Harkonen’s press release accurately presented the raw data and calculated p-values.  The crime, if crime it be, lay in Dr. Harkonen’s drawing a causal inference from a subgroup, p = 0.004, which was not prespecified, in a specified secondary endpoint of survival (p = 0.08), when the subgroup was clearly based upon the goals of the trials, and there was other corroborative evidence in the form of two previous trials, clinical practice, and strong mechanistic evidence.

The government argued that NO inferences could be drawn from a trial that “failed” on its primary endpoint.  The government’s embrace of this statistical orthodoxy greatly misrepresented scientific practice to the courts below.  The only “failed” trial is one that is not conducted.

There are many who would go to great lengths to distort the facts of the Harkonen case in order to demonize the pharmaceutical industry, or to arm the Justice Department with a weapon that can shut down scientific speech about pharmaceutical interventions.  The expansion of the Wire Fraud Act, seen in the Harkonen case, to achieve these political goals will not only affect pharmaceutical company scientists, but also government and academic scientists.  The standard for falsity, drawn from an out-dated, tendentious, and overly rigid conception of hypothesis testing will apply equally to non-industry scientists in False Claim Act cases.  Perhaps in future posts, I can provide some good examples, on condition that any qui tam relators share their bounty with me.

Back in May, Aaron Kesselheim presented (by video) a paper, written with Michelle Mello, of the Harvard School of Public Health, on “The Prospect of Continued FDA Regulation of Manufacturer Promotion in an Era of Expanding Commercial Speech.”  Kesselheim went out of his way to misrepresent the facts of the Harkonen case, as part of his brief against off-market promotion.

By way of background, Aaron S. Kesselheim is a physician and a lawyer, and an Assistant Professor of Medicine at Harvard Medical School.  He is also a faculty member in the Division of Pharmacoepidemiology and Pharmacoeconomics in the Department of Medicine at Brigham and Women’s Hospital.   Given his position and his training in two professions, as well as the extraordinary stakes involved in allowing the government to prosecute scientists for drawing allegedly false conclusions about facts that the government concedes are accurate, Dr. Kesselheim should have exercised much greater care in checking his own assertions more closely.

Dr. Kesselheim focused primarily on the Second Circuit’s recent decision in United States v. Caronia, 703 F.3d 149 (2d Cir. 2012) , which reversed a judgment of conviction for off-label promotion, on First Amendment grounds.  About nine minutes into his presentation, Kesselheim turned to alternative strategies for the government to use to squelch off-label promotion.  One of his suggestions was to follow the model of the Harkonen prosecution, and to prosecute off-label promotion as false and misleading speech.

In his discussion of his suggested strategy, Kesselheim suggested that Dr. Harkonen had made misleading “conclusory, unsubstantiated claims for efficacy,“ and “without reference to supporting evidence.”  It is Kesselheim, however, who seriously mislead his listeners and readers by stating that Dr. Harkonen had made “conclusory, unsubstantiated claims for efficacy.”  The Press Release that was the subject of the government’s indictment set out accurately actual count data and calculated p-values.  No data were fabricated or falsified.  Within the limited space and the informal context of a Press Release, Dr. Harkonen had provided a substantial account of the data from InterMune’s clinical trial, as well as citing a previous, independent clinical trial and its extension, clinical experience, and mechanism research on the action of interferon γ-1b.  Unfortunately, it is Kesselheim who is speaking in conclusory sound bites when he ignores the context and content of the actual Press Release at issue.

Kesselheim went on to suggest that Harkonen’s statement was refuted by a “company-sponsored clinical trial showing that the drug was not effective.” This statement is not only false, but shows a flagrant disregard for statistical analysis and the data in the Harkonen case.  Kesselheim implies that a clinical trial that fails to show treatment efficacy thereby shows that the treatment was not effective.  His statement commits the fundamental error of equating a failure to reject the null hypothesis at a specified level of attained significance with acceptance of the null hypothesis.  This reasoning is fallacious and fundamentally flawed.

To be sure, the prespecified secondary survival endpoint in InterMune’s clinical trial did not meet the 0.05 cutoff (it was 0.08), although the per-protocol analysis for this endpoint came up at 0.055, on a preliminary analysis of the data. When the clinical trial was fully analyzed and written up for publication in the New England Journal of Medicine, the treatment-adherent analysis for survival in the entire clinical trial was 0.02, with a statistically significant hazard ratio for survival, favoring the therapy:

“Analysis of the treatment-adherent cohort of patients showed an absolute reduction in the risk of death of 9 percent in the interferon gamma-1b group, as compared with the placebo group, and a relative reduction in the risk of 66 percent (5 percent of 126 patients in the interferon gamma-1b group and 14 percent of 143 patients in the placebo group died, P=0.02). The hazard ratio for death in the interferon gamma-1b group, as compared with the placebo group, was 0.3 (95 percent confidence interval, 0.1 to 0.9).”

Ganesh Raghu, Kevin K. Brown, Williamson Z. Bradford, Karen Starko, Paul W. Noble, David A. Schwartz, and Talmadge E. King, Jr., for the Idiopathic Pulmonary Fibrosis Study Group, “A Placebo-Controlled Trial of Interferon Gamma-1b in Patients with Idiopathic Pulmonary Fibrosis,” 350 New Engl. Med. J. 125, 129-30 (2004).

Dr. Harkonen, in his Press Release, did focus on what seems like an eminently sensible subgroup, within the survival secondary endpoint, of mild- and moderate-cases, which, a priori, were believed to be the patients mostly likely to benefit from the interferon γ-1b therapy.  (What was not known before the trial was at what point in disease progression might patients no longer respond with greater survival, and hence the difficulty in setting the boundary between moderate and severe cases.)  Kesselheim might argue that the interferon γ-1b clinical trial, standing alone, was inconclusive, but he certainly cannot argue truthfully that the trial showed that the biological product to be ineffective.  Clinical trials do not neatly divide the world of possible results into demonstrations of efficacy and demonstrations of inefficacy.  Not only does the evidence come in degrees, but there is a range of “inconclusiveness” in between the two extremes. Given his background, training, and experience, Kesselheim certainly should know this, and he should apologize for his inaccurate statements.

Kesselheim might well have stopped there, but he went on to acknowledge that the company-sponsored clinical trial at issue did find, in post-hoc analyses, a non-significant trend of benefit in a subset of patients.  Talk of misleading speech!  The p-value at issue was 0.004, uncorrected for multiple comparisons, but no one, not Kesslheim, not the government or anyone else, has offered any appropriate adjustment for multiple comparisons that would inflate that 0.004 to over 0.05.  Kesselheim has no warrant for branding the subgroup finding “non-significant,” until he shows that the p = 0.004, when appropriately modified (if it can be), exceeds 0.05.

Kesselheim mangles other, less technical facts.  He claims that the company saw a ten-fold increase in sales of interferon γ-1b for idiopathic pulmonary fibrosis.  No such fact was ever, or could ever, be established in the Harkonen case.  Kesselheim claims that Dr. Harkonen admitted, in emails, that he did not really believe that the trial “demonstrated” benefit; no such emails were ever adduced at trial, and this seems to be part of a fictional narrative that Dr. Kesselheim has manufactured.  Finally, Kesselheim harrumphs that FDA declined to approve drug.  The company never filed a new drug application for the idiopathic pulmonary fibrosis indication; there was no application to reject.  Perhaps more important is that the Press Release was issued before InterMune had made any formal submission of data to the FDA, an event that did not take place until the following year.

Kesselheim sighs that the Harkonen prosecution will be a difficult act to follow because it requires a case-by-case showing of falsity, with the necessity of expert testimony, and heavy cognitive demands on lay jurors. How ironic that Kesselheim, a lawyer and a physician, and a Harvard Medical School faculty member, buckled under the cognitive demands of his topic. Indeed, Kesselheim’s confusion is a strong argument for why the Supreme Court should put a stop to the practice of asking jurors to second guess whether a scientist has incorrectly inferred causation from accurately presented facts.

Let’s hope Dr. Harkonen gets a fair hearing in the Supreme Court.

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