Why the FDA Should Lift Warnings on Avandia, Even if No One Will Use It

Today was day #1 of the FDA's two day hearing on Avandia. The reason for the meeting is a review of the 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 decision by tomorrow's FDA advisory committee could range from lifting restrictions, to removing Avandia from the market entirely, to doing absolutely nothing.  And regardless of their recommendation, the FDA may do something different.  However, even if Avandia is cleared of all harm, and restored as a safe product in the eyes of the FDA, 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
What we learned today was that 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 in tomorrow's discussion will be whether an un-blinded, large randomized trial is 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 effect 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 or 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 TZD's. This is a shame because the TZD's are the only class of medications to show that they keep a diabetics sugar under control for many years.  Older drugs like metformin and sulfonylureas usually fail after three to six years.  TZD's also don't cause hypoglycemia.  They also have positive benefits on lipids (raising good cholesterol and lower tirglycerides). The TZD's 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 this 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 (DPP4's like Januvia and GLP-1's 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 pro's and con's 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.

Residency Match Results Bad for Primary Care (Again)

Once again, though not trumpeted as much as in previous years, reports of this year's residency match results are in, and some media outlets are claiming this to be good news for primary care.
The LA Times claimed Match Day 2013 results are good for future internal-medicine patients, stating "America’s future doctors are increasingly interested in become primary-care physicians -- good news for America’s future patients."  OBGYN News' claim was my favorite: Primary care spots are hot in largest-ever Match Day.

They are basing this on a few things. First, the actual numbers of US medical student graduates going into primary care fields such as internal medicine have in fact increase. For example, 3,135 students will be going into internal medicine, which is a 19% increase from 2009 and 6.6% increase from last year.
However, the main source of positive news is coming from the NRMP (the folks who do the match) themselves. According to their press release:

Match results can be an indicator of career interests among U.S. medical school seniors. Among the notable
trends this year:
• 3,135 U.S. seniors matched to internal medicine, an increase of 194 over last year.
• 1,837 U.S. seniors matched to pediatrics, an increase of 105 over last year.

• Family medicine matched 1,355 U.S. seniors, 33 more than last year. More than 95

percent of family medicine positions were filled.

Based on these numbers it would seem that more students are choosing careers in primary care. However, this is not the case, and in some instances things are actually worse.

You have to look at the total number of slots as well as the percent that our US students are choosing primary care fields.
Below is a table that has the match results for the last three years. It is important to note that there was almost 1000 more US seniors graduating, which according to the NRMP they attribute to the rising number of U.S. students to three new medical schools graduating their first classes as well as enrollment expansions in existing medical schools.

Despite having almost 1000 new graduating medical students, the addition of these students to the primary care fields are limited.  The real way to see what are students are choosing it to look at the percent of graduating students choosing a specific field (% US grads matching in my table).  The results are pretty bleak. 




There is virtually no change in student choosing internal medicine from 2011 to 2013 (18.9% to 19.1%). Family medicine, which looked to have a slight bump last year is actually down from 2011 to 2013 (8.35% to 8.26%). Peds is up from last year, but still down from 2011 (11.34% to 11.2%).  One also needs to look at how many of the positions that were offered (a major increase from prior years) were filled by graduating US seniors.  Internal medicine, which was filled by 57% of US seniors dropped significantly to just below half!. Family dipped from 48% in 2011 to 44.6% in 2013. Peds dropped by 1%. 

In other words....

• More residency slots were offered across the board in primary care specialties, but more of these new slots were being filled by non-US graduates, than use graduates
• Despite having three new medical schools worth of graduates, the pool of newly minted primary care physicians isn't really expanding that much
• Our US seniors ARE NOT choosing primary care as a career, and if anything, are choosing primary care slightly less than previously, and certainly not more.

While internal medicine hasn't really changed, it is important to note that of those going into internal medicine, only 2% of seniors plan to go into primary care.

I blogged about this in 2011, when the media seemed to decry a boom for primary care. What I said two years ago is even more true today. This is a crisis. Many of the few primary care docs we have are retiring, leaving practice, or going cash only or retainer. If something is not done to increase the value, reimbursement, and job satisfaction of our primary care doctors; we will have no one left to care for our sick and aging population. (And before you post a comment about NP's and PA's filling this gap, those students aren't going into primary care either. A surgical PA makes more money than a primary care MD).

Choose Wisely when Choosing Wisely

Yesterday, the media was a buzz with the latest recommendations from lead medical organizations about overused tests and treatments.

Maggie Fox from NBC news states, "You don’t need an MRI for lower back pain. You don’t need antibiotics for a sinus infection. And you don’t need to be screened for osteoporosis, either, if you’re under 65. " The Washington Post's headline reads "Group releases list of 90 medical ‘don’ts.’"  The New York Times similarly describes this report as a list of "don'ts."

All this stems from the Choosing Wisely initiative from the non-profit American Board of Internal Medicine foundation in conjunction with Consumer Reports. The group ask most of the major physician specialty societies to come up with al list of the most common unnecessary things done in medicine. Each group came up with the top 5, to comprise a list of 90 commonly overused tests and treatments.  A few examples include:
•A feeding tube in patients with advanced dementia. (American Academy of Hospice and Palliative Medicine and American Geriatrics Society)
•A routine annual Pap test if you’re 30 or older, or under 21. (American College of Obstetricians and Gynecologists).
•DEXA (dual-energy X-ray absorptiometry) screening for osteoporosis in women under 65 or men under 70, unless there’s a suspicion of bone loss.
•A CT scan for a child with a minor head injury. (American Academy of Pediatrics)

This work is important as due to our fee for service system that reimburses for ordering tests and treatments whether or not they are effective or worthwhile, has proven to be costly and inefficient. Thus, cutting unnecessary testing or treatment in medicine will both save money and potentially reduce harm.  For example, in many ER's across the country, almost all children that come in after a head injury get a CT scan. Not only has this not been proven to be effective, but radiating a child's head can increase the risk for cancer.

However, a word of caution.....
Based on the headlines, one might think that these tests or treatments should never be done.  Two major media outlets call these a list of "don'ts."  However, this is not what the experts were saying.  These are commonly overused tests and treatments, not useless.  There might be very good reasons to get a CT scan after a head injury in a child that outweigh the very small potential increase risk for cancer.  It is very important to understand this because it is possible that insurances and/or the government will use these recommendations to determine reimbursement. While it is correct that physicians and patients should question the routine use of these tests or treatments, patients and doctors shouldn't have to fight with insurance companies to use these tests and treatments when they feel it is necessary.  Finally, if as a patient you question your physician about a test or treatment they recommend (which is the entire purpose of the Choosing Wisely campaign), be prepared to sign something that states you won't sue them should your refusal of their recommendation turn out to be wrong. While the Choosing Wisely campaign starts to address the problems with our fee for service reimbursement system, it fails to address the other major driver of health care costs- malpractice.  Many physicians would likely gladly give up these over-used tests and treatments, but will not for fear of being sued.

The Future of Health Care is Now Clear

As a physician who is involved in educating medical students, I am often asked for career advice. Medical students are by nature smart and ask very good questions. "Will I be able to pay of my student loans if I choose primary care?" "Will I have a balanced lifestyle if I decide to go into primary care?"
I try to be both encouraging and realistic.  However, far too often I have found myself telling students that the future of medicine, primary care in particular is not clear.
That is no longer true.
The future of health care, and particularly primary care is now very clear.
Several recent events along with trends that have been in place for the last few years have clarified the future of health care over the next few years. The passage of the Affordable Care Act (ACA), the decision of the Supreme Court to uphold the constitutionality of the individual mandate, the re-election of President Obama, and the fiscal cliff/sequester have all set into motion changes to our health care system that are likely irreversible and clarify the future of health care. Essentially, there are two paths:
1. Health Care in Large Integrated Systems.  Health care costs are skyrocketing. The major fixes to the problem that are accepted on both sides of the aisle are an end to fee for service, bundled payments, and incentives for improving quality at lower costs. Accountable Care Organizations (ACO's) are one model being tested.  However, even if the ACO turns out to be HMO 2.0, and ultimately fails; health care will be delivered in large integrated systems. This trend is already occurring with hospitals, academic medical centers and other health care systems gobbling up (through incorporation or outright purchase) smaller private practices.  Because payment will be linked to performance, and performance must be measured and reported; the only way physicians will be able to make money is to not only have a large, robust electronic medical records, but also a staff that can help collect, process and report the important data. Even large private practices don't have the economies of scale to make this happen. Thus, private practice as we know it will cease to exist.  This trend is already happening. According to a report by Accenture, over the past decade, the number of independent U.S. physicians has dropped dramatically, from 57 percent in 2000 to 39 percent in 2012.
The move to large, integrated is not necessarily a bad thing. Integrated systems allow for quality improvement. Large integrated systems like Mayo, Kaiser, and the VA have some of the best outcomes for health care in our country, usually at significantly lower costs. For physicians, being a salaried employee also has its benefits which include a guaranteed paycheck, reasonable hours, good benefits and no worries about running a practice. The current generation of medical students tend to value work life balance over the potential opportunities seen in private practice.  
The down side of large integrated systems is less personalized attention. Rather than seeing your doctor when you are sick, a patient will likely wind up seeing a member of the doctor's care team.Other modalities such as group appointments might be employed.

2. Health Care Outside the System. Some doctors (likely the ones currently in practice) will refuse to join these large integrated groups.  Some patients may decide that access to their own personal physician has some value. These patients are tired of waiting forever to get an appointment or a call back from their doctor, and want to see their doctor when they are sick, not a team member. They are even willing to pay beyond what their insurance premiums cover. These patients and providers will go outside the system.  Growth of retainer (often called concierge) practices, cash-only practice, or direct primary care demonstrate that going outside the system is already happening. This will likely be limited to primary care, as one might be able to pay cash for a doctor's appointment, but not a colonoscopy or cardiac catheterization.

Health care delivery is already occurring in large integrated systems as well as outside the system. The aforementioned changes will cause these trends to continue, squeezing out the current physicians who are still in an insurance based private practice. These changes are certain.  What is unclear is the proportion of health care that will be delivered in either model. Will large integrated systems become so effective, that only the very wealthy will deem it worthwhile to get their care outside the system?  Or, will large integrated systems become so impersonal and inconvenient that only those with modest incomes will be forced to get their care in these systems? The truth is likely somewhere in between, i.e. 70/30, 50/50 or 30/70.

Regardless, medical students and residents who are trying to determine a career path should now have a clearer vision of the future health care. Patients who are currently receiving their care by a private practice physician who accepts their insurance should also realize that their current situation will likely not exist in the next few years.