[Skip to Content]
[Skip to Content Landing]
Download PDF
Table 1. 
Discontinuation Rates in Some Clinical Trials*
Discontinuation Rates in Some Clinical Trials*
Table 2. 
Symptoms Attributed as Possibly Drug Related in Placebo Group*
Symptoms Attributed as Possibly Drug Related in Placebo Group*
Table 3. 
Symptoms Occurring in Placebo Group Independent of Presumed Cause*
Symptoms Occurring in Placebo Group Independent of Presumed Cause*
1.
Barsky  AJSaintfort  RRogers  MPBorus  JF Nonspecific medication side effects and the nocebo phenomenon. JAMA 2002;287622- 627
PubMedArticle
2.
Barsky  AJ Amplification, somatization, and the somatoform disorders. Psychosomatics 1992;3328- 34
PubMedArticle
3.
Aronson  JKDerry  SLoke  YK Adverse drug reactions: keeping up to date. Fundam Clin Pharmacol 2002;1649- 56
PubMedArticle
4.
Ioannidis  JPContopoulos-Ioannidis  DG Reporting of safety data from randomised trials. Lancet 1998;3521752- 1753
PubMedArticle
5.
Walsh  JMEPignone  M Drug treatment of hyperlipidemia in women. JAMA 2004;2912243- 2252
PubMedArticle
6.
Corvol  JCBouzamondo  ASirol  MHulot  JSSanchez  PLechat  P Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Arch Intern Med 2003;163669- 676
PubMedArticle
7.
Serruys  PWde Feyter  PMacaya  C  et al.  Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention. JAMA 2002;2873215- 3222
PubMedArticle
8.
Lesaffre  EKocmanova  DLemos  PADisco  CMCSerruys  PW A retrospective analysis of the effect of noncompliance on time of first major adverse cardiac event in LIPS. Clin Ther 2003;252431- 2447
PubMedArticle
9.
Shepherd  JBlauw  GJMurphy  MB  et al.  Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;3601623- 1630
PubMedArticle
10.
Pfeffer  MAKeech  ASacks  FM  et al.  Safety and tolerability of pravastatin in long-term clinical trials: Prospective Pravastatin Pooling (PPP) project. Circulation 2002;1052341- 2346
PubMedArticle
11.
Byington  RPDavis  BRPlehn  JF  et al.  Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) project. Circulation 2001;103387- 392
PubMedArticle
12.
Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;3607- 22
PubMedArticle
13.
Schwartz  GGOlsson  AGEzekowitz  MD  et al.  Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;2851711- 1718
PubMedArticle
14.
Teo  KKBurton  JRBuller  CE  et al.  Long-term effects of cholesterol lowering and angiotensin-converting enyzme inhibition on coronary atherosclerosis: the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 2000;1021748- 1754
PubMedArticle
15.
 MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999;20725- 741
PubMedArticle
16.
Riegger  GAbletshauser  CLudwig  M  et al.  The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment. Atherosclerosis 1999;144263- 270
PubMedArticle
17.
Herd  JABallantyne  CMFarmer  JA  et al.  Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol 1997;80278- 286
PubMedArticle
18.
Herd  JA The Lipoprotein and Coronary Atherosclerosis Study (LCAS): lipid and metabolic factors related to atheroma and clinical events. Am J Med 1998;104 ((suppl 6A)) 42S- 49S
PubMedArticle
19.
Long-term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group, Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;3391349- 1357
PubMedArticle
20.
Sacks  FMPfeffer  MAMoye  LE  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;3351001- 1009
PubMedArticle
21.
Shepherd  JCobbe  SMFord  I  et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;3331301- 1307
PubMedArticle
22.
Jukema  JWBruschek  AVGvan Boven  AJ  et al.  Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. Circulation 1995;912528- 2540
PubMedArticle
23.
Pitt  BMancini  GBJEllis  SGRosman  HSPark  JSMcGovern  ME Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events: PLAC I investigation. J Am Coll Cardiol 1995;261133- 1139
PubMedArticle
24.
Crouse  JR  IIIByington  RPBond  MG  et al.  Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol 1995;75455- 459
PubMedArticle
25.
Salonen  RNyyssönen  KPorkkala  E  et al.  Kuopio Atherosclerosis Prevention Study (KAPS): a population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995;921758- 1764
PubMedArticle
26.
Furberg  CDAdams  HPApplegate  WB  et al.  Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation 1994;901679- 1687
PubMedArticle
27.
 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;3441383- 1389
PubMed
28.
Dujovne  CAChremos  ANPool  JL  et al.  Expanded Clinical Evaluation of Lovastatin (EXCEL) study results, IV: additional perspectives on the tolerability of lovastatin. Am J Med 1991;91 ((suppl 1B)) 25S- 30S
PubMedArticle
29.
Graham  DJStaffa  JAShatin  D  et al.  Incidence of rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004;2922585- 2590
PubMedArticle
30.
Kroenke  KPrice  RK Symptoms in the community: prevalence, classification, and psychiatric comorbidity. Arch Intern Med 1993;1532474- 2480
PubMedArticle
31.
Medical-Economic Staff, Physicians' Desk Reference.  Montvale, NJ Thompson Healthcare2003;
32.
PDR Consortium, Physicians' Desk Reference. 57th ed. Montvale, NJ Thomson Healthcare2003;
33.
 Mosby's Drug Consult 2003. 14th ed. Amsterdam, the Netherlands Mosby/Elsevier2003;
34.
Keech  ACollins  RMacMahon  S  et al.  Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study. Eur Heart J 1994;15255- 269
PubMedArticle
35.
 Lescol, Lescol XL. Prescribing information East Hanover, NJ Novartis Pharmaceuticals Co2003;
36.
Fukuda  KDobbins  JGWilson  LJDunn  RAWilcox  KSmallwood  D An epidemiologic study of fatigue with relevance for the chronic fatigue syndrome. J Psychiatr Res 1997;3119- 29
PubMedArticle
37.
Buchwald  DUmali  PUmali  JKith  PPearlman  TKomaroff  AL Chronic fatigue and the chronic fatigue syndrome: prevalence in a Pacific Northwest health care system. Ann Intern Med 1995;12381- 88
PubMedArticle
38.
Rief  WHessel  ABraehler  E Somatization symptoms and hypochondriacal features in the general population. Psychosom Med 2001;63595- 602
PubMedArticle
39.
Casper  RCTollefson  GDNilsson  ME No gender differences in placebo responses of patients with major depressive disorder. Biol Psychiatry 2001;49158- 160
PubMedArticle
40.
De Geest  SMoons  P The patient's appraisal of side-effects: the blind spot in quality-of-life assessments in transplant recipients. Nephrol Dial Transplant 2000;15457- 459
PubMedArticle
41.
Spitzer  RLFleiss  JL A re-analysis of the reliability of psychiatric diagnosis. Br J Psychiatry 1974;125341- 347
PubMedArticle
42.
Justice  ACRabeneck  LHays  RDWu  AWBozzette  SA Sensitivity, specificity, reliability, and clinical validity of provider-reported symptoms: a comparison with self-reported symptoms. J Acquir Immune Defic Syndr 1999;21126- 133
PubMed
43.
Mantel-Teeuwisse  AKVerschuren  WMKlungel  OH  et al.  Undertreatment of hypercholesterolaemia: a population-based study. Br J Clin Pharmacol 2003;55389- 397
PubMedArticle
44.
Jackevicius  CAMamdani  MTu  JV Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002;288462- 467
PubMedArticle
45.
Benner  JSGlynn  RJMogun  HNeumann  PJWeinstein  MCAvorn  J Long-term persistence in use of statin therapy in elderly patients. JAMA 2002;288455- 461
PubMedArticle
46.
Kaplan  RCBhalodkar  NCBrown  EJWhite  JBrown  DL Race, ethnicity, and sociocultural aspects predict noncomplicance with lipid-lowering medications. Prev Med 2004;391249- 1255
PubMedArticle
47.
Piercy  MASramek  JJKurtz  NMCutler  NR Placebo response in anxiety disorders. Ann Pharmacother 1996;301013- 1019
PubMed
48.
Psaty  BMFurberg  CDRay  WAWeiss  NS Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis. JAMA 2004;2922622- 2631
PubMedArticle
49.
Piorkowski  JD Bayer's response to “Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis.” JAMA 2004;2922655- 2657
PubMedArticle
50.
Psaty  BMFurberg  CDRay  WAWeiss  NS Author's reply to Bayer's response to “Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis.” JAMA 2004;2922658- 2659Article
51.
Rothwell  PM External validity of randomised controlled trials: “to whom do the results of this trial apply?” Lancet 2005;36582- 93
PubMedArticle
52.
Lacro  JPDunn  LBDolder  CRLeckband  SGJeste  DV Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 2002;63892- 909
PubMedArticle
53.
Lasser  KEAllen  PDWoolhandler  SJHimmelstein  DUWolfe  SMBor  DH Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002;2872215- 2220
PubMedArticle
54.
Avorn  JBenner  JFord  I  et al.  Measuring the cost-effectiveness of lipid-lowering drugs in the elderly: the outcomes research and economic analysis components of the PROSPER trial. Control Clin Trials 2002;23757- 773
PubMedArticle
Review Article
January 23, 2006

Medication-Attributed Adverse Effects in Placebo GroupsImplications for Assessment of Adverse Effects

Author Affiliations

Author Affiliations: Department of Psychiatry (Drs Rief and Barsky) and Division of Pharmacoepidemiology and Pharmacoeconomics (Dr Avorn), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; and Department of Clinical Psychology, Philipps University, Marburg, Germany (Dr Rief).

Arch Intern Med. 2006;166(2):155-160. doi:10.1001/archinte.166.2.155
Abstract

Medication-attributed adverse effects are a frequent reason for poor compliance in practice and in clinical studies and are also common in patients receiving placebo. The occurrence of adverse effects in placebo groups can clarify the assessment of adverse event reporting. We analyzed data from randomized, placebo-controlled trials of statin drugs published since 1992 with sample sizes larger than 100 subjects. Reports of adverse effects and discontinuation rates in placebo groups were evaluated. We compared data on adverse effect profiles in placebo groups between trials and with expected rates from population-based studies. We also sought to determine the range of adverse effect ascertainment methods used in different studies. Methods of ascertainment of adverse events varied widely across studies. Overall, 4% to 26% of patients in the control groups of large trials of statin drugs discontinued placebo use because of perceived adverse effects. The symptom rate in placebo groups varied substantially across trials (up to a ratio of 13:1 for possibly drug-related symptoms, eg, headache, 0.2%-2.7%, or abdominal pain, 0.9%-3.9%) and were often markedly lower than those found in the general population (eg, fatigue, 1.9%-3.4%) in trials of statin drugs vs 17.7% in the general population. In conclusion, the widely varying rates of adverse effects reported by patients taking placebo and the high prevalence of such symptoms in the general population should be considered by both trialists and clinicians. In addition, variability of adverse effect ascertainment is considerable and suggests the need for better standardization in research.

Adverse events are a central part of the risk-benefit profile of a drug, and decisions about which drug to prescribe or take depend heavily on tolerability and the adverse effect profile. Medication adherence in clinical trials, and even more in clinical practice, depends on the subjective experience of adverse effects attributed to the drug. These symptoms may indicate harmful events, but they are also a cause of subjective distress and impaired quality of life.

The placebo groups in randomized clinical trials provide an excellent means to examine the phenomenon of drug adverse effects. Adverse effects reported in placebo groups are typically considered the generic, nonspecific baseline with which the adverse effects of the active drug are to be compared. This nocebo phenomenon1 is substantial; it describes the negative effects attributed to placebo. The knowledge about taking medication or the anxiety about medication effects and illness course can cause patients to monitor symptoms in more detail, resulting in an amplified perception of benign sensations and physical symptoms.2

Although many randomized, controlled trials are of good quality and large enough to detect a therapeutic benefit, many do not provide reliable or detailed information about adverse effects.3,4 However, an adequate risk-benefit assessment depends on the quality of measurement of both efficacy and adverse effects. The better the quality of assessment (eg, reliability and validity of instruments), the more likely effects can be found. If the evaluation of adverse effects is done with less reliable instruments than the evaluation of benefits, the risk-benefit calculation may be flawed.

Adverse effect assessment methods in clinical trials vary substantially. In many studies, patients are simply asked whether they have experienced any symptoms since the last visit. A second source of variability is related to the person recording the symptoms, who must decide whether the reported symptom is relevant, whether its intensity is sufficient to be recorded, and whether it is drug related. In light of the variability and instability of this data collection process, adverse effect assessment that is not structured or standardized may be unreliable.

The purposes of this study were to assess dropout rates because of supposed adverse effects in placebo groups in different trials, to analyze the stability of adverse effect profiles in placebo groups across similar studies, and to compare symptom profiles in placebo groups with reference data from the general population.

METHODS

We conducted a systematic review of trials of statin drugs to study placebo adverse effect reporting. The statin drug trials were chosen because, although many of the participants had coronary heart disease, hypercholesterolemia is asymptomatic and the drugs are often given for prophylaxis rather than treatment. Therefore, in the placebo arms of these trials, noncardiovascular symptoms are likely to be neither drug induced nor illness associated. Our goal was to identify all statin drug trials published between 1994 and 2003 that comprised more than 100 subjects in the placebo arm, using PubMed and additional literature research. Our search identified nearly identical publications as 2 recently published meta-analyses of statin drug trials.5,6 The following trials were considered: LIPS (Lescol Intervention Prevention Study),7,8 PROSPER (Prospective Study of Pravastatin in the Elderly at Risk),9 PPP (Prospective Pravastatin Pooling project; pooled data from CARE [Cholesterol and Recurrent Events study], LIPID [Long-term Intervention With Pravastatin in Ischemic Disease trial], and WOSCOP [West of Scotland Coronary Prevention study]),10,11 MRC/BHF (Medical Research Council/British Heart Foundation Heart Protection Study),12 MIRACL (myocardial ischemia reduction with aggressive cholesterol lowering),13 SCAT (Simvastatin and Enalapril Coronary Atherosclerosis Trial),14,15 German-Czech fluvastatin trial,16 LCAS (Lipoprotein and Coronary Atherosclerosis Study),17,18 LIPID,19 CARE,20 WOSCOP,21 REGRESS (Regression Growth Evaluation Statin Study),22 PLAC (Pravastatin Limitation in Atherosclerosis in the Coronary Arteries study),23 PLAC-2 (Pravastatin, Lipids, and Atherosclerosis in the Carotid Arteries study),24 KAPS (Kuopio Atherosclerosis Prevention Study),25 ACAPS (Asymptomatic Carotid Artery Progression Study),26 4S (Scandinavian Simvastatin Survival Study Group),27 and EXCEL (Expanded Clinical Evaluation of Lovastatin trial28) (the EXCEL trial was included, although published in 1991, because it was a restudy of a larger lovastatin trial). Reported adverse effects for the placebo groups as well as further sample information of these studies were tabulated depending on whether only possibly drug-related symptoms were mentioned or whether symptoms in general were reported. Confidence intervals were computed to compare the base rates that differed most. We sought to distinguish whether variations were limited to nonspecific symptoms that were unlikely to be related to the pharmacologic action of the active drug or whether these variations can be also found for more clinically important adverse effects. One such adverse effect of statin drugs is muscle pain or myopathy, which can indicate rhabdomyolysis.29 Therefore, variations of base rates of muscle weakness also were analyzed.

The reported frequency of adverse effects in the placebo group was also compared with symptom prevalence rates in the general population. Because we could not use lifetime rates (eg, from the ECA [Epidemiologic Catchment Area] study30), we report data from a representative sample of 2552 adults that assessed 33 symptoms for the last 7 days. This survey also enabled consideration of symptom intensity ratings.

RESULTS

Table 1 gives the discontinuation rates for subjects in the placebo arms of these trials and includes only trials in which the causes for discontinuation were reported. At least 5% to 10% of patients in these trials discontinued use of placebo because of perceived adverse effects.

Table 2 summarizes the incidence of symptoms in the placebo groups that were attributed to the study medication (ie, placebo). These figures were mainly compiled from merged data sets (eg, Physicians' Desk Reference32,33) or other publications because many statin drug trials did not report adverse effect symptom patterns in detail. The rates of specific adverse effects in the placebo arms varied widely among the trials. Depending on the specific symptom, the incidence was as much as 3 to 13 times higher among trials (Table 2). Typical examples included headache, with a range of 0.2% (confidence interval [CI], 0.2%-0.7%) to 2.7% (CI, 1.9%-3.5%), or flatulence, with a range of 0.7% (CI, 0.3%-1.0%) to 4.2% (CI, 3.2%-5.2%) across trials; the nonoverlapping CIs confirm significant differences.

Table 3 summarizes data for symptoms in the placebo group irrespective of whether they were attributed to the drug. These symptom frequencies varied substantially. These variations are also found for clinically important adverse effects, for example, muscle pain. In the studies that provided these data, the symptom frequency of this critical symptom varied nearly 8-fold: EXCEL,28 7.5% of subjects in the placebo group reported muscle weakness; PROSPER,9 1% of subjects in the placebo group reported myalgia; MRC/BHF,12,15 at preanalysis, 6% of subjects in the placebo group reported muscle pain or weakness; MRC/BHF, at main analysis, at each assessment about 6% of subjects reported muscle pain or weakness, and during 5 years the total was 33% in the placebo group; WOSCOP, 19 (0.6%) of 3293 subjects in the placebo group reported myalgia and 97 (3%) reported muscle aches; and PPP,10 2% of subjects in the placebo group reported musculoskeletal pain.

In relation to symptom base rates in the general population samples (columns 7 and 8 in Table 3), the rates in the statin placebo groups were substantially lower. Even if only symptoms of moderate intensity were counted in the general population, 20 of 21 comparisons revealed symptom frequencies in the statin placebo group to be outside the CI for the same symptom in the general population. In 17 of these 20 comparisons, the symptom rates in the clinical trials were lower than in the general population sample.

Symptoms such as headache and back pain are common in industrial societies, with base rates greater than 20%,30 while in the statin placebo samples, these rates were reported as less than 10%. For chronic fatigue, stable rates between 17.5% and 19% were found in samples of the US population, in California workers, in the English population, and in health maintenance organization enrollees.36,37 However, the base rates in the statin placebo groups were reported to be in the range of 1.9% to 3.4%.

COMMENT

We found great variability in reported adverse effect profiles in patients taking placebo in different clinical trials. Thus, these nocebo symptoms cannot be considered as stable, constant “white noise” but are subject to various methodologic and other influences among studies. This calls into question the generalizability of adverse effect reports and the comparability of adverse effect patterns across trials. It also suggests that it is hazardous to merge adverse effect data from different trials, although this is frequently done for treatment groups as well as for placebo groups. If the great variability of adverse effect reports in placebo groups is due to unreliable and invalid assessment methods, the same problem applies for adverse effect reports in active treatment groups.

A number of factors could contribute to variability of adverse effect rates among trials, including sex differences, age, comorbidity, and sample selection. However, in the studies reviewed, none of these seem to be strong enough to explain such differences. For sex, odds ratios in symptom reporting for women rarely exceed 1.5 (eg, see REFERENCES 38, 39, and 40). The mean age of subjects in the statin drug trials generally ranged between 58 and 65 years; this small variance cannot account for the differences. Therefore, we believe that differences in data collection and interpretation are likely responsible for these unstable findings. While unreliable assessment method is only one of several possible explanations for these variations, the relevance of other influences (eg, population differences, and expectations of researchers and patients) can be properly evaluated only if the quality of adverse effect ascertainment is high.

Clinical trials tend to report lower rates for physical symptoms than would be expected from epidemiologic survey data. This difference is all the more striking because the higher prevalence of elderly and ill patients in the statin drug trials should be associated with even higher symptom reports. It is likely that the open-ended questions used in clinical trials led to lower adverse effect rates than would be obtained with structured scales asking about specific symptoms. Open-ended assessment strategies may be helpful in detecting rare adverse effects that might not be included in structured symptom lists. However, structured symptom lists produce more reliable and comparable results among trials because they are less prone to interviewer influences.41 With the example of symptoms in 808 patients positive for human immunodeficiency virus, reliability and clinical validity of provider-reported symptoms have been examined.42 Justice et al42 found that patient and provider agreement was poor. Providers underreported symptoms and demonstrated greater variability by study site, and there was poorer test-retest reliability.

Drug use discontinuation and lack of adherence are common problems in clinical trials and practice. This has been well studied for the statin drugs.43,45 Adverse effects are a potent predictor of treatment noncompliance with lipid-lowering medications, with an odds ratio of 3.9.46 Clinical trials tend to include more patients with positive drug expectations and higher adverse effect tolerance than typically seen in primary care.47 The relevance of subjective adverse effects for drug use discontinuation is, therefore, likely even more pronounced in clinical practice than in clinical trials.

RESEARCH IMPLICATIONS
Baseline Assessment

Many adverse effects represent symptoms that are prevalent in persons not taking medication and are also prevalent in study participants before entering a trial. Therefore, adequate baseline assessments of possible adverse effects are necessary.

Multiple Assessment of Subjective Adverse Effects

The assessment of trial completers underestimates the incidence of adverse effects because this is one reason for dropping out. If adverse effects are assessed only at the end of a trial, data for patients who dropped out are excluded. Therefore, multiple assessments and “last observation carried forward methods” are needed.

Use of Reliable and Valid Instruments for Assessing Subjective Adverse Effects

In many trials, adverse effect symptoms are not measured as rigorously as target symptoms. If unreliable methods to assess adverse effects are used, the risk for not detecting them is dramatically increased. The less reliable the assessment instrument is, the more likely are influences of conflict of interest.48,50

Assessment of Symptoms in General, Not Only of Drug-Attributed Symptoms

Symptom-caused attributions by patients or physicians are often erroneous. The symptoms described in Table 2 were all attributed to drugs, but the patients were taking placebo. Therefore, the definition of drug-related adverse effects should be replaced with systematic symptom comparisons between placebo and drug groups at baseline as well as during and at the end of the trial.

Sample Size

Most clinical trials are powered to demonstrate drug efficacy. However, this sample size is generally not sufficient to demonstrate differential rates of adverse effects. For example, if 100 patients are given a drug associated with clinical efficacy in 60% of patients (CI, 50.5%-69.9%) and 3% of them experience drug-induced adverse effects (corresponding CI, −0.3% to 6.3%), this trial can easily demonstrate the efficacy of the drug, but it is unlikely to reveal the adverse effect significantly, because the CI for the adverse effect rate includes zero.

Sample Selection

Adverse effect data from clinical trials of drug efficacy may not be generalizable to clinical practice because of sample selection.51 In some trials, patients are excluded during the run-in period, for example, if they report subjective complaints while taking placebo before the trials begin (eg, see REFERENCES 12 and 34). Compared with clinical practice, clinical trials might include patients with higher motivation to tolerate adverse effects and with more optimistic drug attitudes; these patients are likely to report fewer adverse effects and discontinue use of medication less frequently than patients in clinical practice.52

IMPLICATIONS FOR POLICY

Current methods of assessing drug-induced adverse effects in clinical trials are problematic. For drugs approved by the US Food and Drug Administration, Lasser et al53 estimated a 20% probability of acquiring a new black box warning or being withdrawn from the market during the following 25 years (see also Psaty et al47). In many cases, the detection of adverse effects is delayed compared with the detection of efficacy because of the methodologic problems described.

Policy decisions concerning resource allocation often depend on calculations of quality-adjusted life-years.54 Because quality of life is influenced by the adverse effects of treatments, these decisions also depend on adequate adverse effect assessment. These findings also have implications for drug information leaflets for patients to help prevent both underreporting and overreporting.

CONCLUSIONS

The assessment of non–life-threatening adverse effects is done with great variability in different clinical trials. Merging adverse effect data or meta-analyses of such patterns are not warranted with these data. Adverse effects have a major role for drug use discontinuation in research and in clinical practice. Improved assessment of adverse effects should help to better estimate risk-benefit ratios of drugs and to advise patients more properly. Adverse effect assessment should be done with the same accuracy as efficacy assessment.

Back to top
Article Information

Correspondence: Winfried Rief, PhD, Department of Clinical Psychology, Philipps University, FB04, Gutenbergstrasse 18, 35032 Marburg, Germany (rief@staff.uni-marburg.de).

Accepted for Publication: August 30, 2005.

Financial Disclosure: None.

References
1.
Barsky  AJSaintfort  RRogers  MPBorus  JF Nonspecific medication side effects and the nocebo phenomenon. JAMA 2002;287622- 627
PubMedArticle
2.
Barsky  AJ Amplification, somatization, and the somatoform disorders. Psychosomatics 1992;3328- 34
PubMedArticle
3.
Aronson  JKDerry  SLoke  YK Adverse drug reactions: keeping up to date. Fundam Clin Pharmacol 2002;1649- 56
PubMedArticle
4.
Ioannidis  JPContopoulos-Ioannidis  DG Reporting of safety data from randomised trials. Lancet 1998;3521752- 1753
PubMedArticle
5.
Walsh  JMEPignone  M Drug treatment of hyperlipidemia in women. JAMA 2004;2912243- 2252
PubMedArticle
6.
Corvol  JCBouzamondo  ASirol  MHulot  JSSanchez  PLechat  P Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials. Arch Intern Med 2003;163669- 676
PubMedArticle
7.
Serruys  PWde Feyter  PMacaya  C  et al.  Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention. JAMA 2002;2873215- 3222
PubMedArticle
8.
Lesaffre  EKocmanova  DLemos  PADisco  CMCSerruys  PW A retrospective analysis of the effect of noncompliance on time of first major adverse cardiac event in LIPS. Clin Ther 2003;252431- 2447
PubMedArticle
9.
Shepherd  JBlauw  GJMurphy  MB  et al.  Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002;3601623- 1630
PubMedArticle
10.
Pfeffer  MAKeech  ASacks  FM  et al.  Safety and tolerability of pravastatin in long-term clinical trials: Prospective Pravastatin Pooling (PPP) project. Circulation 2002;1052341- 2346
PubMedArticle
11.
Byington  RPDavis  BRPlehn  JF  et al.  Reduction of stroke events with pravastatin: the Prospective Pravastatin Pooling (PPP) project. Circulation 2001;103387- 392
PubMedArticle
12.
Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;3607- 22
PubMedArticle
13.
Schwartz  GGOlsson  AGEzekowitz  MD  et al.  Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 2001;2851711- 1718
PubMedArticle
14.
Teo  KKBurton  JRBuller  CE  et al.  Long-term effects of cholesterol lowering and angiotensin-converting enyzme inhibition on coronary atherosclerosis: the Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT). Circulation 2000;1021748- 1754
PubMedArticle
15.
 MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999;20725- 741
PubMedArticle
16.
Riegger  GAbletshauser  CLudwig  M  et al.  The effect of fluvastatin on cardiac events in patients with symptomatic coronary artery disease during one year of treatment. Atherosclerosis 1999;144263- 270
PubMedArticle
17.
Herd  JABallantyne  CMFarmer  JA  et al.  Effects of fluvastatin on coronary atherosclerosis in patients with mild to moderate cholesterol elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol 1997;80278- 286
PubMedArticle
18.
Herd  JA The Lipoprotein and Coronary Atherosclerosis Study (LCAS): lipid and metabolic factors related to atheroma and clinical events. Am J Med 1998;104 ((suppl 6A)) 42S- 49S
PubMedArticle
19.
Long-term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group, Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;3391349- 1357
PubMedArticle
20.
Sacks  FMPfeffer  MAMoye  LE  et al.  The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;3351001- 1009
PubMedArticle
21.
Shepherd  JCobbe  SMFord  I  et al.  Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;3331301- 1307
PubMedArticle
22.
Jukema  JWBruschek  AVGvan Boven  AJ  et al.  Effects of lipid lowering by pravastatin on progression and regression of coronary artery disease in symptomatic men with normal to moderately elevated serum cholesterol levels. Circulation 1995;912528- 2540
PubMedArticle
23.
Pitt  BMancini  GBJEllis  SGRosman  HSPark  JSMcGovern  ME Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events: PLAC I investigation. J Am Coll Cardiol 1995;261133- 1139
PubMedArticle
24.
Crouse  JR  IIIByington  RPBond  MG  et al.  Pravastatin, lipids, and atherosclerosis in the carotid arteries (PLAC-II). Am J Cardiol 1995;75455- 459
PubMedArticle
25.
Salonen  RNyyssönen  KPorkkala  E  et al.  Kuopio Atherosclerosis Prevention Study (KAPS): a population-based primary preventive trial of the effect of LDL lowering on atherosclerotic progression in carotid and femoral arteries. Circulation 1995;921758- 1764
PubMedArticle
26.
Furberg  CDAdams  HPApplegate  WB  et al.  Effect of lovastatin on early carotid atherosclerosis and cardiovascular events. Circulation 1994;901679- 1687
PubMedArticle
27.
 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;3441383- 1389
PubMed
28.
Dujovne  CAChremos  ANPool  JL  et al.  Expanded Clinical Evaluation of Lovastatin (EXCEL) study results, IV: additional perspectives on the tolerability of lovastatin. Am J Med 1991;91 ((suppl 1B)) 25S- 30S
PubMedArticle
29.
Graham  DJStaffa  JAShatin  D  et al.  Incidence of rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 2004;2922585- 2590
PubMedArticle
30.
Kroenke  KPrice  RK Symptoms in the community: prevalence, classification, and psychiatric comorbidity. Arch Intern Med 1993;1532474- 2480
PubMedArticle
31.
Medical-Economic Staff, Physicians' Desk Reference.  Montvale, NJ Thompson Healthcare2003;
32.
PDR Consortium, Physicians' Desk Reference. 57th ed. Montvale, NJ Thomson Healthcare2003;
33.
 Mosby's Drug Consult 2003. 14th ed. Amsterdam, the Netherlands Mosby/Elsevier2003;
34.
Keech  ACollins  RMacMahon  S  et al.  Three-year follow-up of the Oxford Cholesterol Study: assessment of the efficacy and safety of simvastatin in preparation for a large mortality study. Eur Heart J 1994;15255- 269
PubMedArticle
35.
 Lescol, Lescol XL. Prescribing information East Hanover, NJ Novartis Pharmaceuticals Co2003;
36.
Fukuda  KDobbins  JGWilson  LJDunn  RAWilcox  KSmallwood  D An epidemiologic study of fatigue with relevance for the chronic fatigue syndrome. J Psychiatr Res 1997;3119- 29
PubMedArticle
37.
Buchwald  DUmali  PUmali  JKith  PPearlman  TKomaroff  AL Chronic fatigue and the chronic fatigue syndrome: prevalence in a Pacific Northwest health care system. Ann Intern Med 1995;12381- 88
PubMedArticle
38.
Rief  WHessel  ABraehler  E Somatization symptoms and hypochondriacal features in the general population. Psychosom Med 2001;63595- 602
PubMedArticle
39.
Casper  RCTollefson  GDNilsson  ME No gender differences in placebo responses of patients with major depressive disorder. Biol Psychiatry 2001;49158- 160
PubMedArticle
40.
De Geest  SMoons  P The patient's appraisal of side-effects: the blind spot in quality-of-life assessments in transplant recipients. Nephrol Dial Transplant 2000;15457- 459
PubMedArticle
41.
Spitzer  RLFleiss  JL A re-analysis of the reliability of psychiatric diagnosis. Br J Psychiatry 1974;125341- 347
PubMedArticle
42.
Justice  ACRabeneck  LHays  RDWu  AWBozzette  SA Sensitivity, specificity, reliability, and clinical validity of provider-reported symptoms: a comparison with self-reported symptoms. J Acquir Immune Defic Syndr 1999;21126- 133
PubMed
43.
Mantel-Teeuwisse  AKVerschuren  WMKlungel  OH  et al.  Undertreatment of hypercholesterolaemia: a population-based study. Br J Clin Pharmacol 2003;55389- 397
PubMedArticle
44.
Jackevicius  CAMamdani  MTu  JV Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA 2002;288462- 467
PubMedArticle
45.
Benner  JSGlynn  RJMogun  HNeumann  PJWeinstein  MCAvorn  J Long-term persistence in use of statin therapy in elderly patients. JAMA 2002;288455- 461
PubMedArticle
46.
Kaplan  RCBhalodkar  NCBrown  EJWhite  JBrown  DL Race, ethnicity, and sociocultural aspects predict noncomplicance with lipid-lowering medications. Prev Med 2004;391249- 1255
PubMedArticle
47.
Piercy  MASramek  JJKurtz  NMCutler  NR Placebo response in anxiety disorders. Ann Pharmacother 1996;301013- 1019
PubMed
48.
Psaty  BMFurberg  CDRay  WAWeiss  NS Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis. JAMA 2004;2922622- 2631
PubMedArticle
49.
Piorkowski  JD Bayer's response to “Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis.” JAMA 2004;2922655- 2657
PubMedArticle
50.
Psaty  BMFurberg  CDRay  WAWeiss  NS Author's reply to Bayer's response to “Potential for conflict of interest in the evaluation of suspected adverse drug reactions: use of cerivastatin and risk of rhabdomyolysis.” JAMA 2004;2922658- 2659Article
51.
Rothwell  PM External validity of randomised controlled trials: “to whom do the results of this trial apply?” Lancet 2005;36582- 93
PubMedArticle
52.
Lacro  JPDunn  LBDolder  CRLeckband  SGJeste  DV Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry 2002;63892- 909
PubMedArticle
53.
Lasser  KEAllen  PDWoolhandler  SJHimmelstein  DUWolfe  SMBor  DH Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002;2872215- 2220
PubMedArticle
54.
Avorn  JBenner  JFord  I  et al.  Measuring the cost-effectiveness of lipid-lowering drugs in the elderly: the outcomes research and economic analysis components of the PROSPER trial. Control Clin Trials 2002;23757- 773
PubMedArticle
×