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A Harvard study published in the New England Journal of Medicine found that drugs approved within the Congress-mandated decision-making deadlines are more likely to have safety issues than those that aren’t. The analysis looks at decades of drug approvals, both before and after the advent of user fees and decision deadlines in 1992. FDA disputed the analysis, saying its own statistics show that the difference is not statistically significant. The writeup in the Asssociated Press casts doubt on the FDA position by proclaiming that the agency “rushed out its own statistics.” It also quotes notorious FDA and industry critic Steve Nissen, even though he had nothing to do with the study.

Why are we telling you about a drug study? Because if it leads to any changes in policy, the changes are likely to filter over to the device side, too, whether they deserve to or not.

FDA’s work on regulations and guidances specific to combination products has advanced very slowly, and recent turnover at the Office of Combination Products hasn’t helped, reports a consultant who keeps close tabs on the OCP. Michael Gross, prinicpal consultant of Chimera Consulting and a member of the Combination Products Coalition, said OCP told him that a regulation regarding quality systems for combination products will come out this year. He spoke at the PharmaMedDevice conference in Philadelphia in March.

Such a regulation is important because it is not clear when firms should follow quality-system practices for devices and when they should follow the ones for drugs. However, Gross said, the OCP once said it would come out in 2007, so nothing about the timetable should be taken for granted. Similarly, he said, OCP has said it will publish a guidance on safety reporting this year, but when it will actually appear is anyone’s guess.

OCP had four directors last year: Mark Kramer, who left in April after more than five years in the post; Joanne Less, who left in October; Patricia Love, who served as acting director from October to December, and Thinh Nguyen, who took over in December. It also lost Jim Cohen, an attorney who was instrumental in drafting its regulations and guidances, and Suzanne O’Shea, its product jurisdiction officer. This turnover is exacerbating the slowness of progress, Gross said.

– From MD&DI’s blog.

FDA Commissioner Andrew von Eschenbach has joined the chorus of those who believe the agency will fail in its mission to protect the public health if its funding is not increased. In a March 26 speech in Washington, he said that his staff is overextended because its regulatory role has expanded without a commensurate rise in funding. Overextension could mean that the quality of the agency’s evaluation and regulation of medical devices could suffer. The commissioner’s comments echo the findings of several reports, including FDA’s own Science Board, and puts him on the same side of the issue as some of the agency’s harshest critics in Congress. However, he said the agency has been focused on how to get out of the crisis, and that the “prognosis is excellent.” His Congressional adversaries would disagree.

von Eschenbach said he asked for more than the 5.7% increase President Bush requested, but did not say how much more. Earlier in March the Senate passed a resolution calling for an additional $375 million for FDA’s budget, which would be an increase of more than 20%.

CDRH has issued two guidances for industry and FDA staff dealing with MDUFMA provisions on user fees for review of certain marketing applications. A portion of the fees collected for reviewing PMAs will help cover costs associated with PMA bioresearch monitoring program (BIMO) reviews and any clinical or nonclinical preapproval inspections. A portion of the fees will also help cover costs related to reviewing information in the PMA’s manufacturing section and to inspecting the applicant’s relevant manufacturing facilities.

FDA notes that the HHS secretary told Congress when the user-fee legislation was approved that the agency is committed to “improve the scheduling and timeliness of preapproval
inspections.”

One of the guidances, titled The Review and Inspection of Premarket Approval Applications under the Bioresearch Monitoring Program, explains BIMO’s process for reviewing PMAs and for assigning, scheduling, and evaluating related clinical or nonclinical preapproval inspections. It also applies to the BIMO review of certain PMA supplements and associated BIMO inspections. The guidance covers the sequence of events as the BIMO program within the Office of Compliance completes a PMA review. It also outlines the administrative process and the projected time frames involved with each step, and explains how the BIMO review of inspection results may influence PMA approval decisions.

The guidance may be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/06d-0228-gdl0002.pdf.

The second guidance, titled The Review and Inspection of Premarket Approval Application Manufacturing Information and Operations, explains the process involved with reviewing a PMA manufacturing section and inspecting the manufacturing operations described in that section. It is also generally applicable to the process involved with reviewing manufacturing information in certain PMA supplements. The guidance covers the sequence of events as the Office of Compliance or the Office of In Vitro Diagnostic Device Evaluation and Safety reviews a PMA’s manufacturing section. It also describes the administrative process and projected time frames associated with each step, and shows how inspection of a manufacturing facility fits into the approval process.

This guidance may be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/06d-0063-gdl0002.pdf.

– James G. Dickinson

CDRH plans to use an interactive review process with industry to smooth out minor deficiencies and to request additional information to complete its review of premarket approval (PMA) and 510(k) submissions. The new interactive review is intended to help speed up submission reviews through “increased informal interaction between FDA and applicants, including the exchange of scientific and regulatory information,” according to a new guidance. It says the interactive review process will be designed to help

• Improve the interaction between FDA review staff and the applicant during the review process.
• Prevent unnecessary delays in the completion of a review, and thus reduce the overall time to market.
• Ensure that FDA’s concerns are clearly communicated to the applicant during the review process, as appropriate.
• Minimize the number of review cycles.
• Minimize the number of review questions conveyed to the applicant through formal requests for additional information.
• Ensure timely responses from
  the applicant.

CDRH expects device application submitters to be up-front about “any major issues” prior to submission to ensure that the submission addresses relevant regulatory and scientific issues. The center’s preferred communication tools for conducting interactive reviews are e-mail and fax transmission, according to the guidance. “One-on-one telephone calls should be used primarily for requests for clarification that the FDA reviewer can easily document (e.g., the location of specific information within the PMA, or interpretation of a graph). Any telephone call that leads to a request for data should be followed by an e-mail from the applicant to FDA that summarizes the commitment(s) made. FDA should respond via e-mail to confirm the accuracy of the commitment(s) and then add the e-mails to the submission’s official administrative record.”

Face-to-face meetings are highly discouraged under the interactive model because of the difficulties in coordinating the availability of key staff between both the sponsor and the agency, the guidance says. “Therefore, FDA and the applicant should consider whether a meeting is the most appropriate and effective communication mechanism to resolve the issue(s),” it says. “Meetings are most effective when there are significant issues regarding the review that cannot be resolved by e-mail, facsimile, or telephone calls.”

CDRH’s guidance says there is no appropriate timing interval for when an interactive dialogue should occur. Instead, “interaction should occur as needed to facilitate a timely and efficient review process.” Also, “when appropriate, FDA should wait until after the review of a particular topic or subject matter area (e.g., software, fatigue testing, device retrieval study) has been completed before interacting with the applicant regarding that topic. [This] ensures that the agency communicates appropriate and comprehensive deficiencies to the applicant.” In addition, timelines for sponsors to respond to FDA’s informal requests for additional information will be set on a case-by-case basis.

The guidance also outlines when it is appropriate for applicants to contact the lead reviewer, such as

• To obtain clarification regarding deficiencies cited by the lead
  reviewer.
• To reconcile any disagreement with a deficiency cited by a consulting reviewer.
• To inquire whether a new time frame may be given to address a deficiency during a review cycle because the initial time frame cannot be met.
• To discuss procedural questions related to the submission.
• To correct errors in the data
  submitted.
• To clarify information in the submission that the applicant subsequently notices is unclear.
• To request or schedule a meeting.
• To alert FDA that it intends to submit new, unsolicited information or data. (Depending on its extent, the information may require a new 510(k) or may be logged in as an unsolicited major amendment for a PMA, PMA supplement, biologic license application [BLA], or BLA supplement.)

If a major review issue arises, FDA will likely communicate its concerns outside of the interactive review using a formal hold letter, according to the guidance. “Some major issues may be informally communicated in detail sufficient to permit the applicant to begin addressing the concerns before the issuance of a formal hold letter,” it says. “However, for major issues, FDA does not expect any response to be submitted within the current review cycle; thus, FDA should not provide a time frame for responding.”

Instead, applicants should submit a complete response to the hold letter, which will be reviewed under existing user-fee time frames. The guidance says that examples of major issues include “the need for additional preclinical testing; supplemental bench, animal, or clinical information to address a specific safety issue; a new statistical analysis of the submitted clinical data set; or additional manufacturing procedures.”

More information about the program can be found at www.fda.gov/cdrh/ode/guidance/1655.html.

– James G. Dickinson

It is no longer a question whether FDA has the resources to accomplish its mission. It does not. This message was brought home again in late January, with the release of a report by the Government Accountability Office (GAO). It concluded that CDRH is so far behind on its inspections of foreign plants that produce medical devices for the U.S. market that it would take 27 years to get to them all. The backlog for foreign food and drug plants is similarly shocking.The agency is so far behind in computer technology that it cannot track how many foreign plants there are, nor can it produce a list of those that need to be inspected. This is particularly a problem in China, where the number of medical device plants has grown sharply in recent years, and more and more of them are starting to produce exports to the United States. Over a six-year period, the agency inspected all of 64 medical device plants in China, yet there are believed to be at least 700 of them.

The GAO report comes on the heels of a report by FDA’s own Science Board that concluded the agency cannot keep up with the growing number of imports, and thus cannot guarantee that they are safe for U.S. consumers. (MD&DI had more on that story in the NewsTrends section of last month’s issue.)

Since 1987, the agency has lost 1311 employees. The talent drain and high turnover rate among scientists are reasons why the agency is having trouble keeping up to speed on emerging technologies. And more attrition is coming: A number of long-time agency employees are expected to retire rather than endure the aggravation of moving when the agency’s new White Oak facility in Silver Spring, MD, is fully up and running.

Adjusted for inflation, FDA’s appropriation from Congress is $300 million less than it was in 1987. Yet, since that time, Congress has passed more than 100 laws expanding or redefining the agency’s responsibilities.

The math doesn’t add up. If you tell an agency to do more things with less money, fewer people, and inadequate technology, you shouldn’t be surprised when it does a poor job and scandals such as the Guidant defibrillator fiasco happen.

Something has to change.

Not surprisingly, more people are starting to notice the agency’s plight. Reaction to President Bush’s proposed fiscal year 2009 budget for the agency was mixed at best, as most of the increase comes from user fees. The Alliance for a Stronger FDA, an advocacy group formed from the merger of the FDA Alliance and the Coalition for a Stronger FDA, was particularly vocal. The group suggested adding $380 million to the president’s proposal. Peter Barton Hutt, a former chief counsel for the agency, went further, telling Congress that FDA’s appropriation should be doubled and its staff increased by 50% over the next two years.

It is clear that FDA does not have enough money for its mission. Much thought must be given to what it would take to ensure that it does. But because funding resources are finite, the debate should not end there. Much thought must also be given to what exactly the agency’s mission should be, and which, if any, tasks it performs now can be streamlined or eliminated. For example, a CDRH inspection has requirements that go beyond those in ISO 13485, which is used by much of the rest of the developed world. Do they really make us that much safer than patients in Europe or Canada? Imagine the cost savings that could happen if the United States used the same inspection system as its Western counterparts. And shorter inspection time means that more plants, domestic and foreign, get inspected in a timely manner. I’m not saying this is the route FDA needs to go, but it’s the kind of thing that needs to be considered. It’s obvious the status quo isn’t working. The agency not only needs to be revitalized, it also needs to be reengineered.

– Erik Swain

The Senate has passed a resolution to give an additional $375 million to FDA’s fiscal year 2009 budget, reports the New York Times. The main impetus appears to have been Baxter’s tainted heparin that might have never reached these shores had FDA inspected the Chinese plant where the problem occurred. For some Senators, that incident amplified the numerous recently released reports stating that the agency does not have nearly enough funds to accomplish its mission.

It is not yet known whether the House would agree to the contents of the resolution. There is no similar language in the budget bills it passed, but as The Alliance for a Stronger FDA points out, it is very rare that budget items are addressed specifically in the language of such bills. However, the Times article implies that there may be a split among Congressional Democrats on the timing of a budget increase; some want it immediately, while others may prefer to wait until President Bush leaves office because they don’t think his administration has any desire to fix FDA’s problems, and they don’t think that top FDA officials are capable of fixing them.

– From MD&DI’s blog.

Medtronic has won a case that went to the U.S. Supreme Court over whether patients could sue manufacturers of PMA-approved devices in state courts. The high court ruled 8-1 that because FDA has already made a determination about the safety and effectiveness of the product, state lawsuits are barred when they would impose different requirements.

The news attracted hoots from industry critics, including some prominent Congressional Democrats. But it’s not the stripping-of-legal rights scenario that some are making it out to be.

The ruling, which pertained to a patient named Charles Riegel who was injured by a Medtronic catheter, held that states via their courts cannot determine the safety and effectiveness of PMA products if they differ from federal regulations. This is explicitly stated in the Medical Device Amendments of 1976, the majority said. But Congressional critics said that Congress did not intend that wording to limit lawsuits, and the law should be changed.

Lost in the backlash is that the decision does not apply to the vast majority of medical device product-liability cases. It only applies to PMA products — which represent about 50 of the 3000-4000 new devices introduced every year. And it still allows the manufacturers whose PMA devices are adulterated or misbranded to be sued in state courts. The Riegel case applied to none of those scenarios. Medtronic’s catheter was not adulterated or misbranded, and the injury occurred because Riegel’s doctor used the catheter in a way not approved by FDA or encouraged by Medtronic.

Had the case been allowed to proceed, notes Kevin Quinley, senior vice president of Medmarc Insurance Group (which provides product-liability insurance for life sciences companies), the jury could have been manipulated into finding Medtronic was at fault when it wasn’t. The jury would have heard all kinds of heart-wrenching testimony about what happened to Riegel, but Medtronic would not have been allowed to tell it about all the successful procedures — and, perhaps, saved lives – that occurred when doctors used the catheter properly. Since Medtronic was the only defendant in the case, Riegel’s story could have prompted the jury to punish the company, even though it did nothing wrong.

This is a victory not only for Medtronic, but for FDA and the device industry as a whole. A loss would have meant that state courts could have made their own determinations as to what constituted safety and effectiveness. This would have undermined FDA’s authority, exposed device companies to increased liability, and potentially thrown the whole medical device regulatory system into chaos.

– Erik Swain

An article published in today’s New England Journal of Medicine finds fault in FDA’s regulatory system for medical devices, using the recall of Medtronic’s ICD lead in 2007 as part of the basis for the criticism. According to author William Maisel, MD, the combination of the number of patients affected, money at stake in the market, and dialogue between doctors and patients about the product’s performance “highlight the shortcomings of the regulatory system…and underscore the urgent need for legislation that will ensure adequate protection for the patients receiving them.” Part of the problem, he writes, is that the Sprint Fidelis lead was approved based on bench testing, not human clinical data. He also says Medtronic failed to notify the public about the potential product defects and continued to sell the ICDs. From Maisel’s perspective, patients have a right to be told about the possible risks of a device that will be implanted to ensure that they can make an informed decision. FDA has the duty to protect the public’s health and is “failing to fulfill that mission,” he says.

– From MD&DI’s blog.