I think this post is a little off the mark.

I disagree that it was a "me-too" drug. Another statin-class drug would be a me-too. A brand new category like ACAT-inhibitors is entirely separate. It would be like saying ACE inhibitors are me-too drugs because calcium channel blockers also lower blood pressure. Even angiotensin receptor blockers, which are very similar to ACE inhibitors in some respects, represent a different class of drugs (though they work within the same system).

I actually think the story of this drug is an example of the system working at its best or near best. First of all, until the trials were done, it was impossible to know whether the drug, or the class, had any inherent value. This was something that was definitely worth exploring, since it was interesting from a theoretical and experimental perspective.

The first trial with the drug, ACTIVATE, was very highly anticipated. Steve Nissen then presented the results and essentially killed off interest in the class It would have been nice to have seen these results earlier, but since all active development (and no marketing or promotion, as with ezetimibe) had been halted, there was far less urgency to the publication.

So I'm not sure there's a big issue here. For sure there are bigger fish to fry, IMO.

Larry Husten
www.cardiobrief.org

Your point about ACAT inhibitors not being "me-too" is well taken IF there was any reason to believe the mechanism of action that might get the same result -- lower cholesterol -- had clinical significance. I'm willing to be educated on that point. What were the pre-trial hypotheses?

Let's look at a few other examples. Among acid indigestion drugs, it makes little difference in outcomes if one takes an H2 antagonist versus a proton pump inhibitor. On the other hand, for blood pressure control medications, some classes of drugs do appear to work better in some people than in others and/or have distinctly different side effect profiles. So it seems to me that "me-too" status is case specific.

Merrill, I don't remember the particular details about this trial and drug, but "cholesterol" is a VERY broad category, and despite the enormous success of the statins there is still a huge, unmet need for new drugs and approaches. Heart disease is still our #1 killer, and would probably remain so even if we put statins in the water.

I think you're also mistaken about H2 antagonists and PPIs. PPIs represent a significant advance over H2 antagonists in terms of fewer side effects, tolerability, efficacy, and duration of action. H2 antagonists were a huge advance when they were first introduced, but PPIs really almost eliminated the problem of chronic ulcers in the general population.

To call PPIs an example of "me-too" drugs is to confuse an important distinction between genuine me-too drugs, in which a company makes a very minor change to an existing drug, and drugs which represent genuine advances over previous exisiting drugs.

Merrill, I don't remember the particular details about this trial and drug, but "cholesterol" is a VERY broad category, and despite the enormous success of the statins there is still a huge, unmet need for new drugs and approaches. Heart disease is still our #1 killer, and would probably remain so even if we put statins in the water.

I think you're also mistaken about H2 antagonists and PPIs. PPIs represent a significant advance over H2 antagonists in terms of fewer side effects, tolerability, efficacy, and duration of action. H2 antagonists were a huge advance when they were first introduced, but PPIs really almost eliminated the problem of chronic ulcers in the general population.

To call PPIs an example of "me-too" drugs is to confuse an important distinction between genuine me-too drugs, in which a company makes a very minor change to an existing drug, and drugs which represent genuine advances over previous exisiting drugs.

A 2003 report in the Journal of the American Medical Association found that sometimes drug companies may deliberately choose lower dosages for the comparision drug when they carry out head-to-head trials, making the company's product do better in the trial. And sometimes trials produce unfavorable results that are not published, or that unfavorable outcomes are suppressed.

As with most clinical trials, investigators never give out information as to how patients are doing. Most trials are failures with respect to actually improving things. The world doesn't find out what happen until after a hundred or five hundred or two thousand patients are treated and then only twenty-four hours before the New England Journal of Medicine publication date.

I can understand about having negative results. Other researchers can learn something from others' failures. Negative results can provide useful information about the effectiveness of treatments. Having ALL the information you can gather for the participants and investigators is essential to maintain good doctor-patient communication.

Collaborations between academia and industry has already brought discernible influence on clinicians, bringing with it erroneous results, suppressed data, or harmful side effects from these drugs.

Every patient who decides to enter a study should know what happened to previous patients. Patients should be treated in real time, on the Internet, with the whole world watching to see how they do.

Having real-time clinical trials in which each patient receives treatment designed for him/her alone rather than a treatment that serves the financial or research interest of the pharma industry or institution which sponsors traditional clinical trials would be more beneficial for patients. Having enough information for the participants and investigators is a good idea.

Even if the FDA does require posting of results, manufacturers may have found a way to get around this requirement too. I've noticed that several recent Phase III trials have been "terminated" after all or most of the data was collected because preliminary analysis showed that the trial would not prove the superiority of the new drug.

I think if pactimibe had been safe and effective, it could have been useful for people who don't tolerate statins or who need an additional drug on top of a statin.

The same is true of ezetimibe. The problem with ezetimibe was not the fact that it was developed, but the *way* it was developed. If a trial with clinical endpoints (i.e., heart attacks, strokes, death) had been done early on, we would know by now whether ezetimibe was safe and effective. Of course, the results of ENHANCE and SEAS make it less likely that it will be ultimately be found to be safe and effective, IMO.

The other problem with ezetimibe was that it was used in people who could have been on a statin. Not only do we know that statins have clinical benefits, but there is reason to think that statins have benefits unrelated to LDL-lowering (i.e., pleiotropic effects). As previously discussed on Gooznews, there is reason to doubt that ezetimibe has comparable benefits.

You state that FDA should set standards for what companies and reseachers should publish in the registry and results databases of www.clinicaltrials.gov, but the responsibility for implementing those sections of the FDA Amendments Act of 2007 rests with the National Institutes of Health, not FDA. FDA is working with NIH on the project, and NIH has held meetings and published information on what companies and researchers must do.