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?


  1. #1 Citizen Deux
    November 24, 2008

    It would be an interesting exercise to note which “legacy” formulations were abandoned by the major pharmaceutical firms as ineffective, unreliable or downright dangerous to their bottom line. I had the pleasure of touring a small drug store’s miniature museum in which several archaic medicines with big name labels were on the shelf.

    It’s time for the FDA to clean house – or at least get tough with the sketchy realm of supplements.

  2. #2 Abel Pharmboy
    November 24, 2008

    Back when I was a wee embryonic bloggling writing under the benevolent guidance of my blog mentor Orac, I said something similar:

    And, yes, even historic evidence of efficacy is a reasonable expectation that is superior to the current situation. In 1962 when the US passed retroactive efficacy rules for marketed drugs, some prescription and over-the-counter remedies in use between 1938 and 1962 (such as acetaminophen) fell in a state of limbo. As a result, the US FDA asked the US National Academies of Science to convene an expert panel to review the literature on older remedies that could not be grandfathered in under the new guidelines passed in 1962. In 1968, the FDA formed the Drug Efficacy Study Implementation (DESI) that incorporated the recommendations of the NAS investigation of effectiveness of drugs marketed between 1938 and 1962. This permitted older drugs to be approved under an expedited process called an Abbreviated New Drug Application (ANDA). Then-over-the-counter drugs were evaluated by a similar retrospective mechanism beginning in 1971.

    Frankly, I don’t see why such a commission could not be assembled today in the US for herbal medicines, although there would be a very low percentage of remedies marketed now that might pass such scrutiny.

    Interestingly, the unapproved drug status of the expectorant, guaifenesin, was wisely exploited by Adams Respiratory Therapeutics with the abbreviated approval for OTC Mucinex. On 25 May 2007, FDA actually went after prescription products containing guaifenesin since Adams was the only manufacturer that had been granted approval. This action has drawn sharp criticism in the business press and pharma marketing blogosphere – perhaps because Mucinex is now almost a $200 million/year product.

  3. #3 Ranson
    November 24, 2008

    This issue hits home with me very directly, working for a contract pharma manufacturer. These DESI drugs, as they are known, are spectacularly common (anyone ever use a benzoyl peroxide acne cream?), but the FDA is beginning to make a big sweep on them. They’re going after the safety end of the spectrum, first, and they are laying the smack down on manufacturers that don’t close out DESI products deemed unsafe. One recent one was topicals using papain to remove dead or diseased tissue. We had stopped our manufacture some time back, but it still chills me a bit to see one of our items shut down. I think hydroquinone is soon to be on the chopping block — it’s been under scrutiny for some time.

    These drugs aren’t just Rx — tons of OTC formulations are DESI. This is a huge project for the FDA, but they are steadily working to fix it. Manufacturers have to take it seriously, because people are being shut down (with great prejudice) for for failing to comply when the FDA says “no” on a DESI.

  4. #4 Ranson
    November 24, 2008

    Dangit, Abel, stealing my thunder when I actually have substance to contribute. *mumble**grumble* 😉

  5. #5 chezjake
    November 24, 2008

    Speaking as one who was on Roche’s team that assembled all the data, scientific literature, etc. in response to the 1962 change of laws, I have a couple thoughts on Orac’s and Abel’s comments.

    First and foremost, back in 1962 there was *no* requirement from FDA to provide any information whatsoever on formulations of existing products. We were required to provide massive bibliographies of every paper in the scientific/medical literature that so much as mentioned either a brand name or generic name of a product — world-wide, no matter who had manufactured and formulated it, but not required to identify papers that referred specifically to our own or any other formulation. Thus, any recognition of those products by FDA did *not* reflect use of a specific formulation. We did compile separate information on different dosage forms (oral vs. injectable in particular) where it was possible, but no data was asked for or submitted about differing formulations for any dosage form. (As an example, if I recall correctly, our bibliographic listing for Prostigmin/neostigmine ran to over 1200 pages, with no annotations.)

    It’s also obvious that FDA is being highly selective about which products it re-examines under newer policies. So far as I’ve been able to determine, there is *no* FDA approved formulation of a standard (5 grain/325 mg) aspirin tablet — correct me if I’m wrong.

    Of course, because of the fact that prescribing information (on a prescription) specifically does not refer to any specific formulation, a physician writing a prescription for one of these older generic drugs (e.g. morphine sulfate) has no idea whether a pharmacist will fill that prescription with an FDA approved formulation of that drug. In fact, the pharmacist probably has no idea of whether the generic formulation he/she has in stock is FDA approved or not. Nothing under current law requires either physician or pharmacist to even be aware of whether a formulation of these older drugs is FDA approved, and there is no requirement for labeling to show FDA approval.

  6. #6 raiseya
    November 24, 2008

    For a number of years I did research on food processing additives. Along similar lines to this blog entry is the GRAS list in 21CFR30. This is the “generally recognized as safe” list of ingredients which can be used in food or in contact with food. Polyethylene is one example (stretch wrap). Polysorbates are another. Polysorbates are oily liquids derived from PEG-ylated sorbitan (a derivative of sorbitol) esterified with fatty acids* — which are used in making ice cream for example. These materials, and many more, are also ‘grandfathered’ into the US food supply.

    Here are two fun ones. Decocaineized coca leaves are on the GRAS list. I have a strong suspicion that the ‘Coke’ formula uses this…since the original formula had cocaine in it. Dimethyl silicone oil is also on the list. This can be found in a popular OTC antacid under the ingredient name ‘dimethicone’. This is essentially the same stuff that was used in breast implants (remember all the lawsuits?).

    There is probably a nice set of studies due on the GRAS list as well.

    Note: * from the wiki entry on polysorbates

    Disclaimer: I cannot prove the use of either coca leaves or dimethyl silicone oil; a good analytical chemist with a budget probably could 🙂

  7. #7 Ranson
    November 24, 2008

    @ raiseya

    While the leaves would be a hard proof, the dimethicone wouldn’t take much. Get your hands on the MSDS for the DS oil, though, and it’d probably list dimeticone as a trade name. Hell, Dow would probably provide you with a sample C of A on any of their silicone products under the dimethicone trade name. That’d list chemical composition and or give the name you’re looking for.

    To be honest, I could probably walk across the building and find out. I may do that for my own edification, later.

  8. #8 Nentuaby
    November 26, 2008

    I know I’m a latecomer, but there’s nothing to prove there. Coca Cola is publicly acknowledged to contain the leaf it’s named after.

    In a telephone interview from Coca-Cola’s Atlanta headquarters, Randy Donaldson, a company spokesman, said, ”Ingredients from the coca leaf are used, but there is no cocaine in it and it is all tightly overseen by regulatory authorities.”

    New York Times

  9. #9 Eric Blood Axe
    November 26, 2008

    Came across some woo for you at Nimukta. Sorry I don’t do referrals.

  10. #10 dianne ranes
    June 29, 2010

    Justice denied in Iowa. Feb 4, 2002-today June 29,2010 Centerville Iowa Bryan Ranes Palatal Myoclonus age 26 years old, 33 day non-disclosed prescription poisoning. Drug-Free- former Presidential Physical Fitness award,- college short-stop,- Iowa’s all time best high school baseball-shares a national baseball record, developed sore throat sold old formulation containing phenylpropanolamine. ICD 9 CM verified neurological damage. Damage to olive. Developed ear clicking and hyponatremia second week. Movement in palate three months later. Ear clicks diagnosed rodchester, palatal myoclonus omaha. 333.2
    Shame,Shame, Shame on GREEDY Pharmaceutical manufacturer with a dark tainted history. Mad-cow tainted polio vacines and diversion of his sinus products into the hands of methamphetamine addicts in over 10 states. Remember Washington’s revolving door? No Commissioner at FDA during 2001. You got it.

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