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Comparative Drug Research

The latest issue of the BMJ contains an editorial recommending that regulators (this is in the UK, but the argument applies in the US and elsewhere) should require pharmaceutical companies to provide research on direct comparison to existing therapies as part of the approval process. The authors, Sorenson, Naci, Cylus, and Mossialos, write:

When a drug comes to market, evidence on the comparative risks and benefits is needed to help regulatory authorities to safeguard public health from inferior and unsafe treatments, to ensure that health technology assessment agencies and payers make funding decisions based on the best available evidence of different treatments, and to aid clinicians’ and patients’ understanding of what therapies work best and their appropriate position in the treatment pathway.

They make a persuasive argument, but there are some interesting angles to this topic.

Comparative efficacy research is definitely valuable, for all the reasons stated by the authors above. In order to get approval, typically a new drug has to demonstrate that it is safe and more effective than a placebo treatment. For many common indications there are also often more than one drug for the same indication. Therefore there may be several drugs approved to treat migraine, gastric ulcers, hypertension, etc., all of which have been compared to placebo, but perhaps not to each other (at least not prior to approval).

Clinicians, therefore, may have difficulty in comparing available options. You can compare the relative effect size with respect to placebo, but this is fraught with confounding factors. No two trials are exactly the same: outcome measures may be different, the subject population may be different, etc.  and therefore comparing the results of two different trials is problematic. There is no substitute, therefore, for a head-to-head comparison of two or more drugs (or any treatments, for that matter) in the same trial.

The issue is also not simply a matter of which drug is better – each may have different strengths and weaknesses, or be more efficacious or safe in different subpopulations. Comparitive efficacy research is often performed, but it is done post-market. The authors are advocating that such research be required pre-market. The primary criterion they are recommending is lack of inferiority – demonstrating that the new drug is at least as effective as existing treatments.

There are advantages and disadvantages to such regulation, in my opinion. The advantages are outlined above – more information for clinicians, regulators, and payors that cannot be obtained any other way. Further they argue that pharmaceutical companies are often reluctant to initiate or sponsor head-to-head research because it is risky for them if their product comes out on bottom. They would rather have ambiguous evidence that all sides can spin to appear to favor their product.

The one potential downside I see is that it would make the drug research and approval process more expensive and longer than it already is. This could delay or even prevent the introduction of new effective drugs to the market. This is always the trade off – the more evidence we require for approval the safer and better evidenced our drug market will be, but the higher the barriers to getting potentially effective drugs to patients. Would this new requirement (for comparative efficacy research) be worth the higher barriers?

Some have also criticized the practice of pharmaceutical companies producing “copy cat” or “me too” drugs for the market, simply to capture their piece of a lucrative pie. There is some legitimacy to this criticism – decisions about which potential new drugs to research are corporate marketing decisions, not decisions made on the basis of societal welfare.  (I am not criticizing the capitalist system we employ in the US for drug development – that is a separate issue I do not intend to explore here – I am simply pointing out one relevant consequence.)

However, I find it very useful to have multiple drug options for a single indication. There are always differences, and this allows for individualization for patients. Some patients may be allergic to one drug, so having another option is critical. And also sometimes one drug simply does not work in a patient while another “copy cat” drug may (perhaps due to genetic differences).

In the end, I find direct head-to-head comparative efficacy research highly valuable, but I am not sure it should be required pre-market. That may be one burden too many on the approval process. Perhaps we should explore other mechanisms to facilitate such research, such as funding independent academic comparative efficacy research (which happens now, but could be increased through funding). Regulations could even require pharmaceutical companies to participate in some way in such research of their drugs, by providing free drugs for the trial or even contribute to funding.

Posted in: Pharmaceuticals

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16 thoughts on “Comparative Drug Research

  1. Harriet Hall says:

    Another issue: sometimes a drug that is accepted as effective on the basis of early research proves on later study to be ineffective, or at least much less effective than was originally thought. If it has been accepted as a standard and a new drug is compared to it and found non-inferior, that may not mean much.

  2. windriven says:

    Two thoughts:

    “The primary criterion they are recommending is lack of inferiority – demonstrating that the new drug is at least as effective as existing treatments.”

    What about the case where the new drug is slightly less effective but offers fewer or much less severe side effects? It seems to me that the authors are looking for bright lines that might not always exist.

    “Some have also criticized the practice of pharmaceutical companies producing “copy cat” or “me too” drugs for the market, simply to capture their piece of a lucrative pie.”

    Multiple sources of similar pharmaceuticals should drive prices down as the companies battle for market share. Sounds like a win to me.

  3. cervantes says:

    The problem is that as soon as the companies get a drug approved, if it’s a potential big seller, they start aggressively marketing it. They will particularly do this when there is a well-established generic and they have created a “me-too” drug for which they now have exclusive marketing rights, but which actually may be no more effective, or even less effective, than the good old cheapo, which also has a well-understood risk profile.

    If there could be a two or three year moratorium on advertising and otherwise pushing newly approved drugs, I’d like your argument better. Unfortunately, our wingnut Supreme Court probably wouldn’t allow it.

  4. “What about the case where the new drug is slightly less effective but offers fewer or much less severe side effects?”

    or what if the accepted standard drug is slightly more effective, but costs 100 times more?

    What exactly would constitute a clearly inferior or superior drug? It must be a little more complex than a single point pass/fail test. Reality is often subtle and nuanced.

    Here’s an interesting hypothetical: What if standard drug A is fairly expensive to manufacture even after expiration of patents, for various reasons (rare or difficult to handle raw materials, time consuming, expensive process, etc). New drug B is slightly less effective, and initially more expensive due to the cost of development and patent protection. If drug B is refused approval due to its being less effective than drug A, it will never have a chance to reach generic production where it could could end up being significantly less expensive than drug A I don’t know how likely this situation is, but it’s interesting food for thought.

  5. Jan Willem Nienhuys says:

    May I point to

    http://blogs.nature.com/news/2011/09/reliability_of_new_drug_target.html

    It often happens that published research (into the effectivity of drugs, for example) is irreproducible – when drug companies start checking the literature. Vice versa (the pharma company’s research also not as good as they say) probably also happens.

  6. windriven says:

    @cervantes

    “They will particularly do [aggressive marketing] when there is a well-established generic and they have created a “me-too” drug for which they now have exclusive marketing rights,”

    Perhaps I misunderstand you but one cannot generally get exclusive marketing rights for a “me-too” drug. If a drug is patentable by definition it (or a new process for making “it”) is novel. If a drug is a “me-too” there has to be at least one more supplier or “me-too” becomes “just-me.”

  7. cervantes says:

    Me too drugs are unique compounds, they can indeed get exclusivity. They have similar biological action to existing drugs. Lipitor is a good example — Pfizer pushed it very heavily because it was a brand name competing with generics. It isn’t really any better.

  8. jmm says:

    “There are always differences, and this allows for individualization for patients.”

    How on earth could you possibly know that this is true for me-too drugs, in the absence of randomized studies that compare a group switching from one drug to a different one to a group switching from one drug to a different container of the same drug? This statement captures exactly the mentality that drug marketing exploits, but this mentality comes from well known cognitive biases in humans, not scientific evidence.

  9. nybgrus says:

    All very good points.

    @jmm:

    How on earth could you possibly know that this is true for me-too drugs, in the absence of randomized studies that compare a group switching from one drug to a different one to a group switching from one drug to a different container of the same drug?

    Put simply (and anyone correct me if I am off on this), it is anecdotal at this point. Many drugs are first line and if they don’t work you simply try others until they do. For example, ACE inhibitors and ARBs are more or less the same re: their efficacy as anti-hypertensives. I have idiopathic hypertension and was started on an ACE and got “the cough.” Many people don’t, but I did. So my doc switched me to an ARB. Then, over time (after I lost 75lbs and started eating better) my BP began to normalize I started getting hypotensive on my meds. Plus I was training for massive cycling races and getting insane cramps. So my doc switched me to a K-sparing diuretic (triamterene). Now I don’t need it at all.

    That is a pretty simple version of it, but essentially one drug simply just doesn’t have the clinical outcome you want in a patient and so you try another until it does. What this proposal is saying is to have actual data to make better decisions with stronger (and specific) a priori knowledge.

    What I really came here to say though is another thought on the benefit of having such legislation require the testing pre-market (I won’t get into the nitty gritty of what the actual rules would say – lets just assume that it is reasonably well worded and puts extreme pressure on “me-too” drugs or “same in class”). In my readings over the years (the history of Merck and The Billion Dollar Molecule come readily to mind) it seems that the innovation in drug development has decreased because it is simply too risky to try and come up with something completely new and class-defining. There is much more ROI on “me-too” and XR versions of existing drugs since those can extend patents and are “safe” to market.

    Perhaps making the barrier to those avenues of drug production higher it would stimulate more innovation in pharmaceuticals?

    I’m just tossing stuff out there and looking forward to reading comments on it.

  10. jmm says:

    @nybgrus, I am very skeptical about anecdotal evidence, as I hope many others at this blog are. But I do completely agree with you that higher barriers to drugs for which treatments already exist could well stimulate and redirect more useful innovation in pharmaceuticals.

  11. nybgrus says:

    @jmm: Don’t misunderstand me. I think everyone here agrees with that sentiment. I was simply describing the system as is: basically trial and error. The notion of doing the head-to-head trials is to ameliorate that reality and give us something besides anecdote and trial and error to go on when selecting from the various drugs that all do the same thing, but with varying efficacy and side effect profiles that we currently can’t fully predict. Even with head-to-head, that would just give us a better idea, and there would still be some degree (probably a fair bit for a long time to come) of trial and error prescription. Until we can actually do and understand genomic analytics for each patient and have data relating that to our pharmaceuticals there will always be that factor. The head to heads would just help make it more evidence based.

  12. Diomedes says:

    “Until we can actually do and understand genomic analytics for each patient and have data relating that to our pharmaceuticals there will always be that factor. ”

    Exactly. People are different. Their response to a drug for a given ailment will be partly determined by their genetic makeup. There are several drugs now in the “atypical antipsychotic” class. We know that people are less likely to experience certain side effects on some than on others (e.g., extreme weight gain). But that doesn’t tell us whether any given individual will fit the “most likely profile” of side effect X.

    Which leads me to a question: When designing these studies, is there an attempt to diversify the population the drugs are tested on, or are they all white Caucasians? There are benefits to both approaches, but I wonder which one is the standard operating procedure.

  13. daedalus2u says:

    The barriers to entry are so high, that they preclude the development of drugs for small markets or for markets that can’t pay high prices. That is why there are multiple boner pills and no new drugs for malaria.

    Because of antibiotic resistance issues, a “new” antibiotic that works via a “new” mechanism is going to be used sparingly so that resistance will not develop. Who wants to develop a drug that will be used sparingly?

    A good idea would be for government funded health care to enroll a fraction of patients automatically into relative effectiveness trials. There have been a number of effectiveness trials out of HMOs that used HOM patient data retrospectively. That is a way to get gigantic numbers, and gigantic numbers are needed to do effectiveness trials on treatments of near equivalent benefits.

  14. jmm says:

    It is very plausible that genetics could lead some individuals to do better on one drug, while others do better on another. But it is not proven. Before jumping to high technology, randomized trials of the sort I mentioned are what is needed. How much of improvements following the switching of drugs can be attributed to placebo effects? This should be answered with respect to placebo switching before we jump to any conclusions regarding the potential personalized genomics. Have any trials ever been done to answer this for any drugs?

  15. jmm says:

    I should also add that for me-too drugs, I don’t think differential response even passes the plausibility test particularly well.

  16. windriven says:

    @cervantes

    Your reasoning seems circular. The drug is a “me-too” drug because it performs similarly to existing drugs but it is an exclusive drug because there are subtle molecular differences.

    An alternative explanation might be that the small differences in fact do matter. To continue with the statin example you mentioned earlier, Pfizer’s Lipitor and Bayer’s Baycol are both statins. The Pfizer drug is a blockbuster while Bayer withdrew Baycol a decade ago because of serious safety issues.

    Perhaps we simply disagree on what it means to be a “me-too” product. To me it means a commodity product differentiated from similar commodities only by marketing.

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