FDA too focused on risks compared to benefits when approving drugs

In my opinion, the pendulum has swung to far in the safety direction when it comes to approving new drugs. Over a decade ago, the reverse was true and medications like Vioxx and Rezulin were approved and prescribed too quickly without either additional studies required before approval or closer follow up after approval. Though a more vigillant approach to safety was certainly needed, now there are many drugs that may never get approval because it appears that the FDA is concerned about virtually any risk at all.

Today, as reported best by Medpage in Panel Votes Against New PDE4 Inhibitor for COPD, despite prior discussions in favor of the drug, the FDA decided not to approve roflumilast (Daxas), a phosphodiesterase 4 (PDE4) inhibitor, for treatment of chronic obstructive pulmonary disease (COPD). Now, I will admit after seeing some of this data, that I was not overly impressed with Daxas. It would never be my "go to" drug for COPD, because we have so many better options such as inhaled corticosteroid/LABA combinations (Advair, Symbicort) and long acting anti-cholinergic agents (Spriva). However, there are still many patients with COPD who take both drugs as well as additional short acting inhalers, and are quite symptomatic. In addition, prior to either of these medications being available, one of the primary treatments for COPD was theophyline, one of the original PDE inhibitors. It had a far worse side effect profile than Daxas (seizures, blood levels needing to be monitored), but was the mainstay of therapy. In fact, there are many doctors still prescribing theophyline today for their COPD; mainly in those patients who can't take or are still symptomatic on the aforementioned inhalers.


Looking at the Daxas data, roflumilast resulted in a significantly greater change in prebronchodilator FEV1, improving it by 48 mL over the course of the study (P<0.0001). This amount of improvement would be minimal for a healthy person or even an asthmatic, but for a patient with COPD, this could be the difference of being able to walk up the stairs or having to live on the first floor. In addition, the number needed to treat to prevent once exacerbation was significant, between 3 and 5. In other words, even though this was not the best medication in the world for COPD, it was certainly beneficial, and would have an important role for patients not well controlled on standard therapy.

Safety concerns were certainly real. A total of 218 cancer/tumor events were reported in 208 patients -- 60% of whom were in the roflumilast group,and 40% of whom were in the placebo group. However, even though there were more cancers in the roflumilast group, many believe these cancers were not caused by the drug because most of the tumors were identified months after treatment, which would be too soon for the drug to have a causative effect. The most common side effect was nausea and diarrhea, and this was the most common reason that the 14% of patients stopped taking the drug. There seemed to be a signal for psychiatric conditions, including suicidality, but again, it is unclear that the drug actually caused this.

Every drug has risks and benefits. My guess is that aspirin would not be approved by the FDA today, since it has an increased risk of GI bleeding, other medications can relieve pain, and the benefit of heart attack and stroke prevention is controversial. The key is to balance these risks and side effects. If there are safer, more effective and similar drugs, then there is no reason to approve a new one. However, in many cases, it is better to have a drug with some known risks associated with it available to patients who have failed other therapies, then to not have the drug available at all. The FDA could have easily approved the Daxas and recommend it for patients who were still symptomatic on more standard therapy. Now, physicians will not have this medication in their tool kit for the select few patients who might actually benefit from the drug.

I believe that because the FDA has come under so much scrutiny regarding drug safety, it has made decisions where risk and benefits were not balanced appropriately. Because of the Avandia scare (which has since been proven to be unwarranted see For the RECORD, Avandia does not cause heart attacks), it is now difficult for any new diabetes drug to be approved. I also recently mentioned how unwarranted safety concerns by the FDA will likely harm far more asthma patients then help (see FDA Blows it on LABA Safety ). When safety or the need to get new drugs on the market is such a major driving force, patients are harmed, regardless of which direction the pendulum is swinging. The safety folks seem to be in the driver's seat and may be harming patients by not giving them access to needed medications. It is time for the FDA to start taking a more balanced approach to approving medications.