Why Do I Love Drug Regulation? Simple: It Keeps Us Safe

4/15/11

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that drugs be tested for safety during pregnancy before they can be approved. Kelsey received an award from President John F. Kennedy for her actions, and in 2010 an annual award was established in her name at the FDA (with Kelsey being the first recipient). Incidentally, thalidomide was more recently developed into an effective treatment for multiple myeloma and for treating lesions in leprosy patients. Its use is now very carefully controlled to keep it away from pregnant women.

Many of you reading this are probably thinking, “These stories are all from years ago. What does this have to do with modern medicine? No one is selling snake oil these days. The only drugs on the market now are those that have been approved by the FDA.”

Unfortunately, this simply isn’t true. In 2006, the FDA started the Unapproved Drugs Initiative to remove unapproved prescription drugs from the market, which are mostly medicines used for coughs, colds, and allergies. The goal is to eliminate prescription medicines that have not been evaluated by the FDA for “safety, effectiveness, or quality” and which are being sold illegally. Efforts to have these drugs yanked off the market are continuing, and the list is surprisingly lengthy, with hundreds of unapproved medicines on it.

Diethylene glycol made a return visit to the annals of medical infamy in 2007 when The New York Times reported it was discovered as a counterfeit substitute for glycerin in cold medicines imported into Central America from China. It also turned up in medicines given in China and in Bangladesh. Once again, hundreds of innocent people died. This was not an industrial accident. Laboratory reports and licenses were forged in order to deceive pharmaceutical manufacturers into buying the counterfeit glycerin.

Not all problematic drugs are made by third world manufacturers. It was discovered in the late 1980s that several generic drug manufacturers had submitted falsified data on applications for their generic medicines. One approach they took to gain approvals: substitute the branded drug for testing in place of the generic drug they were planning on manufacturing. The investigation led to the suspension or recall of dozens of drugs.

Drugs that don’t work are not necessarily harmless. There are three problems associated with them. First, they may actually be toxic and injure you. Second, taking a worthless drug, even if it does no harm, may inhibit you from taking a drug that might actually provide you with some benefit. Finally, even if the drug you are taking is harmless, you are wasting money that could be used to enhance your well being in any number of ways.

Many people are familiar with the first three stages of drug approval in which a drug must clear hurdles of safety and efficacy. In some cases, drug companies are granted accelerated approval for their cancer drugs in exchange for a promise that they will complete follow-up studies to ensure that these medicines actually work. Unfortunately, pharma companies are often either late in doing these confirmatory studies, or they don’t do them at all. A 2005 study showed that follow-up data was submitted in only 9 cases out of 26 accelerated approvals for cancer drugs, some of which were shown to have serious side effects after they were approved for sale. And when drug companies do generate the data, it sometimes shows that the drug does not have a survival benefit. This happened with AstraZeneca’s non-small cell lung cancer drug gefitinib (Iressa), which led the FDA to restrict access to this medicine in 2005.

Takeda Pharmaceuticals recently announced that it is pulling its drug serrapeptase (Dazen) off the market after selling it for 40 years in Japan. The reason? Tests of the drug in 2009 revealed that it was completely ineffective; there was no difference in … Next Page »

Stewart Lyman is Owner and Manager of Lyman BioPharma Consulting LLC in Seattle. He provides strategic advice to clients on their research programs, collaboration management issues, as well as preclinical data reviews. Follow @

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  • http://Xconomy KBrasel

    As usual, another great report on medical/Biotech research from Stewart. If only everyone backed up their reports with as much data and examples as I usually find in yours.

  • http://austinpreclinical.com Eric Austin

    Good stuff as usual Stewart. Makes me feel good to be a toxicologist. Sometimes people need to be reminded that we are in this business ultimately to help save lives. Sometimes that mean we need to prevent bad drugs from getting to the market.

  • KFowler

    I wholeheartedly agree with Stewart. Having worked in Pharma for 30 years I have often thought, “thank heavens for FDA”. It would be tragic if FDA succumbed to the intense pressure to gut regulations that we see in other industries (think oil, mining, and nuclear power).
    This is a great article.

  • Tobin Arthur

    Stewart – I certainly appreciate your defense for the role of the FDA, but I think it misses the point made by Forbes and a litany of other leaders calling for a revamp of the organization. I have not heard anyone, including Forbes, advocate for zero oversight in pharma or other big industries for that matter. Rather, the criticism is directed at the inefficiency and flaws in the organization. They call for more efficient and effective oversight. The intentions of the individuals involved in the organization are not the target in any of the criticism I have seen. Rather, the prime criticism is directed toward the waste and incompetence that grows naturally in bureaucracies like the FDA. Finally, as a finer point, several of the historical examples you shared, and there are plenty more, highlight the fact that watchdogs, a neutral press and the market-place all play equally if not more fundamental roles in weeding out poor drugs, food, cars etc. Regardless, the historical overview was interesting and useful. Thanks for taking the time to provide it.

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  • http://www.lymanbiopharma.com Stewart Lyman

    Tobin, thanks for your comments. Let me reiterate a few points. Forbes (and many others) rail against the FDA and its “capricious hurdles “ that have made clinical trials “cost prohibitive”. It’s unfortunate that he offers no data to back up this claim, but even if he did, the numbers would likely be debatable since they are generated by industry and there is no way to independently confirm their accuracy. The concept of eliminating flaws and inefficiencies in an organization is one that I hear often about many different Government programs and organizations, including Medicare, Social Security, EPA, etc. It is also the formulaic answer to how we are going to save money “We will eliminate the waste and inefficiencies and save millions of dollars”. The fact that this never seems to happen either indicates that waste and inefficiencies are not really the problem, or that these elements cannot readily be removed from these types of organizations.

    A bigger concern for me is a failure to place any of the responsibility here on pharma itself. Why isn’t pharma working on developing new antibiotics? If the potential revenue from an antibiotic can’t begin to fill the earnings hole left by the patent expiration on one of their multi billion dollar blockbuster drugs, why would you expect them to work in this area? As I pointed out in my discussion, I believe that they have chosen (for sound financial reasons) to direct their resources towards chronic diseases like heart disease and arthritis, where they can sell you a pill to take every day for the rest of your life. Given the size of the patient populations, this is much more profitable than selling you a 10 day course of antibiotics. That is why I stressed the need for financial incentives to change this behavior by pharma, which is rational but which ignores a strong public need. We can look at this in a way that should be understandable by a magazine publisher. Do you put more resources into selling subscriptions, where you can get up-front money from a reader for years, or do you focus on selling single issues on the newsstand? Forbes and other magazines use both approaches, but I would guess much more money gets pumped into selling via subscription.

    One final point. The press and other watch dog organizations do play a role in weeding out poor drugs. However, this is usually done AFTER the damage has been done i.e. patients have been sickened or died. This is the advantage of having a top-notch regulatory organization: they should hopefully catch many of the problems while the drugs are still in clinical trials. It was much better to have Frances Kelsey keep thalidomide off the US market than to read a newspaper expose describing how many babies were harmed here as a result of the drug.

  • Alexander Zayachkov

    The only reason that the FDA protects us, is because all prescription drugs are toxic. If they were not toxic, there would be no need for FDA review and approval. Why are drugs toxic? Because they are either synthetic, or denatured “active ingredients” from naturally occurring substances. The greatest true medicines in terms of effectiveness and safety come directly from nature: Opium, Cannabis and various molds. That’s not meant to imply that everything provided by Nature is safe or side-effect free. But Opium’s capacity to alleviate pain is enhanced and balanced by other constituents that are lost when the natural substance is refined (or killed) to produce morphine and related active ingredients.

    While the Pharmaceutical Industrial Complex would like us to believe that only “modern science” is responsible for our relatively robust health, and longevity, the devil is in the details. Remove infant mortality from the equation and life expectancy has remained constant for the last 2000 years. Thanks for nothing, Big Pharma.

    If each of us accepted responsibility for our own Health, (and not everyone else’s) we wouldn’t need an FDA to protect us from the poisons peddled to us.

  • http://www.enterey.com Mike Ferletic

    Stewart,
    I enjoyed the article. I’ve included many of the historical examples in basic GMP training that I deliver for Pharma companies. These are vivid examples of why the FDA is necessary and why pharma/biotech companies must perform their business in such a methodical way to ensure safety.

    That’s not to say there isn’t room for improvement. In that regard, I like your perspectives on how to incentivize future innovation and hope we see continued output from this industry.

  • http://www.testwell.com smartalek

    @ Mr Tobin Arthur 4/15/11 6:09 pm “watchdogs, a neutral press and the market-place all play equally if not more fundamental roles in weeding out poor drugs, food, cars etc.”

    Mr Lyman’s response to this, accurate and crucial as it is (their impact is usually ex post facto for at least some lucky souls), is but one of several problems in relying for product safety on players other than the “heavy hand of gummint regulation.” (I should really add “intrusive,” “job-killing,” “elitist,” and “nanny-state” for my rhetoric to be fully up-to-date — and “busybody” or “know-it-all” to reflect the recent Palinization of the discourse.)
    That is, in our current legal, cultural, and media environments, “watchdogs” and “a neutral press” may no longer be adequate (if they ever were) safeguards.
    Both of these mechanisms presume and require open access to product information. But with firms of sufficient size and resources, the power to ensure long-term non-disclosure often lies with the firms.
    Many readers might recall one of the most infamous instances of this: the Firestone-tire / Ford SUV controversy that blew up (as it were) in 2000. The problem of often-fatal catastrophic tire failure had initially been seen in small numbers as far back as 1991. The rate of failures had become significant by 1993. But partly because every successful legal claim brought against ether firm entailed a non-disclosure agreement as part of the settlement (and not all claims were successful), there was virtually zero public awareness of any problem — and well over 100 preventable fatalities occurred before the problem hit the news.
    (The rate of legal claims in the first place would of course have been artificially lowered by the mis-perception of many victims that their experiences were unique.)
    Another familiar example would be how the dangers of asbestos were kept hidden from the public for decades for similar reasons, and by similar means.
    These, of course, are fights that we know of (albeit very late in the day w/r/t when the damages occurred).
    The Lord alone (well — and possibly some lawyers) knows how many similar — or worse — travesties might be going on around us, even as we speak, of which we have no clue… yet?
    The media can certainly not be relied upon to play the romantic role of crusading fighters for justice — not when a mere 6 multinational conglomerates now control over 70% (IIRC, it’s actually well over that) of the news-distribution networks upon which most Americans rely for their understanding of the world.
    How likely are NBC, MSNBC, or CNBC to dig overdeep into the problems at Fukushima, when corporate owner GE made the reactors in question?

  • Tobin Arthur

    I find the faith and supportive rhetoric of @smartalek curious. While perfectly happy to malign corporations and the vast global media complex, the support for the FDA & its brethren appears un-checked.

    Stewart – The lack of agency stream-lining a la the FDA, FCC, EPA etc. is largely the result of a lack of political will. Anecdotally, I have several friends in senior agency positions. They joined the govt with the best of intentions, but they quickly became caught up on the Washington power/money grab. Still great folks….who punch in at 10ish and out by 5ish and count their days until their full fed pension kicks in. In the aggregate, they are part of the non-defense governmental spending cost that has doubled as a % of GDP since 1970, and a large portion of that in just the past few years. It’s unsustainable as a cost to the taxpayers, not to mention private industry. This topic, I realize is complex and those like @smartalek would rather assign it to the conspiratorial or absurd rather than focus on metrics, costs etc. There are certainly volumes of studies available on the costs and arguably inefficiencies of agencies…but as you suggest they are not easily reigned in.

    My expertise is in health care. There are enormous inefficiencies in the industry. For example, health care payments….they represent somewhere between $3 and $12 for every $100 in healthcare spend. Outrageous. Especially when you compare those costs to the transaction costs in an industry like banking. The problem hasn’t been solved because it’s complex. You cannot conclude that simply because the problem lingers that it is an unsolvable problem. (@smartalek would probably want to blame the costs on Jeffery Immelt or Rupert Murdoch)

    Finally, examples like thalidomide are important, but they fail to highlight as part of the equation the hundreds of thousands of patients sitting on the sidelines with terminal illnesses waiting for the FDA to approve therapies that may give them a better chance of survival…or not.

    As you correctly indicate, unless the financial incentives are maintained/protected to create and test new therapies, pharma and investors will move their resources elsewhere. (there is another entire argument for increasing the patent life-span of at least certain drugs in order to build more incentive for capital investment.)

  • Ted

    There is another side of the FDA’s role that’s worthy of discussion.

    The FDA, like many regulatory agencies, exhibits a powerful leveraging effect. Regulatory compliance, quality systems and record-keeping does not provide for scintillating discussion amongst the chattering classes. Yet, the FDA provides both the guidance, and the periodic audits that make pharmaceutical production both safe and well-characterized. The bulk of these costs are borne by the regulated industry, in clear accord with the expectations of our ‘mixed capitalist’ system.

    Unfortunately, leverage drops with the frequency of audits. If you stop patrolling the highway, people start to speed. If you stop auditing production facilities, cleaning validations start to fall off. If you stop reviewing quality systems, people quit updating their SOPs. The safety afforded by this system is incalculable, yet it’s easy to calculate how much you can save cutting it back.

    The unfortunate trap is when agencies are cut to the point where they’re driven to produce “results” with every audit. Once again, I’d draw analogy to the driving scenario: you’d rather get pulled over when the cops are simply looking to improve safety rather than looking to improve the state’s revenues…

    -t

  • http://www.yourcornerpharmacy.com Rick

    As somebody on the brink of receiving a Pharm.D., let me reply to your antibiotic question – Pharmaceutical companies aren’t currently working on new antibiotics because prescribers have overutilized the shite out of them for the past 50 years, rendering a shocking number of them non-efficacious because bacteria have grown resistant. There are only so many products in the natural (and synthetic) worlds known to be bacteriostatic/cidal- and they all exist in antibiotic forms already. New options and new discoveries that are made often turn out to have poor selective toxicity and are too injurious to humans. Personally, I think in 100 years, people will again be routinely dying from things that the human race thought it had mastered and subjugated in the 20th century.
    One last thing – I don’t think that because a profit-seeking venture exists, there is any inherent nature for it to cause harm. I don’t get this paradigm in which people assume that any and all private enterprise, by default, automatically requires the heavy hand of Nanny Government to regulate it, tame it, and lasso it. I don’t recall that being in the Constitution, or a concern of any of our founding fathers. I imagine the FDA would be much more efficient if it were a private enterprise.

  • Greg Heberlein

    Of Stewart’s many informative columns, this struck me as the finest. It was well-researched, affected almost everyone, and was especially readable for the layman. Keep up the good work.

  • http://www.lymanbiopharma.com Stewart Lyman

    A few final comments to some of the posts above. Thank you all for sharing your thoughts and for the feedback. Tobin, while I sympathize with those individuals who are desperately ill and wanting new medicines, they will only be helped if the medicines they need can be shown to be safe and effective. I know of a drug that was being developed for a terminal illness and was hyped by the company that wanted to get it on the market. The FDA advisory panel that reviewed the drug voted 9-0 against its approval and had virtually nothing but bad things to say about how poorly the trial was conducted and the data misinterpreted. The FDA followed up by refusing to approve the drug. Patients don’t need these kinds of poorly tested medicines. Hopefully they can participate in compassionate use programs to allow them access to drugs that are under development without draining their wallets. We must be vigilant in watching out for charlatans who prey on these individuals with outlandish promises in order to separate them from their money.

    Rick, I am not sure what you are arguing here. The point that antibiotics have been over-utilized is well taken, but this is an area that is not regulated by the FDA. You seem to be against regulation of the type that I am advocating for in my article, but this increase in drug resistant bacteria could have been reduced by the very regulation that you oppose. I would agree that just because a venture is profit-seeking doesn’t make it inherently harmful. Such organizations don’t require regulation until and unless they are shown to be dangerous or abusive, which is exactly what the examples that I cited above illustrate. Drugs didn’t use to be regulated, but companies that sold worthless or dangerous drugs, devices, and procedures forced the government to impose various regulatory laws throughout the last century to protect the citizenry. Large numbers of people were being killed or injured by irresponsible (and sometimes criminal) behavior. I doubt there are many people (aside from those who wouldn’t mind exploiting you) who long to go back to the bad old days of unregulated medicines.

  • http://austinpreclinical.com Eric Austin

    I have been entertained by the discussion…even the more political diatribes and digressions have been “enlightening” if a bit off topic.

    I do not think anyone would argue that the FDA is an inefficient organization. Considering the fact that it has a hard enough time keeping the place staffed with qualified personnel, being a government agency it is at the mercy of typically poorly informed policy makers with personal agendas that might not jibe with efficient drug development.

    I attended a conference last December and the keynote speaker discussed many of the concerns that we all share with the difficulties with developing new drugs. One point he made that piqued my interest was that he said one way that drug development could be sped up would be by enlisting informed patient advocacy groups. He discussed the early days of the AIDS crisis and how patient advocacy groups pushed the regulators and policymakers to speed potential therapies to market, but with the caveat that the patients would have to bear some of the risk burden themselves. I am not saying that all drugs should go this route, but it might be advantageous for patients suffering from life saving illnesses to utilize the same risk/reward discussions with the proper authorities to help push the process a bit faster and possible develop ways to build some efficiency into a painfully inefficient process.

  • CMCguy

    Its hard not to view FDA as an inefficient bureaucracy that follows political whims and operates continually in crisis to crisis mode. I do not attribute fault so much to the staff as more reflects resource limitations vs. expanded responsibilities from Congress/Admins that occurred for past several decades.

    While the FDA and Global agencies do play a vital and necessary role you seem to present a one sided characterization of Industry as bad guys to counter Forbes. I would not suggest the FDA as villains however do view as significant inhibition to innovation in medicines. Regulation is required for proper development and control but there can may be a case made for excessive-regulations and/or inconsistent applications that cause Industry to expend resources for activities of low true value. Many things are done as simplistic matter of course to satisfy info required by FDA without assessment of a true need or overtly to check off the To Do list. A prime example may be FDA has become focused on stringent Statistical Significance for clinical trials results that must be predefined and may sound good/objective yet potential benefits to patients gets taken out of consideration. PIII studies have gotten bigger as consequence which directly increase overall costs. Unfortunately there is an adversarial climate between Pharma and FDA that some view as should be even greater, whereas if there could be more direct collaboration in the process both side would benefits.