After a drug is developed, it is widely tested in the lab for efficacy and safety before it is tested on humans. Clinical trials are conducted using human subjects in five phases before the drug is approved. A drug may be approved for use and then adverse side effects are found during post marketing study in which case it is withdrawn from the market. This paper is an evaluation of cisapride, a drug developed in the 1980s and marketed between 1993 and 1999 before it was withdrawn from the market because of adverse side effects. Post marketing data on the drug is discussed critically to determine if the adverse effects of cisapride would have been determined during clinical trials.
Background of Cisapride
Cisapride was discovered in 1980 and is a gastroprokinetic agent devoid of antidopaninergic and direct muscarinic activity (Reyntjens, Verlinden & Aerts, 1986). It increases the rate of movement of in the digestive tract during digestion and prevents gastric reflux. The drug is an agonist of the serotonin 5-HT4 receptor and causes increased levels of acetylcholine. Besides prevention of gastroesophageal reflux (detected as heartburn), cisapride was used alleviate bowel constipation and to enhance gastric empting. Gastric empting is a common clinical intervention in patients suffering from diabetes gastroparesis. Cisapride is administered as orally as a tablet or a suspension and undergoes hepatic and intestinal metabolism.
After the drug was developed, it underwent all legally required clinical trials to determine its safety, efficacy and tolerability. The side effects noted in these early trials include; stomach pain, diarrhea, nausea, increased urination, flatulence, rumbling bowel sound and head ache (Camilleri et al., 1989; Richards, Valenzuela & McCallum, 1993). The number of study participants who experienced side effects while using cisapride was statistically similar to the number of participants who experienced similar side effects while on placebo. These side effects are not life threatening and the drug was deemed safe for human use. The FDA approved it for marketing in 1993. After the drug was in the market for six years, the FDA received adverse effects reports on 341 patients who developed cardiovascular complications and 80 of these patients died. Cisapride induces the long QT syndrome which is characterized by irregular heartbeats and can be fatal. The FDA advised against the use clinical use of cisapride and the drug was subsequently withdrawn from the market.
Post-Marketing Studies of Cisapride
Post marketing studies are suitable in evaluating the long term effects and the low probability side effect of a drug. This is because the drug is prescribed to and used by a large number of people unlike in the clinical trials where the number of participants is limited and the study parameters are controlled. Collecting and analyzing post marketing data allows for the long term risk assessment and provides evidence for withdrawing the drug from the market. One of the first published post marketing studies of cisapride that indicated the drug may not be safe was published in 1996, just three years into the drugs marketing. In the first 30 months of marketing the drug, 34 patients reported torsede de pointes and 23 developed prolonged QT with four patients dyeing and 16 patients being saved by resuscitation after developing cardiopulmonary arrest (Wysowski & Bacsanyi, 1996). In this group that developed adverse reactions, 56 % were using imidazole or macrolide antibiotics. The findings in this research caused Jassen Pharmaceutica, the company that manufactured cisapride to issue warnings to physicians not to prescribe cisapride to patients taking drugs such as ketoconazole, miconazole, clarithromycin, troleandomycin, itraconazole and fluconazole and to those with a history of arrhythmia and cardiac disease (Wysowski & Bacsanyi, 1996).
In another study, Barbey, Lazzara & Zipes reviewed all cases of adverse effects associated with the use of cisapride which were reported to the health authorities, to the drug manufacturer and in medical literature by October 1999 (2002). The researches obtained 574 reports of which 391 cases were confirmed to be long QT syndrome or isolated QT prolongation. There was a high correlation confidence (p < 0.001) that cases of long QT syndrome and QT prolongation with a high diagnosis confidence occurred in patients with recognized cofactors in 67% of the confirmed cases (Barbey, Lazzara & Zipes, 2002). The immediate inference from this study is that cisapride increases the risk of arrhythmia in patients who are already exposed to risk factors of arrhythmia. Therefore, reducing other risk factors of arrhythmia may reduce the side effects of cisapride. In another recent study, cisapride was associated with doubling the risk of hospitalization for ventricular arrhythmia and an eightfold risk in the initial prescription period (Hennesy et al. 2008).
Drugs available in the mass market should be safe, tolerable and effective. Although cisapride is effective and generally tolerable, it is not safe and should not have been in the market. However cisapride had passed premarket clinical trials indicating it is safe for use and serious side effects were only realized after the drug was in the market. The studies highlighted above conclude that the drug has the capacity to induce arrhythmia and up to 80 deaths were linked to use of cisapride in the six years it was in the market. Safety of a drug is a relative description and varies largely with the proposed use of the drug and the perceived safety levels for similar drugs already in the market. For example, most drugs used in cancer treatment and chemotherapy have significant side effects such as decreased blood cells count, confusion and hallucination, seizures, ringing in ears, fertility impairment, kidney, heart, lung and liver damage, but the drugs are allowed for use because their benefits outweigh their adverse effects. In general, any new drug must be safer than similar drugs already in the market at the same level of effectiveness. For a drug such as cisapride used to prevent heartburn at night, the risk of arrhythmia and sudden death are significant enough to have it removed from the market because the risk is not proportional to the benefits.
Detection of side effects at an earlier stage
The safety issues related to the use of cisapride, were realized only after the drug was in the market. Various factors make it unlikely that these potentially fatal side effects of cisapride could have been predicated at an earlier stage of the drug’s lifecycle. To start with, the drug had passed initial clinical trials of safety and efficacy. Clinical trials are limited in the number of participants and the trial conditions are regulated. For instance it is impossible to test a drugs interaction with all other known physiologically active compound and under all possible patient conditions. Therefore, many drugs which appear safe in clinical trials may prove to have negative side effects when they are available in the market. Flawed research design in the clinical trial such as a poor selection of the sample size produce data that is not accurate (Sakpal, 2010). Most of the early studies on the efficacy and safety of cisapride used less than 1000 participants. Once in the market, the drug was prescribed to over 300,000 patients per year and this larger pool of users makes it possible to determine the long term and low-probability side effects of the drug that could not be determined from the clinical trials.
Another factor that can contribute to the late detection of the adverse effects of cisapride is publication bias. Publication bias is the tendency to publish research results that have a certain finding or point to a certain research direction. In a meta-analysis study of trends in the publication of clinical trial results, Hopewell et al., found that clinical trials with positive findings are more likely to be published in peer reviewed journals than clinical trials with negative or null findings (2009). In addition, clinical trials with positive findings were published sooner (in 4 or 5 years), than those with negative or null findings which were generally published after 6 to 8 years. This demonstrated publication bias makes it possible that clinical trials of cisapride which had found the adverse effects took longer to publish or were not published at all. The FDA withdrew the drug from the market once the potentially fatal side effects were realized. Publication bias is a serious problem in medical research and evidence based care because systematic reviews and meta-analysis studies used to generate evidence do not account for unpublished data that was negative or null (Sterne, Egger & Smith, 2001). Although this ought to have been done on the clinical trial stage, withdrawing the drug has saved many people who would have potentially been affected by it.
Drug development is a long process and the drug is tried in clinical trials to determine safety and efficacy before it is allowed for sale in the mass market. Cisapride was developed in the 1980s and marketed in between 1993 and 1999. It was used in the treatment of nocturnal heartburn and was withdrawn from the market after it was linked to an increased risk of arrhythmia and 80 deaths. It is unlikely that these adverse side effects of the drug could have been realized during clinical trials. Arrhythmia occurred mainly in patients with other risk factors and exclusion of patients with cardiac diseases during the clinical trials may have made it impossible to predict the side effects before the drug was available in the market. In addition, publication bias reduces the exposure of studies with negative findings. Clinical trials should be designed well to ensure that only drugs that are safe and effective are passed to the mass market.
Barbey, J. T., Lazzara, R., & Zipes, D. P. (2002). Spontaneous adverse event reports of serious
ventricular arrhythmias, QT prolongation, syncope, and sudden death in patients treated with cisapride. Journal of cardiovascular pharmacology and therapeutics, 7(2), 65-76.
Camilleri, M., Malagelada, J. R., Abell, T. L., Brown, M. L., Hench, V., & Zinsmeister, A. R.
(1989). Effect of six weeks of treatment with cisapride in gastroparesis and intestinal pseudo-obstruction. Gastroenterology, 96(3), 704
Hennessy, S., Leonard, C. E., Newcomb, C., Kimmel, S. E., & Bilker, W. B. (2008). Cisapride
and ventricular arrhythmia. British journal of clinical pharmacology, 66(3), 375-385.
Hopewell, S., Loudon, K., Clarke, M. J., Oxman, A. D., & Dickersin, K. (2009). Publication bias
in clinical trials due to statistical significance or direction of trial results. Cochrane Database Syst Rev, 1(1).
Reyntjens, A., Verlinden, M., & Aerts, T. (1986). Development and clinical use of the new
gastrointestinal prokinetic drug cisapride (R 51 619). Drug Development Research, 8(1‐4), 251-265.
Richards, R. D., Valenzuela, G. A., & McCallum, R. W. (1993). Objective and subjective results
of a randomized, double-blind, placebo-controlled trial using cisapride to treat gastroparesis. Digestive diseases and sciences, 38(5), 811-816.
Sakpal, T. V. (2010). Sample size estimation in clinical trial. Perspectives in clinical research,
Sterne, J. A., Egger, M., & Smith, G. D. (2001). Systematic reviews in health care: investigating
and dealing with publication and other biases in meta-analysis. BMJ: British Medical Journal, 323(7304), 101.
Wysowski, D. K., Corken, A., Gallo-Torres, H., Talarico, L., & Rodriguez, E. M. (2001).
Postmarketing reports of QT prolongation and ventricular arrhythmia in association with cisapride and Food and Drug Administration regulatory actions. The American journal of gastroenterology, 96(6), 1698-1703.
Wysowski, D. K., & Bacsanyi, J. (1996). Cisapride and fatal arrhythmia. New England Journal
of Medicine, 335(4), 290-291.