I would add the importance of study designs, in which surrogates are used for M&M as well as for benefits. The saga of the arrythmic drugs that Tom Moore has retold is perhaps the most dramatic example.

http://www.holtorfmed.com/topics/statinsssribisphosphonates/use-most-popular-osteoporosis-medications-associated-with-brittle-bones-osteonecrosis-jaw-disintegration-heart-damage-and-muscle-pain

I found an article [link is provided above] titled “Use Most Popular Osteoporosis Medications Associated With Brittle Bones, Osteonecrosis (Jaw Disintegration), Heart Damage and Muscle Pain” to be of particular interest, which I will excerpt here:

“There are a number of studies that demonstrate that the use of bisphosphonate are associated with an increased risk of heart
arrhythmias (1-4). This includes a large study of 1700 women published in Archives of Internal Medicine that demonstrated that current and past users of bisphosphenate
medication such as Fosamax , Actenol, Reclast and Boniva had significant increased risk of potentially fatal heart arrhythmias. It was shown that any individual who had ever used these meds (could have stopped many using many years prior) had a 300% increased risk of
abnormal heart arrhythmia and a 575% increased risk of sustained arrhythmia. In addition, the risk was higher if the mediations were used by those who also had diabetes mellitus or were currently taking statin medication. There are also increasing reports of muscle and joint pain due to bisphosphonate use.

1. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356: 1809-1822.
2. Alendronate and atrial fibrillation. N Engl J Med 2007; 356:1895-1896.
3. Compston J. Treatments for osteoporosis—Looking beyond the HORIZON. N Engl J Med 2007; 356:1878-1879.
4. Use of Alendronate and Risk of Incident Atrial Fibrillation in Women. Arch Intern Med. 2008;168(8):826-831.

Why should the risk of arrhythmia be higher in patients who were currently taking statin medications? In my day-to-day medical practice, I often see patients on literally dozens of prescription pharmaceuticals at any given time, a problem often referred to as “polypharmacy”. The burden on kidneys and liver to metabolize and clear many of these drugs is well-documented. Drug-drug interactions have been well-documented. Are these toxicities synergistic?

“Re: tracking generics, yes, another inadequacy in our system of post-approval surveillance.”
____

Yes generics, and also, every branded drug that has been represented by an ANDA for approval under the same rules as generic drug applications.
Ie: dissolution/absorption tests when an ingredient is changed or when a manufacturing process is changed.
There are generally no post-marketing commitments either way.

It would be interesting to know which branded drugs have not been represented by an ANDA or two or more.

Silly to think one abbreviated application is any more valid than another. The difference may be that a generic maker (trying to gain a first time approval) is more scrutinized. And that a doctor will know that a generic is new. Where he may not know that a branded drug has been altered- so that when a patient presents with a new issue it is not clear where the new problem originated. Drug makers don’t exactly advertise when they make changes to the products you are swallowing.
I think Orange Book has to list them (I may be wrong), but your doctor sure isn’t going to have the time to research every medication every time he writes a refill.

A Greek to English translator might be helpful in making this point. I’ve made it in every way imaginable. Am I wrong?

Appreciate your thoughts. So as to be clear, I did not say that I believed there _was_ a “cover-up”/diversion/distraction re: long-term statings–only, sadly, that I do not entirely trust that there is not.

Baycol may be exactly the example. Depending on which account you believe, Bayer knew several years before withdrawal that there were problems with increased rhabdo relative to other statins, and especially with concommitant fibrate use. They did a great deal to obviate this–knowingly promoting to docs in ways that exaggerated benefits (thus creating a false benefit/risk impression); burying data they themselves generated about rhabdo rates in Baycol relative to other statins; in that context, bringing out higher and higher doses of Baycol; in same context, low-balling, suggesting they were going to bring out a Baycol/fibrate combo product, apparently to divert attention to the known risks of precisely that combination. And so on.

OK. One company. One drug. But it still took years, and not a small number of lives, before the fuller truth emerged. (The FDA was mostly asleep at the switch, and Bayer knew it and, seemingly, counted on it.)

So what does this have to do with other companies and other statins? It leaves the following questions (as questions, not conclusions):

1. How unique was Bayer’s handling of Baycol relative to other companies’ handling other statins? What reasons to do have to believe we that Bayer was, in any significant way, a “worse actor” in this regard?

2. Even if Baycol’s problems were harder to conceal for a _very_ long time, they were concealed long enough. What reason do we have to believe that problems easier to conceal are _not_ being so?

That is the trust issue–that one would even ask such questions and whether the history, as we know it, makes it unreasonable to do so. Again, the issue is the reasonableness of raising the questions–not presuming to know their answers.

Re: tracking generics, yes, another inadequacy in our system of post-approval surveillance.

There is a really, really big hole in your assessment. Once a product goes generic, we tend to have a bigger gap in knowledge. Is there anyone really tracking simvastatin effects in a comprehensive way. Like it or not, Merck had a much better handle on the entire simvastain picture when it controlled the market.

I know you speak of a trust gap and I don’t argue that, but we now have 20 years or more of experience to demonstrate their safety and overall strongly positive risk-to-benefit ratio. Given the large numbers of patients on these products, it doesn’t take terribly long for even rare side effects to emerge–eg, Baycol. Could something still emerge–sure, anything is possible, but it remains unlikely. Moreover, the chances of a side effect emerging that would shift the risk-to-benefit ratio significantly is even more remote.

Finally, we also don’t know the long-term effects of high dose niacin. Sure, we’ve been taking niacin for many years, but high dosages are a more recent phenomenon. There are similar issues with almost every other “natural” product on the market place. Plus, for most of them, no one is truly tracking the negative effects.

Atlex

Personally, I do worry about the effects of long-term use of statins. A lot of this we simply don’t know, but the all-cause morbidity/mortality data are not entirely reassuring.

Worst, though, I am not confident that we will get data that _may_, in fact, be available until more than simvastatin is generic. Sorry to say that on this Merry day, but consider it one example of the “trust gap” that CEO Kindler spoke about.

I would say it to him directly: “I do not trust Pfizer to tell us everything it knows, and suspects but avoids finding out more definitively, about long-term use of Lipitor. Please prove me wrong.”

At the risk of straying a bit off-topic, I’d just like to respond (briefly) to your mention of the statins:

I have never been completely enamoured with statins as the “be all and end all” that they are hyped-up to be by pharma. The statin proponents are so single-minded in their advocacy that I’m sure they would recommend adding statins to our drinking water. Perhaps we should begin to ask whether there might be some long term safety issues as to the wisdom of driving LDL’s down ever further with a parade of progressively more “potent” statins. For a long time I have believed that the mainstream theory of atherogenesis should be reexamined.

The promotion of vytorin and zetia is based on the theory that cholesterol blood levels are key determinants of atheromatous plaque formation in arteriosclerotic vascular disease. This theory may be wrong.

An alternative theory is the hemorheologic-hemodynamic theory of atherogenesis. This theory holds that atherosclerosis is a disease of stasis of blood, which promotes the organization of a thrombus into an atherosclerotic plaque. Risk factors for atherosclerosis create larger areas of decreased shear (flow) by increasing blood viscosity, arterial stiffness, or both. The name reflects the fact that the interaction of hemorheologic, i.e., blood flow, and hemodynamic, i.e., blood velocity, pulsatility, and arterial geometry, factors lead to atherosclerosis.

For a quick overview of the topic see Wikipedia at this link:

http://en.wikipedia.org/wiki/Atherosclerosis

Personally, I would love to see a study or studies which validate the hemorheologic-hemodynamic theory of atherogenesis. Placebo-controlled, hard clinical endpoint studies might only partially support the theory because even if the treatment works, it may work via a different mechanism - as may be the case with the statins. Also if the treatment did not work it would not completely invalidate the theory because the treatment might not have an adequate effect on viscosity or tendency to clot.

Why not undertake head to head, double blinded, placebo controlled studies comparing statins (the present standard of care) with active control arms that might include molecular entities (both new and old) which alter the hemorheologic and hemodynamic properties of blood? For example, we might discover that the efficacy of omega fatty acids, niacin, and vitamin C, can be better explained in terms of their effect on the hemorheologic and hemodynamic properties of blood, i.e. its viscosity and tendency to clot. There may be an ethical problem with relegation of a placebo control group to no treatment.

I would love to see prospective, double blinded, head-to-head comparison between the bisphosphonates and high dose Vitamin D3. I don’t believe that such studies are needed, however, because the safety data have already dealt a knock-out to the bisphosphonates. It’s really just a matter of time.