Disadvantages

Many papers discuss the disadvantages of RCTs. [ 59 ] [ 60 ] Among the most frequently-cited drawbacks are:

Limitations of external validity

The extent to which RCTs' results are applicable outside the RCTs varies; that is, RCTs' external validity may be limited. [ 59 ] [ 61 ] Factors that can affect RCTs' external validity include: [ 61 ]

Where the RCT was performed (e. g. what works in one country may not work in another) Characteristics of the patients (e. g. an RCT may include patients whose prognosis is better than average, or may exclude "women, children, the elderly, and those with common medical conditions" [ 62 ] ) Study procedures (e. g. in an RCT patients may receive intensive diagnostic procedures and follow-up care difficult to achieve in the "real world") Outcome measures (e. g. RCTs may use composite measures infrequently used in clinical practice) Incomplete reporting of adverse effects of interventions

Costs

RCTs can be expensive; [ 60 ] one study found 28 Phase III RCTs funded by the National Institute of Neurological Disorders and Stroke prior to 2000 with a total cost of US$335 million, [ 63 ] for a mean cost of US$12 million per RCT. Nevertheless, the return on investment of RCTs may be high, in that the same study projected that the 28 RCTs produced a "net benefit to society at 10-years" of 46 times the cost of the trials program, based on evaluating a quality-adjusted life year as equal to the prevailing mean per capita gross domestic product. [ 63 ]

Time

The conduction of a RCT takes several years until being published, thus data is restricted from the medical community for long years and may be of less relevance at time of publication. [ 64 ]

Relative importance of RCTs and observational studies

Two studies published in The New England Journal of Medicine in 2000 found that observational studies and RCTs overall produced similar results. [ 65 ] [ 66 ] The authors of the 2000 findings cast doubt on the ideas that "observational studies should not be used for defining evidence-based medical care" and that RCTs' results are "evidence of the highest grade." [ 65 ] [ 66 ] However, a 2001 study published in Journal of the American Medical Association concluded that "discrepancies beyond chance do occur and differences in estimated magnitude of treatment effect are very common" between observational studies and RCTs. [ 67 ]

Two other lines of reasoning question RCTs' contribution to scientific knowledge beyond other types of studies:

If study designs are ranked by their potential for new discoveries, then anecdotal evidence would be at the top of the list, followed by observational studies, followed by RCTs. [ 68 ] RCTs may be unnecessary for treatments that have dramatic and rapid effects relative to the expected stable or progressively worse natural course of the condition treated. [ 59 ] [ 69 ] One example is combination chemotherapy including cisplatin for metastatic testicular cancer. which increased the cure rate from 5% to 60% in a 1977 non-randomized study. [ 69 ] [ 70 ]

Difficulty in studying rare events

Interventions to prevent events that occur only infrequently (e. g. sudden infant death syndrome ) and uncommon adverse outcomes (e. g. a rare side effect of a drug) would require RCTs with extremely large sample sizes and may therefore best be assessed by observational studies. [ 59 ]

Difficulty in studying outcomes in distant future

It is costly to maintain RCTs for the years or decades that would be ideal for evaluating some interventions. [ 59 ] [ 60 ]

Pro-industry findings in industry-funded RCTs

Some RCTs are fully or partly funded by the health care industry (e. g. the pharmaceutical industry ) as opposed to government, nonprofit, or other sources. A systematic review published in 2003 found four 1986-2002 articles comparing industry-sponsored and nonindustry-sponsored RCTs, and in all the articles there was a correlation of industry sponsorship and positive study outcome. [ 71 ] A 2004 study of 1999-2001 RCTs published in leading medical and surgical journals determined that industry-funded RCTs "are more likely to be associated with statistically significant pro-industry findings." [ 72 ] One possible reason for the pro-industry results in industry-funded published RCTs is publication bias. [ 72 ]

Therapeutic misconception

Although subjects almost always provide informed consent for their participation in an RCT, studies since 1982 have documented that many RCT subjects believe that they are certain to receive treatment that is best for them personally; that is, they do not understand the difference between research and treatment. [ 73 ] [ 74 ] Further research is necessary to determine the prevalence of and ways to address this "therapeutic misconception ". [ 74 ]

Narrowing of the studied question

Randomized clinical trials are usually only inspect one variable or very few variables, rarely reflecting the full picture of a complicated medical situation; whereas the case report. for example, can detail many different aspects of the patient’s medical situation (e. g. patient history, physical examination. diagnosis. psychosocial aspects, follow up). [ 64 ]

Statistical error

RCTs are subject to both type I ("false positive") and type II ("false negative") statistical errors. Regarding Type I errors, a typical RCT will use 0.05 (i. e. 1 in 20) as the probability that the RCT will falsely find two equally effective treatments significantly different. [ 75 ] Regarding Type II errors, despite the publication of a 1978 paper noting that the sample sizes of many "negative" RCTs were too small to make definitive conclusions about the negative results, [ 76 ] by 2005-2006 a sizeable proportion of RCTs still had inaccurate or incompletely-reported sample size calculations. [ 77 ]

Cultural effects

The RCT method creates cultural effects that have not been well understood. [ 78 ] For example, patients with terminal illness may attempt to join trials as a last ditch attempt at treatment, even when treatments are unlikely to be successful.

Conflict of interest dangers

A 2011 study done to disclose possible conflicts of interests in underlying research studies used for medical meta-analyses reviewed 29 meta-analyses and found that conflicts of interests in the studies underlying the meta-analyses were rarely disclosed. The 29 meta-analyses included 11 from general medicine journals; 15 from specialty medicine journals, and 3 from the Cochrane Database of Systematic Reviews. The 29 meta-analyses reviewed an aggregate of 509 randomized controlled trials (RCTs). Of these, 318 RCTs reported funding sources with 219 (69%) industry funded. 132 of the 509 RCTs reported author conflict of interest disclosures, with 91 studies (69%) disclosing industry financial ties with one or more authors. The information was, however, seldom reflected in the meta-analyses. Only two (7%) reported RCT funding sources and none reported RCT author-industry ties. The authors concluded “without acknowledgment of COI due to industry funding or author industry financial ties from RCTs included in meta-analyses, readers’ understanding and appraisal of the evidence from the meta-analysis may be compromised.” [ 79 ]