PERT Program

Tip of the Month: March 2005


The PERT Tip of the Month for September 2003 covers NSAID Use in the Elderly. Since that time, one of the NSAID medications discussed has been removed from the market. Vioxx® (rofecoxib) was voluntarily withdrawn from public access in 2004 due to a finding of drug-associated increased risk of heart attack and stroke.

As licensed nurses, we have a responsibility to maintain current knowledge of the risks and benefits of the medications we routinely dispense. In this month's Tip, Dr. Mary Shelkey discusses the strengths and weaknesses of the processes by which pharmaceuticals come to market. In addition, she provides an overview of the specific case of Vioxx® and the need for healthcare professionals to use caution when prescribing or dispensing medications within the NSAID category.


THE VIOXX® DEBACLE:
HOW DO UNSAFE DRUGS MAKE IT TO MARKET?


On September 30, 2004, a press release from the pharmaceutical company Merck announced the withdrawal of rofecoxib (Vioxx®) from the market because of increased cardiovascular risks in patients taking the drug for more than 18 months. By the time it was withdrawn, five years after its release, rofecoxib had been prescribed for an estimated 80 million people. How do drugs that create a public health risk get to market, potentially endangering the lives of million of people? Who is responsible for these dangerous events: the pharmaceutical firms, the U.S. Food and Drug Administration (FDA), or the clinical researchers? This article will review the typical processes that new pharmaceuticals (as well as medical devices) undergo prior to being released for public use. The strengths and limitations of industry funded versus federally funded research, the purposes of clinical trials, and the specific case of rofecoxib will be discussed.


Industry Funded versus Federally Funded Research

Pharmaceutical companies devote millions of dollars of their profits to the development of new pharmaceuticals or devices. Novel treatments are granted patents, generally 20 years from the date of invention, allowing a pharmaceutical company sole access to the sale of their drug. It takes an average of $350–500 million and eight to ten years to get a drug to market, with most of that money and time spent in clinical trials.¹ If successful, companies are able to make billions of dollars in profit from a new drug.

In contrast, U.S. federal funding (such as research support that comes from the National Institutes of Health) for pharmaceutical research is generally more limited. Federal funding relies on political agendas, competing agency requests for monies, and the overall economic climate. Federal funds tend to support domestic and military programs but provide very little support for drug testing.

These different sources of funding create potential ethical and methodological problems. All researchers, including those receiving funding from a pharmaceutical companies, need to remain painstakingly neutral while performing a study. There are always ethical considerations in any research study, such as protecting anonymity, avoiding coercion, and protecting the rights of certain vulnerable research participants (e.g., children, prisoners, people with dementia). Breaches of ethical conduct have heightened both research and consumer awareness of the many ethical pitfalls associated with research. Analysis of research data, seemingly a fact-finding mission, can be interpreted and reported in ambiguous ways. The lay public and media also have a part to play, for better or worse, in interpreting research findings.


Clinical Trials

Before a drug can enter the market, it needs to go through various levels of testing, or clinical trials. A clinical trial is a prospective, organized, systematic exposure of human subjects to an intervention of some kind (e.g., drug, surgical procedure, medical device) to answer some question about the intervention. The FDA carefully monitors these trials. Clinical phases include:²

Phase 1 Clinical Drug Trial: Phase 1 clinical drug trials represent the first test of a drug in a human population. (Prior to Phase 1 trials, only animal and in vitro data are available.) Phase 1 trials are designed to determine toxicity, absorption, metabolism, and safe dosage range and are limited to relatively few subjects (20–80). Sometimes Phase 1 studies are done in healthy volunteers, particularly if the drug is not expected to cause serious side effects. Sometimes, for obvious ethical reasons, Phase 1 testing is more properly done in patients. For example, cancer chemotherapy subjects who have exhausted all alternative treatments may enroll in a Phase 1 trial hoping for therapeutic benefit. The study often involves dose escalation until the maximum tolerated dose is established. This means the dose is increased until toxicity occurs. Obviously, subjects in a Phase 1 clinical trial of a toxic chemotherapeutic agent incur the risk of death from toxicity. Although a subject may receive therapeutic benefit from participating in a Phase 1 study, the objective in conducting the study is to examine drug toxicities rather than their effectiveness in treating a particular disease.


Phase 2 Clinical Drug Trial: Phase 2 studies include the controlled clinical studies conducted to obtain some preliminary data on the effectiveness of a drug in treating a particular disease or medical condition. Phase 2 studies are conducted in patients who have the disease or condition. Phase 2 trials also help identify the common short-term side effects and risks associated with the drug. Phase 2 studies are typically controlled, carefully monitored, and conducted in a relatively small number of patients, usually involving several hundred people.


Phase 3 Clinical Drug Trial: Phase 3 trials usually compare a new treatment with the best currently available treatment (the standard treatment). They may compare
  • A completely new treatment with the standard treatment
  • Different doses or ways of giving a standard treatment
  • A new treatment schedule with the standard one
Phase 3 trials are usually much larger than Phase 1 or 2 trials. This is because differences in success rates may be small, in which case a large number of results are needed to show that the treatment is indeed effective.


Phase 4 Clinical Drug Trial: A Phase 4 clinical drug trial is a post-marketing study of an FDA-approved drug, conducted to gain more information (e.g., to reveal the incidence of a specific adverse reaction or determine the long-term effects of the drug on morbidity and mortality).


One of the most difficult pitfalls in clinical trials is the use of inclusion and exclusion criteria. Inclusion criteria determine who is eligible to participate in a clinical trial. Exclusion criteria impose limits on eligibility. Exclusion criteria often prevent the chronically ill, the frail elderly, or people with multiple medical conditions from participating. Unfortunately, these are often the patients, such in the case of rofecoxib, who may need the new medication. The clinical trial data regarding indications, precautions, and side effects may or may not provide critical information related to those individuals.


The Case of Rofecoxib (Vioxx®)

Rofecoxib is a non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclo-oxygenase 2 (COX2). The COX enzyme, crucial to the formation of prostaglandins, exists in two isoforms, COX1 and COX2. Among their adverse side effects, COX1 NSAIDs (e.g., ibuprofen, naprosyn) have gastrointestinal effects that range from mild GI upset to GI bleeding and death. COX2 inhibitors, compared to COX1 inhibitors, have demonstrated less gastrotoxicity. Approved by the FDA in 1999, COX2 inhibitors soon dominated the prescription-drug market for NSAIDs.

Merck voluntarily withdrew rofecoxib from the market as a result of the data from the unpublished Adenomatous Polyp Prevention on Vioxx (APPROVe) study, a placebo-controlled trial of rofecoxib for prevention of recurrent colorectal polyps in patients with a history of colorectal adenomas. The APPROVe study demonstrated a significant increase of cardiovascular events, heart attacks, and strokes in people taking the drug for 18 months, compared to people taking placebo. The withdrawal of rofecoxib initiated a media flurry and subsequent professional debates about the drug's safety. Juni and colleagues³ in their cumulative meta-analysis of rofecoxib published in The Lancet, a widely respected medical journal, state that as early as 2000, data were available to Merck showing that the use of rofecoxib was associated with an increased risk of myocardial infarction. The authors claim that clinical trials, such as the Vioxx® Gastrointestinal Outcomes Research trial (VIGOR), indicated an increased risk of myocardial infarction and claimed Merck should have examined that risk more closely.

Researchers and clinicians have subsequently disputed the conclusions set forth by Juni and colleagues. Kim and Reicin⁴ criticized flaws in the Juni and colleagues' meta-analysis, notably their inappropriate pooling of results from various clinical trials looking at diverse pharmacologic agents including placebo, non-naproxen NSAIDs (including rofecoxib), and naproxen. They additionally criticize Juni et al., for ignoring data from the Therapeutic Arthritis Research and Gastrointestinal Event trial (TARGET), as well as other data from two placebo-controlled trials of about 2000 patients with Alzheimer's disease. The results of those trials show no difference between rofecoxib and placebo. Lievre and Abadie5 also criticized Juni and colleagues for excluding those trials done in patients with Alzheimer's disease. Debates continue regarding what Merck knew regarding the cardiovascular risk related to rofecobix, when they knew it, and whether Merck acted in a timely manner to protect the public.

Readers interested in the various viewpoints from Merck, the U.S. FDA, and other associated statements are encouraged to read on-line materials provided at www.fda.gov or www.merck.com. Other COX2 inhibitors (e.g., Celebrex and Bextra) continue to be marketed. The long-term risk of these drugs, as well as COX1 NSAIDs, remains partially unknown. All NSAIDs, taken long-term, may prove to have cardiovascular risks because they are sodium-retaining and therefore increase fluid overload and blood pressure. Prescribing clinicians are currently being warned to carefully weigh the risks and benefits of all drugs in the NSAID class. Consumers using these medications for more than 10 days are encouraged to alert their prescribers.


Conclusion

One chapter in the history of rofecoxib has ended for now. However, litigation aimed at recovering damages to people potentially injured by using rofecoxib will continue for some time. Who is ultimately to blame for this debacle: Merck, the FDA, or flawed data analysis? Perhaps all three were responsible. There is always much speculation regarding remedies for these types of problems. Based on past history, rofecoxib will likely not be the last drug to come under scrutiny. An informed, concerned public is needed to help remedy the flaws in this system of bringing drugs to market. Indeed, we are acting on our own behalf.




Dr. Mary Shelkey, PhD, ARNP, Geriatric Specialist, and Director, RN Clinical Research Unit of Benaroya Research Institute, Virginia Mason Medical Center, Seattle, WA, provided this month's Tip. Dr. Shelkey also is Assistant Professor at the Seattle University School of Nursing.



References

  1. Cellexchange. (2001) Pfizer Streamlines Clinical Drug Trial Processes. Online source: http://www.cellexchange.com/press20010706.shtml. Accessed March, 2005.
  2. FDA. The CDER Handbook. (Website.) Online source: http://www.fda.gov/cder/handbook/. Accessed March, 2005.
  3. Juni, P., Reichenbach, S., Sterchi, R., Dieppe, P.A. & Egger, M. (2004). Risk of cardiovascular events and rofecoxib: Cumulative meta-analysis. The Lancet, 364, 2021–2029.
  4. Kim, P.S. & Reicin, A.S. (2005). Correspondence: Discontinuation of Vioxx. The Lancet, 365, 23.
  5. Lievre, M. & Abadie, E. (2005). Correspondence: Discontinuation of Vioxx. The Lancet, 365, 23–24.