Jan 22 2014

New drugs, the FDA and regulatory reform


Reform Party of California Commentary

On Jan. 17, 2014, the Wall Street Journal (WSJ) published an opinion piece discussing the FDA’s rejection of a new drug for treatment of multiple sclerosis (page A13, online here). The drug was recently approved for treating MS in 30 countries, including Canada, European Union countries and Australia. The authors are a hard core conservative (ideologue) associated with the very conservative Hudson Institute and an individual with an unknown but real economic stake in the outcome. Although the article is opinion, not news, and the authors have powerful incentives to spin, i.e., ideology and economic self-interest, the points they raise about how the FDA does its job and their logic nonetheless appear to be genuine and unspun. Their arguments merit serious consideration.


In reviewing new drugs for marketing approval, the job the Food and Drug Administration (FDA) does is based on lots of biological science, but the core mission can be boiled down to two things. First, the FDA must insure that a new drug has a reasonable degree of safety for the disease being treated. Second, the FDA must be satisfied that the drug works at least in terms of seeing beneficial effects in enough patients that statistical significance is attained.

Accomplishing the core mission may sound simple, but it isn’t. Not by a long shot. The science is usually blindingly complex and the data has to analyzed very, very carefully to insure that human bias and/or a flawed clinical trial design does not skew the interpretation of the results or mask the real activity of the new drug or even its lack of activity. It typically takes tens to hundreds of millions of dollars, millions of pieces of data and 5-7 years of clinical trials to get it all right. There are only a handful of ways to do it properly, but there are tens of thousands of ways to fail.[1] It is almost a miracle that any new drug is ever approved for anything.

Criticisms of the FDA

The authors of the WSJ article argue that their drug is both safe and effective, thus meeting the FDA’s core mission criteria for marketing approval. The FDA responds that the clinical trials for the new drug were flawed because they were not double blinded and thus interpretation of the results were subject to human bias and thus efficacy was not proved.[2] The authors point out that it is impossible to single- or double-blind the clinical trials because their drug, administered by intravenous injection, causes the immediate side-effects of headaches and nausea in patients who receive the drug. In other words, both patients and doctors know exactly who is getting the drug and who isn’t. The company sponsoring the new drug cannot give a patients placebo that causes headaches and nausea because that is unethical, illegal and simply not possible given the state of mind of the American public. Given that, how can a standard double-blinded clinical trail be done? Answer: It isn’t possible.

To compensate for that necessary “flaw” in their clinical trial design, the company conducted their trials using another MS drug, beta interferon, and then looked for how well the new drug did compared to the previously-approved beta interferon. The comparison showed that the new drug was a lot better than the old drug and that objective data, e.g., reduced brain atrophy and fewer new brain lesions, also showed that the new drug was effective. Clearly, the new drug works.

The authors of the WSJ article summarized the situation like this: “In these circumstances, the agency elevated the double-blind, placebo-controlled trial to the level of dogma. It simplifies the reviewers’ work and reduces the need to make case-by-case judgments about an appropriate trial design. Most of all, it leaves the agency with wide discretion, at the end of years of development and evidence, to say ‘no’ or ‘tell us more.’ ”

Although the irony of a conservative ideologue criticizing dogma may strike some as off-scale bizarre, in this case the ideologue and the venture capitalist with a stake in the game nonetheless have a valid point. The FDA should have approved the new drug. If the FDA’s concerns really were grounded in efficacy and/or safety, then they could approve the drug but require collection of phase 4 post-marketing data to see if there really is an efficacy and/or safety issue that crops up. Obviously, if something bad does happen and patients are injured or die, that is the risk-reward scenario that society is being asked to accept.

That risk-reward analysis is not entirely the FDA’s call. The FDA is there to do two and only two things, i.e., evaluate safety and evaluate efficacy. The safety evaluation is within the scope of what society is willing to accept, not just what the FDA will accept. Maybe we should ask MS patients, in addition to the FDA, what degree of risk they are willing to accept under these unusual circumstances. The patients should have a voice.[3]

Why should anyone care?

This may sound arcane or trivial. It isn’t. The American standard of living is under serious pressure and it has been for some time. Nothing coming out of either the democratic or republican parties suggests that they have any idea whatever of how to fix the unacceptable situation we are mired in. Good reasons to doubt that the next generation is going to be better off are beginning to feel real, ominous and possibly permanent. Regardless of how one feels about drug prices, new drugs are one way to contribute to the creation of wealth and the progress of medicine at the same time.

America absolutely has to exploit any and all of its competitive advantages to the maximum possible extent. When it comes to innovation, America leads the world. Innovation is where our best and maybe last solid defense of our standard of living is going to be based. In this case, the FDA is unreasonably interfering with the progress of medicine and the last defense of our standard of living. It must get out of the way and stick to its safety and efficacy mandates.


1. Sometimes, the FDA is between rocks and hard places. In the early days of the AIDS epidemic, the FDA approved a drug called AZT (azidothymidine), which was the first drug approved for treating Human Immunodeficiency Virus (HIV) infections. The AIDS activist community was putting enormous pressure on the FDA to rapidly approve AZT, even though the efficacy data was incomplete or weak and the drug was fairly toxic. The ultimate success of AZT was modest because the HIV evolved (mutated) and became resistant to AZT. Now AZT is used in combination with other AIDS drugs to slow the rate of virus evolution to drug resistance. Despite initial criticism of being too slow to approve AZT, the FDA later received criticism for approving AZT too soon in view of the resistance problem and AZT’s considerable side effects. Similar double-edged criticisms have recently been leveled at the FDA over long-term side effects of some cardiovascular or diabetes drugs.

2. Double blinding means that the doctors giving the drug to patients do not know if they are giving drug or placebo, the first blind, and that the patients do not know if they are receiving drug or placebo, the second blind. Double blinding reduces human bias in data gathering and/or interpretation about as much as reasonably possible, e.g., the placebo effect is real and for diseases like MS, surprisingly powerful.

3. There is a big caveat here. The possibility that patients are mostly irrationally exuberant about how safe and effective a new experimental drug is constitutes a real and valid concern. That risk also has to be made brutally plain to MS patients and then their response factored into the analysis. Those patients would need, at the least, a very good basis for informed consent. Don’t forget the placebo effect of footnote 2, i.e., the patients may honestly believe the new drug is far more safe and/or effective than it actually is. None of this is simple.