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2006: A Year of Upheaval

MOVERS AND SHAKERS 2006

The year 2006 was full of excitement, but not always for the right reasons. There were several major developments, some of which were unfavorable to the device industry.

The industry's top-selling product, drug-eluting stents, saw sales fall as studies questioned whether they are too much of a risk because they could cause blood clots. FDA determined that they are safe and effective if used as approved, but 60% of the time they are not used as approved, and the negative publicity made skeptics out of some doctors and patients.

Another top-selling product, implantable cardioverter-defibrillators, continued to attract media attention over malfunctions, and prompted intense debate over how FDA should handle recalls of such devices.
These developments created headaches for Boston Scientific, a player in both technologies thanks to its acquisition of Guidant, and Johnson & Johnson, which decided to shell out for Conor Medsystems in hopes of landing a superior next-generation stent technology.

Government fared no better in the public eye. FDA commissioner Lester Crawford resigned under a cloud, undone by failing to sell off stocks in FDA-regulated companies.

CMS administrator Mark McClellan took off in mid-reform effort, enticed by the private sector. Critics of silicone breast implants howled over FDA's decision to allow them back on the market. And key members of Congress continued to berate FDA for inadequate postmarket surveillance. The latter prompted CDRH to come up with a plan to overhaul how it handles postmarket information—and how the agency interacts with device firms in that sphere.

Such events may seem better suited for gossip columns than MD&DI, but the situations produced valuable lessons for industry, clinicians, and regulators to learn. Many of them are explained in the stories below.


Boston Scientific, J&J Shape Themselves for Future

MOVERS AND SHAKERS 2006

Industry analysts are mostly positive about Boston Scientific CEO James Tobin's ability to fix Guidant's problems.
All eyes have been on Boston Scientific and its CEO, James Tobin, in the past year. The firm completed the largest deal in industry history, acquiring Guidant Corp. for more than $27 billion.

The sheer size of the deal, and the battle Boston Scientific had with its rival Johnson & Johnson (J&J) for the right to buy Guidant, was more than enough to pique interest. But then add that Guidant was reeling from some of the most publicized problems in industry history, and the scrutiny became more intense.

Boston Scientific made the deal to enter the cardiac rhythm management (CRM) market, a field that is extremely lucrative and that is controlled almost entirely by only three companies: Guidant, Medtronic, and St. Jude Medical. It was so desirous of Guidant's CRM products that it agreed to give up Guidant's stent business to satisfy antitrust concerns. That sector was sold to Abbott (Abbott Park, IL) for more than $6 billion.

It's too early to conclude whether the deal was a good idea, but assessments so far are not enthusiastic. Making matters more complicated is that FDA, already displeased about malfunctions of Guidant products, issued a corporate warning letter to Boston Scientific for quality issues at its own plants.

“The Boston Scientific–Guidant deal has been disappointing for Wall Street,” says Thomas Gunderson, senior healthcare analyst for Piper Jaffray & Co. (Minneapolis). “There was an expectation that the implantable cardioverter-defibrillator market would do better than it has. The growth engine was less than originally thought by Boston Scientific and Wall Street. Boston Scientific took on a lot of debt. As it turns out, Abbott, which got the [so-called] leftovers from the deal, has done better.”

But, he adds, if any management team can turn the situation around, it's Boston Scientific's. “For the most part, integration has gone as expected,” he says. “Things are well on course after eight months or so, even though so much needed to be fixed at Guidant on the manufacturing and quality control side.”

Patrick Driscoll, president of MedMarket Diligence (Foothill Ranch, CA), agrees. “It's not a case of biting off more than they can chew; Boston Scientific is a big company,” he says. “But I doubt that anyone would say that the value it expected to get from Guidant is anywhere near the value it has received so far. It has turned out to be a bigger, uglier beast than the company would have liked.”

Although not yet available in the United States, Conor Medsystems' CoStar stent has drawn early praise.

J&J responded to the deal by making a number of deals of its own, most of which were not in the device arena. But a significant one was the pending acquisition of Conor Medsystems (Menlo Park, CA) for $1.4 billion. Conor has developed a bioabsorbable drug-eluting stent technology that could form the foundation of J&J's future efforts in that lucrative market. Industry experts seem to like the deal, especially because of enthusiasm over Conor's technology.

“I've been intrigued by the Conor technology from the very first stages of development. I think it's tremendous,” says Gunderson. “Over the long term, it should turn out to be a good marriage.”

Conor's technology is currently used on the CoStar system, which is approved in Europe but not in the United States. The CoStar is a paclitaxel-eluting cobalt chromium stent with a bioabsorbable polymer. It employs a unique reservoir technology that allows for accurate delivery of multiple drugs. (For more on Conor's technology, see “New Drug-Eluting Stent Technology Shows Encouraging Results,” MD&DI, July 2004.)

Michael Drues, PhD, president of Vascular Sciences (Grafton, MA), likes the acquisition because he believes Conor's technology is well positioned for future developments in combination products. Among device companies, he says, Conor is one that really understands the effect of implantable devices on human biology.

“I have been a fan of Conor's approach for a long time,” Drues says. “They think of the stent as a syringe.”

Copyright ©2007 Medical Device & Diagnostic Industry

FDA Rewards Many Figures in Utah Medical Case

WASHINGTON WRAP-UP

In the year leading up to FDA's defeat in Utah federal court in the Utah Medical Products QSR/GMP case, all but two of the agency employees most closely associated with it received bonuses for what the agency characterized as excellent service. These compensation data for 2005 were obtained under the Freedom of Information Act.

The data do not reveal explicitly what actions each bonus rewarded. However, the perception created must be that being found wrong by a federal judge in a doomed prosecution did not hurt anyone's career or stipend. And, to be fair, many of the employees had other things on their plates besides that disaster.

Highest paid among these employees, the data show, was FDA associate chief counsel for litigation Eric M. Blumberg. He earned $266,161 after $58,733 in bonuses. More than anyone else, he was the person holding the most responsibility for the court case itself.

Second-highest paid among the bonused employees involved in the case was CDRH director of compliance Timothy A. Ulatowski. He earned $230,113 after receiving $34,623 in bonuses.

Next came regional director Dennis Baker. He had flown up from Dallas to lead an FDA listening session with Utah Medical that could have opened up the process to candor, but didn't do so. He received $206,337 after $1000 in bonuses.

Others in the Utah Medical case also got bonuses in 2005. They included the following employees: CDRH quality systems expert Kimberly Trautman with $128,251 (including $1450 in bonuses) and Denver district director Betsy Collins with $126,348 (including $1200 in bonuses). Denver district compliance director Howard Manresa received $113,385 (including $1000), and Denver district compliance officer Regina Barrell earned $99,297 (including $500). Atlanta-based national expert Karen Coleman earned $95,234 (including $600), and then– Salt Lake City resident post supervisor Teresa Thompson received $89,336 (including $250). Thompson is now stationed in Lenexa, KS. Finally, Salt Lake City resident post investigator Ricki A. Chase-Off earned $79,210 (including $250).

However, two notable FDA employees involved in the case did not receive bonuses in 2005. CDRH director Daniel Schultz earned $216,594 base salary, and former associate commissioner for regulatory affairs John Taylor received $222,330.

If FDA had shown any remorse over this case, it might be able to say that the bonused employees would have performed better if they had not been involved in it. But that is not the way this agency presents itself. This case, and the four similar ones that CDRH lost before it, simply are not on any FDA employee's mind today.

FDA Told to Clean Up Clinical Studies

Expect more-stringent FDA attention to human subjects protection issues in clinical trials, warns the HHS Office of Inspector General (OIG). In December, OIG issued a report telling the agency to increase its efforts to implement corrective actions sought by the FDA commissioner in 2003. The actions are meant to address problems that had been identified in an FDA-sponsored bone-mass clinical study for the U.S. Army. In addition, the actions aim to prevent future problems from arising in FDA's human-subject research program.

The corrective actions directed each of FDA's six program centers, which include CDRH and the Office of Science and Health Coordination, to complete six tasks. First, they were to initiate an inventory and audit of clinical studies. They were also to examine research-monitoring programs and develop quality assurance programs, and then establish a policy of accountability to the commissioner. The centers were also to enlist the chief counsel's office's help to ensure appropriate regulatory schemes and to provide additional funding for oversight. Finally, they were to initiate a mandatory education and certification program.

OIG reported that after conducting inventories, the centers submitted 71 human-subject studies to the Office of Science. Those studies had neither been submitted to FDA for approval nor recorded in the agency's IRB database. The Office of Science added the studies to the database. The report said that from March 2003 to October 2005, FDA audited only three of the 297 studies listed in the database.

None of the centers reported having an operational research-monitoring program. Three had started to develop quality assurance programs but had not implemented them. And the Office of Science had drafted an agencywide quality assurance program but had not finalized it.

FDA did not have a written policy setting forth center directors' accountability to the commissioner for noncompliance with clinical research requirements. However, directors from three of the agency's centers did say that they were accountable to the commissioner.

The Office of Chief Counsel's IRB representative said she helped ensure that clinical research reviewed by an IRB complied with applicable regulations. No additional funds had been provided to the Office of Science to strengthen its oversight function, according to FDA officials. The Office of Science had not requested additional funds for this corrective action.

FDA told OIG that in 2002 it began requiring its researchers to complete a course on human-subject research issues. At the end of the course, they must pass an examination to receive a certificate of completion. FDA said it believed the course met the commissioner's directive.

The agency told OIG it agreed with the recommendation that efforts to accomplish the corrective actions be increased.

Von Eschenbach Confirmed over Objections

Over the strenuous objections of 11 dissenters, the U.S. Senate voted 80-11 on December 7 to confirm Andrew von Eschenbach as FDA's permanent commissioner. Senate leader Bill Frist (R-TN) used a cloture vote (89-6) to end all debate and thus lift three senators' holds on the pending nomination.

Grassley thinks the commissioner has shown disrespect for the law.

One of the three senators, Finance Committee chairman Chuck Grassley (R-IA), made a strong effort on the floor to dissuade his colleagues. “I've seen a complete and utter disrespect for congressional authority and hence the law” from the nominee, Grassley said. According to Bloomberg News, Grassley displayed enlarged versions of redacted documents provided to him by FDA in response to subpoenas. He complained that FDA's response to one of his document requests included a redacted version of a letter he had sent to the agency. “It's not OK to impede congressional investigations,” Grassley said. “It's not OK to limit the Senate's access to documents, information, and employees of the executive branch.”

Grassley claims that by denying the committee access to documents requested by the subpoenas, HHS and FDA have claimed “prosecutorial deliberative process,” “confidential communications,” and “agency prerogative to determine who will be interviewed or testify before a jurisdictional committee.” At his urging, the Congressional Research Service examined HHS and FDA's claims and found “no legal basis” for such “executive branch assertions.”

Nevertheless, industry organizations warmly praised the Senate's action. AdvaMed president and CEO Stephen Ubl issued a statement. In it, he said that von Eschenbach's “experience as a medical administrator, educator, urologic surgeon, and cancer survivor makes him keenly aware of the value of medical technology. AdvaMed looks forward to working with him to ensure patients have timely access to safe and effective lifesaving and life-enhancing medical tests and treatments. He is a stellar choice to lead the FDA of the twenty-first century.”

The Medical Device Manufacturers Association, representing smaller companies, did not issue a statement on the confirmation.

Stents Panel Plagued by Conflict-of-Interest Concerns

FDA's Circulatory System Devices Panel was convened to provide the public with a coherent, understandable explanation of the risks associated with drug-eluting stents, according to CDRH director Daniel Schultz. However, the panel has been plagued by conflict-of-interest concerns. (For more on the panel's results, see “Drug-Eluting Stents Come Under Fire.”)

Six panel members were issued conflict-of-interest waivers to allow them to attend the December 7 meeting. During a media briefing, a reporter asked Schultz why FDA redacted the specifics from the waivers about the companies and products that posed the conflicts. Schultz said the decision came from a broader policy and was not specific to this meeting. He said the intent was to have participation from panelists who could provide a balanced view on the issues raised.

Schultz said that although the experts were being asked for their opinions, no formal votes would be taken and their mission was clearly advisory. It would be up to FDA to determine what, if anything, should be done.

At least one critic charged that six waivers was excessive for the meeting. The panelists who received the waivers were Robert Harrington, Duke Clinical Research Institute; JoAnn Lindenfeld, University of Colorado Health Sciences Center; Richard Page, University of Washington School of Medicine; George Vetrovec, Virginia Commonwealth University; Judah Weinberger, Columbia University; and Clyde Yancy, University of Texas Southwestern Medical Center.

“I could think of 100 people who could qualify” as an expert and who would be without financial ties, Massachusetts General Hospital cardiologist Herman Gold told Bloomberg News. Gold presented research to the FDA advisory panel on how coatings on some stents raise the risk of patient blood clots.

FDA's role in allowing conflicted panel members to serve on advisory committees has drawn interest on Capitol Hill. Senate Finance Committee chairman Chuck Grassley (R–IA) has been a frequent critic of FDA's waiver practice on potential conflicts of interest. As recently as last month, the issue came up in a Senate HELP Committee hearing. Although not present at the hearing, Center for Science in the Public Interest project director Merrill Goozner provided written testimony to the senators. He rejected FDA's oft-expressed contention that it is difficult, if not impossible, to empanel a sufficient number of qualified experts as members of scientific advisory committees who have no conflicts in their areas of expertise. In particular, he criticized the “complicated scheme” (comprising four categories of conflict: low, medium, high, and nonwaivable) for managing conflicts of interest.

Goozner cited the experience of the National Institutes of Health Office of Medical Applications of Research (OMAR). It maintains a strict no-conflicts policy for its advisory bodies. “OMAR panels require the same specialized expertise found on FDA advisory panels: biostatisticians expert in interpreting clinical trial data, clinicians expert in treating disease, and scientists who understand the underlying biology,” Goozner said. “They perform the same tasks: understanding the science, evaluating clinical trials, weighing industry and public presentations, and synthesizing published materials. OMAR can find unconflicted scientists. So can FDA, if it just looks hard enough.”

A recent Institute of Medicine report recommended that FDA establish a requirement that a “substantial majority of the members of each advisory committee be free of significant financial involvement with companies whose interests may be affected by the committee's deliberations.” It supported 60% as a threshold for a “substantial majority.” And it said that a reasonable definition of “free of significant financial involvement” is those interests that currently require only disclosure and do not require a waiver. FDA should issue waivers for the remaining 40% “very sparingly.”

Revealing FDA's recent undertakings to address the criticism, FDA commissioner Andrew von Eschenbach said the agency will revise its guidance to identify more clearly the conditions under which conflict-of-interest waivers are granted. In addition, he said, FDA will revise the guidance that specifies when conflict-of-interest waivers will be disclosed to the public and what information will be made available. It will also revise the guidance that specifies when briefing materials used at advisory committee meetings will be made publicly available. FDA also plans to provide greater dissemination of advisory committee schedules through increased mailings to public groups and provide electronic notifications through an FDA advisory committee listserve. Finally, it will implement a more streamlined approach to appointment of members to the agency's drug-related advisory committees.

Radiometer Cited over QSR Problems

FDA in December announced that it had sent, on September 29, a warning letter citing quality system regulation (QSR) violations to Radiometer Medical ApS (Brønshøj, Denmark). The violations were found during an inspection conducted at the company in May. The company manufactures blood gas analyzers, transcutaneous pulse monitors, membrane accessory kits and related accessories, controls, and calibration products. The warning letter also said that an earlier inspection at Radiometer America (Westlake, OH) determined that the company distributes the firm's products in the United States and conducted 42 device corrections and updates between January 2005 and May 2006.

Violations noted at the Danish location included failure to establish and maintain adequate procedures for implementing corrective and preventive actions. The firm also failed to establish and maintain adequate procedures for verifying or validating its corrective and preventive actions to ensure that they are effective and do not adversely affect the finished device.

The warning letter said the firm's response was inadequate because it did not provide specific information on the corrective steps to be taken. The company was given 15 working days to indicate specific steps taken or to be taken to correct the violations. The new response must include an explanation of how the firm plans to prevent the violations or similar violations from occurring again. Documentation of actions taken was also to be included.

FDA and Japan Harmonize by Doing

The United States and Japan are participating in Harmonization by Doing (HBD), an international effort to develop global clinical trials and address regulatory barriers that may impede timely device approvals.

A November 28 update issued by CDRH says a pilot project, launched in December 2003, seeks regulatory convergence between FDA and Japanese agency premarket reviews of cardiovascular device technology. Instead of taking a theoretical approach to harmonization, HBD is using parallel development, application submissions, and review of actual device projects by FDA and the Japanese agencies in conjunction with other stakeholders.

The objective, CDRH says, is to eliminate redundancies, added costs, and time delays inherent in sequential trials. Rather than simply create guidance and discuss policy, HBD's intent is to develop common protocols for investigational clinical studies. These protocols would allow safe and effective breakthrough cardiovascular technologies to benefit patients worldwide, the update says.

For more on the project, visit www.fda.gov/cdrh/international/hbdpilot.html.

Orphan Technology Licenses Offered

The National Institutes of Health (NIH) has launched a Web site offering technologies for commercial licensing related to rare diseases or conditions. An NIH news release said there are more than 500 such technologies listed, including biologics, drugs, and devices. The technologies are available to be transferred from NIH and FDA to the private sector for further research and development, leading to potential commercialization.

NIH said rare disease is defined as one with a prevalence of less than 200,000 cases in the United States. Some 25 million to 30 million Americans have one of more than 6500 known rare diseases. The Web site was developed by NIH's Office of Technology Transfer and Office of Rare Diseases to provide a more collaborative, consolidated, and systematic approach to the development of products for rare diseases and conditions, NIH explained.

To access the listing, visit http://ott.od.nih.gov/licensing_royalties/raredisease_ovrvw.asp.

QSR Violations Alleged at Trionix

An FDA inspection at Trionix Research Laboratory (Twinsburg, OH) last July and August found QSR violations. Trionix manufactures nuclear imaging devices. A recently issued warning letter from FDA's Cincinnati District Office citing the violations included the following:

  • Failing to establish procedures for and implement a corrective and preventive action to prevent recurrence of nonconforming product.
  • Failing to implement procedures for receiving, reviewing, and evaluating complaints; to maintain complaint files; and to review and evaluate complaints to determine whether an investigation is necessary.
  • Failing to ensure that the nuclear imaging device met all final acceptance and in-process acceptance criteria and to authorize device release by signature of a designated individual before distribution.
  • Failing to ensure that equipment is routinely calibrated and inspected.
  • Failing to control products that do not conform to specifications.
  • Failing to use the design process for design changes made to the Biad nuclear imaging system, and failing to have written design change procedures.
  • Failing to have management with executive responsibility ensure that an adequate and effective quality system has been fully implemented and maintained at all organizational levels.

The warning letter also said the firm failed to submit a written report to FDA on a correction made to the detector head of the Biad nuclear imaging device. The correction was initiated to remedy a violation caused by the device that could present a health risk. Specifically, the firm retrofitted the detector head with some screws and changed the gear and belt to prevent the detector head from dropping.

Trionix was told to submit a report within 15 days on steps taken to correct the violations. The company's report is to include an explanation of how the company plans to prevent these or similar violations from occurring again.

FDA Issues Final Breast Implant Guidance

FDA has issued a finalized guidance, Guidance for Industry and FDA Staff: Saline, Silicone Gel, and Alternative Breast Implants. It updates preclinical, clinical, and labeling recommendations laid out in a January 13, 2004, draft guidance. It may be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/04d-0002-gdl0002%20(2).pdf.

A Federal Register notice said the guidance reflects the latest scientific and medical thinking pertaining to breast implants. It is based on an April 2005 General and Restorative Devices Panel meeting, FDA's review of two premarket approval (PMA) applications for silicone-gel-filled breast implants, and comments received on the draft guidance. The notice said the primary changes to the guidance document since the 2004 draft version were to the Mechanical Data, Device Explant Analyses, and Core Study Clinical Data sections. (The Device Explant Analyses section was formerly called Modes and Causes of Rupture.) The agency also combined the former two clinical sections.

Some of the guidance's recommendations apply to all PMA applications for the devices, the notice said, while others are specific to a type of breast implant.

In addition, a new guidance for industry, Medical Device Tracking; Guidance for Industry and Staff, adds silicone gel implants to the list of devices that must be tracked when FDA orders manufacturers to do so. Tracking, the guidance said, is intended to facilitate notification and recall in the event a device presents a serious risk to health requiring prompt attention. It may be accessed at www.fda.gov/cdrh/comp/guidance/169.html.

FDA Deputy Commissioner Resigns

After holding positions at FDA and CMS, Gottlieb will rejoin AEI.

FDA deputy commissioner for medical and scientific affairs Scott Gottlieb announced his resignation in December to return to the American Enterprise Institute (AEI). During the long hiatus between FDA commissioners, Gottlieb was often the agency's primary public voice. He rejoined the conservative DC think tank effective January 16.

In 2003, former FDA commissioner Mark McClellan recruited him from AEI and took Gottlieb with him when he left for CMS in 2004. Gottlieb rejoined FDA in July 2005, from Forbes.com. There, he had been editing a popular investment-advice newsletter that specialized in medical technology stocks and frequently criticized slow approvals at FDA. A December 11 FDA statement on Gottlieb's departure said that during his latest term at the agency, he worked to improve the advisory committee process and to improve product-risk information disseminated to the public.

“Gottlieb also helped to facilitate implementation of important new regulations and policies, including the new drug and biologic products labeling rule and the expanded-access rules to help patients with life-threatening conditions gain access to drugs under development,” the statement added. Gottlieb also assisted with advancing FDA's Critical Path initiative. At AEI, he will rejoin McClellan, who recently resigned from CMS to accept a post as a visiting senior fellow at AEI-Brookings Joint Center for Regulatory Studies.

M&S Acquisition Cited for QSR Problems

An FDA inspection in September at M&S Acquisition's Mentor, OH, facility found quality problems, according to a recently released warning letter. That plant manufactures orthopedic implantable devices, including lumbar screws, rods, nuts, and plates. The warning letter was issued from FDA's Cincinnati District Office.

Violations cited included that changes to methods and procedures needed to correct and prevent identified quality problems were not fully validated and are not effective. The company also failed to validate certain processes. In addition, it failed to establish monitoring procedures and to monitor and control the process parameters for validated processes.

Cincinnati district director Carol Heppe said some of the firm's responses to the FDA-483 findings were adequate. Others did not address how the firm will ensure that corrective steps address all the identified problems. The company was told to respond within 15 days with a listing of steps already taken and those planned to correct the violations and to prevent them from recurring.

Counterfeit LifeScan Test Strips Recalled

FDA has classified two earlier recalls involving counterfeit blood glucose test strips as Class 1. The test strips are used in LifeScan's One Touch monitor. The first recall involves three suspect lots of One Touch Basic Profile test strips. “These counterfeit test strips could give incorrect blood glucose values, either too high or too low, which might result in a patient taking either too much or too little insulin,” FDA says.

The second recall involves one lot of One Touch Ultra test strips that have been found to “give erratic results that do not meet the manufacturer's specifications.”

Copyright ©2007 Medical Device & Diagnostic Industry

Seven Steps to Systematic Literature Reviews

Formal literature reviews play a significant role in device development. This is especially true when they support quality and regulatory compliance for these medi- cal devices. But some people may react to being assigned with conducting a formal literature review with apprehension.

It's understandable that a quality, regulatory, clinical, or R&D professional would be intimidated when asked to conduct and report on a literature review. Many of these project recipients do not regularly perform formal research on scholarly articles. A literature review is a large task that could easily require 60–80 hours of focused effort.

But literature reviews are a wise investment. They are often used to support design of clinical investigations, and they may even be used to support a literature route to conformity for CE mark approval. Several guidance documents are available that can help to ensure compliance with applicable regulations. Two regulatory guidance documents that focus on conducting literature reviews are MEDDEV 2.7.1, “Evaluation of Clinical Data: A Guide for Manufacturers and Notified Bodies,” and Annex A of ISO 14155-1, “Clinical Investigation of Medical Devices for Human Subjects: General Requirements.” Following these documents can help a reviewer organize the literature and ensure that the information gathered is of high quality.

As with most complex and challenging projects, literature reviews are less overwhelming if they are approached in a systematic fashion, one small piece at a time. To make the project a success, here are the steps to follow:

  1. Write a detailed plan that outlines the purpose, objectives, and methods to define the literature review.
  2. Perform the search using a methodical approach.
  3. Select and obtain articles.
  4. Summarize highlights from the selected articles.
  5. Prepare a data analysis spreadsheet to consolidate information.
  6. Create report tables.
  7. Write the report text.

It should be noted that a formal literature review is not the result of a Google-type search. It requires considerable planning, methodical searches, and attention to detail. The information discovered in the process provides valuable input to the development of safe and effective medical devices.

Start with a Plan

Creating a plan is the first step in the literature review process. It is always tempting to skip the planning stage with any project. Override this temptation and follow the MEDDEV suggestion to develop and approve a written plan. A detailed written plan ensures a systematic review of the literature. At a minimum, the plan should define the literature review purpose, objectives, and methods.

Purpose. Declare the purpose of the literature review and provide background information as necessary (e.g., The purpose of this literature review is to evaluate the risks associated with coronary implant devices to support development of the XYZ Company's Alpha device).

Objectives. Declare the objectives of the literature review in measurable terms. In many cases, it is helpful to identify questions that the literature review is intended to answer (e.g., This literature review will attempt to answer the following questions: What is the rate of death associated with coronary implant devices? What other serious adverse events are reportedly associated with coronary implant devices? What is the reported incidence of adverse events?).

Methods. Define the methodology for searching and selecting the literature, including:

  •  
    Reputable Data Sources and Search Tools

    Databases that provide reputable sources can be difficult to find. The best sources are those from recognized scientific journals and textbooks. Technical papers can provide valuable information. PubMed (www.pubmed.gov) is a respected site. Other sources include the Academic Search Premier, the Scientific Citation Index, and the Social Sciences Citation Index.

     
    Reputable data sources (see the sidebar, “Data Sources and Search Tools”).
  • Search terms to include.
  • Search terms to exclude.
  • Search limits (e.g., randomized con- trolled studies, adult patients, English language, studies less than 10 years old, etc.).
  • Article selection criteria (e.g., peer-reviewed scientific publications, devices with similar intended use, etc.).

While preparing the literature review plan, it is important to perform preliminary searches to experiment with various inclusion and exclusion search terms. Although these searches are not considered formal searches, they do help ensure that the plan is designed to find relevant scientific articles that align with the objective.

For more-complex literature reviews, it may be necessary to develop methods for weighting the different articles and studies. It may also be useful to define the statistical methods of analysis to be employed. Statistical analysis of data from several studies is known as a meta-analysis. The University of Maryland Department of Measurement, Statistics, and Evaluation provides helpful meta-analysis resources on its Web site: http://edres.org/meta/.

Perform the Search

Perform the literature search in a reputable search engine following the methodology defined in the plan. Use the correct format for Boolean operators (e.g., “and,” “or,” etc.) as required by the search engine, and note that the use of quotation marks around search terms may significantly affect search results.

Review the list of search results. Because research is serendipitous, it may be necessary to add or remove inclusion and exclusion criteria as necessary. This helps narrow the search results to a reasonable quantity and to eliminate search results that do not align with the literature review objective. For example, if only 10 search results appear, it may be useful to add inclusion criteria or remove exclusion criteria. If about a thousand search results appear, remove inclusion criteria and add exclusion criteria. In most cases, an initial search results list of 20–50 articles is sufficient.

Citation indices provide an alternative way of finding documents. Two such indices include Science Citation Index and Social Sciences Citation Index. Note that additional articles may be discovered when reviewing bibliographies of selected documents.

It is prudent to perform additional cross-check searches to ensure that all relevant major studies have been captured in the literature review. For example, if the original search did not include the trade names of similar products, perform a search using these names with the same search limits defined in the plan. Scan the search results. If relevant and important articles appear on the list, it may be necessary to refine and save the search.

When the search process is complete, save and print the search results lists for inclusion as a literature review report attachment, providing traceability on the extent of searches performed and the sources of the data.

Select and Obtain Articles

Determine whether all of the articles on the search results lists are relevant to the literature review objectives. Irrelevant articles can be screened out initially by reviewing the titles and, if it is unclear from the title, reviewing article abstracts. Graphs and charts may also be developed during this step to complement data tables. When using PubMed as the search tool, abstracts are easily available for review with the click of a mouse button. Develop a coding system as necessary to document rationale as to why the screened articles do not meet the selection criteria.

When reviewing articles, pay attention to the authors and investigational centers. If the same group of authors published several articles on the same study, consider which articles are most relevant to the literature review, and exclude any articles that feature duplicate information. Be sure to provide exclusion rationale in the literature review report.

Obtain copies of all selected articles. Note that copyright charges add up quickly, so be prepared for a large expense. Many companies have an internal reference library and subscribe to scientific journals, so use whatever literature resources are already available. Articles may be purchased from various sources including the publisher, PubMed, and biomedical libraries. Delivery options range from online downloads of PDF files to mail delivery of photocopies.

After receiving the articles, make a temporary working copy for each article. Add highlights and notes to the working copies and place the originals in the final report or the company reference library.

Review and Summarize Selected Articles

Peruse each of the selected articles and underline or highlight information that relates to the literature review objectives. This step of the process helps literature reviewers become acclimated to the topic, and it provides an initial survey on the level of reporting consistency in the selected articles. Some may find it easier to take separate notes, rather than highlighting, to help with retention of the material.

It is helpful to develop a literature article summary table to include relevant and key information from each of the selected articles. The table provides a handy resource in the appendix of the literature review report. In addition, the process of creating the table further helps to distill and broadly categorize the large volume of information in the selected articles.

Table I. (click to enlarge) A literature review summary table should include relevant information in an organized and consistent manner so that readers can quickly understand it.

Consider the following columns for the literature article summary table (or customize as appropriate): author and article reference, study design and devices used, follow-up, and miscellaneous comments and findings. A final column should be specific to the literature review objectives (e.g., reported adverse events). See Table I for an example of a literature article summary table.

Prepare a Data Analysis Spreadsheet

Table II. (click to enlarge) A data analysis spreadsheet should consistently categorize data. Use footnotes to explain special data-handling methods. Here, the author Anderson did not address stroke so NR (not reported) was entered, rather than zero.

The next step is to develop a data analysis spreadsheet (see Table II). The spreadsheet is critical to ensure that the data are consistently categorized to allow for an apples-to-apples comparison. Such a comparison can be quite challenging considering the inconsistent reporting methods that are used by various authors. When necessary, use footnotes to explain unusual or unique circumstances and any special data-handling methods used. For example, if an article reports the percentage of events and all other articles report a quantity, it may be necessary to calculate the quantity for comparison purposes. A footnote can clearly document that the quantity was calculated and to show exactly how the values were derived.

If one article does not address a category that is described in other articles, enter NR (not reported) in the data field rather than entering a zero. It is not reasonable to assume that zero events occurred just because the event was not mentioned in the article; the protocol may not have required observation and recording for that particular event.

It is possible that articles will need to be excluded during the data analysis process. If so, explain the rationale for exclusion in the literature review report. It is likely that the summary table created in the previous step may require changes and updates based on information learned during this step.

Create Report Tables

Table III. (click to enlarge) Within the body of the report, tables should focus on information crucial to the literature review objectives, such as deaths associated with the device.

Analyze the objectives defined in the literature review plan and determine what data should rise to the level of report tables in the literature review report. Give special consideration to the categorization of data that would be most beneficial for the particular product or subject of the literature review. For example, with stent products it may be beneficial to categorize the data by drug-eluting stents and bare-metal stents. Several tables may be required, depending on the complexity of the literature review. See Table III for an example report table.

Write the Report

If a systematic approach has been used, writing the report is relatively easy. There are some format and content guidelines for the literature review report including purpose, objectives, review method, search results, device description, analysis, and conclusion.

Purpose. Rewrite the purpose statement from the literature review plan using past tense (e.g., The purpose of this literature review was to evaluate the risks associated with coronary implant devices to support development of the XYZ Company's Alpha device).

Objectives. Rewrite the objectives from the literature review plan using past tense (e.g., This literature review attempted to answer the following questions: What is the rate of death associated with coronary implant devices? What other serious adverse events are reportedly associated with coronary implant devices? What is the reported incidence of adverse events?).

Literature Review Method. Define the methods used for obtaining the literature that was reviewed. The information in this section should be similar to what was defined in the literature review plan. Describe the actual methods used and provide rationale for any deviations from the plan. Include information such as the data sources, the search terms included, and the search terms excluded.

Search Results and Article Exclusions. Provide a summary of the searches that were performed, the number of results, and the number of articles excluded. Also, provide a reference to the appendix where the search results documentation will be located, along with the rationale for article exclusions. As previously mentioned, it is helpful to develop a simple coding system that can be used to document article exclusion rationale directly on the search results list(s).

Device and Product Description. Provide a brief description of the device or product referred to in the purpose section. Include intended use and principles of operation.

Analysis of Reviewed Literature. This is the heart of the literature review report. This section should provide a comprehensive summary and analysis of the information discovered in the literature review process, both favorable and unfavorable, and it should address each of the literature review objectives. The report tables that were created in the previous step of this procedure provide the outline for writing this section. Write a brief introductory paragraph for each table. Below the table, discuss the most notable points from the table. For example, describe the overall rate and range of events, and then discuss the articles that reported the greatest number of events. If relevant, mention articles that reported the least number of events. Provide author quotes and references, where appropriate. Rather than just reproducing the literature, write this section with a natural flow that tells the story of an unbiased and critical analysis of the literature.

Conclusion. Provide a brief summary to indicate how the objectives of the literature review have been met. If appropriate, include a top-level data summary table.

Appendices. Suggested appendices for the literature review report include

  • Bibliography. All articles referenced in the literature review should be included in the bibliography. For consistency, use a standardized format for bibliography entries.
  • Literature article summary table (optional).
  • Detailed data analysis tables and spreadsheets.
  • Literature search results list and detailed criteria for article exclusions.

Report Approval. The literature review report should be signed by the author, or if it was ghost-written, by the report owner. In either case, it is important that the report approver is adequately qualified and has demonstrated objectivity. (Refer to MEDDEV 2.7.1 for guidance.)

Trust the Process

Literature reviews are complex projects that require a lot of time and effort. But these projects can also be enjoyable because they involve research, discovery, learning, and focus. In addition, literature reviews result in a valuable treasure trove of information for both medical device developers and manufacturers.

When the next literature review project shows up on the product development project plan or the department action list, follow the steps of this systematic approach. The project may seem overwhelming at first, but relax and trust the process. Take one small step at a time to break the challenge into manageable tasks, and plan to cross the finish line of this marathon project with the ultimate deliverable: a comprehensive literature review report.

Barb Danson is founder of QWS Consulting LLC (Maple Grove, MN). She can be reached via e-mail at bdanson@comcast.net.

Copyright ©2007 Medical Device & Diagnostic Industry

GE Consent Decree: Not Your Problem? Don’t Be Too Sure

FROM THE EDITORS

GE Healthcare's recently signed consent decree may have more to it than meets the eye. Taken at face value, the need for a decree makes it seem as though the problems were so egregious that FDA felt that an injunction was the only way to get the company to fix them. But take a closer look, and you may see serious implications for you and your company.

GE's problems included failure to establish and maintain adequate procedures for validating the device design and also failure to establish and maintain adequate procedures for implementing corrective and preventive actions (CAPA). GE is a large company with significant resources, so how it got to this point may be puzzling.

“Sometimes the agency's agenda is not exclusively driven by what it sees at a particular company, but rather by the industry that the company is in and whether the agency wants to make a statement about compliance within that industry,” says Arthur Levine, a partner with Arnold & Porter in Washington, DC. Levine was formerly deputy general counsel for litigation at FDA and served as FDA's legal adviser on compliance and enforcement matters.

When FDA wants to send a message to industry, he says, the agency identifies an industry leader and assesses its quality programs. “FDA proceeds with a high-visibility enforcement action such as an injunction in order to promote deterrence in that segment of the industry generally.”

The problem is that it is really difficult to decipher how FDA decides which companies it wants to approach to be enjoined, says Levine. Sometimes FDA accepts the enhancement program and corrective actions that you submit to the agency, and the agency is content to monitor the process through further inspections. In other circumstances, however, FDA loses patience with your progress, he says. At that point, it takes a more aggressive step.

“There's very little doubt in my mind that GE Medical Systems responded to FDA's inspectional observations. I have no doubt that the company did take corrective measures and improve its quality systems,” he says. “The fact that FDA has proceeded with an injunction should not be understood by anyone that the company has not been responsive. It's just that the agency for one reason or another has remained not fully satisfied.”

According to Levine, the companies that FDA chooses to focus on, to some extent, are based not just on the inspectional findings but also on higher enforcement priorities about certain industries or industry segments. “FDA's threshold for patience with regard to corrective actions and quality system enhancements is influenced by its enforcement priorities,” he explains. Even if you do everything you believe is reasonable, FDA may have a larger goal.

So, if FDA is sending a message to the entire industry, what measures should you take? “You need to carefully consider the first inspection outcome and try to give a response that is sufficiently engaged. When FDA thinks about an FDA-483 response, it wants a company to respond in a systemic way.”

Some observations lend themselves to a very targeted response, but he says that more often FDA is often looking for a comprehensive response that addresses the system as a whole.

Now more than ever, you need to be extremely diligent in responding to warning letters and you need to make sure that your response is sufficiently comprehensive. Your response must address the root causes of the issues that are of concern to the agency. You must look at the implications of the warning as well as the wording.


Sherrie Conroy for the Editors

Freedom of Information Act Requests: A Primer

REGULATORY OUTLOOK

Marlene Bobka
When device manufacturers add revealing FDA documents to their arsenals of information, it can make it easier for them to bring products to the marketplace and to keep them in compliance. That is why understanding the intricacies of the Freedom of Information Act (FOIA)—including learning how to submit a request and knowing where to turn when the wait for requested documents proves excruciatingly long—is extremely important.

FOIA allows companies to peruse minutes of a closed-door meeting between FDA and a competitor and to study FDA-483 notes written by an agency investigator. They may also browse the resumes of potential product reviewers or learn about the precise deficiencies a firm encountered during its most recent FDA inspection.

Nancy Singer

Of course, a request under FOIA does not ensure that companies will receive everything they want, whenever they want it. However, the act—passed in 1966 to encourage transparency in government—does provide an avenue by which manufacturers and other interested parties can view information that might otherwise never be seen outside a government employee's desk drawers.

What Are the First Steps?

Before spending time and effort on an FOIA request, it is necessary to determine whether the type of information requested does indeed exist. Contact FDA officials to learn the status of specific documents by using agency phone numbers and e-mail addresses listed online at http://directory.psc.gov.

Keep in mind that the FOI office at FDA is not a personal reference library, and officials there are not obligated to create any original documents. If a report was not prepared, a firm may never receive the information it is looking for. However, if you are reasonably sure that the information exists, you should first visit FDA's Web site to see whether the documents are already listed there.

The FOIA currently requires that releasable documents that are requested three or more times be placed online. Every so often, FDA places high-profile documents on its Web site because it knows that they will most likely be requested by more than three interested parties. For example, an FDA-483 issued to Guidant Corp. on February 9, 2006, was placed online immediately. The intense public and media interest over the firm's recent troubles with its implantable cardioverter-defibrillators and pacemakers warranted this action.

Other documents that are quickly posted online include documents of interest to a wide audience, such as guidelines and warning letters. However, if a particular document is sought, it may not be wise to wait for it to be posted online. There is a distinct possibility that FDA may not receive three or more requests for it.

If the information exists but isn't available online, then FOIA requests can be fruitful. Remember, though, that documents dealing with personal information (such as patient records), confidential business information (trade secrets or customer lists, for example), and ongoing legal action may be held back or redacted by FDA. (There are also six other FOI exemptions that are not commonly applicable to FDA documentation.) Redaction, or censoring those parts of a document withheld because of the exemptions to FOIA, is done by designated FDA staff within a particular office or district. Occasionally, agency staffers may inadvertently release confidential information. Although they usually are disciplined for this type of error, no FDA staffer has ever been criminally charged for such a transgression.

In addition, even though a document may exist, it doesn't mean FOI staff will be able to find it. Once records have been retired, they are extremely difficult to find, and many older preelectronic documents may be damaged or unreadable. Bear in mind that despite all of these potential drawbacks, documents received via an FOIA request are valuable and may include information not available elsewhere. These documents can give manufacturers unique insight into what FDA is thinking and how the agency handles particular situations, notably those that may arise during the approval process or facility inspections.

What Information Should a Request Letter Include?

Write FOIA request letters clearly and concisely, and be as specific as possible to ensure the fastest possible reply by FDA. Identify a contact name, company affiliation, mailing address, e-mail address, and phone and fax numbers. Providing a phone number is important because FOI office staff will most likely attempt to call if they have a question about the documents that are being sought.

Next, invoke FOIA by informing FDA that the letter serves as a Freedom of Information Act request, and explain exactly what you are looking for. The more specific the request, the better the chance is of quickly receiving accurate documents. The letter also should inform the FOI office of how much the firm is willing to spend to receive a copy of the requested information. Such a statement could read, “If the cost of providing these documents will exceed $150, please call us first for authorization of the charges.”

Commercial-use requesters are charged search and review fees of $20, $40, or $72, depending on the grade level of the FDA employee who fulfills the request. Duplications cost $0.10 per page and $0.50 for a sheet of microfiche; certifications are $10 each. Computer charges are the actual cost for time involved in retrieving the information. Charges for electronic forms and formats are the actual cost of the form and format requested. Non-commercial-use requesters, such as students, journalists, educators, and public interest groups, only pay duplication fees, with no charge for the first 100 pages that are duplicated. Other requesters, including consumers, pay the same search and duplication costs as commercial-use requesters. However, consumers are not charged for the first two hours of the search or for the first 100 pages of duplication.

It is also important to specify in a request letter whether the firm would like to receive all of the information that is available on a certain subject—which usually takes a much longer time to process—or just the material that can be disclosed, which means portions of the document will most likely be redacted when it is received.

Once the letter is completed, it should be mailed to: Food & Drug Administration, Office of Management Programs, Division of Freedom of Information (HFI-35), 5600 Fishers Lane, Rockville, MD 20857. (For addresses of agencies other than FDA, visit www.usdoj.gov/oip/index.html.)

Sidebar:
Effectively Using an FOIA Log

When the request is received by FOI office staff, it is registered in the FOIA log (see the sidebar, “Effectively Using an FOIA Log”). If the request is for a document that is in their control, such as copies of previously released FOIA documents that already have assigned FOIA control numbers, then they usually fulfill the request. If not, the staffers pass the request along to the proper center, regional office, or district office where the document is maintained. Center or office staff then are responsible for locating the document and determining whether it can be fully disclosed or whether it needs to be redacted. The document is then sent to the requester.

What Factors Slow Down FOIA Requests?

Although FOIA specifies that the requester will receive a response to an FOIA request within 20 days, this reply is only an acknowledgement that the request has been received by the FOI office. The time it takes for the document to actually follow can take much longer and, in some cases, it may take years.

The wait for documents depends in large part on the type of information that is requested. FDA places FOIA requests into one of two categories: simple requests and complex requests. Simple requests are documents that the FOI office can process relatively quickly. They generally involve receiving information from only one particular FDA office. Conversely, complex requests are more likely to be released at a slower pace, because more than one agency office must typically become involved.

For example, if a requester asks for all of the Inspection Reports and FDA-483s for a particular competitor with multiple sites, the request would be considered complex because it would involve requesting documents from all relevant FDA district offices. One way to avoid such a complex request would be to file separate FOIA requests for FDA-483s at each of the competitor's facilities. Those requests would be considered simple and, theoretically, they would be processed faster.

What Information Can Be Gained through FOIA?

Several important documents can be obtained through an FOIA request, including establishment inspection reports (EIRs) and FDA investigator notes and diaries, as well as FDA-483s and responses.

Device companies can learn a lot from reviewing EIRs that are issued to competitors. This includes learning what happened during an inspection, who at the firm was in charge at the time, and which employees were interviewed by the FDA investigator. The EIR also may include information about the inspected firm's various programs that the agency found acceptable. This could be helpful information for a manufacturer wondering whether a comparable program it employs at its own company would be deemed satisfactory by FDA.

EIRs do not only include information on observations made by the FDA investigator. They also provide a detailed account of any discussions the investigator had with management. An FDA-483 also may be attached to the EIR, along with a response by the manufacturer.

When constructing an FOIA request for an EIR, specify the name of the company that received the EIR, as well as the firm's location and a rough time frame when the inspection occurred. The time frame does not have to be the exact date of the inspection; rather, you could request the most recent EIR that the manufacturer received. It is a good idea to request the FDA-483 in addition to the EIR.

Diaries and notes that were compiled by an investigator who was assigned to a specific facility inspection may also be requested. Diaries provide an insight into an investigator's thought process when inspecting a firm and may contain valuable information that could reveal what the investigator thought of certain manufacturing processes. Do not send that request to the FDA district office that conducted the investigation; rather, send it to the FOI office in Rockville, MD.

Having this information gives manufacturers an edge because it allows them to build up information about FDA investigators who may inspect their facilities. It also provides insight into how companies that manufacture competing products and use similar manufacturing processes fared during inspections. This can help companies be more prepared for the next agency inspection and help them avoid errors that other firms have made.

In addition, it makes sense for manufacturers to use this information when creating standard operating procedures. By reading other firms' inspection reports, a company can learn what FDA did and didn't like, and therefore bolster its procedures to fit agency expectations.

Can 510(k)s Be Requested?

Through the FOIA process, manufacturers also may review 510(k) submissions. Although 510(k) summaries often are posted on FDA's Web site, those small bits of information don't provide the level of detail that full 510(k)s do. In addition, more-complicated 510(k)s can provide valuable preclinical and clinical trial results and other useful information.

Full 510(k)s can be used in different ways. For example, if a particular device is similar to a firm's product, that firm could use the device's 510(k) as a template. And, because that marketed device's 510(k) has been approved, the firm also may consider plugging its own numbers into the document and submitting essentially the same form. However, bear in mind that requesting a 510(k) through the FOIA process could take 18 months to three years, which is among the longest response times for FOIA documents. Although FDA does allow the 510(k) submitter to mark trade secret and confidential commercial information as exempt from disclosure, the FOI office will review these redactions for adherence to the strictures of FOIA.

What Other Documents Can Be Requested?

Other interesting documents that can be requested include résumés, curricula vitae, and government employment forms (SF-171s) for FDA investigators, as well as training modules investigators follow when learning how to inspect device manufacturers. These documents may provide insight into the investigators' education, background, and experience, and show what they are being taught by FDA when it comes to facility inspections.

Correspondence, minutes, and transcripts between FDA and manufacturers also may be of use. For example, if you are aware that a particular manufacturer is meeting with FDA, you can submit an FOIA request for the minutes of the meeting in an effort to learn about issues affecting devices currently in the marketplace that the competitor manufactures. In addition, correspondence between the company and the agency may reveal other product issues. However, you should be aware that FDA will redact any information in these records that is exempt from public disclosure.

Finally, reviewing inspection reports, warning letters, and correspondence is a good way to research a private company that your firm may be considering buying, entering into a joint venture with, or using as a subcontractor.

What if an FOIA Request Is Denied?

Although some information may be redacted before documents are released, FDA does in fact approve a majority of FOIA requests. In 2005, the agency denied only 37 out of a total of 17,528 requests; another 39 requests were granted only in part.

Once FDA decides a document should be denied, it is unlikely that it would overturn that position on appeal. However, should you decide to appeal an FOIA denial, you must send the appeal in writing within 60 days of receiving the initial denial letter. FDA recommends that the letter be clearly marked “Freedom of Information Act Appeal” and sent to the FDA's FOIA staff at the aforementioned address. According to the agency, the letter will then be hand-carried to the Deputy Assistant Secretary for Public Affairs (Media), Department of Health and Human Services.

Make sure to write “Freedom of Information Act Appeal” in the text of the letter and on the front of the envelope. It is also important to include in the appeal letter the initial request number and the name of the FOI office staffer who handled the request. No specific language is required to be written in the appeal letter, although you may choose to explain why you believe the document you requested should be released.

Conclusion

Although the FOIA process can at times prove somewhat tricky and time-consuming, the benefits of requesting and receiving unpublished documents are extraordinary. With just a little patience and perseverance, you can open doors of information that could help your company more effectively ensure FDA compliance, create world-class standard operating procedures, or more easily release a new product. This service is open to anyone, anywhere, at any time. Take the initiative and exercise your right to request information under FOIA.

Marlene Bobka is vice president of FOI Services Inc. (Gaithersburg, MD). She can be reached via FOI Service's Web site, www.foiservices.com. Nancy Singer is founder and president of Compliance-Alliance LLC (Arlington, VA). She is available via e-mail at nancy_singer@juno.com.

Copyright ©2007 Medical Device & Diagnostic Industry

Drug-Eluting Stents Come Under Fire

MOVERS AND SHAKERS 2006

Since their introduction to the U.S. market in 2003, drug-eluting stents have been the most lucrative medical device. But that status was threatened in the past year when several studies showed that they are more likely than bare-metal stents to cause blood clots in certain patient populations.

The U.S. Pivotal Study Taxus IV compares Boston Scientific's Taxus bare-metal stent with its Taxus Express paclitaxel-eluting stent nine months after implantation.
Over the summer and fall of 2006, conferences in the cardiovascular world were dominated by drug-eluting stent discussions. The naysayers got so vocal that FDA convened a special meeting of its Circulatory System Devices Panel to look into the safety issues of drug-eluting stents and recommend any actions the agency should take.

The panel determined that when used as approved, drug-eluting stents are safe and effective, and their benefits outweigh their risks. However, at least 60% of the time, they are used off-label, on patients sicker than those who participated in clinical trials. For such real-world patients, there is not enough data to conclusively determine whether drug-eluting stents are too risky for them. (A number of studies on those kinds of patients have commenced within the past year, but results won't be known for a few more years.)

So all the panel could suggest is for doctors to be cautious about using drug-eluting stents on high-risk patients, and to consider prescribing anticlotting drugs for longer than what Johnson & Johnson, maker of the Cypher stent, and Boston Scientific, maker of the Taxus stent, have recommended.

The meeting and the discussions that preceded it are not likely to cause much drop-off in use of drug-eluting stents, as cardiologists are now aware of the issues, experts said.

“I think the benefits outweigh the risks for most situations,” says Neal Kleiman, MD, director of cardiac catheterization at Methodist DeBakey Heart Center (Houston). “The data are pretty good for drug-eluting stents, including safety, though there are still some questions. I don't think FDA needs to do anything different, at least right now.”

But Patrick Driscoll, president of MedMarket Diligence (Foothill Ranch, CA), believes that “FDA is not being as aggressive as it should be. It is too beholden to industry. It takes major events to prompt action from it.”

The U.S. Pivotal Study Sirius compares Cordis's Bx-Velocity bare-metal stent with its Cypher sirolimus-eluting stent. The target end point includes cardiac death, myocardial infarction, and revascularization after nine months of implantation.

Another force at work, he says, is that J&J and Boston Scientific were too slow to acknowledge the problems because “when you invest in a $5-billion market, that gives you a lot of reasons to protect the status quo.” Quicker action may have spared some of the negative publicity and slowed the rate of doctors who decided to go back to using bare-metal stents, he says.

Michael Drues, PhD, president of Vascular Sciences, who has served as a consultant to a number of cardiovascular device companies, says the backlash was fairly predictable.

“I and a small number of other people were talking about these exact issues more than five years ago,” he says. “Nobody [from industry] listened. They continued to line up and drink the Kool-Aid.” His message has been that materials such as metals and polymers are inherently hostile to human cells. He says that device companies need to do a better job of assessing their implantable devices' effect on human biology, and designing around it.

“My biggest concern is that this [backlash] might make it more difficult for future development efforts for combination products, when we'll get to some really advanced stuff,” Drues says.

What is causing the clotting? Nothing has been proven yet. Many have suggested that it may have to do with the polymers on the stent that elute the drug. They remain inside the body after the drug is gone and may not be well tolerated by human cells.

Drues suggests that it may have to do with the drugs. (Cypher elutes sirolimus, a drug developed to help in kidney transplants; Taxus elutes paclitaxel, a drug developed to fight cancer.) “The drugs we are currently using to inhibit restenosis essentially inhibit all cell division,” he says. “The problem is that they are not selective. We want to discourage the production of certain cells, but we also want to encourage endothelial cells to proliferate. They help the body adapt to the stent and have no effect on blood flow.” But inhibiting all cell division and enabling the stent to stay in the middle of the artery may be inhibiting blood flow, he says.

Now that the extent of the problems are known, sales of drug-eluting stents have likely bottomed out and should improve from here, says Thomas Gunderson, senior healthcare analyst for Piper Jaffray & Co. “There will be a gradual increase in the use of drug-eluting stents going forward,” he says. “How much, remains to be seen.”

And, it is hoped, industry will figure out what's causing the problems before the next generation of drug-eluting stents hits the market. It had better, says Gunderson, because “the next generation will be looked at less for effectiveness and more for safety.”

Copyright ©2007 Medical Device & Diagnostic Industry

Effectively Using an FOIA Log

REGULATORY OUTLOOK

If you haven't heard from FDA in a long time and are curious about the status of your request, you may check with FOI office staff or obtain a copy of the FOIA log to see at which FOI office the request is pending. The log, which can be obtained by submitting a separate FOIA request, lists all requests in a particular time period. It also includes specific information, such as the name of the requester, the FDA office the request is assigned to (CDRH, CDER, CBER, etc.), the date the request was received, and the subject of the request.

The log's subject lines can be difficult to read. Some of the information that is provided in the subject lines is cut off because FOI staffers who input the requests run out of room on the electronic forms. In addition, a number of codes that are used can prove confusing because they can't be deciphered easily. Although some of the more common abbreviations include “EIR” (establishment inspection report), “DKT” (docket) and “C/R” (correspondence), there is no hard-and-fast rule for the types of abbreviations that are used in subject lines. In addition, other subject lines may only reference a year and a control number. Those entries represent requests that were submitted in the past. Therefore, for those older FOIA requests, it may be necessary to conduct additional research by reviewing older logs from the year those requests were first submitted to get a more detailed description of the documents that were originally asked for.

Keep in mind that while you will be able to review all of the documents that any competitors are seeking, they will be able to do the same. For example, if you submit an FOIA request asking for all of the 510(k)s that were filed for a particular type of device because your company is considering manufacturing a similar product, a competitor could quickly find that information in the FOIA log and easily discern the nature of the device your company may soon be working on.

Nevertheless, the log can also be helpful in suggesting files you may like to review. By citing a control number of an earlier request, you can submit a follow-on, or piggy-back, request to receive the original request letter and response supplied to a competitor.

Copyright ©2007 Medical Device & Diagnostic Industry

ICDs Become Poster Child for Postmarket Surveillance

MOVERS AND SHAKERS 2006

Implantable cardioverter-defibrillators (ICDs) suffered from a loss of reputation in 2006, but the debate also spurred action from several groups that could change the industry in regard to how manufacturers should handle recalls. The debate rages on, as industry juggles the opinions of the medical community, the government's response, and the need to convince the public that industry is doing everything it can to produce safe and effective devices.

In 2005, serious malfunction issues concerning ICDs from major manufacturers were brought to light, and bad press continued into 2006. “The hypercoverage from the media, in particular the New York Times' stories, has hurt the reputation of all ICDs,” says Thomas Gunderson, senior healthcare analyst for Piper Jaffray & Co. The scandal spurred increased scrutiny from FDA, motivated a response from CMS, and prompted a panel discussion from the Heart Rhythm Society (HRS). The results of those actions are still playing out.

In July 2006, CMS decided to post data on its Web site about ICDs. Those data showed about 4% of patients having at least one complication during an implant. Although those complication rates varied by doctor and hospital, the decision to post such information was understandable given the growing public demand for disclosure about medical procedures. CMS had also released a tentative plan to cut payments for defibrillator implants by one-fifth. Much to the relief of industry, CMS removed that language from its plans in August.

Also in August, HRS released a 24-page report based on the panel discussion. The report detailed a coordinated approach that was widely lauded by industry.

Among other practices, the report advocated using wireless and remote monitoring for identifying abnormal devices automatically, establishing an independent committee of experts to analyze device performance and to recommend appropriate actions, and having device makers communicate directly with patients to notify them of potential malfunctions. The recommendations also stressed the need to provide a standardized format for reporting a pertinent device.

Most notably, the report suggested that FDA stop using the word recall in public communications about problems with heart devices, on the theory that consumers believe that a recalled device must be removed immediately. HRS said that the word tends to cause alarm because it implies that the product is unsafe and the problem is so serious that the product must be fixed or replaced immediately. But as applied to devices, it often just means that the device could fail, and may not imply that it is life-threatening. In non-life-threatening cases, the terms advisory notice or safety alert would be more appropriate, the report stated.

Stories about implantable cardioverter-defibrillators appeared in several major news outlets nearly every month in 2006.

Most of industry agrees. “There is no question the terminology is confusing,” says Larry Pilot, a partner at McKenna, Long & Aldridge LLP (Washington, DC). “The language should be changed.” Pilot explains that in the 1970s, when FDA worked out the current system, the term recall worked fine. “Patients had less information at their fingertips. The first time they would have heard whether anything was wrong, it would be from the doctor, who could explain the significance.”

When FDA released its comments about the HRS report in September, it supported much of what the society said, including the expansion of its cardiac advisory panel's duties into evaluating postmarket safety and effectiveness issues. But it did not say whether it would adjust the recall language.

In November, FDA announced its plan to strengthen device monitoring with the creation of a Postmarket Transformation Leadership Team. The actions included creating internal performance measurements that track how CDRH handles postmarket issues (including recalls), revising adverse-device-event reporting, and increasing the Medical Products Safety Device Network.

The companies involved in the ICD situation have had varied luck recovering from the recalls. An FDA analysis concluded that Guidant ICDs were 10 times more likely to fail than the company had let on. However, a Cleveland Clinic study showed that among patients who had recalled devices in 2005, Guidant's devices did not increase the risk of death, compared with other recalled ICD brands. What it really demonstrates is that Guidant's failure to disclose caused more problems for the company and its patients than the faulty ICDs themselves.

Medtronic issued a safety alert to doctors for 87,000 ICDs in February 2005, saying the devices may have faulty batteries. Pilot says the company may not have even needed to recall the products, under the current FDA definition. “The complications, to my understanding, could not have come out during a normal clinical trial; the flaws could not have been predicted,” he says. “In some ways, a recall is inappropriate because it expresses a violation of action.”

However, Medtronic recently lost a bid in federal court to dismiss the hundreds of lawsuits that resulted.

Although the reputations of both companies have suffered from ICD issues, they have continued to show strong presence in the market, and FDA recently commended Boston Scientific on its efforts to fix Guidant ICDs' problems. “The worst seems to be behind them now, and the upgrades in quality and the increased visibility of the medical community to the data are helping to return a more positive view to ICDs,” says Gunderson.

Moving forward from the recall situation is entirely in the hands of industry, says Pilot. “Trade associations should step forward with a reasonable and responsible approach to changing the language of recalls,” he says. “And device companies need to stop being afraid to defend their products and processes from FDA. If FDA is not challenged, the whole system becomes weaker.”


Copyright ©2007 Medical Device & Diagnostic Industry

Management Software Leads to Better Business Performance, Study Finds

NEWS TRENDS

Less than one-third of medical device companies show their employees results within 24 hours, thus many daily meetings are not looking at recent issues.
(click to enlarge)

A research firm has completed a study that found that medical device companies that have manufacturing execution systems (MESs) are more likely to improve in most financial and business metrics than those that don't.

Industry Directions (Cummaquid, MA) concluded that a plantwide MES improves company performance in a number of ways. An MES gives a firm more data from production to determine how or where to make improvements and replaces less-efficient paper systems. It is also an effective tool for device history record recording and reporting and ensures compliance with best practices. The study was funded by Camstar (Charlotte, NC), an MES provider.

Of the device companies that responded to the survey, one-third had such systems, and all of them had gained market share in recent years. Of the two-thirds that did not have an MES, only one-third had gained market share.

“Medical device manufacturers have an opportunity to grow at a nearly unlimited rate, but most are stymied by a lack of speedy, accurate information from their production processes,” said Julie Fraser, Industry Directions' lead analyst, in a statement. “As a result, the market cap for these companies does not look nearly as healthy as their profit margins suggest they should. Increased investment in plant software systems will be a cornerstone of medical device companies' ability to measure and improve performance as well as grow.”

Firms using an MES also showed greater performance than those that don't in metrics such as earnings before interest, taxes, depreciation and amortization; economic added value; revenue per square foot; yield; overall equipment effectiveness; and overtime reduction.

A major benefit that an MES brings to the table, the report found, is speed. Firms without an MES often cannot determine the key performance indicators of their manufacturing operations within a time frame fast enough to take action. But operations personnel at firms with an MES can see results from key performance indicators fast enough to change course and maximize performance (see figure on page 20).

An MES also improves the speed and accuracy of data collection by automating the process, the study found. In that way, it reduces the opportunity for data-entry error and for word-of-mouth mistakes that are never formally reported and can get repeated.

Copyright ©2007 Medical Device & Diagnostic Industry