Definition of a Guinea Pig: Ask the FDA!

Barely Half of Postmarket Studies Completed After 5 Years

FDA fails to enforce requirements

• by Larry Husten, CardioBrief September 20, 2017 
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Pharmaceutical and device companies are often taking advantage of a lenient (or, some would say, negligent) FDA to shirk their obligation to perform timely post-approval studies, a new Perspective published in the New England Journal of Medicine shows.

The topic has gained increasing  visibility and importance as the FDA has granted approval to many new drugs and devices without all the evidence that might ideally be required.For safety as well as efficacy, the FDA has allowed much of the burden of proof to shift from pre-approval to the post-approval period.

But in an analysis of 614 post-approval requirements and commitments imposed by the FDA in 2009 and 2010 (the first full years after the FDA gained the power to require these studies), Steven Woloshin at Dartmouth Institute for Health Policy and Clinical Practice and colleagues showed that only 54% of these studies were completed after 5-6 years. They found that 20% of "required" studies had not been started and 25% were delayed or ongoing as of September 2015.

"It's not a secret that we need a better post-market system," said former FDA Commissioner Robert Califf, now at Duke University. "The good news is that technology is no longer the limiting factor -- it's all about culture, organization and priority setting by policy makers, clinicians and patients and their 'carers' (families and loved ones)."

The authors observed that in many cases there didn't appear to be any good reason for the delays. For instance, more than 5 years after approval of buprenorphine/naloxone film (Suboxone), no protocol had been submitted for assessing the risk of QT-interval prolongation, "even though the design of such studies is highly standardized and participants are observed for a limited period."

"The slow, irregular pace of post-approval studies contrasts starkly with the short, rigid deadlines and other shortcuts used to speed marketing approval," the authors wrote.

The FDA should "do more to ensure that sponsors meet post-approval deadlines," the authors urged. Although the FDA has the power to impose fines or other penalties on companies that fail to live up to their obligations, "to our knowledge, it has never imposed such fines." They also recommend that the FDA set shorter deadlines for post-approval studies.

"Woloshin and colleagues offer some useful insights into the FDA's use of post-approval studies to confirm and further evaluate drugs' safety and efficacy at the time of approval," said Joe Ross of Yale University. "While more than half were completed, many were not. This study is only made possible by the efforts at FDA to provide public transparency of the post-approval requirements, but more information could help the public and the profession understand why certain requirements were not fulfilled, whether these studies were intended to provide key clinical information to inform practice (as opposed to safety info that instead came from another clinical study), and even for those studies that were completed, whether the results were published and made available."

Sanjay Kaul of Cedars-Sinai Medical Center said that it is not unreasonable to shift "the regulatory burden from the pre-approval phase to a life cycle-based approach. However, the success of such an approach is predicated on a rigorous and timely post-approval phase. That 1 in 5 post approval studies had not even been started after 5 to 6 years calls into question the degree to which the changes in the FDA's regulatory authority in 2007 have resolved the challenge of reducing the number of unfulfilled post-approval requirements. This can hardly be reassuring given the 21st Century Cures Act which calls for faster marketing of drugs and devices at the cost of stringent evidentiary standards! Even though the FDA has congress-legislated authority to revoke approval of drugs and devices that failed to confirm clinical benefit on post approval studies, it rarely does so! It is difficult to put the genie back into the bottle."

The "bottom line," said Kaul, is that "marketing drugs and devices faster can only be justified if there are much better post-market data to reliably support efficacy and safety."

• https://www.medpagetoday.com/cardiology/cardiobrief/68035

Harvard public health expert: Patient Safety Needs Federal Regulation

Like aviation, patient safety needs federal regulation

A new federal agency should be established to oversee patient safety at healthcare facilities to reduce medical errors, Lucian Leape, adjunct professor of health policy at Harvard T.H. Chan School of Public Health, said December 10, 2015 at a National Academy of Medicine symposium on advances and challenges in patient safety and healthcare quality.

The symposium marked the 15th anniversaries of the landmark Institute of Medicine reports To Err Is Human: Building a Safer Health System and Crossing the Quality Chasm: A New Health System for the 21st Century.

“We really ought to have a federal patient safety agency like the Federal Aviation Administration (FAA)” that exists for airplane safety, Leape said in his remarks, according to a December 11, 2015 MedPage Today article. “That’s what we need and we should have said that [in the report], and I’ll say it right now,” said Leape, a member of the committee that created the report. “The thing the FAA does is that it sets standards, enforces standards, and works with industry and makes sure the standards are the right ones and that people are all on board.”

Now, he said, “The only people who pay for medical mistakes are patients. There have to be consequences for the failure to do what we know is the right thing to do. We’ve spent 15 years relying on goodwill and persuasion, but there needs to be an element of discipline.”

Read the MedPage Today article: Expert: More Oversight Needed for Health Facility Safety

http://www.medpagetoday.com/PublicHealthPolicy/HealthPolicy/55192

PUBLIC HEALTH & POLICY 12.11.2015

http://www.hsph.harvard.edu/news/hsph-in-the-news/like-aviation-patient-safety-needs-federal-regulation/?utm_source=Twitter&utm_medium=Social&utm_campaign=Chan-Twitter-General

Expert: More Oversight Needed for Health Facility Safety

Lucian Leape, MD, calls for an 'FAA-like' federal agency

by Joyce Frieden  News Editor, MedPage Today 

WASHINGTON -- The federal government should create a new agency to oversee basic practices at healthcare facilities and cut down on the rate of medical errors, according to Lucian Leape, MD, adjunct professor of health policy emeritus at Harvard School of Public Health, in Boston.

"We really ought to have a federal patient safety agency like the Federal Aviation Administration (FAA)" exists for airplane safety, Leape said Thursday at an event here commemorating the 1999 release of the National Academy of Medicine's landmark report on medical errors, "To Err is Human."

"That's what we need and we should have said that [in the report], and I'll say it right now," said Leape, who served on the committee that developed the report.

"The thing the FAA does is that it sets standards, enforces standards, and works with industry and makes sure the standards are the right ones and that people are all on board," he told MedPage Today.

Leape acknowledged that human beings are more complicated than airplanes, but he added that right now, "The only people who pay for medical mistakes are patients. There have to be consequences for the failure to do what we know is the right thing to do." Examples of the types of standards the agency would enforce include 100% handwashing, flu vaccines for all employees, and no central line infections, Leape said, adding that this would not involve questioning a physician's judgment regarding a specific patient.

Although "carrots," or positive incentives, would be the preferred way to get health facilities to do the right thing, Leape acknowledged that "sticks" might be needed too. "We've spent 15 years relying on goodwill and persuasion, but there needs to be an element of discipline," he said.

Other speakers at the event, which also celebrated the 2001 release of "Crossing the Quality Chasm: A New Health System for the 21st Century," included Dan Ariely, PhD, a professor of psychology and behavioral economics at Duke University in Durham, N.C. Ariely discussed ways to help patients comply more easily with their treatment regimens.

The basic idea, Ariely explained, is that people are more interested in the short term than in the long term, so providers can use that knowledge to motivate people in the short term to do something that will be good for them in the long term. For example, Ariely said, when he was diagnosed with hepatitis C and had to give himself a shot of interferon three times a week as part of a clinical trial, he dreaded doing it because the side effects were extremely unpleasant.

However, he knew that taking the interferon could cure the disease and prevent the need for a liver transplant down the road, so he rewarded himself immediately after each shot with watching a video that he was really looking forward to. "A year and a half later, I was free of hepatitis C. My physician told me I was the only patient in the protocol that took the medication on time," he said.

Another strategy to help with compliance involves "loss aversion" -- the idea that people hate to lose money or something else they value more than they enjoy gaining something, Ariely continued.

In one experiment, "We gave people $3 a day to take their medication on time. What happened? Absolutely nothing," he said. "What if we took away $3 every time they didn't take their medications on time? The [institutional review board] wouldn't let us do that ... but what they allowed us to do is pre-pay people as if they took the medication for 3 months in advance ... and then take the money back, and that worked better."

During a question-and-answer session, Ariely was asked how motivational techniques could be used to help physicians and other providers comply with rules like handwashing. "I don't think it's about small punishments or rewards. These things we need to treat very differently ... they need to be either habitual or ritualistic," he said.

For instance, "Very few physicians don't wash their hands when they go to the OR. But the OR has a tremendous ritualistic element -- the surgeons stand there, people dress them -- there's a whole ceremony around it that's incredibly addictive."

As with the rituals surrounding religion, "It's not just about the action, but providing a higher-order meaning," he said. "A lot of things in medicine should look like that, but if you have 12-minute appointments and lots of paperwork to fill out, it's a little harder to feel a connection to a higher-order meaning."

Audience members also heard from experts in other industries whose structures might also apply to healthcare. For instance, Conrad Grant, head of the air and missile defense department at Johns Hopkins University Applied Physics, Laboratory, in Laurel, Md., compared hospital intensive care units (ICUs) to defensive weapons systems.

"In the ICU [unlike a weapons system], many systems have been designed for individual purposes, and have not been integrated into a coordinated set of systems," he said. "In certain situations, [these systems] may even be working at cross purposes if they are not correctly configured. There are so many straightforward improvements we could make today with an immediate reduction in preventable harm."

Grant gave one example in response to a question about "alarm fatigue" ICU nurses get from having device alarms -- many of them false -- constantly going off. "In weapons systems we also have alarms ... that go off with threats that present themselves or when the conditions of the ship aren't what we want them to be."

"We have carefully tried to engineer that so they're not so repetitive and constant that they become overwhelming," he said. "Part of the way to eliminate alarms is to cross-correlate systems that trigger the alarm ... if you couple it with second sensors that would recognize the same set of conditions and look to see if both of them are showing that same condition before you trigger the alarm, you have some verification."

Public Citizen blasts FDA for weak regulation of implanted surgical mesh.

FDA Wants High-Risk Label forTransvaginal Mesh

Published: Apr 29, 2014

By Charles Bankhead, Staff Writer, MedPage Today, 

Public Health & Policy

FiDA highlight

WASHINGTON -- The FDA has proposed reclassification of surgical mesh for transvaginal repair of pelvic organ prolapse (POP) as a "high-risk device," a designation that mandates an FDA review of safety and effectiveness prior to considering approval.

The agency also wants to reclassify certain instruments used to perform POP repair as "intermediate-risk devices," as opposed to the current low-risk designation.

"The FDA has identified clear risks associated with surgical mesh for the transvaginal repair of pelvic organ prolapse and is now proposing to address those risks for more safe and effective products," William Maisel, MD, of the FDA's Center for Devices and Radiological Health, said in a statement. "If these proposals are finalized, we will require manufacturers to provide premarket clinical data to demonstrate a reasonable assurance of safety and effectiveness for surgical mesh used to treat transvaginal POP repair."

The proposal does not affect surgical mesh used to treat stress urinary incontinence (SUI), abdominal POP repair, hernia repair, and other nonurogynecologic indications. The proposal is subject to a 90-day public-comment period prior to a final decision.

The proposed reclassification follows other FDA actions and statements related to transvaginal POP repair materials going back 6 years:

         October 2008 -- Released a Public Health Notification about serious complications associated with transvaginal placement of surgical mesh for POP and SUI

         July 2011 -- Released an updated safety communication about serious complications associated with transvaginal POP repair with surgical mesh

         July 2011 -- Released a review of urogynecologic surgical mesh adverse events and scientific literature, identifying serious safety and effectiveness concerns

         September 2011 -- FDA's Obstetrics and Gynecology Devices Panel recommended reclassification of surgical mesh for transvaginal POP repair from class II to class III and require premarket approval

         January 2012 -- FDA ordered manufacturers to conduct postmarket surveillance studies to address specific safety and effectiveness concerns about surgical mesh used for transvaginal POP repair

Some materials to repair POP come as kits that include the mesh and instruments used to place, attach, and secure the mesh. Instruments also are sold separately from the mesh, and the FDA proposal to reclassify instruments pertains to the instruments that are not included in kits.

The FDA action represents a case of "too little, too late," according to Michael Carome, director of Public Citizen's Health Research Group, a Washington-based public health advocacy group. Public Citizen has petitioned the FDA to recall all surgical mesh products from the market.

"Today's action comes nearly 3 years after our petition and after an FDA advisory committee recommended such action," Carome said in a statement. "Moreover, the proposed timeline for full implementation of the FDA's order, if finalized, will take several more years.

"As a result of the FDA's reckless delays and inadequate action regarding surgical mesh for transvaginal POP repair, thousands of women will continue to be unnecessarily exposed to a wide array of serious risks, many of which can permanently alter women's quality of life."

Conflict of Intere$t: Medical Leader$ are Conflicted!

Public Health & Policy

Following the Money: Gold in Ivory Towers

Published: Apr 1, 2014

By John Fauber, Reporter, Milwaukee Journal Sentinel/MedPage Today

Academics who moonlight for drug companies have faced intense scrutiny in recent years, but new research suggests much larger sums of money are being paid to their bosses -- the leaders of medical schools and hospitals who serve on drug company boards.

Looking at the world's 50 largest drug companies, researchers found that 40% had at least one board member who held a leadership position at a U.S. academic medical center -- including medical school deans, chief executive officers, department chairs, and university presidents.

The average annual compensation from the drug companies was $313,000, according to the paper published today in the Journal of the American Medical Association.

"These relationships present potentially far-reaching consequences beyond those created when individual physicians consult with industry or receive gifts," the researchers wrote.

Big Jobs, Big Bucks

Others who were not involved in the study said such lucrative moonlighting for drug companies with vested interests simply should not be done by university leaders who oversee independent research and the instruction of medical professionals.

"I don't know how they can manage a conflict like that," said Susan Chimonas, PhD, who frequently writes and lectures on conflicts of interest in medicine. "My gosh, there is so much money they are making for a little side job."

Serving in dual roles raises so many potential conflicts that it would be wiser to eliminate them, said Chimonas, associate director of research for Columbia University's Center on Medicine as a Profession.

Unlike faculty or staff, top leaders of academic medical institutions are involved in business decisions and corporate partnerships, said Paul Levy, the former president and CEO of Beth Israel Deaconess Medical Center in Boston, which is affiliated with Harvard University.

Those decisions and partnerships could include performing clinical trials for drug companies, allowing drug samples to be given out in hospitals and clinics, allowing doctors to engage in drug company promotional speaking, endorsing and offering drug company funded continuing medical education (CME), and deciding what drugs to allow on a hospital's formulary, said Levy, who headed Beth Israel Deaconess from 2002 to 2011.

"You cannot serve two masters, even if you are highly intelligent," said Levy, who now blogs about the health industry and serves as senior adviser at Lax Sebenius, of Concord, Mass. "In fact, if you are highly intelligent, you will rationalize the problems away by saying that you cannot be personally corrupted."

By the Numbers

The JAMA paper did not list individuals, though it did name medical schools, universities, and academic hospitals whose officials served on drug company boards of directors. It also named drug companies, including Pfizer, Merck, GlaxoSmithKline and Johnson & Johnson.

For the study, the researchers only looked at the year 2012.

The Journal Sentinel and MedPage Today used proxy statements filed by the companies to identify some of the board members and find out how much they were paid.

From the Yale School of Medicine in New Haven, Conn., to the David Geffen School of Medicine at UCLA in Los Angeles, the institutions include some of the most prominent academic medical centers in America.

For instance, Robert Alpern, MD, dean of the Yale School of Medicine received $259,000 in total compensation serving on the Abbott Laboratories board of directors in 2013, according to the company's proxy statement.

As of Jan. 1, 2014, he also held 11,656 shares of restricted Abbott stock.

In its proxy, Abbott said Alpern's relationship did not impair his independence.

In an email, Karen Peart, a spokeswoman for Yale, said Alpern would have no role in any of the above decisions such as clinical trials, drug samples or drug formularies.

"If ever he had the opportunity to be involved in a decision affecting Abbott, he would recuse himself," she said.

She said the university encourages its faculty to consult widely and to engage in activities that may benefit the university and the public.

A. Eugene Washington, MD, dean of the UCLA School of Medicine, joined the Johnson & Johnson board of directors in November 2012. In 2013, he was paid $261,000 in total compensation by the company, according to its proxy statement. As of Feb. 25, 2014, he was listed as the beneficial owner of 5,129 shares.

In an email, a spokesman for Washington said UCLA does not allow drug companies to provide samples and prohibits faculty from promoting drugs.

"Dr. Washington manages any potential conflict of interest in accordance with university policies and makes no decisions regarding the purchase of pharmaceutical products or clinical trials," Dale Triber Tate, a UCLA spokesman said.

Mary Sue Coleman, president of the University of Michigan, also serves on the Johnson & Johnson board and was paid $276,000 in total compensation in 2013, according its proxy statement. As of Feb. 25, 2014, she was listed as the beneficial owner of 34,465 shares. That stock was worth nearly $3.4 million at Tuesday's price of about $98 per share.

In an email, Kelly Cunningham, a spokeswoman for the university, said the university already has banned drug company funded doctor education and drug samples from all companies.

She said Coleman is not involved in decisions involving Johnson & Johnson purchases or investments.

"The University of Michigan does not see President Coleman's service on the Johnson & Johnson board as a conflict of interest," Cunningham said.

In its proxy statement, Johnson & Johnson said it sells healthcare products and services to both UCLA and the University of Michigan. It also listed research grants and consulting fees with Michigan. It said neither of its board members from those institutions had any "direct business relationships" with the company.

The company also said its board determined that neither of the relationships conflicted with the interests of the company or impaired "the relevant nonemployee director's independence or judgment."

"It is a potential conflict of interest that is not often discussed," said senior author Walid Gellad, MD, with the VA Pittsburgh Healthcare System and an assistant professor of medicine at the University of Pittsburgh. "If a pen or a $150 dinner presents a conflict for a doctor, what does it mean if you get $300,000?"

Gellad noted that the research only involved drug companies. It did not include medical device companies and health insurance firms.

"I would say this is just the tip of the iceberg," he said.

AAOS conference on joint repair: closed meeting to Consumers

AAOS Opens in NOLA With Joint Repair Topping Agenda

Published: Mar 10, 2014  FiDA highlight

By Sarah Wickline , Staff Writer, MedPage Today

NEW ORLEANS -- An appearance by Louisiana governor Bobby Jindal (R) is among the highlights of this year's annual meeting of the American Academy of Orthopaedic Surgeons, which begins here Tuesday and runs through Saturday.

Jindal will address the meeting on Wednesday. He is a former assistant secretary of the Department of Health and Human Services, as well as former secretary of the Louisiana Department of Health and Hospitals.

AAOS President Joshua J. Jacobs, MD, is also excited about the 825 papers, 569 posters, 217 instructional courses, and more than 88 scientific exhibits being presented at this year's meeting.

Live streaming of 13 symposia via webcasts will be available on demand through March 23.

Featured symposia to catch either in person or via webcast include "Lessons on the Outcomes of ACL Reconstruction Surgery from International Registries," "Tips, Tricks, and Technical Pearls," "Hot Topics and Controversies in Shoulder Surgery," "The Multiple Ligament Injured and Dislocated Knee," and "Complex Skeletal Reconstruction in Infection, Post Trauma, and Tumor."

A last-minute addition to the schedule, the "Health Care Reform: How Can We Adapt?" symposium, will start at 8:00 a.m. on Friday. At the same time, "Can We Improve Surgical Outcomes for Orthopaedic Patients? A Compelling Need for Change," will be moderated by James H. Herndon, MD, of Massachusetts General Hospital in Boston.

There will also be "Ask an Expert" sessions for attendees to pick the brains of leaders in hip and knee, spine, hand and elbow, trauma, shoulder, tumor, foot and ankle, hand, pediatric, and sports medicine orthopedic surgery.

A special electronic skills pavilion will provide attendees with a chance to learn about the latest technology and applications to help further their practice. Several presentations will focus on social media, managing reputations on the Internet, marketing, and privacy in the realm of medical health apps.

The AAOS tradition of hosting a Guest Nation will continue this year, with France as this year's guest.

_______________________________________________________________

Consumers Union media at New Orleans airport baggage claim

Consumers Union Safe Patient Project will be outside the convention to elicit opinions/support of orthopedic surgeons about/for warranty on implanted joint products.  Please text your thoughts to 30644 

________________________________________________________________

The text reads:  The safest, most successful surgeries happen when physicians and patients team up as active partners.  Which means plenty of candid questions and honest answers from each.  Bone up on patient safety at orthoinfo.org/patientsafety.  A public service message from American Academy of Orthopedic Surgeon, who remind patients and doctors that communication is the best medicine.

Patient outcome research needed for heart implant devices!

Big Changes to Heart Devices OK'dWithout New Data

Published: Jan 22, 2014

By Todd Neale, Senior Staff Writer, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania

Action Points

         Many cardiac implantable electronic device models currently used by clinicians were approved via the pre-market approval supplement process, not as original pre-market approvals.

         Most new device models are deemed safe and effective without requiring new clinical data, indicating the importance of post-approval surveillance.

Many of the high-risk implantable cardiac devices in use today were approved through a supplement pathway that does not require new clinical data on the safety and effectiveness of changes made to the products since their original approval, a review of an agency database showed.

From 1979 through 2012, 77 original pre-market approval (PMA) applications -- which required the manufacturers to provide clinical data on the safety and effectiveness of the devices -- were cleared by the FDA, according to Aaron Kesselheim, MD, JD, MPH, of Brigham and Women's Hospital in Boston, and colleagues.

During that same time, however, those original PMAs were subject to 5,829 approved supplement applications, which covered everything from relatively minor changes to labeling, materials, or packaging to substantial design changes, often without the need for additional clinical data, they reported in the Jan. 22/29 issue of the Journal of the American Medical Association.

"It behooves physicians and patients when they're considering a device to understand not only that the device has been FDA approved but to understand the process through which the device was FDA approved and any data that exist about the device," Kesselheim said in an interview.

The FDA uses the PMA process to evaluate new high-risk medical devices, which include pacemakers, implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. But changes to previously approved devices can be introduced using the supplements.

"The benefits [of the supplement pathway] are the more rapid approval and clinical use of new technology," commented Michael Rinaldi, MD, director of clinical research at Carolinas HealthCare System's Sanger Heart & Vascular Institute in Charlotte, N.C., who was not involved in the study. "Requiring a large randomized trial for every proposed iterative device improvement would slow and potentially stop needed improvements in technology."

But it also means that many of the devices clinicians are implanting into patients currently -- which may be substantially different from the device included in the original PMA after numerous small changes -- have not been subject to rigorous clinical testing.

Kesselheim and colleagues noted that the Medtronic Sprint Fidelis and St. Jude Medical Riata ICD leads -- which were recalled in 2007 and 2011, respectively -- were both approved through the supplemental process and were never tested in clinical studies before entering the market.

"The pitfalls [of the supplement pathway] are that it is difficult to know the impact of even seemingly small changes in actual use without clinical data. And as there are usually multiple supplements, many small changes add up," Rita Redberg, MD, of the University of California San Francisco, who co-authored an accompanying editorial, told MedPage Today. "As we learned from the Fidelis and Riata leads, what seems like a good idea may not turn out that way when implanted in patients."

The Study

During the study period, there were original PMAs for 46 pacemakers, 19 ICDs, and 12 CRT devices, according to the FDA's PMA database. But each device was subject to a median of 50 supplements (ranging from 0 to 306) by the end of 2012.

The median period of activity for a PMA -- the time from the original approval of the device to the most recent approved supplement -- was 15 years. And more than three-quarters (79%) of the original PMAs approved during the study had at least one supplement approved in the most recent year of the study period.

"The long active life of ... PMA approvals suggests that minor design changes may accumulate over time and in some cases may add up to substantial changes from the device approved in the original PMA application," the authors wrote.

"To guard against this outcome, the FDA could mandate an expert panel review of each PMA every 5 to 7 years in which it is active to evaluate the extent to which clinical data from older models still apply to newer ones," they suggested. "Another possibility would be more widespread implementation of rigorous post-market studies to evaluate device performance once approved for clinical use."

Risk-Benefit Balance of Supplements

The fact that most supplements are approved without additional clinical testing is not necessarily a bad thing, Kesselheim and colleagues wrote, because preclinical testing can be superior in some cases.

"For example, mechanical testing of ICD leads can simulate years of clinical conditions relatively quickly, and animal studies may allow for repeated induction of arrhythmias that would be impossible in a human model," they wrote. "Thus, our results should not be interpreted to indicate that the FDA is failing to review PMA supplement applications to determine safety and effectiveness."

But, preclinical testing may not uncover all of the problems that will occur when the implants are placed in the human body, Redberg and co-author Steven Goodman, MD, PhD, of Stanford University in Stanford, Calif., noted in their editorial.

"The tricky part is that it is hard to know in advance when changes approved by supplements without clinical data will turn out to be dangerous or even life-threatening in clinical use," Redberg told MedPage Today. "This is a particular issue for implanted devices, as they can be risky to remove. One cannot recall implanted medical devices when they are defective, as one does for a car."

The current study does not provide a way to assess the relative risks and benefits of using the supplement pathway to get modified devices approved for use, according to Rinaldi.

"There are risks in over-regulation by slowing useful and clinically beneficial innovation. There are also risks in under-regulation by not detecting well-intended but ultimately harmful innovation," he said. "While the ICD lead recalls were highly visible and clearly harmful to patients, the real question is: how often did rapid approval lead to harm and how often did it lead to benefit and what was the overall magnitude of the harm and benefit?"

He said that FDA is in a difficult position regarding device approvals.

"If they are too conservative, they will slow the pace of improved care and put the U.S. even farther behind other industrialized countries in terms of access to new technology, and they will be criticized by advocates for rapid innovation," he said. "If they are too liberal, then they are at risk for missing problems and will be pilloried by patient safety advocacy groups."

Rinaldi said he thinks the agency does a reasonable job, pointing out that "for all the device changes reported in the article, very few of them have resulted in harm. While the ICD lead problems are used to illustrate the downside of less strict regulation, no examples are provided of how patients were helped by iterative advances through this process or harmed by lack of access to improvements."

Kesselheim is supported by a Robert Wood Johnson Foundation Investigator Award in Health Policy Research, a Greenwall Faculty Scholarship in Bioethics, and a career development award from the Agency for Healthcare Research and Quality. One of his co-authors was supported by a Harvard Medical School fellowship. Another is the Lois Green Scholar at the Hebrew SeniorLife Institute for Aging Research and is supported by a career development award from the Harvard Catalyst Clinical and Translational Research Center and a Paul B. Beeson career development award in aging.

Kesselheim and one of his co-authors reported previously publishing research funded by the FDA on comparative medical device regulation. That co-author reported serving as a consultant to the FDA's Circulatory Systems Advisory Panel.

Redberg reported being a member of the FDA's Circulatory System Devices Panel and a member of the California Technology Assessment Forum. She is the editor of JAMA Internal Medicine. Goodman did not report any conflicts of interest.

From the American Heart Association:

         Science News: ESC 2013: Intervention & Devices

Primary source: Journal of the American Medical Association
Source reference: Rome B, et al "FDA approval of cardiac implantable electronic devices via original and supplement premarket approval pathways, 1979-2012" JAMA 2014; 311: 385-391.

Additional source: Journal of the American Medical Association
Source reference:Goodman S, Redberg R "Opening the FDA black box" JAMA 2014; 311: 361-363.

http://bit.ly/KMAGKH

Huzzah! Canadian Patient Outcomes Research on Joint Replacement: U.S. PCORI=none?

New Hips More Troublesome in RA ThanOA

 Published: Nov 21, 2013

 By Nancy Walsh, Staff Writer, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania

 Action Points

         Note that this large cohort study of Canadian recipients of hip or knee replacements demonstrated higher complication rates among those with rheumatoid arthritis compared with those with osteoarthritis.

         Be aware that there may be unmeasured confounders that could affect the interpretation of these results -- for example the degree of immunomodulatory therapy received by the RA group.

Patients with rheumatoid arthritis were at higher risk than those with osteoarthritis for adverse outcomes following joint replacement surgery, a Canadian study found.

After adjustment for potential confounders, having a diagnosis of rheumatoid arthritis was a significant and independent predictor of dislocation following total hip arthroplasty, with a risk almost double that for osteoarthritis (HR 1.91, 95% CI 1.29-2.82, P=0.001), according to Bheeshma Ravi, MD, of the University of Toronto, and colleagues.

Patients with rheumatoid arthritis also were at greater risk for developing an infection after total knee arthroplasty (HR 1.52, 95% CI 1.11-2.09, P=0.03), the researchers reported online in Arthritis & Rheumatism.

"Over the last decade, the age-sex standardized rates of total hip arthroplasty and total knee arthroplasty have increased in North America by approximately 25% and 65%, respectively," wrote Ravi and colleagues.

These surgeries have been linked with a risk -- albeit small -- for serious complications including dislocation, infection, venous thromboembolism, and even death.

However, most data on these complications have been drawn from the patient population with osteoarthritis, and little is known about risks for those with rheumatoid arthritis, a much different disease in its causes, prognosis, and treatment.

The researchers previously conducted a systematic review and meta-analysis in an effort to fill this knowledge gap, but were hampered by limitations in many studies such as the possibility of diagnostic misclassification and lack of adjustment for confounders.

Therefore, they undertook a study in which they analyzed data from the Canadian Institute for Health Information Discharge Abstract Database, identifying patients with a primary elective hip or knee replacement between April 2002 and March 2009.

The diagnosis of rheumatoid arthritis was confirmed using an algorithm that necessitated hospitalization with a diagnostic code specifically for rheumatoid arthritis or three physician claims, at least one being from a specialist such as a rheumatologist or orthopedic surgeon, within the previous 2 years.

This validated algorithm has a specificity of 100% and a sensitivity of 78%.

The researchers adjusted for patient age, gender, income, residence, and comorbidities such as congestive heart failure and diabetes.

They also controlled for frailty, which has been linked with loss of muscle strength and immune system abnormalities and therefore could contribute to dislocation and infection.

During the study period, there were 89,713 knee and 60,305 hip arthroplasties performed in Ontario. A total of 3% of the hip replacements and 4% of the knee surgeries were in patients with rheumatoid arthritis.

Compared with recipients with osteoarthritis, those with rheumatoid arthritis were younger, more often women and frail, and had more comorbidities.

They also were more likely to have any type of complication following surgery (5.7% versus 4.7%, P=0.01), but less likely to develop venous thromboembolism (HR 0.35, 95% CI 0.15-0.82, P=0.02).

The lower risk for venous thromboembolism was unexpected, according to the researchers, and may reflect selection bias.

Among all patients experiencing a dislocation within 2 years, the median time to the event was 211 days for rheumatoid arthritis compared with 263 days for osteoarthritis.

And among those who developed articular infections, the median time to the event was 196 days for rheumatoid arthritis compared with 468 days for osteoarthritis.

The researchers noted that dislocation within a short time of total hip arthroplasty is a "serious complication."

"In addition to being very painful and necessitating revision arthroplasty and/or aggressive rehabilitation following closed reduction, it is estimated that dislocations increase the hospital costs of a primary total hip arthroplasty by over 300%," they observed.

Possible reasons why patients with rheumatoid arthritis were more likely to experience this complication were the use of smaller implants and different surgical techniques, along with disease-related factors such as acetabular protrusion and soft tissue problems.

Explanations for why infections were more common in the rheumatoid group included the use of immunomodulatory treatments, but it wasn't clear why the increased risk was only for knee replacement and not also for the hip.

Strengths of the study included the specificity of the algorithm used for diagnosis and large patient population, while limitations were the lack of information about the specific implants used and the possibility of unmeasured confounders.

"As both dislocation and infection lead to significant morbidity and drastically increase healthcare costs, research is warranted to elucidate explanations for this increased risk among patients with rheumatoid arthritis. This information will be valuable to inform patient management decisions, including the development and implementation of strategies designed to target modifiable risk factors," Ravi and colleagues concluded.

The study was supported by the Canadian Institutes of Health Research.

The authors reported no conflicts of interest.

Primary source: Arthritis & Rheumatism
Source reference: Ravi B, et al "Patients with rheumatoid arthritis are at increased risk for complications following total joint arthroplasty" Arthritis Rheum 2013; DOIi: 10.1002/art.38231.