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Janssen Pharmaceuticals Accused of Hiding Risperdal's Breast Effects In Boys

This article is more than 8 years old.

Risperidone is an antipsychotic with known side effects that clinicians must balance against its benefits for a subset of autistic people. Although it can, for some autistic people, help reduce self-injurious and aggression-related behaviors, the drug can also lead to weight gain and even a movement disorder.

And like other antipsychotics, its use is associated with increased levels of a hormone called prolactin, which is regulated in the brain. Prolactin has many roles, and one is promoting milk production. In a 2012 study of autistic boys taking the drug, half of them ended up developing gynecomastia, or breast enlargement, whereas a fifth who weren't taking the drug did. And half of the boys taking risperidone had elevated prolactin levels, although not all of this group developed gynecomastia.

Now Janssen Pharmaceuticals, Inc., a Johnson & Johnson company that markets this drug as Risperdal, has been accused of hiding evidence back in 2003 that would have alerted clinicians and regulatory authorities to the connection among risperidone, increased prolactin, and gynecomastia.

Jessica Wright, reporting at Medpage Today and SFARI, writes that a 2003 publication of the findings allegedly did not include results showing a significant relationship between the increased prolactin in boys taking the drug and development of prolactin-related side effects.

This study was one of a reported 44 that Johnson & Johnson was 'managing' to promote sales of Risperdal, according to a report in the Chronicle of Higher Education.

Three years after the 2003 paper was published, the US Food and Drug Administration (FDA) approved risperidone for irritability in autistic children. The drug is also used for several other conditions, including schizophrenia and bipolar disorder. Its connection with gynecomastia has now been well established.

But this side effect wasn't known established in pediatric populations back in the early aughties, when clinicians began prescribing it off-label for autistic children with self-injurious and other aggressive behaviors.

In 2013, the New York Times reported on the risperidone-related settlement that Johnson & Johnson agreed to that year, at that time the third largest such settlement in history:

Johnson & Johnson has agreed to pay more than $2.2 billion in criminal and civil fines to settle accusations that it improperly promoted the antipsychotic drug Risperdal to older adults, children and people with developmental disabilities, the Justice Department said on Monday. ... Johnson & Johnson ... did not admit to wrongdoing for the civil portion of the settlement, which involves claims that the company promoted the drug’s use in children and the developmentally disabled, as well as accusations that it paid kickbacks to doctors and pharmacists in exchange for writing more prescriptions.

Wright describes one of the individual lawsuits, brought by

a now-20-year-old man with autism who grew size 46DD breasts after taking Risperdal from 2002 to 2006. In February, a Philadelphia jury awarded him $2.5 million. (A Janssen spokesperson said the company would continue to vigorously defend against the suit's claims and intends to file an appeal.)

In case of the 20-year-old man, the plaintiff, from Alabama, was prescribed risperidone in 2002, when he was 8 years old. Before the drug's 2006 FDA approval for autism, according to the Chronicle of Higher Education, Johnson & Johnson, Janssen Pharmaceutical's parent company, "aggressively" marketed the drug to pediatric clinicians.

The Alabama man, Austin Pledger, was prescribed the drug off-label in 2002. According to news reports, a Janssen sales rep visited Pledger's pediatric neurologist more than 20 times to urge off-label prescription of the drug. Pledger's case was the first jury trial among the 1,250-plus cases in Philadelphia alone awaiting litigation on this matter.

Evidence in two of these cases has centered on an early version of the 2003 study manuscript that included two tables of data. Analysis of the data in these tables reportedly shows a direct link between increased prolactin levels and side effects like gynecomastia.

But these findings allegedly were scrubbed from the manuscript that ultimately was published. The published version says that prolactin levels initially increased but then quickly fell and were not related to any common prolactin-associated side effects.

According to local news reporting on testimony in two individual cases that have gone to trial, the unreported findings also were never provided to the FDA. Much of the testimony described centers around whether or not Janssen scientists decided to adjust how they analyzed the data to mask the relationship.

The first author on that 2003 paperRobert Findling, director of child and adolescent psychiatry at Johns Hopkins, has acquired the original data and is in the process of having these unrevealed findings reanalyzed by an independent biostatistician, Wright reports. He and another author, Denis Daneman, a professor and chair of pediatrics at the University of Toronto, neither of whom were Janssen employees, were displeased to learn about these allegations and became concerned after the $2.2 billion settlement was announced.

According to Paul Basken, writing at the Chronicle of Higher Education, Daneman asked the publishing journal, the Journal of Clinical Psychiatry, to remove his name as an author, but the publisher declined. Three other authors on the paper were Janssen employees and a fourth author is deceased.

According to Wright, Findling and a co-author are coordinating the reanalysis to determine whether or not the 2003 paper should be retracted and what any retraction would cover.

In the meantime, Janssen has provided a couple of statements regarding the court cases and the specific allegations related to these tables. As reported by Dave Schatz writing at New Brunswick Today (NJ):

During the two recent trials in Philadelphia, Janssen presented evidence showing that the FDA-approved label properly warned of RISPERDAL®'s potential side effects and the plaintiffs’ prescribers were aware of those side effects. In addition, Janssen presented evidence that it appropriately analyzed and reported data from clinical trials.

And Wright quotes a company spokesperson as follows:

the company has "acted responsibly regarding informing physicians and patients about the risks and benefits of Risperdal."

Correction: In a useful Twitter exchange with me, a clinician noted that the literature contained references to gynecomastia in adults in relation to antipsychotics in the 1990s, so I have amended the sentence to be specific to the pediatric populuation.

UPDATE: In addition, I have received by email the following statement from Robyn Reed Frenze, who is identified in the email signature as a director of product communication, global pharmeuticals communication and public affairs, Janssen Pharmaceuticals.

I have posted the email content in full below, but first, two observations. (1) The first part of the communication from Frenze contains information about reporting the rate of gynecomastia from clinical trials but does not specify results allegedly related to data that are cited as having gone unreported in the 2003 publication and to the FDA. The rate cited for boys in clinical trials was 2.3%. The prevalence of gynecomastia in boys in general is around 4%, and studies have reported an incidence of gynecomastia in teenaged boys as high as 40%. The allegations reported in this story center on whether or not a significant relationship between prolactinemia and gynecomastia was reported, not whether or not rates of gynecomastia were.

The email also notes that gynecomastia was reported previously as an adverse event in adults, which I have amended in the post based on insight from a clinician exchange on Twitter, which made it clear I had not specified pediatric populations in that statement and should have. It's unclear how the rates of gynecomastia would look now for adolescent boys taking risperidone. One recent large study found that boys and young men taking risperidone had four times the risk of developing breast enlargement compared to those not taking it; in those under 18, the risk was five fold.

(2) The second part of the statement from Frenze, the "Findling analysis" section, says that data from five 'different' studies were 'considered' for the 2003 paper and that all data that were 'clinically significant' were published in that study. It goes on to say that the data were shared with the FDA with the NDA submission and that "each of these five studies was eventually published." This language does not directly address the allegation others have made that the original data in question that allegedly indicated significant results were subsequently regrouped to efface that significance (thus removing them from the above-referenced "clinically significant" data that were published).

Certainly, the two non-industry-employed authors on that study appear to be displeased about it. We will have to await the results of the Findling reanalysis by the independent biostatistician.

The emailed statement from Frenze:

Availability of gynecomastia information – The various risks of antipsychotics are well known by the medical community.  Contrary to your assertion that the risk of gynecomastia was not known as late as the 2000’s, when RISPERDAL® was initially approved in the U.S. in December 1993, the original label listed gynecomastia as a rare adverse event as reported in pre-marketing clinical trials in adults.  It alsocontained the following language in the Precautions section under Hyperprolactinemia:

“Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients.”

When the irritability in autism indication was approved in October 2006, the pediatric use section was updated to include new information about gynecomastia, including the 2.3% rate as reported in clinical trials in children and adolescents.

  • Findling Analysis – Data from five different studies were considered for this 2003 paper and all data that were clinically significant were published in it.  The safety data from these studies were shared with the FDA when we submitted our supplemental New Drug Application to treat autism on Dec. 19, 2003.  Each of these five studies was eventually published.
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