NEW BRUNSWICK, NJ–In two lawsuits alleging that Johnson & Johnson’s antipsychotic drug Risperdal caused boys to grow female breasts, a biochemist for the company testified that the Food Drug Administration (FDA) was never given an internal analysis showing a link between the two.
Ivo Caers, a VP of Neuroscience Development at Janseen Research & Development, has been employed with J&J for the past 36 years.
He introduced himself to a jury on March 6 as “Compound Development Team Leader,” adding that he was managing a team from Beerse, in Northern Belgium.
Caers said he's been working with Risperdal for about 18 years, according to the transcript from the most recent Risperdal trial in Philadelphia, William Cirba v. Janssen pharmaceuticals.
Caers was then asked by Attorney Tom Kline, if Janssen ever brought tables 21 or 34, the evidence that showed the association, to the FDA.
“No, not as such, no,” said Caers.
"Why not?" asked Kline.
“Analysis that you eventually, after the input of the clinicians and in this case also the endocrinologists, make clinical sense and have clinical value, those are things that you bring forward at the appropriate moment,” answered Caers.
"But all the different exploratory findings, you don’t share," he continued.
By now, Caers' words did not surprise Kline. The attorney had already cross examined this witness in the Austin Pledger v. Janssen Pharmaceutical's Risperdal trail a month earlier, in February. According to that transcript the attorney questions Caers about his use of the term “Exploratory Analysis,” telling Caers that he had testified for 12-hours in one deposition for the Risperdal cases and “never used [the] term before” coming “in front of this jury.”
Caers simply said that it was “very common terminology,” but Kline told him he did not ask if it’s common terminology. Instead Pledger's attorney wanted Caers to tell the court whether or not he had ever used the wording “prior to coming in front of this jury?”
“I cannot – that may be, I don’t know. I can’t reread all my depositions,” said Caers, according to the court transcipt.
Shortly after, Kline established that when “the pooled analysis began … and before there were any statistics run a first time and a second time, before it began, there was the concept of the Janssen scientists, you included to do a pooled analysis.” He asked if it was correct that the pooled analysis did not have a plan to divide anything by SHAP (A) and SHAP (B).
Caers answered that it was “not really correct,” stating that Dr. Denis Daneman, the “Toronto child endocrinologist” [one of the "Findling Paper" authors, who has also asked that his name be removed from the article] from a consultation in 2001, told Janssen to be careful about grouping “these all together under the one umbrella SHAP, because there are certain … observations that are most likely not prolactin-related.”
But Kline was quick to point out that this represented brand new testimony, and direct Caers to a meeting that took place in January of 2002 in which endocrinologists Thomas Moshang and Daneman were present for. Caers then testifies that he was not at the meeting, and states that he did not ever talk directly with Dr. Daneman.
“So anything you are telling us about what you say Dr. Daneman says, which is not in the meeting minutes, is something that you want us to believe that someone told you that he said… Correct?” asked Kline.
After Caers responds that he did not talk to him, Kline asks the witness: “In fact, there was no plan from the beginning, no plan, to do SHAP (A) and SHAP (B). Would you admit it, sir?”
But Caers says “no, no, there was – that’s totally wrong,” referring to a discussion from the previous day in court and pointing out that what Kline presented as an “analytical plan” was “not and analytical plan.” After some sparring over when the SHAP terms were first used, Kline, who is clearly controlling the cross examination brings to attention notes of the meeting that Caers received via email.
Kline states that there is “no mention of breaking the kids up in SHAP (A) and SHAP (B)” in the letter within the email.
“That terminology came in later but the concept,” said Caers, not finishing the sentence. After a rebuttal by Kline, Caers asks to see the email and is given time to read it.
Kline’s first question pertains to the opening paragraph which he says states: “A quick update on the prolactin expert meeting” He notes: “So you had experts.”
“In January is when the study gets started, correct?” asks Kline.
“It’s not a study, it’s an analysis,” says Caers adding that the study had already been done.
Kline asks the witness if it is correct that he was not at the meeting. Caers answers in the affirmative.
“Did you get conferenced in live, did you get conferenced in by phone, did you get conferenced it by telecommunications?” asks Kline.
Caers makes it clear that he was not at the meeting, and when Kline questions back that he thought it was a very important meeting, Caers says: “Well, this is one meeting on one of the nine development plans I was running at that moment worldwide…There were meetings going every day all over the world on Risperdal… I can’t clone myself, you know?”
The rest of the email was read to the jury and Kline questions Caers about what he said versus what is contained in the email.
Kline then asks the witness an unexpected question: “Are you the guy they send to the FDA to make the arguments?” which is objected to by Janssen’s attorney Diane Sullivan, of Weil Gotshal & Manges LLP.
Later in the transcript Kline asks the witness if “this writeup, as we see here, does not appear in the Findling paper, can we agree?”
“In the final paper, that’s correct,” answers Caers.
Kline asks if they could agree that the writeup is based on Table 21, and Caers states “That is correct.”
However, Caers states that he cannot remember if he made any changes to the manuscript before it was submitted to the journal.
“Did you at any point say we should put back in this information here about Table 21?” asks Kline.
“I don’t think so,” answers Caers.
Risperdal was not approved for any use with children until 2006, but J&J aggressively marketed the drug to child psychiatrists and others treating children, according to the federal government, reported the Chronicle of Higher Education.
"The drug was known to have a series of negative side effects on children, including instances of boys’ growing breasts, the Justice Department said in court filings," wrote Paul Basken in the Chronicle.
"By the way, Doctor, is there any dispute that Janssen knew that physicians were prescribing Risperdal off-label to children in the 1990's or early 2000's?" Kline asked Caers accordng to the Cirba transcript.
"We were aware of that, yes," said Caers.
In the course of applying to expand the drug's approved use in 2005, J&J sent the FDA a "Findling" medical journal article titled "Prolactin Levels during Long-Term Risperdone Treatment in Children and Adolescents."
The analysis takes roughly 20 cases into account and was published in November of 2003 by the Journal of Clinical Psychiatry.
It explored "any relationship with side effects hypothetically attributable to prolactin (SHAP)," according to the Journal.
But the FDA rejected usage of the drug for autism in May 2005 due to concerns that it elevated prolactin levels, according to attorney Stephen A. Sheller.
Sheller's law firm (Sheller, PC) represents hundreds of boys who were prescribed Risperdal and then grew female breasts, a condition known as gynecomastia.
“What they knew is that they weren’t submitting the analysis even though they should have. That’s what Dr. David A. Kessler says in his expert report,” Sheller told New Brunswick Today.
In the report, originally prepared for a 2012 case that settled out of court, Kessler describes how Janssen had illegaly marketed Risperdal. The report also finds fault with the statistical analysis detailed in the Findling paper.
While preparing for Risperdal cases, Sheller discovered many documents that were not provided to the FDA by Janssen. The documents included tables that were originally part of the Findling paper. He says that J&J removed them from what it submitted to the FDA when it was seeking to get Risperdal approved for children.
"Table number 20, 21, and 34 came out at trial and are now public,” says Sheller.
“An important thing about Caers’ testimony is he admits under oath never giving the analysis in table 20, 21 and 34 to the FDA. Certainly table 21 contradicts the abstracts claim in the Findling article that there was ‘no correlation’ found between adverse events and abnormal prolactin levels related to Risperdal ingestion. Table 20 also finds the association at a 90 percent statistical certainty.”
Sheller says that Kessler had already addressed, in his report, parts of the Findling article that were not accurate.
"The abstract of the Findling article says that there was no correlation between elevated abnormal prolactin and adverse events, well, that’s a false statement,” said Sheller.
In 1996, Janssen first sought a change in Risperdal’s labeling to include pediatric use, according to Kessler's expert report which details Risperdal’s regulatory history in children, and was filed by the FDA on October 2, 2012.
By September 1997, the FDA wrote to Janssen stating that it had been presented with inadequate information and could not expand the drug’s use to include pediatric patients.
The administration told Janssen that the drug company provided very little information to support the proposed labeling changes.
“You acknowledge that the supplements provide no interpretable efficacy data,” Kessler quotes FDA’s Dr. Paul Leber, Director, Division of Neuropharmacological Drug Products, Office of Drug Evaluation, Center for Drug Evaluation and Research as writing to Janssen.
Five years later, on December 19, 2003, Janssen submitted a supplemental new drug application “for use and treatment of autism in children and adolescents.”
Needing to support its claim that Risperdal was safe for use by kids, Sheller says J&J omitted at least two tables which show that the adverse event gynecomastia, would occur in 98 out of 100 children and adolescents taking the drug.
Tables 20 and 21 indicate that children given Risperdal would show abnormal prolactin levels within 8-12 weeks of going on the drug.
“Those were the kids that would, to a 98.5% statistical significance, be the ones likely to develop Gynocomastia and similar adverse events,” said Sheller.
However, J&J tried to convince the FDA that the association was not important.
“The FDA was lead to believe, even though you have abnormal prolactin you don’t have to monitor for it, ‘because it doesn’t mean anything,’ ” said Sheller, noting that in 2001 a consultant told J&J to monitor children’s prolactin levels while on the medication.
“Kids should be monitored regularly. Before they are put on the drug you should always get a baseline prolactin level to see what their normal level is. Then, every few weeks they should be checked again," says Sheller noting that the check-ups would distinguish breast tissue development from just fat.
He says that if physicians were directed to monitor pediatric patients’ prolactin levels, few adolescents would remain on Risperdal drugs past their first and second blood test. But the examinations couldn't be performed by pscychologists or certain other prescribers. The need to have qualified physicians do the check-ups would be a downside in terms of marketing and selling the drug.
Moreover, J&J could not release the analysis and other documents because doing so would support the fact that abnormal levels of prolactin increase the risk of gynecomastia and competing drugs don't have that problem, according to Sheller.
"Drugs such as Seroquel, Zyprexa, Giadan, and Abilify don’t increase children’s prolactin levels when used at recommended doses and don’t pose excessive risk," says Sheller.
Table 34 is important because the researchers were trying to determine if Risperdal really helped kids or not, other than them saying “I feel better,” according to Sheller. But the chart shows that the only time researchers were able to confirm efficacy to a statistical degree was when kids had been on the drug between 3-6 months and already had abnormal prolactin levels in the blood.
"You wouldn’t want to take a drug that the only time it was proven statistically significant to work was when you had an abnormal level of hormonal prolactin which we now know causes gynecomastia and other bad things," said Sheller.
“…That discussion, for want of a better term, ignores Table 34 and its efficacy finding, correct?” asked Kline, according to the Cirba transcript.
“That is correct,” responded Caers.
“And it is ignored for what reason,” asked Kline.
“Well, because it doesn't make clinical sense. Once again, as I said earlier, that you find – that you correlate something at the end of the study or during the study, all over the study duration with one single time event on plasma levels, “said Caers."
Sheller says that before Caers testified in Philadelphia State Court, in both the Austin Pledger and William Cirba Risperdal-Gynecomastia trials, this information "never got out" to the FDA, doctors, or the public, yet Janssen has known about it since 2002 and not disclosed it.
"By the way, Doctor [Caers], is there any dispute that Janssen knew that physicians were prescribing Risperdal off-label to children in the 1990s or early 2000s?" asked Kline, wanting this fact to be heard by the jurrors and become part of the record.
"We were aware of that, yes, said Caers, according to the Cirba transcript.
In the Pledger trail, Caers also stated that before Risperdal was approved to treat irritability associated with autism in children in 2006, Janssen wanted to modify the label to provide prescribers with supplemental information for pediatric use. He ackowledged that physicians were prescribing high doses "for off-label use."
Kessler may not have know about table 34 when he wrote his expert report criticizing Janssen. That table was only made public a couple months ago during the Cirba trial by Janssen’s Caers, says Sheller.
"…if I can put Table 34 back up [as a court exhibit] and maybe you can side by side it to Table 21, what you had, sir, are two tables, not one, two tables, which are not mentioned in the Findling article, correct?" asked Kline, according to the Cirba transcript.
"Yes," responded Caers.
"Both related to prolactin, correct? Prolactin elevation and something that happens when there's prolactin elevation?, asked Kline.
"Yes," said Caers again.
“In my view, obviously the defense has admitted to never giving the information from table 34 to the FDA, the families or prescribers or treating physicians,” says Sheller.
“Obviously that is something I believe most families and doctors would want to know and need to know before giving the drug to a child or adolescent in deciding whether to prescribe it.”
Janssen had no right to deny making the information public says Sheller.
"They have now had over 10 years to repeat those tests to prove the information wrong. Why haven’t they? Assuming they haven’t if they believe the data wrong or irrelevant," said Sheller.
"It was their trial and why did they bother collecting the data if it was meaningless and chart it in Table 34?"
Sheller has been battling the judiciary for several years to make documents involving the dangers of Risperdal public and his firm has filed several motions starting in October 2009 with an advisory panel of judges in the Superior Court of Middlesex County, which was denied releasing the data.
In all, three different judges have blocked his ability to present the information to the public and his efforts to protect children, he says.
Then, on January 5, 2010 Sheller's office made a request to appeal the Middlesex County court decision. It was unsuccessful.
"[The data] doesn’t strike me as being confidential at all. So then shortly after, I filed in Pennsylvania, before another judge and that was denied," said Sheller.
Then, on December 16, 2011 he filed in the Philadelphia Court of Common Pleas but the judge followed New Jersey and “turned down my motion to declassify the documents being confidential for public health protection and there was nothing confidential about them, Sheller told NB Today.
Finally, armed with newly disclosed information, including table 21, Sheller made another appeal on March 13, 2014 which went back to Judge Arnold New again. But J&J and Janssen demanded the following order: “The documents identified in plaintiffs challenge shall retain their confidentiality designation and be treated accordingly.”
“[Judge New] turned down our request to make these key documents public adding almost another year until the trial in February and March of this year,” said Sheller.
“[This prevented] us from protecting thousands of children I believe were put at risk by denying their families and prescribers and treater’s the important information that would help protect them from the adverse events from Risperdal such as hyperprolactinemia, gynocomastia, and gallacteria.”
Sheller told NBT that he filed a citizen’s petition with the FDA in 2012 to make the documents public.
Although his citizen petition also called for the medication to be revoked for use by children, he wanted, at minimum, the information to be public.
The petition asked the government to get Janssen to release the documents publicly. Alternatively, if the drug company did not furnish the information, then he asked the FDA to get it from the company.
The attorney explained that he’d obtained the missing tables as well as various other documents, including emails pertaining to Risperdal’s safety, from previous Risperdal litigation on individual cases beginning in 2002. However, he could not make any of it public because it was sealed under confidentiality orders.
The petition demands that J&J put a black-box warning on the label saying that there’s no evidence of long term safety that’s been documented on the drug. It also asks J&J to change the warnings to require monitoring while patients are on the medication so that if children showed abnormal prolactin levels they’d be instructed to stop taking the medication.
But J&J told him that they are not obligated to give him the documents. The drug company said he had “no standing,” says Sheller. As far as providing it to the government, J&J told him that it was not obligated to produce the information for the FDA because it was “their” analysis.
“They can say they did their analysis and they don’t have to tell the FDA what their analysis is,” he says.
In an anomaly, his petition was both granted and denied. He said the FDA got some of the documents from J&J but would not let him see which ones. They granted it, in part, because the FDA claimed they got the documents from Janssen, said Sheller.
He added: “They wouldn’t even let me see what they got to confirm that they got what they should have gotten."
Asked what the FDA actually granted, Sheller said: "My request that they get the documents."
"But we didn't know until the Pledger trail that they never got them," said Sheller.
"Finally, some but not all of the documents are available in the trail - but how is the public going to find them? They are not going to get the court record, right?"
An FDA spokeswoman said in an email to NBT that she was not able to comment on questions about this story because they relate to a pending lawsuit.
"We do not comment on pending litigation," wrote the spokesperson, who also directed this reporter to FDA's response to Sheller's citizen petition.
In other testimony from the Cirba trail, Kline asked Caers what Janssen did following the FDA's rejection of the company's proposal to incorporate lanquage on appropriate dosing of Risperdal in children.
"Well, the company then proposed -- rather than giving guidance on how to dose, the company proposed to repeat the text that the efficacy and safety of Risperdal in children has not been established to repeat that once more under the Dosing and Administration section of the label. Because, obviously, when somebody intends to use Risperdal in a certain population, and particularly in children, they're going to look for the Pediatric section in the label. And we repeat there, 'Hey, guys, be aware this product has -- safety and efficacy of this product in children has not been established. Be aware of that,' " said Caers, according to court records.
In an email statement to NBT, Janssen said: "Autism can be incredibly difficult for individuals and their families, and we sympathize with those who must deal with this issue every day. 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.
"RISPERDAL® continues to help countless children and adults around the world who suffer from the debilitating effects of schizophrenia, bipolar mania and irritability associated with autistic disorder in children."
More than 1,200 cases involving numerous plaintiffs who have been injured as a result of taking the strong medications Risperdal or Invega, and are suing J&J, have been filed in the Philadelphia Court of Common Pleas. The third trial will begin the day after Memorial Day, May 26.