Political Lobbying Drove FDA Process
By ALICIA MUNDY
WASHINGTON -- The recent approval of a new device to treat knee injuries followed a lobbying campaign that overcame repeated rejections by scientists within the Food and Drug Administration, agency documents show.
The FDA's internal dissent over Menaflex, which targets the most-common knee injury afflicting everyone from high-school athletes to baby boomers, is straining a government agency that oversees a quarter of the U.S. economy. Some senior FDA staff members complained in documents that the handling of Menaflex, made by ReGen Biologics Inc., shows how political and industry pressure can influence scientific conclusions.
The Menaflex implant serves to reinforce damaged or weakened tissue in the knee. It was approved under fast-track rules.
At issue isn't just the efficacy of the device -- that remains in dispute -- but the nature of the FDA's own approval process.
In one instance, emails show the FDA's integrity office excising language from a draft letter an FDA lawyer said would "document special treatment for ReGen." (Read the emails.)
Menaflex was approved under fast-track rules that don't require clinical trials needed under a full review. "There's something wrong with how that decision [to go the fast-track route] was made," said Andrew von Eschenbach, who was head of the FDA in December, when Menaflex got the go-ahead. "We fumbled that process."
Dr. von Eschenbach, who stepped down in January with the arrival of the new administration, is calling for an overhaul of the way the $200 billion-a-year medical-devices business is regulated. The fast-track system "has gotten out of control," he said.
President Barack Obama has yet to name his choice to run the FDA. Administration officials say they want someone to shake up what they see as the agency's culture of deference to companies. Industry groups, concerned that red tape could prevent new important medical advances from reaching market quickly, are lobbying for their own candidates.
ReGen, based in Hackensack, N.J., says Menaflex can help thousands of knee-injury patients get back into action. In letters to the FDA and in interviews, ReGen executives accuse the FDA's staff scientists of bias. "This is a very important product," said ReGen CEO Gerald Bisbee, "and it is safe."
Daniel Shultz, who heads the FDA's medical-devices division and approved Menaflex, says he followed normal procedures in approving the device.
Menaflex is a C-shaped pad the size of a silver dollar used to repair a torn meniscus, a rubbery substance that acts like a shock absorber between the knee bones. Surgeons do about a million meniscus repairs in the U.S. annually.
The traditional treatment is to sew up the torn tissue. ReGen says its research shows the Menaflex pad, made from cow collagen, encourages tissue regrowth.
Menaflex is aimed at a booming market of athletes of all ages who suffer meniscus tears. Surgery can patch up tears, but they are liable to recur, which is why many doctors say they are desperate to find a better way to repair meniscus tissue.
Read a memo from FDA Review Team Leader John S. Goode detailing why he opposed approving the ReGen device (Aug. 14, 2008 )
Read FDA lawyers' memos about language that might "document special treatment" for ReGen (Nov. 3, 2008)
The FDA process for approving medical devices in general is coming under scrutiny. In January, the Government Accountability Office, the investigative arm of Congress, said the agency is too quick to allow a fast-track approval process known as "510(k)." The 510(k) process doesn't require clinical trials because it's meant to apply to products that are similar to already-existing products.
Menaflex was approved under 510(k) rules. However, "There really are no other devices like [Menaflex] on the market," says Jay Mabrey, the chief of orthopedic surgery at Baylor University Medical Center in Dallas and chairman of the FDA advisory committee that considered Menaflex. For this reason, Dr. Mabrey says, the FDA's decision to approve Menaflex was wrong.
Dr. Mabrey also says, "In retrospect, I think they [the FDA] were stacking the committee to get the decision the company wanted."
In January, a group of nine FDA staff scientists in the device division wrote to Congress, and to the Obama transition team, calling on the president to remove top FDA medical-device regulators. The device-approval process has been "corrupted and distorted by current FDA managers," the letter says. The letter's authors haven't been publicly identified.
Sen. Chuck Grassley (R., Iowa) is also looking into the Menaflex approval process.
Dr. Schultz, the FDA official who signed off on Menaflex, says he found ReGen "adversarial" and "extremely aggressive" but didn't let the company's pressure affect his decision.
A ReGen representative said the firm needed to be "aggressive" and "adversarial" because if it hadn't "confronted" delays caused by the FDA, "ReGen would have been out of business and a very valuable device would have been unavailable to patients."
Menaflex has been approved in Europe for several years, where it has been used in about 2,800 patients, a small proportion of meniscus-repair operations. ReGen says it has received very few complaints.
European regulators generally require only that medical devices perform as stated and don't apply a risk-benefit evaluation akin to the FDA's full approval process.
In the U.S., ReGen originally didn't seek fast-track approval. Instead it filed an application for full approval of Menaflex in 2004, and pushed ahead with a $35 million clinical trial.
The next year, that clinical trial ran into trouble. The FDA sent a warning letter to ReGen describing violations in record-keeping. ReGen hired an independent auditor, which it says showed no data-integrity issues.
In December 2005, the company made an important strategic shift: It decided to seek the fast-track 510(k) approval, avoiding the need to eventually present full clinical-trial data.
Twice in coming years -- in August 2006 and September 2007 -- scientists in the FDA's medical-devices division issued formal rejection letters concluding that Menaflex didn't qualify for fast-track approval. To qualify, a new device must be of "substantial equivalence" to existing devices.
The half-dozen or so FDA scientists involved in the Menaflex decision described the product in numerous internal documents as a new kind of device that required rigorous review because it was being placed inside the knee and would be subject to a daily pounding. ReGen countered that Menaflex was substantially similar to an approved shoulder implant and other devices, including a hernia treatment, and therefore qualified for the fast-track approval process.
While fast-track status was being sought, the clinical trial proceeded. In a September 2006 letter, the FDA issued a formal warning about the conduct of the clinical trial. The letter, to the Vail, Colo., research foundation managing the trial, noted that a top ReGen executive was serving as vice chairman of a review panel whose role is to provide independent oversight of the trial, violating conflict-of-interest requirements.
ReGen said it would fix the problem by limiting the executive's role on the review panel and promised to "prevent similar conflicts of interest in the future," according to its written reply.
After the FDA's second rejection of fast-track status, in September 2007, ReGen asked lawmakers from New Jersey, its home turf, for help. Supporters included Democrats Sen. Robert Menendez; Rep. Frank Pallone, chairman of the Health Subcommittee of the House Energy and Commerce Committee; Rep. Steve Rothman of Hackensack; and Sen. Frank Lautenberg.
Messrs. Menendez, Lautenberg and Rothman signed a letter to the FDA in December 2007 asking for Dr. von Eschenbach, the FDA commissioner, to review the issue personally. Mr. Menendez talked with the commissioner by phone, his office said.
The four lawmakers defend their actions, saying they were simply assisting a constituent tangled up in government bureaucracy. "Our effort to help them was solely to ensure they received a fair and unbiased FDA review," Rep. Rothman said in a statement.
Congressional support helped ReGen land a meeting with Dr. von Eschenbach on Jan. 23, 2008. Two days later, ReGen in a letter called on Dr. von Eschenbach to put the matter in the hands of Dr. Schultz, head of the FDA's device division.
In the same letter, ReGen also asked that the FDA staffers who previously had opposed Menaflex be excluded from the decision-making process.
Dr. von Eschenbach wrote back, "I believe it is imperative that FDA follow its well-developed procedures."
In subsequent months, ReGen got much of what it wanted. Dr. Schultz confirms that he took personal charge of the decision-making process. (Read the letter.)
In July 2008, the company announced what it described as "successful" results in the clinical trial that had prompted the earlier FDA warnings. ReGen reported that patients "regained significantly more pre-injury activity" compared with people who underwent traditional meniscus surgery.
Within the FDA, some scientists examining this clinical-trial data noted in documents that they saw some patients who needed another operation after receiving Menaflex. In some cases, patients had to have the device removed, these scientists said.
ReGen says the scientists' concerns were based on an incorrect analysis of its data. It says the reoperation rate is low.
That same month, ReGen presented its third and final application for 510(k) fast-track approval for Menaflex. FDA scientists recommended issuing what would have been a third rejection letter. (Read the recommendation from FDA Review Team Leader John S. Goode.)
That letter was never sent. Instead, Dr. Schultz says, he decided to assemble a special panel of outside doctors to help decide whether Menaflex met the 510(k) test. Setting up a committee like this is an unusual step, but Dr. Schultz says he decided to because Dr. von Eschenbach had urged him to resolve the dispute in a timely manner.
ReGen began pushing its own views on who should be named to that committee, and what its agenda should be, according to FDA documents and the company. On Oct. 28, a staffer for Rep. Pallone on the House Energy and Commerce Committee called the FDA's integrity office director to discuss those issues.
In a statement to The Wall Street Journal about his involvement in the Menaflex matter, Rep. Pallone said, "I was obligated to get involved because FDA was applying an inappropriate and possibly illegal standard" in judging the device's safety and efficacy.
Michael Hutton, a lobbyist for ReGen, said the company didn't want the panel to have many knee-replacement surgeons, because they might stand to lose money if a new device made knee replacements less common.
ReGen requested that the panel include sports-medicine experts, according to documents and Mr. Hutton. It also asked that none of the FDA scientists who previously criticized Menaflex be allowed to address the committee, Mr. Hutton said.
ReGen's actions triggered a debate at the FDA about how to respond. In November, agency officials drafted a letter to ReGen saying the FDA had taken into account the company's "criteria" for the "structure and composition" of the panel, according to emails reviewed by the Journal.
The FDA's acting chief counsel warned against that language, saying it would "document special treatment for ReGen." Another FDA lawyer said the wording would "cause significant problems for the agency" because other companies don't have the same "opportunity."
The director of the FDA's integrity office replied, "I'll excise the language."
The final letter didn't include the language.
The integrity-office director, William McConagha, said the original draft letter had been an effort "to defuse...tensions" with ReGen and tell the company it was being heard. In the end, "We did ensure the integrity of our own process," he said.
The eight-person committee included five sports-medicine experts chosen as temporary members from outside the FDA's regular pool of orthopedic-device experts, according to FDA memos written in the weeks before the panel's Nov. 14, 2008, meeting. A letter to ReGen from the FDA noted that the inclusion of the sports-medicine experts was "per [ReGen's] request."
None of the FDA reviewers who had previously criticized Menaflex spoke at the panel, a break from usual practice. Dr. Schultz said he took that step because of ReGen's allegations of bias among the reviewers.
The FDA's regular committee process was circumvented, says Dr. Mabrey, the Baylor surgeon and committee chair, because members were given only six days to review hundreds of pages of documents instead of the usual several weeks.
When Dr. Schultz summed up the meeting in a letter afterward, he said the committee "clearly and unanimously" found Menaflex to be at least as effective as other surgical meshes on the market.
A majority of the eight committee members, including Dr. Mabrey, said in interviews that Dr. Schultz was wrong in saying the members were unanimous. "I made a point of noting that we were not unanimous," Dr. Mabrey says. "The important thing is that we didn't say the device was substantially equivalent to other devices." In addition to Dr. Mabrey, at least two committee members expressed reservations. Dr. Mabrey says if he had known Dr. Schultz was going to approve the device citing the panel, he would have strongly spoken out against it.
ReGen had also asked that a scientist from the FDA's science and engineering laboratories be brought in. The FDA responded by asking Larry Kessler, the lab's director, to review Menaflex. His opinion: The device wasn't similar enough to others to qualify for 510(k) fast-track approval.
"The device will be placed in a region of the body that will undergo weight-bearing forces that are not comparable to those experienced by...products with which we are familiar. We believe this sets a precedent that concerns us," Dr. Kessler wrote in December to Dr. Schultz.
"There is no statistical basis demonstrating effectiveness for this product," Dr. Kessler wrote. He also warned of a potential risk that patients might need a second operation to undo the first one.
In an interview, Dr. Kessler, who now heads the Health Services Department at the University of Washington, said the Menaflex affair "shows the FDA at its worst." Dr. Kessler retired from the FDA last month for reasons unrelated to the Menaflex debate.
On Dec. 20, Dr. Schultz approved Menaflex. He wrote in the approval that ReGen's "efforts to demonize the staff and circumvent the process, the final decision notwithstanding, did nothing but complicate and delay this decision." Dr. Schultz says Menaflex was similar enough to other devices to earn approval.
ReGen says it felt that it had encountered obstacles that justified its tactics. "We had to push the FDA," said Mr. Bisbee, the ReGen CEO. "Even when they promised to move forward, we kept having to go back to where we were."
ReGen has raised $9 million from investors to market Menaflex, which was formally introduced last week at a medical convention in Las Vegas.
-Jared A. Favole contributed to this article.