Is the FDA responsible for hundreds of thousands of deaths?

No. But the WSJ would like you to believe so.

One libertarian talking point I hear a lot (Cato of course loves this story), and is repeatedly pushed by the WSJ, is that the market and consumers should decide the safety and efficacy of drugs – not dirty gov’mint bureaucrats who want nothing but death and suffering for cancer patients. The latest is this commentary from Ronald Trowbridge and Steven Walker which has some fun with math to suggest the delay in approval of cancer drugs has led not to dozens, or hundreds, or thousands, but hundreds of thousands of premature deaths.

Is there any basis in fact for these accusations? Is the FDA somehow worse than Hitler? Hmmm.

Let’s take a look at their argument.

Gleevec set a tragic standard for loss of life at the hands of FDA bureaucrats. Coming out of Phase I testing in 1998, it was known beyond any reasonable doubt to be safe and effective. The Alliance started requesting access to the drug for chronic myelogenous leukemia (CML) patients in June 2001. By the time FDA approved Gleevec in March 2003, approximately 3,600 patients had been denied access to the drug. Many died waiting. More than 80% of the small number of patients who got Gleevec in clinical trials before the drug was approved are alive today.

Gleevac truly was a revolutionary drug, exceptionally so. It is a drug that specifically inhibits the product of the bcr-abl fusion gene formed by chronic myelogenous leukemia (CML), and surprised everybody when it actually forced CML into remission in a majority of patients – it wasn’t absolutely clear that inhibiting the fusion gene would cure the cancer but it does. While it is unfortunate that people died while the drug was being tested, the problem here is that hindsight is 20/20. How were they to know if the tyrosine kinase inhibitor would only affect the bcr-abl protein? There are lots of tyrosine kinases in the body, some of them are critical and if inhibited, even in a minority of patients due to some mutation, people would have dropped dead (insulin receptor TK anyone?). It is simply impossible to know ahead of time if a drug is going to be safe, and they have to be tested. While the goal of speeding up promising drugs is a noble one, the idea of throwing any cancer drug in a clinical trial at patients simply because they have terminal illness strikes me as reckless and dangerous. Especially considering there were existing treatments for CML that had survival rates of about 50% after 5-10 years (interferon alpha and bone transplantation both had success at treating AML). Gleevec raised the progression-free survival rate to 84% which was excellent, and caused a trial comparing it to interferon alpha to be stopped so all patients would get the drug. But there was simply no way to know if the long-term survival, relapse rates etc., would outperform alpha interferon or bone marrow transplantation. In the window that was studied, alpha interferon had a 81% 3-year survival rate vs Gleevec at 96%, a clear benefit over interferon – but it’s not like other treatments at the time didn’t exist or didn’t need to be carefully compared to the new drug.

It’s arguable that Gleevec could have gone through faster, it’s safer than most cancer drugs, but how about some of their other examples?

Eloxatin, for advanced colorectal cancer, was summarily rejected by the FDA in March 2000 despite its being approved in at least 29 other countries. In January 2002, we started to ask the FDA to allow patients access. The agency delayed approval until August. In between, about 40,000 Americans died without ever getting the drug.

Erbitux, for the treatment of colorectal and head and neck cancers, was rejected by FDA in December 2001 when the agency refused to review the sponsor’s application. The Alliance had begun asking the FDA to allow patient access to the drug six months earlier. The FDA delayed approval until February 2004. Almost 179,000 people with colorectal and head and neck cancer died waiting.

Ah, the appeal to “other countries”. I’m not sure I want the regulatory bodies in Mexico or China and even many European countries to be cited as authorities, and it’s funny that this is the one time you’ll see appeals to the policies of other countries in the WSJ. Usually they prefer to use the evil socialist medical care as an example of how valued treatments are delayed due to their communistic universal coverage. But I digress.

This is where their argument gets weaker. Few drugs are as effective as Gleevec was for CML. How does Eloxatin(Oxaliplatin) and Erbitux (Cetuximab – a monoclonal antibody to EGF receptro) compare to standard treatments? Did people die because of lack of access? Well not really. While these drugs have increased the median survival from that of 5-FU alone, about 11 months, to about 21 months they by no means are revolutionary cures like Gleevec. While such an increase in survival is excellent news, and these drugs are a valued addition to the medical armentarium to say that people died due to lack of access is somewhat inaccurate. Some deaths would have been delayed, but to say 40,000 or 179,000 people are dead due to lack of access is gross hyperbole.

The Alliance began working for access to Revlimid, for multiple myeloma and myelodysplastic syndrome, in June 2002. Patients had to wait until December 2005 for FDA approval. Nearly 74,000 patients with these terminal cancers died without ever getting Revlimid.

And what would Revlimid (Lenalidomide – a drug similar to thalidomide) have done for multiple myeloma and myelodysplastic syndromes? For myelodyplastic syndroms about 60% of patients given the drug have to stop or lower the dose because of severe hematologic side effects. About 58% that can tolerate it have a some hematologic response and decreased need of transfusion – mostly in patients with a specific cytogenetic anomaly.

It’s also used in therapies for Multiple Myeloma where it’s been shown to be as good (or possibly better) than thalidomide. However Lenalidomide has significant safety issues including risk of thromboembolism similar to thalidomide.

Have 74,000 patients with Multiple Myeloma or MDS died because of lack of access to this drug? Decidedly not. It’s not clear that it is superior to current combined therapies using thalidomide for MM although it has a clear benefit in reducing transfusions in a specific subgroup of MDS patients (identified in the 2005 study) for whom it has been approved.

They go on to list example after example, and sure enough, even though none of these drugs are absolute cures, and there are already existing therapies, they make it sound like nothing was done at all for hundreds of thousands of people while studies of drug safety and efficacy are pursued.

One more example because it’s just too much:

In June 2002 we began our efforts to gain access to Alimta for lung cancer patients. FDA didn’t approve it until February 2004. In the interim, approximately 249,000 lung cancer patients died without the chance of trying this drug to see if it would control their disease or extend their life.

Now here they’re really abusing the numbers. Alimta (Pemetrexed) is approved for mesothelioma and small cell lung cancer because it provides similar response rates in refractory cancers as other drugs. The suggestion is a quarter of a million people are dead because they didn’t try this drug – but no drugs currently available for these types of cancers are remotely curative, and other drugs already existed with similar efficacy to Alimta.

Their summary:

In sum, these 12 drugs — had they been available to people denied entry to clinical trials — might have helped more than one million mothers, fathers, sons and daughters live longer, better lives. We have actually underestimated the number of “life-years” lost at more than 520,000, because we have not included other safe and effective uses of these drugs that the FDA has yet to approve.

Now Orac has written before about this conflict between drug safety testing and access to lifesaving drugs. While I similarly understand the desire of people facing life-threatening illness to do anything to try and extend their lives, these attacks on the FDA and drug safety regulation are misleading, inappropriate and exaggerated. Many of these drugs represent potential increases in life, or maybe palliation, but in each case they’re representing the unapproved drugs as the only treatment modality – or as a potentially curative one. Most of these drugs represent incremental advances or equivalence to existing treatments. They also are universally poisons (possibly excepting Gleevec) – chemotherapeutics tend to be very dangerous and potentially deadly drugs with huge side-effects and safety issues. To suggest that doctors should be able to prescribe these drugs without adequate knowledge of their side-effects, issues in specific patient populations, and knowledge of which organ systems to monitor is simply nuts. Not every doctor can treat their patients as if they’re enrolled in a clinical trial – monitoring every organ system, and every available biomarker. Trials don’t just tell us that drugs work or don’t work. They tell you which patients are most likely to benefit, what kinds of problems to expect, what to watch, what to ignore, etc.

I feel a great deal of sympathy for these advocates, but the FDA is not their enemy. And undermining the precautions in place to monitor and enforce drug safety for the goal of promoting reckless experimentation on patients is not admirable.