Monday, February 1, 2010

Generic Antibiotics: Effective and Safe?

Today I am going back to the FDA’s Advisory Committee (AIDAC) meeting on a new antibiotic, telithromycin (Ketek), in December, 2006. Telithromycin is an antibiotic distantly related to erythromycin and azithromycin (Zithromax, Z-Packs) that is active against strains resistant to the older antibiotics. During this meeting, the committee recommended that its marketing approval be withdrawn for the indications of sinusitis and bacterial exacerbations of chronic bronchitis. Telithromycin was contentious from the start. Bob Moellering and I wrote a Perspective on the entire process for Lancet Infectious Diseases in 2008 if you are interested in a summary of telethromycin’s history. But the argument at the AIDAC in 2006 essentially boiled down to the following logic:
1. The FDA has decided that superiority or placebo controlled trials would be required to show efficacy for self-limited infections like otitis media, sinusitis and bacterial exacerbations of chronic bronchitis.
2. Telithromycin is associated with rare but serious liver toxicity, aggravation of myasthenia gravis (a rare neurologic condition) and more common visual disturbances that are generally not very serious.
3. Because telithromycin was not subjected to superiority or placebo controlled trials to prove efficacy in sinusitis and bronchitis, the FDA asked, what is its benefit:risk ratio?
Predictably, the committee found that, since efficacy had not been proven, and telithromycin was associated with some toxicity, the benefit:risk ratio was poor (some might say 0). A few of us at the meeting, including the FDA itself, pointed out that generic antibiotics, like augmentin and others, had never been subjected to placebo controlled or superiority trials in the same indications and that they too had toxicities not unlike those associated with telithromycin. We asked what the FDA would do about that situation. The response from Dr. Jenkins of the FDA is quoted below from the meeting transcript:

DR. JENKINS: We definitely hear your concern about a fair level playing field for all the antimicrobials that have the indication and we will take that back and put on our thinking caps about what approaches there might be to get the level of evidence that we would like to have today for all of those products. But I can assure you it will be a very complex endeavor and maybe similar to me trying to climb Dinali.

Clearly, if one is to buy the arguments as posed by the FDA and its Advisory Committee in 2006, since in terms of numbers of prescriptions those for generic antibiotics far outweigh those for brand antibiotics, the potential risk for Americans is that much greater for generics. So, either the FDA does not really think that these drugs have no proven efficacy, or they do not believe their own data on the toxicity of generic antibiotics or they just have not yet been able to figure out what to do with their homemade conundrum.

To me, the solution is simpler. To require placebo-controlled trials dooms us to never having another new antibiotic for otitis, sinusitis or bronchitis. This is another example of the FDA requiring infeasible trials for approval. The FDA needs to put on their thinking caps about new trial designs that are feasible. Then, they need to ask whether the generics have come to an acceptable level of proof based on a more feasible approach. If the answer is “yes” then we’re done. If not, then marketing approval for the generics for these indications must be denied until they achieve the same level of proof the FDA is requiring for new antibiotics.

I have been trying to follow-up with the FDA since it has now been three years since they started their attempt on “Dinali.” So far, no one seems to be home.


  1. Dave, what would be a feasible trial design for a self-limiting infection like ABECB, otitis, etc? Do you think there should be no placebo control? Presumably you believe that antibiotics do make a difference - in speed of improvement? Reading this week's article in Newsweek on the lack of effectiveness of anti-depression agents [relative to placebo] gave me pause. In that case it does appear that the drugs are acting via a placebo effect - and that the apparent side effects of the drugs encourage patients to believe they are getting the drug, and this may enhance the placebo effect. I would think, on the other hand, that antibiotics do help otitis or bronchitis exacerbations in some way. So, based on what you [or others] think they are doing, how would you structure the trial?

  2. Clinical response at a set timepoint. For bronchitis this is well demonstrated in the Cochrane database article. I believe the same could be done for otitis and sinusitis. In fact, for sinusitis, there is already a nice study showing benefit for antibiotic at a set timepoint.

    Antidepressants are different. They do not cure the disease or hasten its cure. They relieve symptoms and frequently have to be taken for prolonged periods of time. Antibiotics cure the disease. It is true that there is a large placebo effect in the anti-depressant trials related to the natural waxing and waning of symptoms in chronic depression. There may also be a role for our poor diagnostic acumen for depression in this. But I actually am convinced that antidepressants work and that there, you absolutely have to have a placebo arm in the trials. Comparative trials would be helpful for antidepressants as well allowing us to gauge relative benefits of one drug vs. another.