I was pleased when the FDA approved telithromycin (Ketek) in April 2004. A new non-beta-lactam antibiotic with activity against every common bacterial respiratory pathogen including multiple-drug-resistant Streptococcus pneumoniae was cause for celebration. It could share a therapeutic niche with the respiratory fluoroquinolones. This could reduce usage of fluoroquinolones, and potentially prevent the potential development of resistance to them.
Ketek seemed relatively safe. It had been prescribed more than 30 million times in 50 countries including Sweden, Germany, the United Kingdom, and Norway. And it's a close relative of our apparently safe old friends, the macrolides. So it's all good, right?
Two years and five million U.S. prescriptions later, the makers of Ketek became the subject of congressional investigations. The FDA slapped a black box warning on the drug (don't use in patients with myasthenia gravis) and added a bold admonition to beware hepatotoxicity. The agency also eliminated two formerly approved indications (acute bacterial sinusitis and acute exacerbation of chronic bronchitis), leaving only one indication: mild to moderate community-acquired pneumonia.
So what happened? In short, health care clashed with the American profit motive. Again. None of us should be surprised.
Economics, Politics, and Health Care
A patient may benefit more from being cured of S. pneumoniae pneumonia by, say, 10 days of Ketek than from modifying a cardiac risk factor by taking a daily medication for decades. But the pharmaceutical industry serves stockholders, not patients. Would they prefer to sell a patient 20 Ketek pills or 11,000 Lipitor tablets?
The cost to develop a new drug is between $100 million and $800 million. The cost recovery for an antibiotic is about $100 million per year compared with more than $1 billion per year for a long-term drug. The pharmaceutical industry has done the math, and the introduction of new antibiotics has decreased by 56 percent over the past 20 years. Only one percent of the drugs currently in development are antibiotics. (Clin Infect Dis 2004;38:1279.)
There have been accusations of incompetence and even deliberate misrepresentation during the FDA's Ketek approval process. (N Engl J Med 2007;356:1675.) Sen. Chuck Grassley (R-Iowa) is spearheading an investigation of the FDA and the manufacturer. Jobs may be lost, and policies are already changing.
Through the 1990s and until 2004, the FDA standard procedure was to approve new antimicrobial treatments for outpatient respiratory tract infections on the basis of “noninferiority” trials. These trials are designed to show that the new treatment is not significantly worse than a previously approved treatment. New treatments for otitis media serve as examples. Single-dose ceftriaxone was shown to be not significantly inferior to oral trimethoprim/sulfamethoxazole (Pediatrics 1997;100:157), and single-dose azithromycin was shown to be not significantly inferior to high-dose amoxicillin. (Ped Infect Dis J 2005;24:153.)
To merit approval, in addition to being “not inferior,” the new treatment should offer “advantages in safety, tolerability, cost, or convenience.” (Ann Int Med 2006;145:62.) The single-dose treatments for otitis media seem to offer, at least, improved convenience. The FDA has decided that “noninferiority” studies should no longer be used to approve new treatments for diseases that tend to be self-limiting and nonfatal. More rigorous standards might be a good thing. But what about Ketek? The question of safety became its downfall.
Who Can We Trust?
So how safe do we demand that antibiotics be? The answer is, as always, it depends. We accept treatment risk proportional to a combination of disease risk and treatment success rate. Consider this statement: “In February 2005, seven months after the drug was introduced to the U.S. market, the first death from Ketek-associated liver failure — in a patient treated for a mild respiratory tract infection — was reported to the FDA.” (N Engl J Med 2007;356:1675.) Our reaction might be different if it had been a moderately ill, penicillin-allergic, quinolone-intolerant, 63-year-old with presumed S. pneumoniae lobar pneumonia. It's a question of risk vs. benefit. Clinical judgment needs to be exercised. But who can a patient trust?
Patients probably shouldn't trust pharmaceutical companies. The company must serve its stockholders, not patients. Maybe we can trust our politicians. They serve constituents, including patients. Maybe Sen. Grassley will bring us legislation that will fully and adequately fund the FDA with federal tax money so we will no longer have the uncomfortable current situation in which the FDA must receive substantial sponsorship from the pharmaceutical industry, possibly promoting coercion and even fraud. Maybe I'm too cynical, but I suspect that the good senator from Iowa will not promote his reelection with a platform of higher taxes and more government control of medicine. So maybe the patient can trust the FDA, although charges of incompetence, underfunding, deception, and fraud make that difficult at the moment.
We all know who the patient can trust, right? They can trust us, their caregivers. Unfortunately, the Ketek story puts that trust into question. One study purporting to demonstrate its safety has been the subject of criminal investigation that has uncovered fraud resulting in one physician currently serving a 57-month sentence in federal prison. (N Engl J Med 2007;356:1601.) Other criminal investigations are ongoing.
The good news is that the FDA will use criteria that are better than “noninferiority” trials to approve new treatments. More good news is that post-marketing safety evaluation will be more and more thorough.
The bad news is that this could discourage future attempts to develop antibiotics and further jeopardize the dwindling supply of new antibiotics. If and when S. pneumoniae develops increasing resistance to respiratory fluoroquinolones, telithromycin will become a very important part of our armamentarium to treat pneumonia. So let's not throw out the baby just because we are angry at the person who drew the bath.
Now I'll tell you who the patient can trust. He can trust me. I honor the oath I took when I received my medical degree. I vowed to always put the patient's well-being ahead of my personal interests. If he has moderately severe pneumonia that could be from multiple-drug-resistant S. pneumoniae, a reason not to take a beta-lactam antibiotic or a fluoroquinolone, and no indication of myasthenia gravis or hepatic disease, he can trust me to treat him with telithromycin. I believe the benefit outweighs the risk. And it just might save his life.