Puzzles of Therapeutic Efficacy Flashcards
“if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind — and all the worse for the fishes”
Oliver Wendell Holmes, 1860
Kefauver–Harris Amendments of 1962
Gave rise to the Phase I, II, and III clinical trial standard of the FDA.
Passage owed in part due to the thalidomide panic which preceded it the same year.
Thalidomide panic of 1962
Caused limb-reduction malformations in children of women who took the drug while pregnant
Initial rise to popularity of RCTs (timeperiod)
1940 (Hill’s standardization of RCT criteria) to 1970’s
WWII and the rise of the pharmaceutical industry during this timeperiod played a large part
1960’s to 1990’s: A history of RCTs in the US
1962: The thalidomide scare and passage of the Kefauver–Harris Amendments to the Food, Drug, and Cosmetic act (Phase I, II, and III clinical trials)
1970: FDA requires RCTs as a standard for clinical evidence (better definition of phase III)
1980’s: Pharmaceutical industry begins to fund some of their own RCTs
1990’s and on: Pharmaceutical industry funds more than half of all RCTs
“Superiority of innovation” bias
Just because x had no demonstrable effect from an RCT does not mean that x+y will not have a demonstrable effect from an RCT.
Sometimes true, for sure, but a repeated application of this argument gets us nowhere. We will be running in circles and tweaking to infinity.
Nirvana fallacy in science
Ex: “Since RCTs are not fullproof and many well-run trials fail to change clinical practice or are later found not to be generalizable, what is the point of having them be required and treated as a gold standard?”
Just becaue they aren’t perfect does not mean they don’t hold any weight, we just need to train physicians who are capable of interpreting data well and capable of setting up good trials. Not perfect doesn’t mean bad, and in fact they are an incredible source of evidence even though they aren’t perfect, they are just nuanced.
How do we manage patients with a rare or severe condition for which there are potentially life-saving drugs that have not gone through standard trials yet?
Expanded access/compassionate use legislation has existed for some time under FDA regulation, allowing access to investigational drugs that are not undergoing a clinical trial accessible to the patient. 99% of applications are approved. This is only allowed when there is no other reasonable treatment alternative which has been proven.
‘Right-to-try’ legislation now exists, but whether or not this is a good thing is hotly debated. These laws allow someone terminally ill to try a drug that has passed at least a phase I clinical trial.
Notable, “right-to-try” drugs are 1) free of all ties of liability by company ad physician, 2) uncovered by insurance, 3) drug companies do not have to provide if they don’t want to.
In truth, most drugs don’t make it out of phase IV trials becuase they are dangerous or ineffective
Passage rate for each clinical trial phase
Phase I: 70% pass
Phase II: 18% pass
Phase III: 50% pass
Phase IV: N/A
Net: 6.3% pass, or 9% of those that pass phase I (eligible for right to try)
Utilizing a “right-to-try” drug in Phase II clinical trial
There is a >90% chance this drug is either unsafe or ineffective
CROs
Contract Research Organizations
Emerged in 70’s as third party that conducts research trials. Contributed to a shift in principal investigators in U.S. trials away from physician-scientists in academic teaching hospitals and toward nonacademic physicians working in the private sector on a contract basis.
Better medical definition of the placebo effect
In a broad sense, placebo effects are improvements in patients’ symptoms that are attributable to their participation in the therapeutic encounter, with its rituals, symbols, and interactions.
Placebo vs Albuterol, Self-reporting vs FEV1
Nocebo effects
Perceived side effects of medications that are actually caused by anticipation of negative effects or heightened attentiveness to normal background discomforts of daily life in the context of a new therapeutic regimen.
The therapeutic bias
Supportive and attentive health care (preferably with effective medications, but even without) legitimately creates a “therapeutic bias” in patients toward hope and an experience of relief and reprieve. This is the theoretical basis for the placebo effect.
