Paying for unapproved drugs

One of the handful of key themes that run through this blog day in, day out, week in, week, out, and year in, year out is that science and the application of the scientific method represent the most successful strategy that humans have yet come up with to improve human health. A consequence of this theme, of course, is the consideration of unscientific “therapies,” specifically those known as “complementary and alternative medicine” (CAM) or, sometimes, “integrative medicine” (IM). As chronicled here (and many other places), the vast majority of CAM therapies are based on prescientific concepts that are incredibly implausible on a scientific basis (for example, “energy healing” and homeopathy) and have no compelling evidence that they have any therapeutic effect above and beyond the placebo effect. Part and parcel of this theme is my unrelenting and unapologetic attacks on antivaccine idiocy coming from the likes of Jenny McCarthy and the pseudoscience- and quackery-supporting crew over at Age of Autism.

Contrary to what critics may say, however, this theme is not limited to unscientific CAM modalities, although admittedly that tends to be the main focus of the blogging here. And, yes, sometimes (OK, a lot of the time) that blogging tends towards the sarcastic and “insolent,” if you know what I mean (and if you’re a regular reader I know you do). Another corollary of the overarching theme of this blog is that public health policy and medical policy should also be based on the best available science, which is one reason why I was so disturbed to find out that the Obama Administration was considering Robert F. Kennedy, Jr. for head of the EPA. It’s also why I’m rather disturbed to read about this:

Taxpayers have shelled out at least $200 million since 2004 for medications that have never been reviewed by the government for safety and effectiveness but are still covered under Medicaid, an Associated Press analysis of federal data has found. Millions of private patients are taking such drugs, as well.
The availability of unapproved prescription drugs to the public may create a dangerous false sense of security. Dozens of deaths have been linked to them.

The medications date back decades, before the Food and Drug Administration tightened its review of drugs in the early 1960s. The FDA says it is trying to squeeze them from the market, but conflicting federal laws allow the Medicaid health program for low-income people to pay for them.

The AP analysis found that Medicaid paid nearly $198 million from 2004 to 2007 for more than 100 unapproved drugs, mostly for common conditions such as colds and pain. Data for 2008 were not available but unapproved drugs still are being sold. The AP checked the medications against FDA databases, using agency guidelines to determine if they were unapproved. The FDA says there may be thousands of such drugs on the market.

Although I had known that there were a number of unapproved drugs still on the market, “grandfathered in,” I had no idea the problem was as widespread as this.

What is amazing is that in 2008 there are still a number of drugs on the market that are not FDA-approved. We’re not talking about supplements, either. I’ve lambasted the Dietary Supplement Health and Education Act of 1994 (DSHEA) multiple times before because it in essence exempts most dietary supplements from FDA oversight, as long as they do not make claims to treat disease. Of course, that doesn’t seem to stop supplement sellers from making implicit claims, with a “nudge, nudge, wink, wink.” In any case, if the DSHEA is such a bad idea because it’s a bad idea to have unregulated potentially biologically active substances being sold by making unfounded claims for their ability to treat disease and, in essence, without regulation, how much worse an idea is it for pharmaceuticals still unapproved by the FDA to be still on sale and still being paid for by the government? Yet, that seems to be what has happened, thanks to a loophole and lack of resources in the FDA:

That unapproved prescription drugs can be sold in the United States surprises even doctors and pharmacists. But the FDA estimates they account for 2 percent of all prescriptions filled by U.S. pharmacies, about 72 million scripts a year. Private insurance plans also cover them.

The roots of the problem go back in time, tangled in layers of legalese.

It wasn’t until 1962 that Congress ordered the FDA to review all new medications for effectiveness. Thousands of drugs already on the market were also supposed to be evaluated. But some manufacturers claimed their medications were “grandfathered” under earlier laws, and even under the 1962 bill.

Then, in the early 1980s, a safety scandal erupted over one of those medications. E-Ferol, a high potency vitamin E injection, was linked to serious reactions in some 100 premature babies, 40 of whom died.

In response, the FDA started a program to weed out drugs it had never reviewed scientifically. Yet some medications continued to escape scrutiny.

One thing that should be made clear here is that we are not talking about so-called “off-label” use of FDA-approved drugs for unapproved indications. Off-label use is fairly common, and it’s a common fallacy that off-label use of drugs is necessarily not science- or evidence-based. Sometimes it is, and oftentimes it is not. It all depends upon the understanding of the scientific literature and the judgment of the physician doing the off-label prescribing. Although it is currently illegal for pharmaceutical companies to market drugs for off-label indications, it is not illegal for physicians to use them that way. Steve Novella wrote an excellent primer on the issues involved in off-label prescribing, which is beyond the scope of this post. Perhaps someday I’ll write a post giving my perspective on this issue.

What this issue all boils down to seems to be a morass of conflicting laws, conflicting regulatory requirements, and bureaucracies, more than likely aided and abetted by the muscle of pharmaceutical companies, which argue that the drugs they are marketing don’t require FDA approval because they were “grandfathered in” before the 1962 law. Another problem is that the FDA has no system to compile a master list of unapproved drugs and then work on getting them approved. Instead, it works on a “case-by-case” basis when there is a problem or a complaint:

“The problem I see is bureaucrats don’t want to make a decision,” Grassley said. “There is no reason why this should be such a house of mirrors when so much public money is being spent.” Grassley is considering introducing legislation to ensure that consumers are told when a medication is unapproved.

Which would not be a bad idea. In fact, it should be applied to supplements as well.

One other wrinkle is that many unapproved drugs are not dangerous; they are simply old drugs that have not been approved in the current formulation that they are being manufactured in. The FDA requires more than that the ingredient be safe and effective. It also requires modernization of manufacturing techniques and updating of the labeling. In an educational interview, Dr. Jason Woo, Associate Director for Scientific and Medical Affairs in the Office of Compliance for the Center for Drug Evaluation and Research of the FDA, explains:

Well, the way the law is written, it emphasizes that drugs not only should the drug ingredient itself be shown to have been safe and efficacious, but the manufacturing also needs to be modernized as well as the labeling. So, many of these drugs have been around for many years, for example, morphine is an example of a drug that has been around for 100s of years. However, the way that morphine was manufactured has changed over time and certainly the way the drug is labeled has changed. So, you have some manufacturers out there who continue to make the drugs without having submitted the information again of safety and efficacy to the Agency and again with the information that demonstrates they can manufacture the drugs safely and with the appropriate labeling information that will allow consumers and prescribers to use that drug safely.

Of course, one argument that is often used in favor of unapproved drugs is that anecdotal evidence supports their use. If you’ve been a regular reader of this blog, you know how reliable “anecdotal” evidence is in determining the efficacy of any medical intervention as a general rule, namely not very. Fortunately, Dr. Woo understands and explains why the FDA does not accept such evidence:

Well, for an unapproved drug product, a patient or prescriber may believe that a drug is safe or effective because of that individual experience, but FDA has found that the subjective experiences can be misleading and are really insufficient to establish a drug’s safety and effectiveness. In fact, when FDA first reviewed the clinical information available after the 1962 law change that required drugs to be proven to be both safe and effective, only 12% of the drugs reviewed were found to be effective despite the widespread use of many of these drugs by physicians based on their anecdotal experience, so FDA relies really on carefully designed clinical trials that weigh the risks and benefits of taking a drug compared with taking a placebo or another accepted therapy, and in many cases FDA finds that the original hypothesis that a drug is safe and effective isn’t correct. Carefully designed clinical trials have repeatedly demonstrated that the safety and effectiveness of drugs can’t be adequately established from anecdotal evidence or consumer or prescriber preferences. Another concern with anecdotal experiences is that even if there is no affirmative evidence of the safety problem with the specific drug that is not proof of the absence of a problem. We know safety and efficacy problems can be difficult or impossible to detect without well controlled studies in larger populations and drug failures or adverse effects may be masked by an individual patient’s disease or wrongly attributed to another cause, so indeed history has shown that reliance on physicians’ anecdotal clinical experiences are insufficient to establish a drug safety and efficacy.

This is, of course, what I’ve been saying all along. It’s also, of course, exactly the opposite of what both pharmaceutical companies and purveyors of woo argue, which is that anecdotal evidence should be sufficient to establish the efficacy and safety of their wares. The FDA may have many flaws and problems, not the least of which are inadequate resources to fulfill its mandate, but on this issue it’s in the right. Two things will likely have to happen before this problem can be resolved. First, the FDA will require more resources, which will allow it to compile an official list of unapproved drugs. Second, there will likely have to be new legislation that makes it clear that Medicaid may not pay for drugs that are not FDA approved. Finally, one additional policy change that could be helpful would be to require that drugs that are not FDA-approved be clearly labeled as such, the thought being that few, if any, third party payers would reimburse for such drugs if it were made more clear that they are not FDA-approved.

Of course, one other thing that I’d also like to see happen is the repeal of the DSHEA. After all, there is no reason other than the political clout of CAM-friendly legislators such as Ron Paul, Tom Harkin, and Dan Burton than any valid policy or scientific rationale, or at the very least include supplements in any law that requires labeling of unapproved drugs. I realize that will never happen, but a guy can dream, can’t he?