Consumer Safety Vs. Multimillion-Dollar COX-2 Pain Pill Manufacturers

Discovered in 1988 by a former Harvard researcher, the cyclooxygenase-II or COX-2 enzyme was determined to be responsible for pain and inflammation. The data on it was then allegedly pirated by the large pharmaceutical company Pfizer, the firm the discovering researcher had contracted with. COX-2 selective inhibitors are members of a drug class of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) market-targeted for pain, arthritis, and menstrual cramps.

The COX-2 painkillers, including Pfizer's Celebrex (celecoxib) and Merck's Vioxx (rofecoxib) released in 1999, went on to make millions, while the contract Pfizer was said to have violated is still under litigation against them. Today these pain killers, like many NSAIDs, are also known for their adverse side effects, including renal failure, increased risk of cardiac events, thrombosis, and stroke. Enough evidence of adverse events such as myocardial infarction and stroke was compiled against Vioxx to induce Merck to voluntarily withdraw it from the market in 2004. Other similar drugs are under fire as well. One law firm is pursuing 31,000 claims against the manufacturers of major NSAIDs Celebrex, Mobic, Vioxx and Bextra.

Consumer Protection Critical Regarding Pharmaceuticals

This article documents some of the consumer protection efforts of Dr. Sidney Wolfe and the Public Citizen's Health Research Organization (HRO) to warn the public about the dangers of these drugs and how this advocacy group was instrumental in Merck's recall of Vioxx. The Public Citizen HRO is a private consumer group that performs safety and effectiveness reviews of all drugs, and issues Do Not Use warnings for drugs that, while approved by the FDA, were developed by manufacturers purely for profit to replace older adequate ones whose patents are expiring (income loss), or that may perform the same as older drugs yet have more serious or unproven side effects.

Once patents expire and formerly patented drugs can be sold over the counter (OTC), the drug's new status may cause its price to plummet sufficiently for the company to withdraw the drug and replace it with a different, higher priced, prescription-required, less safe version.

Public Citizen's guidelines encourage consumers to refuse to take drugs that have been on the market for less than seven years, since much less human safety testing is performed today prior to FDA approval and marketing than ever before. Instead, most serious adverse side effects are discovered through the general public's use within the first seven years of drug marketing. Drug release date information can be obtained from any pharmacist or from the Physicians Desk Reference (PDR) in any library or pharmacy.

The Celebrex Story and More

The following is a brief history of Celebrex, and details some of the interventions by the Public Citizen's Health Research Group to protect the public from it and from other dangerous COX-2 inhibitors and NSAIDs, as well as from the FDA, which seems more concerned with protecting the drug companies than the public.

In December of 1998 just before FDA approval of NSAIDs Celebrex and Vioxx, Dr. Sidney Wolfe made a cautionary statement (HRG Publication #1465) before the FDA's Arthritis Drugs Advisory Committee decrying their fast-tracking Celebrex until long-term safety studies on side effects were done comparing them to older comparable drugs.

In February of 2001, Dr. Wolfe again testified before this committee, this time with Larry Sasich, Pharm. D, MPH, regarding highly advertised and competing NSAIDs Pfizer's Celebrex and Merk's Vioxx (HRG Publication #1555) advocating the need of a second box warning included in the packaging regarding adverse side effect risks of cardiovascular toxicity and mentioning the now-accumulated evidence of heart damage caused by them.

In September of 2002, a letter was sent to Health and Human Services Secretary Tommy Thompson (HRG Publication #1637) by Public Citizen's Health Research Group staff, Research Analyst Elizabeth Barbehenn, PhD., Deputy Director Peter Lurie, MD, MPH, and Sidney M. Wolfe, MD and Director. This letter raised ethical concerns about the National Institute on Aging (NIA) conducting an Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) using NSAIDs, stating that it was unethical and should be stopped immediately because the trials had no real scientific footing and NSAIDS had not only not been shown to be effective against Alzheimers, but had the real possibility to inflict harm. Dr. Wolfe further questioned the misleading 'informed consent' documents and strongly urged that those enrolled in the trial be provided with information denied to them about serious possible health risks, and those being recruited be provided with assurances that trial participants need not fear losing their Medicare coverage for not participating.

His letter stated "Three agencies under Health and Human Services (HHS) are involved in this trial: Center for Medicare and Medicaid Services (CMS, formerly HCFA), which is involved in recruiting, the Food and Drug Administration (FDA), which has responsibility for approving the protocol, and the NIA, which has provided funding and oversight. If the Medicare rolls and the imprimatur of HHS are to be used to recruit patients, it is of the utmost importance that a) the trials be on a reasonable scientific footing (not like here), b) that full informed consent be obtained (not like here), and c) that the recruitment letter makes it absolutely clear that enrollment is voluntary and that one will not lose Medicare coverage if one does not enroll (as done here)."

On September 30, 2004, in response to Mercks' same-day withdrawal of Vioxx from world markets due to side effect complaints, Dr. Wolfe issued a statement (HRG Publication #1707) that Vioxx and other 'super-aspirins' were really 'super disasters', and cited that other COX-2 alternatives had safety issues too.

In late January of 2005, two letters (HRG Publications #1720 and 1721) were sent from Public Citizen's Health Group Staff Researcher Dawn Jennings-Peterson and Sidney M. Wolfe, MD, to Dr. Lester M. Crawford, Acting Commissioner of the FDA; one to petition the FDA to remove the COX-2 Inhibitors Celebrex and Bextra from the market due to documented adverse cardiac events, and the other to reveal an unpublished clinical trial located on the PhRMA web site revealing statistically significant heart dangers for Celebrex users.

In February of 2005, Dr. Wolfe again testified (HRG Publication #1725) before the FDA Arthritis and Drug Safety Advisory Committee concerning the dangers of COX-2 drugs, stating "Given that Celebrex and Bextra are making an important contribution to the estimated 100,000 deaths and 2.1 million serious injuries a year from adverse drug reactions, I hope you will recommend a ban of these two drugs."

At the same time, Dr. Wolfe wrote a letter to the Editor of the New York Times (HRG Publication #1727) on COX-2 painkillers, referencing an Army Captain in the medical corps testifying that COX-2 drugs were "essential to the war on terrorism". Dr. Wolfe refuted this by stating that "annually, [there were] thousands of extra heart attacks, many fatal, with additional heart attacks caused by Celebrex and Bextra. A growing number of physicians are rejecting the use of these drugs because of their unique risks."

In another document released shortly afterward (HRG Publication #1734), Dr. Wolfe stated: "The FDA has taken Bextra off the market, [but] it has recklessly allowed Celebrex to continue to be sold. An unpublished study finished in 2000 indicated increased cardiac risks associated with Celebrex." Additional information appeared in the Worst Pills, Best Pills Newsletters regarding Public Citizen's HRO recommendations for the drug Bextra:

• Do Not Use! Lawsuit Reveals Serious Safety Problems with the Nonsteroidal Anti-inflammatory Drug Valdecoxib (BEXTRA) Lawsuit filed September 2004.
• Do Not Use! New Safety Warning Added to the Arthritis Drug Valdecoxib (BEXTRA) Worst Pills, Best Pills News article in January 2003.

The Worst Pills Best Pills Newsletter - Do Not Use These Drugs

In February of 2005, Worst Pills Best Pills Newsletter published Cutting Your Drug Bill While Reducing Your Risk Of Avoidable Adverse Drug Reactions: Six Examples. This article discussed potential savings by using alternatives recommended in Worst Pills Best Pills, rather than six listed by them as DO NOT USE drugs. All six are in Drug Topics Magazine in the list of Top 200 Selling Drugs in the U.S. in 2003.

The DO NOT USE drugs are: celecoxib (Celebrex) used for arthritis and pain; the Alzheimer's disease drug donepezil (Aricept); drospirenone with ethinyl estradiol (Yasmin 28), an oral contraceptive; esomeprazole (Nexium) the "new purple pill" for heartburn; montelukast (Singulair), a drug approved for both asthma and hay fever; and valdecoxib (Bextra), an arthritis drug very similar to celecoxib. The combined sales of these six DO NOT USE drugs was $8.1 billion with more that 75 million prescriptions dispensed just in 2003.

In June of 2005, the FDA removed Bextra from the market, and issued a Public Health Advisory with major new warnings for other NSAIDs, also stating "If you are currently taking celecoxib (Celebrex), you should contact your physician to consider alternate NSAID treatment."

In May of 2006, Worst Pills Best Pills Newsletter published DO NOT USE! Celecoxib (CELEBREX) May Double the Risk for Heart Attacks Compared to Older Arthritis Drugs, presenting new research published in the March 2006 Journal of the Royal Society of Medicine that Celebrex may double the risk for heart attacks compared to older arthritis medications, and that, at this time, the older drugs such as naproxen, ibuprofen, and acetaminophen are safer for the heart

In April of 2007, Dr. Wolfe petitioned the FDA (HRG Publication #1803) to order Pfizer to immediately stop its
dangerous, misleading 2 ½ minute television commercials for Celebrex that began airing on April 2^nd, and he documented their misleading statements. Once again It became clear that for years Public Citizen has been doing the FDA's work for them protecting consumers against dangerous drugs.

In December 2008, Worst Pills Best Pills Newsletter published Update on Drugs that Can Cause High Blood Potassium, listing 68 drugs (some NSAIDs) that can cause high blood potassium (hyperkalemia) resulting in nausea, fatigue, muscle weakness or tingling sensations, as well as heart abnormalities (showing up as an abnormal electrocardiogram). In some cases it can be fatal. The article states "If you are taking any of these drugs, be especially careful if you have diabetes or kidney disease. If so, you are at increased risk, and your doctor will have to weigh the risk of giving you these drugs. Also, the older you are, the more likely you are to develop hyperkalemia."

February 2009,Worst Pills Best Pills Newsletter published Nonsteroidal Anti-Inflammatory Drugs Can Make Blood Pressure Hard to Control, noting 20 different NSAIDS that can adversely affect blood pressure control.

While consumer protection organizations like Public Citizen are working behind the scenes, eventually the headlines come to the surface proving the value of their work, and leaving many to only guess how many lives may have been saved, and others benefited, from their advocacy and warnings.

An Associated Press article entitled Doctor Accused of Fabricating Pain Studies appeared on MSNBC on March 11, 2009, revealing a large number of falsified 'studies' by a Massachusetts anesthesiologist, weighted with made-up data and false results. Dr. Scott Reuben had published 21 papers between 1996 and 2008 in anesthesiology journals in which he fabricated some or all of the data, and which made-up data and results had been relied upon by unknown numbers of doctors and influenced them to use Vioxx and Celebrex for their patients' pain.

Reuben had been working on numerous research grants for Pfizer for five years (2002-2007), and was a member of Pfizer's speakers bureau, giving talks to colleagues about Pfizer's drugs. According to the MSNBC article, the journal Anesthesia & Analgesia retracted 10 of these studies last month, and so far the journal Anesthesiology has retracted three. "Doctors have been using (these) findings very widely," said Dr. Steven Shafer, editor of Anesthesia and Analgesia. "His findings had a huge impact on the field."

As yet, there is no information regarding negative impacts on patients who may have been part of these 'studies'.