Category Archives: Drug And Device Safety

Pain Medicine Rocked by Perception of Conflicts

Controversy around payments to physicians from companies that make pharmaceuticals and medical devices has been much in the news lately, especially related to pain medicine.

ProPublica reported on deep ties between two physician leaders in pain treatment and the pharmaceutical industry. A nifty page created by ProPublica lets viewers search for their physician’s name in the database of payments reported by industry.

The Milwaukee-Wisconsin Journal Sentinel reported that the steep increase in use of pain medications in recent years is paralleled – and their headline says “fueled” – by a network of physicians, researchers and organizations pushing for greater access to narcotics while taking money from drug companies. They published a nifty graphic and a case study to help make the case.

Most recently, the New Haven (Conn.) Independent reported that a dozen doctors in the state continued to receive money or gifts from drug companies while being sanctioned by the state for prescription-related offenses.

Dr. Jerome Schofferman (SHERRY BOSCHERT/IMNG Medical Media)

At the annual meeting of the American Academy of Pain Medicine, I asked one of the speakers at a session on ethics to comment on all this. Dr. Jerome Schofferman said he is not a trained bioethicist but he follows ethics with a passion. How passionate is he? Dr. Schofferman refused to wear the lanyard that all attendees received in their registration package because it had a company’s name on it. (A lanyard is the ribbon that clips onto the name badge, to be worn around the neck.) He brought his own lanyard.

Part of the problem, he said, is that drug companies develop a lot of “me-too” drugs that work like other available drugs, then avoid doing head-to-head comparisons so that no one can say their drug isn’t as good as another, and pour their resources into marketing their drug to boost sales.

“There’s no doubt that these drugs are overmarketed and probably overprescribed, but they work for a lot of people,” so we need to keep the potential benefits in mind in all of this too, he said.

Relationships between industry and physicians or patient advocacy organizations can be a mutually beneficial thing and aren’t inherently bad, but the lack of full and up-front disclosure of the relationships gives the impression that something’s not right and prevents people from making informed judgements, he said.

In the articles on industry and pain medicine, “No one has ever really shown in this context that this is bad. It’s just the perception is that it can’t be good. It can be good if the American Pain Foundation accomplishes a lot of good things,” Dr. Schofferman said. Too many groups and physicians hide their industry connections instead of making them easy to find. “If there had always been disclosure at the top of their Web site or their publications, a lot of this wouldn’t come up. It wouldn’t be a story, and it wouldn’t have that oomph factor,” he added.

In his talk at the meeting, though, Dr. Schofferman was a bit stricter than in our interview, arguing that disclosures alone are not enough.

He cited an article by social scientists suggesting that 61% of physicians say that conflicts of interest do not influence their decisions, but 84% of physicians admit that conflicts of interest might compromise other physicians (JAMA 2003;290:252-255). Bias and influence are neurobiological social processes that can alter behavior in unconscious ways, he explained. People may want and choose to behave ethically but still be influenced by economic factors because human nature inherently reverts to reciprocity and self-interest, functional MRI studies suggest.

Dr. Schofferman suggested several ways to personally minimize industry influence:

Dr. Jerome Schofferman (SHERRY BOSCHERT/IMNG Medical Media)

1) Don’t be in a company’s speakers bureau. These are “marketing by proxy,” he said.

2) Don’t attend industry-sponsored satellite sessions or marketing dinners at meetings. Get your medical education from accredited sources.

3) If you’re an educator, divorce yourself from industry, or at least provide full disclosure including dollar amounts of anything you receive.

4) Don’t be an industry “advisor” or “consultant” unless you truly are a thought leader and innovator with specialized skills, knowledge, or experience that you bring to the relationship. Spell out that relationship in a written contract describing details of the work product to be delivered and a timeline for delivery. Charge only fair market value for your time and expertise.

5) If you are an industry speaker, advisor or consultant, do not seek leadership positions in professional medical associations.

6) Professional medical organizations and conferences should limit industry participation to ads in journals and to exhibit halls (“But don’t put food in there!”), and stop splashing corporate logos on everything, such as lanyards. “We’re like NASCAR drivers” at these meetings, Dr. Schofferman complained.

Starting in September 2013, industry payments and gifts to physicians will be posted online under the Physician Payment Sunshine Act.

–Sherry Boschert (@sherryboschert on Twitter)

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Recycle to Reduce Drug Overdoses

Recycling and prescription drug overdoses have something in common.

Recycling has become second nature in many parts of America. Bins and containers to collect excess paper, bottles and cans are ubiquitous. Yet, only a few a few decades ago, recycling seemed foreign, was not convenient, and took some effort and resolve on an individual’s part.

Keith N. Humphreys, Ph.D. (Sherry Boschert/Elsevier Global Medical News)

That same evolution has to happen in the way that we handle leftover medications, Keith N. Humphreys, Ph.D., told physicians at the American Academy of Pain Medicine annual meeting. There’s an epidemic of opioid overdose deaths in the United States, and the most common source of misused opioids is leftover medications obtained from friends and family.

He’s talking about a huge cultural shift – with consumers going from saving and sharing costly medications that can be hard to come by in the current health system to recognizing their potential for harm and routinely returning leftover drugs on “take-back days” organized by law enforcement or even depositing them in specialized “recycling” bins.

The number of opioid prescriptions dispensed by U.S. retail pharmacies increased from 76 million in 1991 to 210 million in 2010, according to a report by the National Institute on Drug Abuse. And since 1990, the rate of drug overdoses has tripled, increasing approximately from 4 per 100,000 people to 12 per 100,000 people, the Centers for Disease Control and Prevention report.

As someone who worked in hospices for a decade, Dr. Humphries knows the valuable role that opioids can play in relieving pain. So, how do we make opioids available but reduce the risk of addiction, abuse and accidental overdose?

There is no policy framework that will eliminate the tension between these two goals, but some policies will help avoid it, said Dr. Humphreys, acting director of the Center for Health Care Evaluation, Veterans Health Administration, Menlo Park, Calif., and a professor of psychiatry at Stanford University. He recently served as senior policy adviser at the White House Office of National Drug Control Policy, and  reports having no financial conflicts of interest on this issue.

Here, he said, are five emerging public policies, codes of practice, and cultural norms that “most people can agree on” while working toward harder-to-implement options like expanding addiction treatment programs:

1) Build prescription monitoring programs (PMPs). The idea is that physicians could check to see if a patient has received another opioid prescription recently before handing over a new prescription, to prevent drug-seeking patients from “doctor-shopping” to get more opioids. Thirty-six states have PMPs, though most are early versions that are slow, clunky and virtually worthless. Fourteen states and the District of Columbia have enacted legislation to create PMPs, and two states have no PMP plans.

PMPs “may be resisted and resented by many professionals, but they’re inevitable” and deserve support to quickly improve, Dr. Humphreys said. Plus, there’s a bonus for prescribers: In some states, checking with the PMP before prescribing an opioid gives physicians presumptive immunity from legal liability.

2) Lock doctor shoppers into one prescriber. Every week, a West Virginian dies of a drug overdose while holding prescriptions from five or more health care providers. Public and private insurers could tell patients who have opioid prescriptions from multiple providers that they must get all prescriptions from a single provider if they want their insurance to cover costs.

Recycling bins at the Palm Springs (Calif.) Convention Center, where the AAPM met. (Sherry Boschert/Elsevier Global Medical News)

3) Make prescription “recycling” a cultural norm. Legally, opioid narcotics can be returned to any Drug Enforcement Agency law enforcer, though some states also allow pharmacies to take back leftover drugs. When sheriffs in one small Arkansas town (population 20,000) organized a drug take-back day, residents brought in 25,000 pills, Dr. Humphreys said. A physician at the meeting from Santa Maria, Calif., said a drug take-back day organized by sheriffs there was so successful that they installed a permanent drop-off box outside the sheriff’s office. Dr. Humphreys urged physicians to promote drug take-back days in their communities.

4) Make abuse-resistant medication approvals easier. Currently, developing an abuse-resistant version of an addictive medication requires a new drug application, engendering a lengthy approval process and potentially hundreds of millions of dollars in costs. Government regulators should find a way to ease this massive disincentive for pharmaceutical companies to develop safer pain medicines, he said.

5) Change opioid-related medical practice. A potpourri of short- and long-term strategies could improve practice, he suggested. Patients should be told that sharing opioids is dangerous and illegal. Both patients and physicians need to learn that opioids are not the only response to pain. Emergency physicians should break their habit of automatically writing prescriptions for 30 days’ worth of a drug, and write for shorter time lengths when appropriate. Health care workers need to get better at recognizing addiction, and more attention should go toward ways of preventing “iatrogenic” addiction caused by the health care system itself.

Physicians need to lead the way in these efforts. “Who else?” he asked.

–Sherry Boschert (@sherryboschert on Twitter)

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H5N1 Flu Moratorium: A Pause that Refreshes?

The announcement last Friday of a 60-day moratorium on H5N1 research underscored the controversy swirling around this work.

The moratorium statement, coauthored by the lead pair of airborne H5N1 flu researchers and 37 other influenza researchers from around the world, also highlighted the degree to which these scientists stand behind the importance and safety of airborne H5N1 research.

image courtesy Wikimedia Commons

 

The statement, published online on Jan. 20 in Science and in Nature, received bylined support from an international group of flu researchers from the United States, the Netherlands, United Kingdom, Japan, China, Canada, Germany, and Italy, including staffers from the Centers for Disease Control and Prevention and the National Institutes of Health.

They said that the airborne H5N1 avian flu research, which first became public knowledge a month ago, “is critical information that advances our understanding of influenza transmission. However, more research is needed to determine how influenza viruses in nature become human pandemic threats, so that they can be contained before they acquire the ability to transmit from human to human, or so that appropriate countermeasures can be deployed if adaptation to humans occurs.”

The authors acknowledged the “perceived fear” about possible escape of the ferret transmissible H5N1 that labs in Rotterdam and Madison, Wisc., created, and they reaffirmed that “these experiments have been conducted with appropriate regulatory oversight in secure containment facilities by highly trained and responsible personnel to minimize any risk of accidental release.”

Finally, the moratorium group explained what they hoped to achieve with their 60-day pause: “We recognize that we and the rest of the scientific community need to clearly explain the benefits of this important research and the measures taken to minimize its possible risks. We propose to do that in an international forum in which the scientific community comes together to discuss and debate these issues.”

An interview that also ran in Science on Friday with Ron Fouchier, the Rotterdam virologist who leads one of these H5N1 studies, quoted him as saying that an international forum will be organized in the next couple of weeks, and that he hopes it will include representatives from the World Health Organization and the U.S. government. In the interview with Martin Enserink, Fouchier said that the idea for the moratorium began with himself, Yoshihiro Kawaoka, who independently also produced an air-transmissible H5N1 strain in ferrets, and Adolfo Garcia-Sastre, a flu researcher at Mount Sinai Medical Center in New York.

Fouchier also drew the inevitable comparison between this moratorium and the one called by recombinant DNA researchers prior to their historic 1975 meeting at the Asilomar Conference Center in California.

What seems most notable about the moratorium statement is the number and diversity of the signatories, and their willingness to stand fully behind this work despite the criticisms leveled against it over the past month. The upcoming public forum is something to look forward to.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Can Pill Color Prompt a “Nocebo” Response?

What’s the opposite of a placebo? An active drug, of course. But what’s the opposite of a placebo response? That would be a “nocebo” response, in which placebos produce adverse side effects.
 
“It’s somewhat hypothetical, but you can imagine that if somebody feels they will get better, they will get better, and if they feel that they’re taking something that’s not good for them, they might get worse,” according to Dr. Allan Krumholz, professor of neurology and director of the Maryland Epilepsy Center, Baltimore.

Image courtesy of Dr. Tricia Y. Ting

Pill color and appearance have been identified as a potential source of “nocebo” response, and differences in appearance between brand-name and generic drugs have been postulated to explain why some patients experience increased adverse events when they switch from brand-name to generics.

In response to this growing concern, in August 2010 the Food and Drug Administration solicited proposals for bioequivalence studies of the impact of switching from brand-name antiepileptic drug lamotrigine (Lamictal) to generic among patients with epilepsy in the outpatient setting.

This is a new way of conducting such trials. “Pharmacokinetics trials across all areas of medicine have traditionally been highly controlled single-dose studies in healthy volunteers dosed in the laboratory setting,” said lead investigator Dr. Tricia Y. Ting, a neurologist who works with Dr. Krumholz at the UMD epilepsy center.

Because the brand-name Lamictal and its generic counterparts look very different, the investigators decided to over-encapsulate the pills with identical coverings in order to “blind” the patients to which formulation they were taking.

But in order to do that, they first needed to determine whether the color of the pill would impact the patients’ perception of safety and efficacy. A group of 80 adult epilepsy patients were shown standard AA size capsules in five “global colors” (white, yellow, gray, caramel, maroon) and asked to select any color(s) considered “unacceptable” and to rank their preferences.

More patients deemed gray, caramel and maroon colors “unacceptable” (21%, 19%, and 20%, respectively) compared with the white and yellow (5% and 4%, respectively). There was a clear preference for white and yellow pills over the other, darker colors, without much difference between white and yellow.

But, there were patients who selected maroon as their “preferred” color. “Some people didn’t have any preference. Some had a very strong preference. One patient, an artist, liked the darker colors. It was different for different people,” noted Dr. Karen M. Aquino, a neurology fellow who worked on the nocebo study.

So what pill color will the bioequivalence study use? “To optimize drug adherence, white colored capsules will be used for over-encapsulation,” Dr. Ting wrote in her poster, which was presented at the American Epilepsy Society’s annual meeting in Baltimore. Dr. Krumholz and Dr. Aquino presented the pill color preference data in a separate poster at the meeting. The bioequivalence results are expected in 2013.

-Miriam E. Tucker (@MiriamETucker on Twitter)

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Is Abstinence Contraception?

For many women, abstinence is a reliable way to prevent unwanted pregnancy. But is it a valid form of contraception for young women who are taking the powerful teratogenic drug isotretinoin?

Courtesy Wikimedia Commons user Diacritica

Advisers to the Food and Drug Administration danced around that topic at a meeting examining whether the risk management program for isotretinoin — called iPLEDGE — was effectively reducing the number of pregnancies in women of child-bearing age who take the drug.

Isotretinoin is indicated for a severe, scarring form of acne, but is used off-label for other types of acne, as well.

iPLEDGE began in 2006. As part of the program, young women who are capable of getting pregnant are required to have monthly pregnancy tests during their course of treatment, and to use two methods of birth control. But it’s left up to the women to decide what they will use. According to data submitted to the FDA by isotretinoin maker Mylan Pharmaceuticals, after birth control pills, abstinence was the top choice for all women as a primary method of birth control.

About 13% of women who became pregnant on the program were using abstinence as their primary method, with no back-up contraception. Twenty-five percent of women in the program who were not pregnant used abstinence and no back-up, and another 10% used abstinence as their primary method, with oral contraceptives as the secondary method.

Among isotretinoin-using pre-teen and teenaged girls, abstinence was listed as the primary method. It was the second most popular contraceptive technique for 20- to 29-year-olds.

Mylan reported that there have been 836 pregnancies in the 5 years since iPLEDGE began. Four hundred women chose to end their pregnancies, possibly because of the risk of birth defects. The company does not know the outcomes in 282 of the pregnancies. There were 45 live births; of those there were 8 children born with congenital anomalies.

Pregnancies are declining, though, as reported in our news coverage of the meeting. But even Mylan said in its background materials that, “the most common reason for iPLEDGE pregnancy as reported by the prescriber and the patient, was failure to comply with the iPLEDGE contraceptive requirements (e.g., did not use two forms of birth control, did not use contraception on the date of conception, unsuccessful at abstinence).”

How many pregnancies could be avoided with more specific education for prescribers and for young women about which birth control methods are the most effective?

The FDA advisers heard from Dr. Eleanor B. Schwarz, a University of Pittsburgh ob.gyn., who pleaded for the iPLEDGE program to make a strong recommendation for young women to use IUDs or contraceptive implants.

Some members of the advisory committees agreed that perhaps it was time to provide a more comprehensive guide to the effectiveness of various contraceptive techniques.

FDA officials were largely silent on that matter. And it’s hard to imagine them — or the isotretinoin makers — weighing in on such a dicey topic as which birth control method young women should be using.

What do you think? Should the iPLEDGE program be giving young women more evidence-based information about contraceptives?

—Alicia Ault (@aliciaault on Twitter)

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Approved or not Approved? That is a Good Question.

In a move last month that apparently took at least two device manufacturers completely by surprise, one center of the Food and Drug Administration recommended against an intended use of their products, despite the products’ approval and licensure by another FDA center.

PharmaJet's Stratis is used to vaccinate a Cambodian child against measles. Photo courtesy of Heather Potters.

Recent jet injector models, including Bioject’s ZetaJet and Biojector 2000 and PharmaJet’s Stratis, were approved and licensed by the FDA’s Center for Devices and Radiological Health (CDRH) as needle-free alternatives for injecting vaccines and injectable medications. Both companies had been marketing their devices for influenza immunization in the current flu season.

On October 26th, the FDA’s Center for Biologics Evaluation and Research (CBER) issued a notice  advising healthcare professionals that inactivated influenza vaccines should be administered only with a sterile needle and syringe. The reason: “Safety and effectiveness information that would support labeling inactivated influenza vaccines for delivery by jet injector have not been submitted to FDA.” However, CBER said, individuals who have already received a flu vaccine with a jet injector do not need to be revaccinated.

Currently, only the measles-mumps-rubella vaccine is approved and specifically labeled for administration by jet injector.

So what’s the concern with influenza vaccine? “A jet injector subjects the vaccine to a different pressure than it would receive during administration by sterile needle and syringe and as a result the effectiveness and the safety profile of the injected vaccine may be altered,” according to the CBER document.

Evidently this information had not been previously communicated to the manufacturers. “We were provided no notice by FDA of any concerns about Jet Injectors or FDA’s statement. To our knowledge, no other needle-free injection manufacturer received notice or an opportunity to discuss this matter with FDA,” PharmaJet said in a statement.

Bioject’s President and CEO Ralph Makar was similarly taken aback by the FDA notice. “The FDA communication on the use of jet injectors with influenza vaccines was surprising given that Bioject’s Needle-Free Injection Devices…are both FDA 510(k) cleared with indications for use that describe their use in delivery of subcutaneous or intramuscular injections of vaccines and other injectable drugs,” he said in a statement.

In a public comment at the October meeting of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices, PharmaJet Inc’s chairman Heather Potters said, “Last year we scaled up to provide several hundred thousand syringes, and this season we were expecting to sell several million. Now, our domestic sales have virtually stopped, except for [investigational trials].”

The companies are expected to meet with the FDA in early January to work this out. According to Mr. Makar, “We are looking into the matter to better understand the situation and the FDA’s concerns. A number of Bioject’s Needle-Free Injection devices have been on the market for many years and we are committed to resolving this matter with the FDA in a timely manner.”

-Miriam E. Tucker (@MiriamETucker on Twitter)

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TAVI Trek Begins

It took just two days after the Nov. 2 FDA approval of the Edwards SAPIEN transcatheter aortic valve for New York-Presbyterian Hospital/Columbia University Medical Center to claim bragging rights as the first center in the United States to implant the device as an FDA-approved standard of care.

The center will be one of four sites to train U.S. doctors in the procedure, and is promising to lead a live demonstration tomorrow (Nov. 9) at the annual Transcatheter Cardiovascular Therapeutics symposium in San Francisco for those eager to get a front row view of transcatheter aortic valve implantation (TAVI).

Courtesy Edwards Lifesciences

The FDA approval also put the U.S. in the rare position of following the footsteps of some 40 countries that have already approved the SAPIEN valve including Latvia, Iran, and Russia. This fact elicited a good laugh at the recent Heart Valve Summit 2011 in Chicago, but also prompted much dialogue about some of the thorny ethical and economical consequences that still lay ahead.

“Is anyone at the government talking about rationing of care?” asked Dr. Stephen Strelec, an anesthesiologist at University of Pennsylvania Medical Center, at the summit. It’s not just the 92-year-old who says “I want to live,” but the younger patient facing a valve procedure who decides they don’t want to be on anticoagulants and undergo surgery because they can afford this expensive new transcatheter valve in 2 years. “There’s an economic consequence to that decision as well,” he said.

Dr. Robert Bonow, director of the center for cardiovascular innovation at Northwestern, said the issue is being looked at by federal agencies and insurers, but added that it is “one of the biggest hot-button items about this whole technology because it’s not going to be cheap.”

Dr. David Adams, chair of cardiothoracic surgery at Mount Sinai Medical Center, said they’ve already had their share of 90-year-olds wheeled in from the nursing home by family members who read about TAVI in the newspaper and want mom to stay alive.

The suggestion was made that surgeons and interventional cardiologists will have to hone their skills in making the very specific diagnosis of medical futility, and that a board-certified palliative care physician will be one of the most valuable members of the multidisciplinary teams treating these patients.

“Every PARTNER site looking back over their patients can name patients that they wish they didn’t enroll in the trial and done the valve on,” said Dr. Howard Herrmann, director of interventional cardiology and cardiac catheterization at the Hospital of the University of Pennsylvania. “The question is how to recognize them up front.”

Edwards Lifesciences and the FDA are setting up an intensive training program with simulations, an expert review of cases and a proctoring system. Still, the challenge for Edwards and other companies that will follow will be enormous in terms of launching this technology outside the clinical trial setting, said Dr. Adams, co-principal investigator of Medtronic’s CoreValve trial.

“You can not overestimate the amount of company support you’re going to need to do these things safely,” he said. “This is not a new widget you can pick up in one or two tries like a new ring or new stent…It’s a whole new process.”

The European experience, albeit the initial experience, suggests there’s a distinct learning curve to TAVI. A meta-analysis of 12 TAVI trials presented at this summer’s European Society of Cardiology Congress, reported a flattening of mortality curves 8 years after the first human case in 2002, with procedural mortality decreasing from 16.7% in 2004 to 0.0-0.6% in 2010 and 30-day mortality plummeting from 67% to 11% over the same time period. The authors, led by Dr. Pablo Salinas, University Hospital La Paz, Madrid, credit technical improvements in the devices, better patient selection and on-site case proctoring as helping to shorten the learning curve.

—by Patrice Wendling

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