Unapproved drugs: FDA gets tough on “grandfathered” active ingredients

Over the last year or so, the US FDA has grown tougher on withdrawing prescription and over-the-counter drugs that have not met the modern burden of proof for safety and efficacy that was officially required by the 1962 passage of the Kefauver-Harris amendments to the 1906 Federal Food and Drug Act (WaPo overview from June 2006 here). This legislation not only gave us the modern structure of preclinical and clincal trials, but it also required that drugs sold previously between 1938 and 1962 had to meet this standard of proof of safety and effectiveness.
But, it didn’t make financial sense for these companies to be required to submit to the full battery of preclinical and clincal tests required of new drugs. So in 1966, the National Academy of Sciences convened a special group to assess the existing clinical literature on 4,000 of these drugs and the FDA took their recommendations to keep or ban these agents in 1968 by forming the Drug Efficacy Study Implementation (DESI) administrative proceedings. Very common drugs like aspirin and acetaminophen were “grandfathered” in under this literature review process.
Not well-appreciated was that the FDA did ultimately require companies selling these drugs to conduct prospective clinical trials within some ill-defined timeframe. Drugs like phenobarbital for epilepsy and chloral hydrate for sedation and alcohol withdrawal are two examples of drugs that continue to be sold as “unapproved” drugs. However, there was little financial incentive for a drug company to support such trials and the FDA had for many years a rather relaxed attitude toward these agents. But, as the FDA notes:

“[F]or a variety of historical reasons, some drugs, mostly older products, continue to be marketed illegally in the United States without required FDA approval. Many healthcare providers are unaware of the unapproved status of some drugs and have continued to unknowingly prescribe unapproved drugs because the drugs’ labels do not disclose that they lack FDA approval. Often these drugs are advertised in reputable medical journals or are included in widely used pharmaceutical references such as the Physicians’ Desk Reference (PDR).
“While some unapproved drugs may have benefits, there may also be risks. Patients and health professionals should carefully consider the medical condition being treated, the patient’s previous response to the drug, and the availability of approved alternatives as part of discussing the benefits and risks of any unapproved treatment. “

Continuing this action against unapproved drugs, the FDA announced last Friday that they were banning suppositories containing the old drug, trimethobenzamide, often used to treat nausea and vomiting. The FDA cited that there was no evidence for effectiveness of trimethobenzamide when used in suppositories and that many other products for nausea and vomiting are available as both prescription and OTC drugs. (Addendum 13 Apr: Reader chezjake notes below that oral and injectable forms of trimethobenzamide remain on the market because their efficacy has not been questioned.).
Sometimes these actions result from more than just many more options being on the market. Last summer, the FDA removed products containing the antihistamine, carbinoxamine, from the market due to the unusual sensitivity of children under age 2 to this drug that resulted in 21 deaths reported to the agency.
This FDA link gives a detailed overview of the unapproved drugs initiative, including a search engine that allows you to search for your drug to determine if its ingredient(s) is/are formally approved. (For fun, compare phenobarbital with aspirin – note that while phenobarbital is no longer approved, FDA is not likely to remove it because thousands of patients still use it, effectively, for epilepsy).
Interestingly, Tuesday’s Wall Street Journal Health Blog noted that this renewed enthusiasm against unapproved drugs has provided a market advantage to Adams Respiratory Therapeutics, the company that markets Mucinex brand of the expectorant, guaifenesin (“Mucinex in, mucus out.”). A story in Brandweek reveals that the since the makers of Mucinex properly jumped through FDA hoops to get approval for this old drug, FDA was able to order their five competitors to stop selling guaifenesin products.

Mike Valentino, Adams’ CEO, told investors at Merrill Lynch’s Global Pharmaceutical Conference in New York in February, “Through lobbying efforts . . . the FDA created a draft policy. And that draft policy basically said once an approved [drug] comes into a therapeutic area, the other products would be removed after a grace period.”

As a result, Mucinex is now at about $123 million of annual sales, with another $80 million expected from their new product initiatives.
So, there are indeed some old drugs out there that can meet the burden of proof to be reclassified from unapproved to approved. Unfortunately, neither the Brandweek article nor the WSJ Health Blog stated how much it cost Adams to gain FDA approval for guaifenesin. But it was most certainly far less than the $800 million figure often quoted for new drug approvals.
You can bet that drug manufacturers are looking at the cache of unapproved drugs to see if they can work some marketing wizardry to create similar financial magic.


6 thoughts on “Unapproved drugs: FDA gets tough on “grandfathered” active ingredients

  1. First, a minor correction. You said above, “Continuing this action against unapproved drugs, the FDA announced last Friday that they were banning suppositories containing the old drug, trimethobenzamide, often used to treat nausea and vomiting. The FDA cited that there was no evidence for effectiveness of trimethobenzamide and that many other products for nausea and vomiting are available as both prescription and OTC drugs.”
    I believe the FDA only said that there was no evidence for effectiveness of trimethobenzamide *when administered as a suppository.* They did not pull the oral or injectable forms. (It just so happens that I was the person who, working for Roche at the time, compiled the complete bibliography of all published literature on trimethobenzamide worldwide for submission to the FDA under the requirements of the Kefauver-Harris amendments.)
    Also, correct me if I’m wrong, but I suspect that in the guiafenisin case (and any others that may follow) the FDA has not necessarily permanently pulled the non-Adams products. They can’t give Adams the equivalent of patent protection. All they can do is insist that all other brands must prove that their formulations/dosages are as safe as and can provide equivalent blood or serum levels to the Adams product. In other words, since Adams has proved the efficacy and basic safety of guiafenisin, all the others have to prove is that their products are fully equivalent to Adams product. That would call for much less investment of time and money than what Adams put into it.

  2. This is what happens when one has a group of very experienced and detail-oriented readers. Thanks, chezjake, for clarifying that trimethobenzamide lacks efficacy in suppository form but not p.o. or as a parenteral. I was offered a job at Roche in my younger years; perhaps we would’ve been co-workers.
    Your clarification on the Adams case is also correct: any company selling guaifenesin-containing products is free to submit a formal application for approval, so pulling the other products was not a permanent action. But Adams is certainly taking advantage of this lag time – stopped by the pharmacy last night and saw Mucinex going for $21 for a 40 tab box!
    From FDA’s Q&A about marketing of approved and unapproved products containing the same drug:

    How does FDA intend to handle situations where there is an approved and unapproved version of the same drug?

    In deciding whether, and in what manner, to take enforcement action against an unapproved drug, FDA will consider, among other factors, whether there is also an approved drug available to serve consumers who need the drug. Allowing continued marketing of unapproved drugs that compete against approved counterparts challenges the integrity of the drug approval system that is designed to avoid the risks associated with potentially unsafe and ineffective drugs. Allowing continued marketing of these drugs also undermines the incentives needed to conduct the scientific studies to determine the safety and effectiveness of drugs, which benefits the public health.

  3. Perhaps in 2026 they will withdraw the drugs approved between 1990 and 2010 that were based on manipulated research, conflicted academics, ghostwritten by companies, and then approved by dismal regulators who treat those they regulate as clients.
    Let’s read the rollcall Z oloft, C isapride, P axil, Actonel, Z yprexa, B aycol, V ioxx ………….
    “Modern burden of proof for safety and efficacy” — I don’t know — the evidence seems to indicate otherwise.

  4. If the FDA claims that trimethobenzamide (Tigan, etc.) is ineffective – in rectal suppository form – for nausea and vomiting , it is going to astonish physicians (especially pediatricians) and pharmacists who have used and dispensed said drug over many decades.
    The suppository drug is safe and apparently effective, as evidenced by years of clinical use. Perhaps its “sin” is that it is no where near as expensive as newer branded N/V treatments in children.

  5. This is why our system of government is great. You have three competing interests: consumer, producer, government. When nobody is corrupt, the system is market-driven and works.

  6. I am an electroneurodiagnostic technologist at the only hospital in Tucson that uses chloral hydrate for sedation for EEG and BAER examinations, age groups being 1-4 years old. Since chloral hydrate liquid is nasty-tasting, our conscious sedation nurses prefer suppository application rather than being spewed with the liquid form. Our pharmacy is no longer able to supply us with the suppository form, and we have fewer successful EEG and BAER examinations.

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