Merck to Pay $58 Million In Settlement for Vioxx Ads

Washington Post

By Martha Raffaele

Associated Press
Wednesday, May 21, 2008; Page D02

Merck agreed to pay $58 million as part of a multistate settlement of allegations that its ads for the painkiller Vioxx deceptively played down the health risks. The agreement announced yesterday also calls for Merck to submit all new TV commercials for its drugs to the Food and Drug Administration for review before they can be aired.  Another provision of the settlement bars the company from "ghostwriting," a practice in which scientists are paid to take credit for positive research articles prepared by company-hired medical writers.

The civil settlement ends a joint three-year investigation by 29 states and the District into Merck's advertising practices involving Vioxx, Pennsylvania Attorney General Tom Corbett said.

Vioxx was taken off the market in 2004 after research showed that it doubled the risk of heart attacks and strokes. That triggered thousands of lawsuits against Merck. A pending $4.85 billion settlement would end most of those claims.

Because of aggressive marketing that began in 1999, hundreds of thousands of consumers demanded Vioxx prescriptions before doctors had a chance to understand the side effects, Corbett said.*  The FDA does not require drug companies to submit advertisements for approval except in cases in which it has pursued enforcement actions over false and misleading claims, agency spokeswoman Rita Chappelle said.

For a seven-year period, Merck agreed to submit all new TV ads for its drugs to the FDA for review and to follow through with any changes the agency recommends before airing them. Additionally, for a 10-year period, Merck must comply with any FDA recommendations to delay television commercials for newly approved pain medications.

Two studies published in April in the Journal of the American Medical Association mentioned alleged ghostwriting by Merck and contended that the company tried to minimize deaths in two studies that showed Vioxx didn't work at treating or preventing Alzheimer's disease.

Merck called the reports biased because five writers of the articles were paid consultants for people who sued Merck over Vioxx's heart and stroke risks, and a sixth testified about Merck and Vioxx's heart risks before a Senate panel.

Merck is not admitting any wrongdoing under the settlement and defended its marketing of Vioxx. "Today's agreement enables Merck to put this matter behind us and focus on what Merck does best, developing new medicines," said Bruce Kuhlik, Merck's general counsel.

*This is an understatement, Merck in seven separate cases pressured doctors who were to go public concerning Vioxx causing heart attacks and strokes.  In one instance, for example, Merck threatened to withdraw research dollars from the University of Rochester, if one of their doctors brought up at a conference the health risks associated with Vioxx.  Merck had reviewed the doctor’s paper to be delivered at the conference. 

bashes generic drugs. 

Journalistic independence ends with the purse.  The below article is a good example, for it  regurgitates out every industry used argument as to why a consumer should be over three times as much for the same active ingredient.  Though this article has a LA Times staff-writers name, the structure, thoroughness, and style suggest the pen of Big PhARMA.  The lack of balance is a key reason, the very failure for example to acknowledge that certain arguments could be turned 180 degrees, is strong evidence—given the journalistic norm of including a statement from the other side—that Big PhARMA was involved.  AT the bottom I supply a rebuttal. 

FDA standards for generics are questioned

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By Melissa Healy, Los Angeles Times Staff Writer
March 17, 2008

In carrying out its mission to ensure that generic drugs are "the same medicine" with "the same results" as the pioneer drugs they follow, the Food and Drug Administration rigidly applies a standard of what is called "bioequivalence." Measured in laboratories and in simple, small-scale human trials, a generic must deliver the same active ingredient to the bloodstream of patients in virtually the same amount at virtually the same rate as the pioneer drug.

The FDA considers "bioequivalence" a good surrogate for "therapeutic equivalence" -- the equal ability of two drug formulations to ease symptoms or cure disease. Physicians and pharmacologists say that for some copycat drugs, showing bioequivalence to the original is not proof enough that the "same medicine" will yield "the same results."

There are several potential flaws in the FDA's standards of comparison, drug experts say.

1)  First, the agency's tolerance for variance in the content and release of a drug's active ingredient -- the healing compound -- may be too broad.

2)  Second, the FDA does not demand realistic trials of different formulations in large patient populations.

3)  And third, by measuring a generic medication's ability to deliver a drug compound to the bloodstream, the FDA may be looking in the wrong place. Most drugs work their magic not in the blood but in organs, cells or tissue elsewhere.

In fact, a brand-name drug's generic counterpart is rarely an exact replica. Though the two share equal amounts of the same active ingredient, they generally look different. And those differences, say some pharmacologists, can result in small variations in how they work in patients.

A brand-name drug and its generic in most cases are formulated with different colorants, fillers and binding materials. Though all of those must come from an FDA-approved list of pharmaceutical ingredients, they are, in most cases, assembled differently in each manufacturer's product. One version of a drug might use lactose or sugar as an inactive ingredient; another might not. But incidental ingredients like these can affect the way patients dissolve and metabolize a drug's active ingredient -- faster or slower. And that, in turn, can result in variations in the two formulations' effects.

4)  In almost all cases, the FDA permits a generic drug to release 80% to 125% of an active ingredient into the bloodstream, compared to that released in a single dose of the original medication. That range would make little practical difference in the effect that most drugs have. And the FDA and generics manufacturers defend the allowable range of variance as the same that is permitted among "batches" of brand-name drugs.

5)  But medical and pharmacology specialists warn that the FDA's range may be too broad for some drugs, especially in cases where a drug has a "narrow therapeutic index" -- the fine line between an ineffective dose and a dangerous one.

6)  Variations in the rate at which a brand-name and its generic (or two generics) release their active ingredient could court disaster with some drugs, as well. On this front, experts said "extended release formulas" -- doses usually taken no more than once a day -- can pose particular problems.  If one formulation releases its therapeutic agent evenly over 20 hours and another releases a large percentage in the first five hours and very little in the final five, a patient might get a toxic concentration of drug in the morning and limp along with a dangerously ineffective dose late in the day. In lab tests and in small samples of human subjects, FDA measures release rates at periodic intervals. But pharmacologists warn that those intervals may not always be fine enough.

7)  "Bioequivalence and therapeutic effectiveness are not necessarily the same," wrote neuropsychiatrist Dr. Giuseppe Borgheini in a 2004 article published in the journal Clinical Therapy [Clinical Therapeutics, Volume 26, Issue 6, June 2003, Pages 1578-1592]. Borgheini reviewed medical literature documenting differences in the effects of generic psychoactive drugs and their brand-name counterparts. In the case of three anti-seizure drugs -- phenytoin, carabamazepine and valproic acid (marketed under the commercial names Cerebyx, Tegretol and Felbatol, respectively), studies found that generic formulations either failed to release the correct dose to patients' bloodstreams or eventuated in higher rates of "breakthrough seizures."

8) Finally, the agency demands little clinical evidence that a proposed generic drug will work the same as a pioneer drug in a broad cross section of real patients. The agency conducts quality-control tests on generic samples periodically after marketing begins, and patients and physicians can report problems with a generic drug to the FDA’s adverse-event monitoring system. But neither generic-drug manufacturers nor the FDA does post-marketing studies that might indicate patients are responding differently to a generic than to its brand-name counterpart.

In the generics approval process, the FDA typically requires a manufacturer to administer a single dose of its proposed product to a group of 24 to 48 healthy volunteers, then to sample their blood levels periodically to gauge concentrations of the active ingredient. The generic's performance is then compared with the pioneer drug in the same group.

But that may not be a good gauge of how large populations of sick patients will tolerate or respond to a variant of the medication they've already been on, say critics of the approval process.

"We don't use these medicines in normal volunteers: our patients are old, their hearts, their livers, their kidneys don't work so well," said Pennsylvania State medical center cardiologist Dr. Gerald Naccarelli. "They test these generics on a healthy 30-year-old and test his blood levels and say, 'OK, close enough.' And they translate that into an 80-year-old-guy who's on nine different meds? I would suggest that someone who knew nothing about medicine would say that's problematic."

melissa.healy@latimes.com

The above arguments assume that the pharmaceutical company has figured out the ideal amount and the ideal rate of absorption.  However, there research is too limited to arrive out this conclusion.  It is equally possible that the generic formulation could produce superior therapeutic results.

4)  One reason for permitting such difference is that different people have different rates of absorption and percentage of absorption.  Moreover, there is in most cases an even greater variance in absorption for the same person depending on what is in the stomach (drugs and food) and the persons activities during the time of absorption.  Digestion for example is nearly shut down during strenguous activity.  Variation is the norm. 

5)  Narrow therapeutic index is rare, for the drug industry recommends higher doses of their medication, and most doctors obligingly prescribe the higher dose.  Receiving less has little or no effect upon the therapeutic course.

6)  Release rate is measured in so far if a generic is rapidly released, it will show up as a greater amount upon the initial measurement.  (Delayed release assumes absorption throughout the small intestines.)

7)  The smoking gun, supposed proof of a clinically confirmed negative difference.  That such a difference would be found is not surprising giving the confluence of funding by the industry for such research, and that the literature had been scanned for negative findings.  The experimenter’s bias calls the results in question. 

8)  The reason testing is not required comes from a well-proven principle of medicine, that with identical molecular structure, drugs have the same therapeutic effects.   Generic drugs are required to mimic in method of delivery the patented drug. 

The only thing worse than generic drugs (from big PhARMA viewpoint) are those which are both cheap and not patentable—such as barbiturates, aspirin, and niacin

From American Heart Association at http://www.americanheart.org/presenter.jhtml?identifier=163

Niacin (nicotinic acid)
This drug works in the liver by affecting the production of blood fats. Niacin is prescribed to lower triglycerides and LDL cholesterol and raise HDL ("good") cholesterol.

Niacin side effects may include flushing, itching, and stomach upset. Your liver functions may be closely monitored, as niacin can cause toxicity. Non-prescription immediate release forms of niacin usually have the most side effects, especially at higher doses. Niacin is used cautiously in diabetic patients as it can raise blood sugar levels.

NOTICE how in the following end comment of the above they caution against the non-prescription source. 

Niacin comes in prescription form and as “dietary supplements.” Dietary supplement niacin must not be used as a substitute for prescription niacin. It should not be used for lowering cholesterol because of potential very serious side effects. Dietary supplement niacin is not regulated by the U.S. Food and Drug Administration (FDA) the same way that prescription niacin is. It may contain widely variable amounts of niacin — from none to much more than the label states. The amount of niacin may even vary from lot to lot of the same brand. Consult your doctor before starting any niacin therapy.

It should be noted that the American Heart Association receives funds from big PhARMA and also its directors receive their funds.