American College of Physicians: Internal Medicine — Doctors for Adults ®

Thursday, July 11, 2013

Why the FDA should lift warnings on Avandia, even if no one will use it

In June the FDA conducted a two-day hearing on Avandia to review of controversial RECORD trial. I have blogged about Avandia extensively. In case you are not up to speed on what's happening, Matthew Herper at Forbes has one of the best summaries I have read called "Battleground FDA: How Tomorrow's Avandia Panel Could Help Shape The Future Of Diabetes."

The FDA's panel eased restrictions on the drug, but few doctors will likely ever prescribe this medication. Since rosiglitazone is off patent, it could be generic, but it is unlikely that any generic company will invest in bringing it to market. For the same reason, it is unlikely the GSK will start marketing the medication again. However, I believe there are important reasons why Avandia should be exonerated, even if few additional patients end up taking it.

1. The un-blinded RECORD analysis is enough reassurance
The re-analysis of RECORD was consistent with the original findings that Avandia did not lead to cardiovascular death or heart attacks. In addition, the Duke group that did the re-analysis did a pretty darn thorough job. Thus, the central issue of the discussion was whether an un-blinded, large randomized trial was enough to prove safety and negate the results of a meta-analysis.

The gold standard for science is the double-blinded, randomized control trial. Double-blinded means that when the researchers are analyzing the data, they don't know which group is the treatment group and which is the control, and patients don't know whether they are taking the experimental drug or a placebo. The reason for blinding is that it reduces potential bias. When patients are enrolled in a study, if they think they are taking a medication that will help them, it will help them, even if the drug is a placebo. The more they think the drug is helping the more it is likely to help.

So, if you did a headache study and gave half the patients Tylenol and half the patients nothing, the patients taking Tylenol would surely do better, but you couldn't prove that Tylenol relieves headaches because your results might have just been due to the placebo effect. In other words, in a study of efficacy, not blinding patients to a treatment may bias a study in favor of that treatment.

In the RECORD study, the investigators were blinded to the results (single blinded), but patients knew whether or not they were taking Avandia. There were several reasons the investigators did this, one being that in Europe (RECORD was an international study), Avandia was not indicated with insulin. However, having open label treatments in RECORD should not affect the results, primarily because record is a safety study. If anything, if you are patient in a safety study and you know you are taking the drug they are studying (must be something wrong with it if they are studying safety), you would be more likely to have adverse events. This is known as the nocebo effect.

It is the reason why if you read the all the information they give you at the pharmacy when picking up a prescription, you are much more likely to think you have one of the millions of side effects listed. In other words, in a study of safety, not blinding patients to a treatment may bias a study in favor of the control. However, in spite of this bias, the RECORD study still showed no harmful effects of Avandia. Thus, if anything, the un-blinded design of the RECORD study should lead the FDA to be even more assured about Avandia's safety.

2. The TZD class is good for treatment of diabetes.
When the Nissen publication was released and the Avandia storm began, patients got worried. Some patients simply stopped taking Avandia altogether, without substitution. Many doctors switched their patients to Actos, the other thiazolidinedione (TZD) available. Merck got lucky and launched Januvia around this time, so when physicians were looking to add a medication to metformin, due to TZD fear, and presumed safety of a new class of medications, they started prescribing Januvia. In other words, while Actos ended up getting most of the TZD scripts, fewer doctors were writing for TZDs.

This is a shame because the TZDs are the only class of medications to show that they keep a diabetic's sugar under control for many years. Older drugs like metformin and sulfonylureas usually fail after three to six years. TZDs also don't cause hypoglycemia. They also have positive benefits on lipids (raising good cholesterol and lower tirglycerides).

The TZDs are not perfect drugs. They increase fluid retention and can lead to congestive heart failure in patients who have decreased heart function. There is a small risk of osteoporosis, and with Actos there may be an increase in bladder cancer. Yet, while not perfect, most of these risks are manageable. Heart attacks are not, and so due the Avandia fiasco, the TZD class is likely underutilized. Pioglitazone is available without restrictions and is now generic. Thus, exoneration of Avandia would likely (and appropriately) increase prescriptions of these medications.

3. Other options may be less safe than once thought.
There are two reasons why in 2010, the FDA chose to severely restrict Avandia. The first was due to concerns of missing data and a non-independent analysis in the RECORD trial (which we now know was unfounded). Second was the notion that Actos seemed just as good as Avandia, but didn't have the risks, and therefore many saw no reason to keep Avandia on the market.

However, what we now know is that Actos may be associated with bladder cancer. (In fact the FDA knew about this in 2010, but brushed it under the rug at the July meeting--see page 213 of the original transcript). While pioglitazone may have a slight edge over rosiglitazone in a number of areas, in patients with a higher risk of bladder cancer (smokers), I might use Avandia over Actos.

Also, the new agents (DPP4s like Januvia and GLP-1s like Victoza) were new at the time. We now know that these agents may have risks of their own including pancreatitis, and the FDA is even looking into pancreatic cancer as highlighted by a recent New York Times article. Now there are pros and cons to all agents. A physician's job is to weigh the risks and benefits of each medication and choose the most appropriate product. However, this is made particularly difficult for diabetes when the specter of heart attack looms over the TZD class. Lifting the heart attack risk from Avandia will truly give diabetics more options (even if they don't take Avandia).

4. Clearing Avandia may help restore public confidence in the FDA, and possibly pharma.
The problem with the whole Avandia fiasco was it decreased the public's confidence in both the FDA and the pharmaceutical industry. The heavily marketed Vioxx was a lesson in caution. However, certain doctors and journalists made a name for themselves looking for the next Vioxx, and Avandia was a great target.

The FDA knew about the risk seen in their own meta-analysis but wisely chose to wait on any restrictions or warnings until other trials, including RECORD, were complete. We now know that this was the correct decision. However, some inside the FDA were not happen with this decision and made sure that the data got to the public. Hysteria ensued.

While industry watchdogs are necessary, they can sometimes to more harm than good. Ask any physician, and they will tell you that, in general, most patients are afraid to take any medications. This was not nearly as true 10 years ago. Today, patients don't trust drug companies or the FDA. The Avandia fiasco played a major role in this. The FDA can now right this wrong.

Matthew Mintz, MD, is a Fellow of the American College of Physicians. He is board certified in internal medicine and has been practicing for more than a decade. He is also an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients. This post originally appeared at Dr. Mintz' Blog. Conflict-of-interest disclosures are available here.

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Members of the American College of Physicians contribute posts from their own sites to ACP Internistand ACP Hospitalist. Contributors include:

Albert Fuchs, MD
Albert Fuchs, MD, FACP, graduated from the University of California, Los Angeles School of Medicine, where he also did his internal medicine training. Certified by the American Board of Internal Medicine, Dr. Fuchs spent three years as a full-time faculty member at UCLA School of Medicine before opening his private practice in Beverly Hills in 2000.

And Thus, It Begins
Amanda Xi, ACP Medical Student Member, is a first-year medical student at the OUWB School of Medicine, charter class of 2015, in Rochester, Mich., from which she which chronicles her journey through medical training from day 1 of medical school.

Ira S. Nash, MD, FACP, is the senior vice president and executive director of the North Shore-LIJ Medical Group, and a professor of Cardiology and Population Health at Hofstra North Shore-LIJ School of Medicine. He is Board Certified in Internal Medicine and Cardiovascular Diseases and was in the private practice of cardiology before joining the full-time faculty of Massachusetts General Hospital.

Zackary Berger
Zackary Berger, MD, ACP Member, is a primary care doctor and general internist in the Division of General Internal Medicine at Johns Hopkins. His research interests include doctor-patient communication, bioethics, and systematic reviews.

Controversies in Hospital Infection Prevention
Run by three ACP Fellows, this blog ponders vexing issues in infection prevention and control, inside and outside the hospital. Daniel J Diekema, MD, FACP, practices infectious diseases, clinical microbiology, and hospital epidemiology in Iowa City, Iowa, splitting time between seeing patients with infectious diseases, diagnosing infections in the microbiology laboratory, and trying to prevent infections in the hospital. Michael B. Edmond, MD, FACP, is a hospital epidemiologist in Iowa City, IA, with a focus on understanding why infections occur in the hospital and ways to prevent these infections, and sees patients in the inpatient and outpatient settings. Eli N. Perencevich, MD, ACP Member, is an infectious disease physician and epidemiologist in Iowa City, Iowa, who studies methods to halt the spread of resistant bacteria in our hospitals (including novel ways to get everyone to wash their hands).

db's Medical Rants
Robert M. Centor, MD, FACP, contributes short essays contemplating medicine and the health care system.

Suneel Dhand, MD, ACP Member
Suneel Dhand, MD, ACP Member, is a practicing physician in Massachusetts. He has published numerous articles in clinical medicine, covering a wide range of specialty areas including; pulmonology, cardiology, endocrinology, hematology, and infectious disease. He has also authored chapters in the prestigious "5-Minute Clinical Consult" medical textbook. His other clinical interests include quality improvement, hospital safety, hospital utilization, and the use of technology in health care.

Juliet K. Mavromatis, MD, FACP, provides a conversation about health topics for patients and health professionals.

Dr. Mintz' Blog
Matthew Mintz, MD, FACP, has practiced internal medicine for more than a decade and is an Associate Professor of Medicine at an academic medical center on the East Coast. His time is split between teaching medical students and residents, and caring for patients.

Everything Health
Toni Brayer, MD, FACP, blogs about the rapid changes in science, medicine, health and healing in the 21st century.

Vineet Arora, MD, FACP, is Associate Program Director for the Internal Medicine Residency and Assistant Dean of Scholarship & Discovery at the Pritzker School of Medicine for the University of Chicago. Her education and research focus is on resident duty hours, patient handoffs, medical professionalism, and quality of hospital care. She is also an academic hospitalist.

Glass Hospital
John H. Schumann, MD, FACP, provides transparency on the workings of medical practice and the complexities of hospital care, illuminates the emotional and cognitive aspects of caregiving and decision-making from the perspective of an active primary care physician, and offers behind-the-scenes portraits of hospital sanctums and the people who inhabit them.

Gut Check
Ryan Madanick, MD, ACP Member, is a gastroenterologist at the University of North Carolina School of Medicine, and the Program Director for the GI & Hepatology Fellowship Program. He specializes in diseases of the esophagus, with a strong interest in the diagnosis and treatment of patients who have difficult-to-manage esophageal problems such as refractory GERD, heartburn, and chest pain.

I'm dok
Mike Aref, MD, PhD, FACP, is an academic hospitalist with an interest in basic and clinical science and education, with interests in noninvasive monitoring and diagnostic testing using novel bedside imaging modalities, diagnostic reasoning, medical informatics, new medical education modalities, pre-code/code management, palliative care, patient-physician communication, quality improvement, and quantitative biomedical imaging.

Informatics Professor
William Hersh, MD, FACP, Professor and Chair, Department of Medical Informatics & Clinical Epidemiology, Oregon Health & Science University, posts his thoughts on various topics related to biomedical and health informatics.

David Katz, MD
David L. Katz, MD, MPH, FACP, is an internationally renowned authority on nutrition, weight management, and the prevention of chronic disease, and an internationally recognized leader in integrative medicine and patient-centered care.

Just Oncology
Richard Just, MD, ACP Member, has 36 years in clinical practice of hematology and medical oncology. His blog is a joint publication with Gregg Masters, MPH.

Kevin Pho, MD, ACP Member, offers one of the Web's definitive sites for influential health commentary.

MD Whistleblower
Michael Kirsch, MD, FACP, addresses the joys and challenges of medical practice, including controversies in the doctor-patient relationship, medical ethics and measuring medical quality. When he's not writing, he's performing colonoscopies.

Medical Lessons
Elaine Schattner, MD, FACP, shares her ideas on education, ethics in medicine, health care news and culture. Her views on medicine are informed by her past experiences in caring for patients, as a researcher in cancer immunology, and as a patient who's had breast cancer.

Mired in MedEd
Alexander M. Djuricich, MD, FACP, is the Associate Dean for Continuing Medical Education (CME), and a Program Director in Medicine-Pediatrics at the Indiana University School of Medicine in Indianapolis, where he blogs about medical education.

More Musings
Rob Lamberts, MD, ACP Member, a med-peds and general practice internist, returns with "volume 2" of his personal musings about medicine, life, armadillos and Sasquatch at More Musings (of a Distractible Kind).

David M. Sack, MD, FACP, practices general gastroenterology at a small community hospital in Connecticut. His blog is a series of musings on medicine, medical care, the health care system and medical ethics, in no particular order.

Reflections of a Grady Doctor
Kimberly Manning, MD, FACP, reflects on the personal side of being a doctor in a community hospital in Atlanta.

The Blog of Paul Sufka
Paul Sufka, MD, ACP Member, is a board certified rheumatologist in St. Paul, Minn. He was a chief resident in internal medicine with the University of Minnesota and then completed his fellowship training in rheumatology in June 2011 at the University of Minnesota Department of Rheumatology. His interests include the use of technology in medicine.

Technology in (Medical) Education
Neil Mehta, MBBS, MS, FACP, is interested in use of technology in education, social media and networking, practice management and evidence-based medicine tools, personal information and knowledge management.

Peter A. Lipson, MD
Peter A. Lipson, MD, ACP Member, is a practicing internist and teaching physician in Southeast Michigan. The blog, which has been around in various forms since 2007, offers musings on the intersection of science, medicine, and culture.

Why is American Health Care So Expensive?
Janice Boughton, MD, FACP, practiced internal medicine for 20 years before adopting a career in hospital and primary care medicine as a locum tenens physician. She lives in Idaho when not traveling.

World's Best Site
Daniel Ginsberg, MD, FACP, is an internal medicine physician who has avidly applied computers to medicine since 1986, when he first wrote medically oriented computer programs. He is in practice in Tacoma, Washington.

Other blogs of note:

American Journal of Medicine
Also known as the Green Journal, the American Journal of Medicine publishes original clinical articles of interest to physicians in internal medicine and its subspecialities, both in academia and community-based practice.

Clinical Correlations
A collaborative medical blog started by Neil Shapiro, MD, ACP Member, associate program director at New York University Medical Center's internal medicine residency program. Faculty, residents and students contribute case studies, mystery quizzes, news, commentary and more.

Interact MD
Michael Benjamin, MD, ACP member, doesn't accept industry money so he can create an independent, clinician-reviewed space on the Internet for physicians to report and comment on the medical news of the day.

PLoS Blog
The Public Library of Science's open access materials include a blog.

White Coat Rants
One of the most popular anonymous blogs written by an emergency room physician.

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