Ann Milgram, the Attorney General of New Jersey, launched a high-profile investigation in February 2008 over the financial disclosures of clinical investigators involved in the clinical trials of Synthes’ ProDisc products ProDisc-L and ProDisc-C.
The investigation started after a January 30, 2008, New York Times article (“Financial Ties Are Cited as Issue in Spine Study”) called into question the validity of the clinical trials that the FDA relied on to determine that the ProDisc devices were safe and effective. The Times article written by Reed Abelson questioned the bias of the clinical investigators.
Clinical Bias Debunked
Once again, critics of spine surgery, such as Richard Deyo, M.D. and Charles Rosen, M.D. were trotted out to fear-monger patients and disparage spine surgeons developing new devices and procedures to alleviate America’s back pain.
Robin Young, Orthopedics This Week’s publisher, took issue with that Times story and dug into the details of the trials. His digging showed that clinical investigator bias was not a factor in the outcome of the trials.
In an article titled “A Fatally Flawed NY Times Article” (OTW, Volume 4, Issue 5, February 12, 2008), Young wrote:
“Researchers who had any financial ties had their clinical trial results examined and compared with researchers who did not have financial ties.
That data did find its way to the FDA. We asked some of the researchers what the data showed and we were told that there was no statistically significant difference in the ProDisc results coming from researchers with financial ties and those with none.
Furthermore, on a non-statistically significant basis, the data from the researchers with financial ties was actually less favorable to ProDisc than the data from researchers with no financial connections.”
Young also noted the facts about the ProDisc study that failed to appear in The Times article:
- Not one single investigator in the ProDisc study determined which patient received ProDisc and which patient in the study received fusion. Not one.
- The study was a randomized, double-blinded study. The day before surgery, each investigator in the ProDisc trial called an 800 number where an independent outside agency told him which device would be implanted in the patient. Even the patient’s name was hidden so that the entity assigning ProDisc didn’t know who specifically was getting ProDisc.
Not one single investigator in the ProDisc study handled the data from the study. Not one. The radiograph images of each patient’s implant (which were used to measure outcomes in the study) were also blinded and sent to an independent, outside agency for measuring and evaluation.
Amicable Agreement
That was then. What’s the result of all the smoke?
On May 1, Attorney General Milgram announced that her office and Synthes had reached an “amicable” agreement “without need for further action.”
Synthes agreed to sign an “Assurance of Voluntary Compliance” (AVC) agreement and reimburse the Attorney General $236, 000 for the cost of paying their lawyers for the investigation.
No fine, no penalties, no acknowledgment of wrongdoing, not even a hint that the clinical trials were biased in any way by any financial interest of the clinical investigators.
In its official comment about the AVC agreement, Synthes said, “The AVC reinforces Synthes’ compliance policies regarding the collection and dissemination of information about relevant financial relationships of its clinical investigators.”
New Jersey’s Deputy Attorney General Megan Lewis told us in an interview and email:
“The bottom line is that they [Synthes] did not disclose the substantial investments of their clinical investigators in the product they were testing, as required by the FDA. They can characterize it as reinforcing their existing compliance programs, but they did not actually make the disclosures as required by federal law.
As we said to the FDA, many of the forms were blank and others were signed but had none of the required details attached. Moreover, they have agreed to disclose the interests to the public, which is something that they have not had an obligation to do in the past, and to the clinical trial sites―which is critical to the reform effort in this area, because often doctors refuse to provide this information to the Institutional Review Boards approving the clinical studies for each hospital.”
In return for Synthes signing the AVC and paying the attorney fees, the State of New Jersey agreed to release Synthes “from any and all civil claims which the state could have brought prior to this [AVC] agreement.”
More Subpoenas
The New Jersey attorney general also announced on the day of the agreement that five other medical device companies were presented with subpoenas. Lewis told us that those subpoenas were directly related to this matter.
AG: “The FDA Did Nothing”
Who got the brunt of criticism by the attorney general?
The FDA.
General Milgram wrote Acting FDA Commissioner Joshua Sharfstein, M.D. a letter on May 5 expressing her “grave concern about the rampant undisclosed financial conflicts of interest of physicians participating in the clinical trials of drug and medical devices.”
She stated that Synthes acquired ProDisc while the trials were underway and didn’t disclose the financial interests of the investigators to the FDA when the company submitted the devices for approval. Synthes told OTW that it had disclosed to the FDA all the information that had been made available to it.
Milgram wrote, “This failure should have been obvious from even a cursory review of its [Synthes’] submissions. The FDA did nothing. A number of disclosure forms were signed, dated and left blank. Others indicated a significant equity interest but did not attach the requisite details.”
When the FDA receives a marketing application, it performs an administrative check to ensure that sponsors have included the required information, including financial forms. If sponsors neglect to submit financial forms, the FDA can refuse to accept a marketing application for review.
FDA reviewers are required to evaluate the financial information in the application. If they suspect that disclosed financial interests compromised data integrity, they are required to take actions to ensure the reliability of the data.
Milgram copied Senator Chuck Grassley on her May 5 letter.
It should come as no surprise to anyone knowledgeable about the FDA that the agency didn’t do its job and ONCE AGAIN, a company has been cast in an unfavorable light because of a broken regulatory agency.
OIG’s Critical FDA Audit
A January 2009 report by the Office of Inspector General (OIG) of the Department of Health and Human Services (HHS), “The Food and Drug Administration’s Oversight of Clinical Investigators’ Financial Information, ” outlined an audit of all 118 marketing applications approved by the FDA in FY 2007.
Here’s what the OIG found. Of those 118 approvals:
- 42% were missing financial information
- 23% were missing required attachments
- 31% showed that the FDA did not even document reviewing the financial information.
The report also concluded that the FDA “cannot determine whether sponsors have submitted financial information for all clinical investigators…because it does not have a complete list of clinical investigators.”
Eroding Public Trust
This case demonstrates again that public confidence is eroded when regulators are not doing their jobs. It is in the best interest of patients, physicians and industry to have a strong, well-funded and competent FDA that inspires public confidence instead of press conference opportunities for prosecutors.
It might also cut down on ill-informed stories in the national media.
Once again Ms. Abelson and The Times inexplicably stumbled with the follow-up to this story.
In a May 6 article titled “Medical Device Maker Settles Conflict Inquiry in New Jersey, ” Abelson writes:
“As part of its investigation last year, the New Jersey attorney general’s office also issued a subpoena to the Viscogliosi Brothers, the New York investment firm that helped found the original maker of the ProDisc in the United States.”
While the firm was issued a subpoena, the disclosing of financial interests of clinical investigators to the FDA had nothing to do with the Viscogliosi Brothers. Synthes submitted the PMA application and it is at that point that disclosures need to be made.
Sponsors of PMA applications must submit financial information to the FDA only when they submit their market application after clinical trials end. Synthes acquired ProDisc while the trials were still going on.
Assurance of Voluntary Compliance Agreement
Since we think it’s likely that the companies receiving the new subpoenas will be subject to signing the same AVC agreements, we are summarizing what was in the Synthes agreement.
In sum, this voluntary agreement provides more transparency and disclosure to the public about the financial interests of clinical investigators. We’ve always supported full disclosure and transparency and think other companies will soon sign similar agreements with the state of New Jersey.
Now if the regulators would only get their act together, device manufacturers and physicians could slowly work to regain public confidence in their efforts to help patients.
Assurance of Voluntary Compliance Highlights:
- Prohibit clinical investigator compensation that is tied to the outcome of the clinical trial
- Pay clinical investigators “fair market value compensation” for their clinical trial work, as well as any other consulting services they provide to the company
- Collect information on financial interests from clinical investigators
- Create a Financial Interest Information Database that will record all relevant financial interests related to clinical investigators
- Disclose all financial interests of all clinical investigators on the company’s website
- Provide complete disclosure of clinical investigator financial interests to the FDA and conduct reasonable due diligence to ensure that the disclosures are complete and accurate
- Disclose all clinical investigator financial interests directly to healthcare facilities serving as clinical trial sites
- Provide Financial Interest and Disclosure training to employees.
