There was a nice series of articles in the journal Circulation that appeared in 2002 with free full text online. These articles offer specific lessons about evidence-based medicine.
†In the August 6 issue, DeMets and Califf tackle the difficult topics of
- surrogate outcome measures,
- composite clinical endpoints,
- and subgroup analysis.
†In the August 13 issue, DeMets and Califf continue with a discussion about
- independent data monitoring committees,
- publication bias,
- non-inferiority trials,
- the FDA requirement for two confirmatory trials,
- and the use of primary and secondary endpoints.
In the August 20 issue, Califf and DeMets show that most therapies
- have modest effects,
- have quantitative but not qualitative interactions,
- influences (for better or for worse) on unintended biological pathways,
- behave unexpectedly when combined with other therapies,
- have long term effects that are different from short term effects, and
- are not easily lumped into classes of drugs.
In the August 27 issue, Califf and DeMets continue with observations that most therapies
- have a mix of helpful and harmful effects, and
- cannot be justified on purely economic benefits.
They also conclude that randomized clinical trials
- are necessary for the development of clinical guidelines,
- ignore may underserved areas, and that doctors
- and need greater participation from doctors and patients.
Many of the topics discussed in this series of papers relate to my web page, Mountain or Molehill, which talks about the clinical importance of research findings. When I get a chance, I want to update that page to incorporate many of the examples discussed in this excellent series.
Other recent articles have valuable lessons as well.
In the past, women have been unfairly excluded from clinical trials. In a 2000 NEJM review article by Harris et al [Medline], the authors show that some recent gain have occurred but more progress is still needed. A 2001 JAMA review article by Lee et al [Medline], reaches the same conclusions and also points out that elderly patients are still being underrepresented in clinical trials. For example, patients over the age of 75 are responsible for 37% of all myocardial infarctions, but in the 1990s they were included as only 9% of all patients in trials studying this condition. This is an improvement over the participation rate from earlier times, but still short of what it should be.
Griffith et al discuss left ventricular hypertrophy as a surrogate marker. Kelloff et al also discuss surrogate endpoints. In an AIM 2003 paper, Messerli discusses secondary endpoints, a topic also covered by Moye in 2001.
Left ventricular hypertrophy: a surrogate end point or correlate of cardiovascular events in kidney disease? Griffith TF, Reddan DN, Klassen PS, Owen WF. Nephrol Dial Transplant 2003: 18(12); 2479-82. [Medline] [Full text] [PDF]
Perspectives on surrogate end points in the development of drugs that reduce the risk of cancer. Kelloff GJ, Sigman CC, Johnson KM, Boone CW, Greenwald P, Crowell JA, Hawk ET, Doody LA. Cancer Epidemiol Biomarkers Prev 2000: 9(2); 127-37. [Medline] [Abstract] [Full text] [PDF]
ALLHAT, or the Soft Science of the Secondary End Point. Messerli FH. Annals of Internal Medicine 2003: 139(9); 777-780. [Abstract] [Full text] [PDF]
Random research. Moye LA. Circulation 2001: 103(25); 3150-3. [Medline] [Abstract] [Full text] [PDF]
You can find an earlier version of this page on my original website.