Dr. Peggy Pence took the stand all day. Pence, a PhD and expert in regulatory affairs has more than 40 years in the business of bringing drugs and medical devices to market.
Her background is not only in designing clinical trials, but in analysis of that data. She's worked with more than 50 companies and has prepared numerous regulatory submissions to the U.S. Food and Drug Administration (FDA).
Dr. Pence has been an expert brought into numerous pelvic mesh trials including Jo Husky, Linda Batiste, Linda Gross and Joan Budke, among others.
She is clearly experienced at giving expert testimony, turning to the jury frequently to explain, in a concise, calm manner, terms to a layman audience.
Predicting the questions that Defense will ask, Tim Goss (Freese and Goss) asked Pence if she is being compensated? Yes, she said, at a rate of $500 an hour, a common rate of compensation for an expert witness, Pence said was her understanding.
Prosima was to be the newest pelvic floor polypropylene mesh intended to treat pelvic organ prolapse (POP). J&J was in catch-up mode. Competitors had launched their own version of POP repair kits to hold up sagging pelvic organs - the Pinnacle (Boston Scientific) and Elevate (AMS).
No worries. Prosima was predicted to bring in $300 million each year it was used in a projected 500,000 surgeries annually.
In 2004, Dr. Marcus Carey, a surgeon from the University of Melbourne, Australia had the idea for Prosima. Ethicon ( J&J) purchased the intellectual property rights from Dr. Carey in September of that year for $500,000. After marketing began he would make another $400,000, then $100,000 with the publication of his work in a peer-reviewed journal. Dr. Carey would also receive royalties based on sales. His studies, along with a Dr. Mark Slack, would provide the data needed for a projected mid 2007 launch. It never happened.
Prosima received FDA 510(k) clearance in February of 2007. It was finally launched for sale in the U.S. in January 2010, despite a chorus of waving red flags.
Ms. Cavness received her implant on April 24, 2012, a date that would be repeated often as Tim Goss (Freese & Goss) recounted the chronology of events that brought Prosima to market.
Prosima was made with Gynemesh PS (Prolene Soft) the same mesh used in the Prolift, another large mesh kit launched by Ethicon in 2005. Prosima would be a smaller mesh kit, anchorless unlike the Prolift, with only two fixation points. Its predicate device, the basis for an FDA clearance, was Prolene Soft, a hernia mesh.
Dr. Pence continued in her chronology of the lifetime of Prosima.
Key Opinion Leaders (KOL) were an important part of acceptance of a new product in the medical community. Dr. Vince Lucente worked as a consultant for Ethicon and was considered a KOL and one of the original three surgeons in the U.S. to teach the procedure. He was also a preceptor (teacher/consultant) for the TVT (transvaginal tape) since its introduction in the late 1990s.
As the KOL of the Prosima project called Project Mint, and even though he was paid a total of $1.7 million for his work, Dr. Lucente didn't feel Prosima was an effective procedure for a serious prolape as Ms. Cavness had, considered a Grade 3. During a trip to Australia, one doctor reported about Dr. Lucente "he was quite scathing of Prosima being a reckless product."
Doctors who had tried Prosima felt it "might not provide an adequate apical support; the procedure was felt insufficient to treat lateral defects regarding the posterior repair, it was felt that just placing the arm of the mesh in contact with the sacrospinous ligament would not provide a strong attachment such as would suture or passage of the arm of the mesh through the ligament (Prolift)."
Lucente's comments during a visit to Australia for the company "if true were unhelpful," said Jonathan Meek in an email April 24, 2008. “It appears that Dr Lucente may have some concerns that are being voiced via inappropriate channels that are unresolved" it said.
He was not alone. Dr. Martin Weisberg, the medical director of Ethicon, had earlier voiced his opinion in an email to the marketing director in September 2, 2005. "Why would we want to introduce a synthetic graft product that does no better than a native tissue repair?"
In other words, Pence reminded the jury, the benefit must outweigh the risk and an early failure rate of a prospective observational study at eleven investigation centers found a 28.4% failure rate. In fairness, some of the women did not show for their followups. Still, in research, that's considered a failure, said Dr. Pence because usually they are having problems.
Dr. Pence called approval of Prosima then a clear "No Go." In April 2008 the Prosima failed to be launched for a second time under current CEO Alex Gorsky.
The U.S. Food and Drug Administration (FDA) was at work preparing to issue in October 2008 the first Safety Communication warning about pelvic mesh. It noted 1,000 reports of serious complications associated with transvaginal placement of surgical mesh in repair of pelvic organ prolapse and stress urinary incontinence.
"Although rare, these complications can have serious consequences." Complications coming into the FDA from surgical mesh manufacturers included mesh perforations, erosion a significant decrease in the quality of life, discomfort, pain and dyspareunia (painful sex).
Dr. Pence reminded jurors as few as one in 100 event are ever actually submitted to the FDA's MAUDE database of complications.
That could be one in 100,000? asked Goss? Right, she said.
Johnson & Johnson celebrated its successes at a conference in the Orange Blossom Bowl in Orlando February 7, 2009. with opening remarked by Renee Selman, World Wide President.
The Prolift pelvic mesh kit was on the market and on the agenda as was Prosima, which was 11 months from being launched. The TVT-Secur, a polypropylene single incision sling marketed for use in SUI, had bad results coming in. The perception of the product was a negative for the company.
In an email from Andrew Meek, Professional Education manager for the US team, to marketing's Jonathan Meek on the day of this summit, Meek said a number of KOLs (key opinion leaders) liked the +M (Prolift) and planned to use it, the feelings were very negative towards Prosima. Concern was expressed about the lesser experienced surgeons or "less skilled generalists."
"At a time when the scrutiny against mesh is at an all time high, why would we want to put a product with questionable date in this groups hands?” “One KOL said they would no longer work with the company as matter of principle if we launched Prosima.” Others called it a “Big mistake” Don’t do it."
Another surgeon, Fah Che Leong, MD a Professor of Female Pelvic Medicine and Reconstructive Surgery at Saint Louis University School of Medicine wrote to Scott Jones, a marketing director at Ethicon, as shown in an exhibit:
"I am currently involved in getting a patient to the OR who had an anterior and posterior Prolift implanted by another physician. She will likely lose any coital function as her vaginal length is now 3 cm, and there is mesh extruding literally everywhere. Also there is a large stone in the bladder from a bladder perforation with the anterior arm.” “I will hold off on doing any of these procedures. The bottom line is that I bet a majority of the practitioners using these mesh kits are not qualified to do so. I taught Perigee, Apogee in the past – no longer. This patient will have a permanently destroyed vagina and I am only hoping to get her out of this without more morbidity.”
Pence told jurors the comparisons are fair because the Gynecare Prolene Soft mesh is the same in the Prolift as the Prosima.
Even Dr. Piet Hinoul, warned against overpromising success with the Secur SUI mesh (90%) and the Prosima.
“I feel that sticking to one of the predefined outcome measures would be more appropriate and less misleading: I’d quote that 88.3% of patients were above the level (not at) of the hymen in the treated compartment. This is still a very good result and will strike the surgeons as believable. Quoting a 94% success may lead the surgeons to have unrealistic expectations.”
Pence called this good behavior for a company but not enough to delay the launch of the Prosima. Remember, Piet Hinoul was mindful that his company must compete with the Pinnacle and Elevate and "aggressive sales techniques."
Goss: "Would a reasonable manufacturer put this on the market?" "No," said Pence.
What was the next thing they did? Launch the product in January 2010.
By the end of the first quarter a inner company email from Kevin Frost said:
The FDA continued to monitor the MAUDE database of adverse events coming in concerning pelvic mesh and hernia mesh products. Two months short of a second Safety Communication notice, which would now call mesh complications "not rare," Ethicon requested a meeting with FDA officials to have an "open dialogue about SUI (stress urinary incontinence) and PFR (pelvic floor repair). That meeting took place May 3, 2011.
"FDA is in learning mode" said the talking point notes. "Listening to advocacy groups and KOL's." The FDA Ob/gyn branch admitted it was "Green" in understanding the use of surgical mesh for SUI and POP repairs.
Even with sparse information, the agency concluded that adverse events for stress urinary incontinence are low and said it, "understood the risk vs. benefit of mesh in SUI vs. traditional repair."
The opinion notes say the "FDA is overwhelmed by all of this and cannot see the forest." Ethicon promised individual product meetings would help show the FDA the safety and effectiveness of new products.
"This will be easier in SUI vs PFR (pelvic floor repair) mesh."
The second FDA notice in July, 2011 came at a time the agency was under investigation by the Office of Criminal Investigation. It is now ten months before Ms. Cavness is implanted. The FDA had received an additional 1,500 reports of mesh complications associated with POP mesh.
Did the new adverse event reports make it into the product's label? asked Mr. Goss.
"No," answered Dr. Pence.
Is there anything in the IFU about multiple surgeries will not resolve the complications. Is that in the IFU?
"No," she said.
Should a reasonable manufacturer do that?
"Absolutely," said Pence.
Would a reasonable and prudent manufacturer put that inability to engage in sexual intercourse in the IFU? Did the company change the IFU at all after the FDA warning? "No, it did not."
Would a reasonable and prudent manufacture take action to make sure surgeons knew about this notice?
"Yes," said Dr. Pence. "The doctors are on the front line if they are not aware of this information they are missing this safety information helps to guide them in making appropriate choices to offer their patient."
In January 2012, the FDA ordered manufacturers including Johnson & Johnson to study its controversial meshes. The adverse event reports were coming in. Under Section 522 of the Federal Food, Drug and Cosmetic Act, the FDA had the authority to require post-market surveillance of the devices. They would be called the "522 studies."
Emails within Ethicon show the next step the company would take. If the Prosima and other problematic meshes were removed from the market, the company would likely not have to conduct the 522 studies. The company would save face and save an estimated $4 million to $5 million in additional research dollars.
Notes, shown to the jury and taken by a company rep chosen to do a deposition, said the decision to withdraw four meshes came before the FDA announced the 522 studies.
An email from marketing's Laura Angelini said they arrived at the decision to withdraw four mesh products in June 2012,
“after considering the commercial viability of the product in the United State in light of the complex of the clinical study requirements, the significant adverse publicity and the litigation environment. The size and competitiveness of the market place and the availability of other treatment options for women were also a factor in our decision.”
Attorney Goss reminds the jury 45 days before Ms. Cavness surgery, "this company has in place an exit plan" which was not communicated to anyone, especially her surgeon.
Tim Goss concluded the day by asking Dr. Pence, with her 40 years of experience if Ethicon had violated the post-market safety of Prosima; a standard of care; the premarket development of Prosima; and its own credo in putting Prosima on the market?
Yes, she said, they did.
"They violated their own credo and did not put patient safety, their doctors, and patients first." she concluded. #