Hazard an opinion: Could scientific views not shared by FDA mean prosecution?

Be forewarned you debaters of science, you presenters of data.

If a ruling this week by a three-judge panel is upheld by the entire US appeals court, and then the Supreme Court, in a case involving statements made a decade ago in a press release, any biopharma official or medical researcher could be in jeopardy of being convicted of fraud for publicly expressing their scientific opinions if those views are not shared by the US government, said Los Angeles lawyer Mark Haddad, a partner and co-chair of the global appellate practice at Sidley Austin.

"The central issue is whether the government may criminally prosecute a speaker for his scientific interpretation of valid study results," Mr Haddad told Scrip. "The Supreme Court has long protected the constitutional right to freedom of scientific expression by requiring the courts to perform a searching and independent review of allegedly false scientific opinions."

The decision by the three-judge panel from the US Court of Appeals for the Ninth Circuit, which heard oral arguments in the case last December, "calls into question the lawfulness of many opinions routinely offered in the publications of scientists throughout the country, as well as the methodology underpinning future government decisions regarding the allocation of health care treatments and procedures," Mr Haddad asserted (scripintelligence.com, 10 December 2012).

The case involves the September 2009 wire fraud conviction by a trial jury of Dr Scott Harkonen for the former InterMune CEO's role in creating and disseminating an August 2002 press release, which federal prosecutors said contained "fraudulent" statements about Actimmune (Interferon gamma-1b), the company's bioengineered form of interferon gamma, a protein that acts as a biologic response modifier through stimulation of the human immune system.

Dr Harkonen was sentenced by a district judge to three years of probation, with six months of home confinement, and ordered to pay a $20,000 fine and perform 200 hours of community service.

But Dr Harkonen appealed on the grounds his statements in the press release expressed a scientific view protected under the First Amendment of the US Constitution and that his conviction did not meet the criteria for prosecution under the US wire fraud laws – arguing that genuine debates over whether a given treatment caused a particular effect are outside the scope of the statute, which does not permit juries to choose one side of a scientific disagreement over another.

Unpersuaded

The Ninth Circuit panel, however, said it was "unpersuaded" by Dr Harkonen's arguments.

To be convicted on a count of wire fraud, the person has to knowingly participate in a scheme to defraud, use the wires in furtherance of the scheme and have a specific intent to deceive or defraud, the judges noted, pointing out that "Statements are fraudulent if 'misleading or deceptive' and need not be 'literally false.'"

The First Amendment, they said, "does not protect fraudulent speech."

Prosecutors had alleged Dr Harkonen's claims about Actimmune in treating idiopathic pulmonary fibrosis (IPF), an unapproved indication, were part of a scheme to boost sales of the drug, which is approved in the US as a therapy for children and adults with chronic granulomatous disease, a genetic disorder in which certain immune system cells are unable to kill some types of bacteria and fungi, and severe malignant osteopetrosis, a bone disease that makes bones abnormally dense and prone to fractures.

The 2002 news release described certain results from a 330-patient, randomized double-blind, placebo-controlled trial, known as GIPF-001.

Difference of opinion

InterMune acknowledged within the first graph of the 2002 statement that the study missed its primary endpoint of progression-free survival in IPF.

But it was the headline and the subhead that apparently ticked off prosecutors and the FDA: "InterMune Announces Phase III Data Demonstrating Survival Benefit of Actimmune in IPF," and "Reduces Mortality by 70% in Patients With Mild to Moderate Disease."

InterMune's statement asserted there was a "40% decrease in mortality" in favor of Actimmune versus placebo, with a p-value of 0.084.

"A 40% relative survival benefit for a drug that's designed to treat a fatal disease where patients die within two to three years of diagnosis is a huge benefit," Mr Haddad said in a 6 March interview.

But prosecutors, backed up by testimony from Dr Thomas Fleming, a professor of biostatistics at the University of Washington in Seattle, who served as the chair of the data safety monitoring board and a frequent participant on FDA advisory committees, argued that InterMune's press release overstated Actimmune's benefits in IPF – declaring the trial results negative because the p-values for all of the pre-specified endpoints exceeded 0.05.

But Mr Haddad contended that p-values should not simply "trump what doctors would consider the practical or clinical significance of a result."

Dr Harkonen's conclusions about the data were not improper, but were a "fundamental difference in scientific views" from those of the government, his lawyer said.

Mr Haddad noted that one pulmonologist, Dr Paul Noble, currently the chair of the Department of Medicine at Cedars-Sinai Medical Center in Los Angeles, who participated in a panel discussion at the November 2002 CHEST conference in San Diego, where the full results from GIPF-001 were presented, remarked that "when you look at the data in total, it's compelling."

"So when you talk about that, there is a lot of patients that are interested in using interferon gamma, and I prescribe it," Dr Noble said at the conference. "I don’t think it's the end of the story. I think it's a very important first step."

"In my mind," said CHEST panel moderator, Dr Marvin Schwarz, co-head of the medicine division at the University of Colorado at Denver, "this was a positive study."

There "appears to be a survival benefit, particularly in those patients that are not very advanced, so my feeling is that it does have a tendency to stabilize this disease,” he said.

Dr Schwarz added that he would "certainly discuss this with every patient that I see."

Mr Haddad said the video of the panel discussion was presented at Dr Harkonen's sentencing.

He said other evidence also was presented at sentencing that included "very powerful declarations from two of the nation's most prominent biostatisticians" – one from Harvard and the other from Stanford – plus a declaration from one of the nation's leading experts in treating IPF.

But in a footnote to its ruling, the Ninth Circuit panel said it could not reverse the verdict based on evidence the jury never considered.

Nonetheless, Mr Haddad said, "Leading and nationally recognized scientists stated under oath that the challenged press release was not false or misleading."

Lack of independent review

"The decision in the Harkonen case did not identify a single false statement, let alone evaluate independently whether the study results reasonably supported the opinions for which Dr Harkonen was prosecuted," he declared.

"Failing on appeal to address an issue of fundamental constitutional importance sends a chilling message that government officials have unfettered discretion to prosecute speakers who publicly express views about science with which government officials disagree," Mr Haddad contended. "This is intolerable in a society that protects the freedom of scientific speech, particularly where, as here, potentially life-saving medical treatment is at issue.”

If the Ninth Circuit panel's ruling is allowed to stand, the implications of the decision "are profound," he said.

"The ramifications are enormous," Mr Haddad insisted.