Approval from the U.S. Food and Drug Administration to market a new drug is a critical waypoint along the path to profits for pharmaceutical manufacturers. Unfortunately, recent case studies have illustrated that FDA approval does not necessarily provide assurances of effectiveness and safety. In last month’s Georgetown University Health Policy seminar, we discussed two examples, anemia drugs and the diabetes drug rosiglitazone (Avandia), which were prominently featured in recent articles by Peter Whoriskey in The Washington Post.

 

Harmful drugs

The original impetus for the development of the anemia drugs Epogen, Procrit, and Aranesp, which mimic the  actions of the hormone erythropoietin, was to spare dialysis patients with severe anemia the inconvenience and risks associated with periodic blood transfusions. However, noted Whoriskey, pharmaceutical companies moved aggressively to market these drugs to a far larger patient population who were much less likely to benefit from them:

The trouble would arise as the drugmakers won FDA approval for vastly expanded uses, pushing it in larger doses, for milder anemia and for patients with a wider array of illnesses. Very quickly, the market included nearly all dialysis patients, not just the roughly 16 percent who required blood transfusions. The size of average doses would more than triple. And over the next five years, the FDA would approve it to treat anemia in patients with cancer and AIDS, as well as those getting hip and knee surgery.

Image courtesy of scienceblogs.com

Doctors were motivated to give more doses of these drugs due to generous financial incentives (estimated at between $100,000 and $300,000 annually for a typical oncologist) and the seductive thinking that if some drug was good, more was better. Even the publication of a 1998 study in the New England Journal of Medicine showing no survival advantage to boosting hematocrit levels to normal ranges in cardiac patients did little to discourage overprescribing. Not until 14 years later did an independent researcher obtain access to the complete study report from the FDA and conclude that the NEJM authors had used statistical slight-of-hand to obscure an increased risk of heart attacks and death in the normal-hematocrit group. In the meantime, lobbyists working for the drug manufacturers successfully blocked efforts by Medicare administrators to stop paying for the higher (harmful) doses.

 Similarly, the evidence that rosiglitazone (Avandia) increased the risk of heart attacks was slow to come to light, due in part to the drugmaker’s research emphasis on the surrogate outcome of glycemic control. Although a 2007 meta-analysis first sounded the alarm about rosiglitazone’s cardiovascular risks, the manufacturer successfully stalled regulatory action in the U.S. for three more years, during which thousands of new patients were prescribed the drug.

 

Could the FDA do more?

Could the FDA and other U.S. government agencies do more to protect patients from the effects of biased research and aggressive sales tactics for newly marketed drugs? What concrete steps could health policymakers take to encourage research to identify unexpected harms earlier in the drug approval process?


First Posted at Common Sense Family Doctor on 6/2/2013

Kenny Lin, MD, MPH
Host, Common Sense Family Doctor. Dr. Kenny Lin is a board-certified Family Physician and Public Health professional practicing in the Washington, DC area. He also Associate Deputy Editor of the journal American Family Physician and teach family and preventive medicine at the Georgetown University School of Medicine, Uniformed Services University of the Health Sciences, and the Johns Hopkins University Bloomberg School of Public Health.

3 COMMENTS

  1. I have to respectively disagree with you on this one. The implication of your post is that pharmaceutical companies bias research and inappropriately market products that do not help and often lead to harm. While the industry has had its share of bad examples in the past and must be monitored closely, you suggest this is an ongoing problem in need of stricter regulations.
    In the first example, Epogen and Procrit are safe and effective drugs when used in the appropriate patients. The problem was that they were over used in the wrong populations of patients. While the drug companies did promote the expanded use (as they have a fiduciary responsibility to do so), the main reason for the increased use according the Post article you site was “at the center of any explanation of the popularity of these drugs are the nation’s doctors, clinics and hospitals, and the choices they made for patients.” While you do cite this reason, your focus is on biased research and aggressive sales tactics, not greedy hematologists and nephrologists. If this drug were like other drugs (where doctors don’t receive additional compensation for prescriptions), use would have been far less.
    In your second example, your timing is pretty bad. Recent data shows that Avandia is likely to be safe after all. The FDA is meeting tomorrow to decide whether or not restrictions should be lifted.

    While on the one hand, I agree with you that it is incredibly important to have a strong regulatory process to ensure the medications that we prescribe to our patients are safe and effective, I am concerned when we slam the drug industry and imply that so many of the drugs we prescribe may not do any good and likely cause harm. The consequences of this kind of thinking are not insignificant. First, patients are now likely not to trust any medications we prescribe. I am sure you will agree that statins are the most well studied medication with the clearest risk benefit ratio for patients with cardiovascular risk. In addition, atorvastatin is now generic. Yet, so many patients who could benefit from this medication refuse to take this or any drug because of what they read on the internet and what they see on TV (especially laywer ads). Secondly, increasing regulations makes it harder for new treatments to come to market. Because of the Avandia scare (which has now been shown to be a hoax) all diabetes medications must go through an extra regulatory step to prove they don’t cause heart attacks. This has caused the delay of many good therapies.
    Our job as physicians is to do what’s best for our patients. We need to be cautious of the industry (pharmaceutical or otherwise) to ensure that they are providing safe and effective products for our patients, while at the same time being careful not to over state concerns which lead to fear and panic.

  2. Hi Dr. Mintz,

    Thanks for these thought-provoking comments. Like you, I’m a primary care physician and am also disgusted at the unscrupulous behavior of specialist physicians and hospitals that were overprescribing Epogen and Procrit to patients who were unlikely to benefit and often likely to be harmed. I certainly didn’t intend to paint all drug companies with the same broad brush of corruption. Yes, the purpose of a business is to make money, and that applies to drug companies as well as medical practices. However, the “fiduciary responsibility” of drug companies doesn’t exempt them from the obligation to practice ethical behavior. Slanting research findings to hide serious adverse effects and playing politics to sell more drugs regardless of the human consequences is unethical.

    As for Avandia, I strongly disagree with your assertion that the findings of harm have “been shown to be a hoax”; the convening of an FDA meeting to reexamine the evidence hardly proves that the substantial body of literature showing an association with increased heart attacks and deaths is suddenly null and void. Even if a drug has harmful side effects, it shouldn’t necessarily be pulled from the market – as long as the benefits outweigh the harms for a group of patients. In my mind, Avandia doesn’t pass this test, as it’s never been shown to improve patient-oriented outcomes (CVD, death) and there are safer alternatives available. Finally, speaking on behalf of my patients with diabetes, I think it’s great that the FDA is now requiring manufacturers of new diabetes medications to demonstrate that they don’t cause heart attacks BEFORE these drugs go on the market, given the alternative.

  3. Well, this is in response to the comment by Matthew. As a person that has permanent damage from dangerous meds approved by the fda and given out by a Dr that was beyond careless…your comment makes me want to put my fist through a wall. Dr’s are unaccountable for their actions as are hospitals and pharmacies. I know this, it’s not just my opinion…it’s my experience. Dr’s also cover each others behinds when the stuff hits the fan as well…saw this too. No, there are very few meds that are safe and they are only tested for six months at best while being tested behind closed doors by the people standing to profit from them. If this isn’t biased, flawed testing at its best….what then, is?!
    Most Dr’s have an ego the size of the Texas and don’t start spewing arguments about how delays getting drugs available is hurting patients, it’s all a scam and if you don’t realize this you must be part of the problem as well. I’ve dealt with the damage from a Dr’s errors, if someone did renos on your house and did a crappy job you would sue them. Good luck suing a Dr, especially where I live.
    Why don’t you test these beautiful meds on your children to see how safe they are. Quit your whining buddy, crocodile tears don’t gain sympathy with me so grow up and realize you are in a very dangerous business of causing great harm to the people you are most likely trying to help. Just because you put the white coat on doesn’t mean you have the right to consider outside opinions are incorrect. These meds for the most part are POISON and nothing but.

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