Monday, April 13, 2009


The Comparative Efficacy Debate

As all here will know, the Obama administration has set aside $1.1 billion dollars for comparative efficacy guidelines. Many have expressed concerns that the results could be used by private and public insurance to deny coverage for certain treatments. Some of the most recent statements coming from administration officials are not entirely reassuring on that score.

Below excerpts from a WSJ article on the topic. It is striking that people as otherwise ideologically separated has John Kyl and Russ Feingold have tried, unsuccessfully, to pass legislation intended to prevent the CE results from impacting insurance coverage.

All of us know that comparative efficacy based on large populations may or may not be relevant to particular patients. We also know that there are already de facto comparative efficacy differentials in private insurance. Most that will pay for generic simvastatin will not pay for brand-name Lipitor, even though there are definitely patients who respond differently to the two medications (I happen to be one of them). Perhaps most relevant, the comparative efficacy plan as currently conceived will rely on existing, published studies. And that will provide even more incentive toward the cherry-picking and spinning of data, endpoints, etc. that characterize so many published studies.

That is where the boondoggle comes in........

APRIL 14, 2009
Push to Compare Treatments Worries Drug, Device Makers


WASHINGTON -- Federal health-care agencies are getting $1.1 billion in economic-stimulus funds for research comparing the effectiveness of various treatments. But drug and medical-device makers, along with some members of Congress, say they are worried the findings will be used to limit patients' options.....

Peter Orszag, director of the White House Office of Management and Budget, told lawmakers last month that the research won't necessarily lead to coverage denials. "At the extreme, if something is shown not to be effective, it could simply not be covered," he said. But he also suggested the government could pay "more for the things that work than the things that don't."
Dr. Clancy, an appointee of former President George W. Bush, said the Centers for Medicare and Medicaid Services, the agency that manages Medicare, already uses AHRQ research to help decide what treatments it will cover. Dr. Clancy said, however, that her agency isn't the one making regulations or insurance-payment decisions, nor does it recommend what treatments are best.....

Sen. Jon Kyl (R., Ariz.) unsuccessfully pushed a measure recently to bar federal health programs from using comparative-effectiveness research to deny coverage. His amendment got 44 votes, including those of Sens. Charles Grassley (R., Iowa) and Russ Feingold (D., Wisc.), who have played major roles in health-care legislation.....


  1. My thought on this is probably predictable coming from a manufacturing background but here goes.

    Anything that forces one company to compare its product to another company's product is a good thing. Let’s not let pharma pull the wool over our eyes again.

    May the best product/company for all illnesses win and let the honest and fair games begin for the consumer’s dollar.

    It appears factions from both sides are already positioning themselves to get out in front of the issue by making assumption statements about possible outcomes. The problem with these statements are that they often sound logical but may not be based in fact. Anyone remember preemption?

    Therefore the side with the largest marketing and lobbying force will win as they will blanket the debate with their spin and buy up the opposition.

    Huge amounts of money stand in the balance and investing huge amounts to protect your piece of the future pie will be approved. Oh and let’s try to keep the consumer out of the picture for as long as we can. They really don’t need to know about this, it will just confuse them.

    Here we go again, big pharma, the government and the consumer’s dollar.

  2. Agree, Jaynesday, but there are several competing big interests--particularly, insurance versus pharma/devices, not to mention the gov.

    Perhaps this will get me a job at PhRMA (wow, that would be interesting!), but the more I learn about comparative efficacy studies, the less I compelling I find them. Again, they are premised on the data being accurate for each comparator. From what I gather, the Obama proposal will be based on meta-analyses of existing journal articles.

    If what goes in contains its share of "garbage," what comes out.....

    If one did a CE study of essentially all the SSRI antidepressants versus nothing (placebo), we know now that the SSRIs would only very slightly "win," and obviously carry increasing risks of various kinds.

    Assuming that was true, how would you feel if a national healthcare plan chose not to cover SSRI antidepressants?

  3. Justice, given that the pharma/FDA practices are untrustworthy at best we see the root of all kinds of difficulties.

    If you don't have a base of honesty and forthrightness you certainly can't expect to build, expand or improve upon that base.

    In fact whatever you try to do to improve will likely be worse that what you started with, mainly because it requires one to continue to build with corrupt tools and methods just to hide the corruption that already exists.

    As we all know the old saying "Oh what a tangled web we weave when at first we seek to deceive." Unfortunately too much of pharma practices are based in deceit.

    So concerning SSRI's I would hesitate to allow any approval until I could be sure about the facts of the drugs. SSRI's are so obscured by conflicting "facts" and hidden studies that any decision for or against would (for me) require completely starting over. At the expense of the companies that perpetrated the mess of course.

  4. What's concerning about the approach here is using already published data and comparing studies. The FDA has sent Warning Letters to numerous manufacturers for using this same technique as not being substantial data. Again, making policy decisions based on a practice that the FDA has condemned as "cherry-picking" makes the government look like the right hand doesn't know what the left hand is doing.

  5. While I'm interested in comparative efficacy, I'm going to sidetrack and bring you this li'l gem from downunda. Merck is defending itself in court for the Australian Vioxx trial and some very interesting things are coming out as court records.

    The first article deals with Merck hiring doctors to write up Merck's research on Vioxx and present it as original and independent to journals. As if that weren't enough, Merck then created a journal to pass off their studies in a fabricated independent, peer-reviewed publication. Fun so far?

    The second article is based on the sophisticated marketing techniques and line-by-line cheatsheets (called "objection handling" cards) that were used to teach detailers how to deflect doctors concerns of heart risks with Vioxx. le sigh...

    Thank you for letting me say my piece. I'll now return you to your thread....

  6. Keep it coming, Harpy. The cardio card stuff is, I think, pretty well known if you follow Vioxxiana. It was one of the things that triggered the Sept. 2001 FDA warning letter in the U.S..

    The Merck-created journal is new to me.

    In any event, it is on topic, since, as noted above, comparative efficacy as envisioned in the Obama proposal would rely on analyses of studies in "peer-reviewed journals."

    In other words, on the same old sheep.

  7. Comparative studies at what cost?

  8. Everyone--Please see GEJ's post on the Vladeck thread, which is directly relevant to this one.

  9. Boondoggle!

    This issue is about Quality by Design or like experiments toward implied sameness.


    "However, the criteria Pfizer used was not requested by the FDA to show bioequivalence and was different from the FDA criteria, according to an FDA spokeswoman. She adds that the FDA was unable to review the study protocols before Pfizer proceeded and the agency doesn’t know why Pfizer chose different acceptance criteria. Nonetheless, the agency did approve the new Dilantin."


    I have lived it. Am living it still as I am on a sustitute that, while my current generic is better than Pfizer's NMP, I have lost my wellbeing.

    Read the
    "FDA-Pfizer CRADA: Quality by Design and Process Monitoring of Pharmaceutical Manufacturing at Pilot-Scale" here:


    A very tiny collection of the horror stories (it is 20 pages of reading but if you really want to know...) here:


    Fortunately the Senate Finance Committee did question Orszag about the practice of changing the name of these altered drugs so that doctors and pharmacists would at least know that there is a change in what they are dispensing. For those of us that need to continue on the innovator- that doesn't do much good. It would mean that no one is blindsided again.

    "Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation."
    (end of graph 4)


    Seriously, this is about your drugs being changed to reduce costs. It is partially about FDA being better able to monitor drugs- if the Comparative Efficacy actually worked. If it doesn't work- FDA has had it's hands all over it in advance and good luck with trying to get anyone to take one of these cases. Good luck getting a response of any kind from anyone.

  10. "The European Union found the risk of Celebrex to be sufficiently high that it has refused to allow the PRECISION trial to be conducted there. Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, believes the PRECISION trial exposes volunteers to unacceptable level of risk. He told the Center that the U.S. reviewers of the trial should also have 'disallowed the study on ethical grounds." You may read the full story by clicking on "Questions..."

  11. Just a Thought,

    Thank you for the links. I found your comments on Pharmalot particularly helpful in answering a question about the manufacture of Seroquel XR.

  12. Very good comments here.

    Anyone who watches the current Celebrex commercial knows how much gamesmanship has gone into its continuing marketing. Everything is qualified and euphemized in order to suggest that Celebrex has the same risks as ibuprofen or naproxen. The magnitude of risk is entirely obfuscated.

    DDMAC approved this garbage. Shame on all of them.

  13. You're very welcome, Anonymous. I know virtually nothing about Seroquel XR. I went back and read my comments on Pharmalot though and this one question that I asked remains. In fact it may sum up this debate completely.

    As branded drugs are being allowed to reduce cost and quality once they go off patent... if comparative efficacy is the way of the future... will FDA force smaller companies to change their generic products to match the reduced quality of reformulated reference products?

    Because, as it stands, some generics are better than the reformulated reference drugs. To make changes to those generics would be a nightmare for people such as myself. Comparative efficacy is about exchangability between like products. So let's ruin them all?

  14. Just a Thought,

    I do not have an answer for your question, however I wanted to post MedPAC's definition of comparative effectiveness here for further discussion:

    "Comparative-effectiveness analysis evaluates the relative impact of medical services, drugs,
    devices, therapies, and procedures used to treat the same condition. Effectiveness means the
    outcomes of clinically relevant alternatives provided to patients with diverse clinical
    characteristics in a wide variety of practice settings. The outcomes that researchers assess in
    comparative-effectiveness studies may include: clinical outcomes, such as mortality and major
    morbidity; functional outcomes, such as quality of life, symptom severity, and patient
    satisfaction; and economic outcomes, including cost effectiveness."


    If I understand your question (correct me if I am wrong), you are concerned about the bioequivalency of drugs which contain the same active pharmaceutical ingredient (API). In other words, two products which are said to be bioequivalent would be expected to be, for all intents and purposes, the same.

    In regard to the quality issue, I will break your question down into two parts:
    1) will the FDA lower the quality of manufacturing standards for all bioequivalent products (drugs); and
    2) would this action reduce the clinical effectiveness of the drugs?

  15. Basically, Anonymous, but there's more.

    Most people tend to believe that if there is the same amount of active ingredient- the branded drugs are exchangeable with generic drugs. This simply is not so in some cases. Once upon a time you would hear major manufacturers arguing my very point. Now, however, they appear to be looking at the bigger prize of reducing costs. They know the dangers. If FDA doesn't know the dangers then they are in the wrong line of work. It was laughable when Pfizer reformulated and came out saying that they were not even going to charge more for their improved treatment. OMG! Dilantin is now a generic that didn't even meet their own in-house protocol!

    BUT there is a much bigger problem with Quality by Design and these kinds of diagnostics. Their purpose is to reduce costs and set minimum standards. Unfortunately some companies are going to choose to use the minimum standards... which are touted to be set for foreign manufacturers (right). As long as the minimum standards come within someones idea of an acceptable range for Cmax, AUCo, Tmax, & T-1/2 and the like- that drug will be acceptable no matter what they toss into the mix?

    I am on a generic (not Pfizer's). Some lots find me living on Benedryl to counter itching and inflammation in my eyes, nose, ears, and throat- as well as on my scalp. This was the case for some people taking Pfizer's new formula as well. We must be concerned with severe and deadly allergies (Google- Stevens Johnsons Syndrome). Quality by Design doesn't appear to look at those things. And if they don't THESE DIAGNOSTICS ARE INCOMPLETE... as are the one dose studies used to gain ANDA approvals through the Office of Generic Drugs.

    This process allows manufacturers to use the cheapest available excipients which can, in turn, render these drugs completely useless if they cannot be tolerated.

    I am not trying to throw a monkey wrench into the big scheme because I feel wronged. I am seriously concerned that I will no longer have a treatment available to me. I have tried other products such as Lamictal but these are not 'one size fits all' drugs and I just want my drug back. It isn't that no one has the ability to make a good quality product. I was on Dilantin for well over a decade, with very little trouble, until it was reformulated. I'm so damn sick all the time now that I am unable to let this go forth without letting people know what the potential outcome will be for all drugs.

    Take this statement by a highly accredited Neurologist, who, when we contacted him for help, he dismissed us and told us to contact Pfizer and FDA (click my name for Steven Schachter's 1999 address to the FDA). Advocate? If I find that this Associate Professor of Neurology at Harvard Medical School might be helping to decide the "best practices" our govermnment wants to use to incentivise doctors and drug companies, I have to throw my hands in the air completely. There's this little conflict- which I won't go into. But in 1999 he was spot on.

    I don't know what more can be said. I've done my best.

  16. Just a Thought,

    Thank you for this informative report. I have read reports by others who say that the medication formulation that worked so well before was no longer effective after reformulation and/or a change in the manufacturer of the drug. A group of patients who take Nardil for depression have reported this problem.

    The FDA Scientific Board will be meeting in May. Why don't you contact Carlos Pena and ask how to get this issue on the agenda? Click on Anonymous for more information.

    Carlos Pena , Designated Federal Official
    Office of Science and Health Coordination, Office of the Commissioner
    5600 Fisher Lane, Rm. 14B-08
    Rockville, MD 20857
    phone: 301-827-3340

  17. Anyone who reads an insurance certificate of coverage knows that insurance companies and/or their PBM subsidiaries can and do base reimbursement and formulary decisions on this type of research.

    Take Medicare Part D for example, the companies that offer medicare part D plans can and likely will factor in this research when writing their drug formulary and/or deciding whether or not to pay claims.

    From a mjor health insurer's certificate of coverage:

    " Benefits for covered services may be payable subject to an approved treatment plan. Only medically necessary care is covered. Although we do not provide Benefits for covered services that do not meet our definition of medical necessity, you and your physician must decide what care is appropriate. The fact that a physician may prescribe, order, recommend or approve a service, treatment or supply does not make it Medically Necessary or a Covered Service and does not guarantee payment. If you choose to receive care that is not a covered service or does not meet our definition of medical necessity, we will not provide Benefits for it. Delete name bases its decisions about referrals, prior authorization, medical necessity, experimental services and new technology on medical policy developed by 'our insurance company'. 'our insurance company' may also consider published peer-review medical literature, opinions of experts and the recommendations of nationally recognized public and private organizations which review the medical effectiveness of health care services and technology.

  18. Here is a good example of comparative effectiveness research and the medical decision-making process:


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