Abstract
What is the purpose of clinical research? In other words, what is the aim of the approximately 10,000 clinical trials conducted each year in the United States alone? 1 Well, in the context of integrative and complementary medicine, there may be a wide range of aims, but the vast majority of trials are concerned with the discovery, investigation, approval, and application of new drugs. Clinical trials follow clear rules and a rigid step-by-step model:
At least in pharmacology, it always starts with the search for potential target structures such as receptors, key signaling molecules, or disease-specific molecules for new but mostly for known diseases. 2,3 Numerous candidates for suitable substances that interact with the target structure are then tested. And while Alexander Fleming’s discovery of penicillin was a lucky find involving a forgotten and slowly going moldy petri dish during a holiday, today this search and testing is highly structured and standardized. Not least because millions in revenue or losses depend on it.
In preclinical studies, i.e., in vivo studies (on cell cultures, isolated organs, and organelles) and in vitro studies (on animal models), the pharmacodynamics, pharmacokinetics, and toxicology of the substances are investigated. And for many test substances, the journey already ends here: only 10% of the promising substances tested in preclinical studies enter the market.
In phase I, or first-in-human, studies, the basic safety and tolerability of the substances are then tested in healthy people. The probability of market entry here is 20%, i.e., 8 out of 10 substances that make it to phase I never enter the market.
Phase II, or first-in-patient, studies then serve to determine the dosage and to verify safety, this time in patients. The market entry probability is 30%.
Phase III studies are what most people think of when they hear the words “clinical trials.” In pharmacological research, these are almost always randomized, placebo-controlled, and double-blind studies. The primary goal here is to test efficacy. The majority of the substances tested in phase III studies (65%) enter the market. But that also means that over a third do not. 2,3
But even that is not the end of the story: in phase IV, or pharmacovigilance studies, drugs are examined in routine use after approval in the real-life therapeutic setting. The focus here is on the systematic and continuous monitoring of clinical experience, with the aim of identifying very rare adverse drug reactions and other risks. Almost 10% of approved drugs are withdrawn from the market as a result of phase IV studies.
Clinical trials in drug research, i.e., in the vast majority of cases, thus follow clear rules and stages, with the threat of discontinuation of efforts and writing off millions of dollars worth of costs at each of these stages. In addition, drugs in the approval process are subject to a variety of regulatory hurdles due to country-specific laws, regulations, and authorities. And even after approval, economic hurdles remain, for example, because in most countries, health insurance companies do not automatically cover the costs either.
But is this always the case? Are health decisions always made on the basis of this strict and highly regulated approach, and, thanks to approval procedures, are made possible in the first place? Let’s look at an extreme example:
From January 1998 to November 2000, 1,802 patients awaiting nonemergency coronary artery bypass surgery were enrolled in the multicenter STEP study. 4 Patients were randomized to one of three groups: for patients in the first group, a Christian faith community prayed for them daily for 2 weeks; the patients were blinded to the intervention, so that they did not know whether they were being prayed for or not. Patients in the second group were also blinded, but no prayers were directed at them. Patients in the third group were prayed for in the same way as the first group, but they knew that they were receiving the intervention. The main outcome measure was the rate of postoperative complications. What result would you expect? That probably depends on your own beliefs as to whether you expect a positive effect from prayer. When I ask my medical students about this, they all expect the best effect in group three, i.e., the unblinded verum group. However, the results of the STEP study did not confirm this assumption: complications occurred in 52% of patients who received intercessory prayer and were blinded to the intervention, in 51% of those who did not receive intercessory prayer and were blinded to the intervention, and in 59% of patients who received intercessory prayer and knew that they were receiving it. 4,5 So, the complication rate was highest in the group in which we would have expected the lowest rate a priori.
The STEP study authors made it clear as early as in the abstract of the protocol: “STEP is not designed to determine whether God exists or whether God does or does not respond to (intercessory prayer).” 4 But that’s only on the sidelines. Much more important are the implications: will people stop praying for their sick relatives because research suggests that it is futile, perhaps even dangerous? Should not guidelines advise against praying for patients before bypass surgery or, if you absolutely must pray, at least not tell them, so as not to endanger them? An unimaginable infringement on the freedom of religious practice and also otherwise rather an absurd idea.
Let’s take an even more extreme example: once a year, over Christmas and New Year, the BMJ publishes a Christmas issue. The research articles in the BMJ Christmas issue are “light-hearted fare and satire,” but “adhere to the same high standards of novelty, methodological rigour, reporting transparency, and readability as the regular issue.” 6 BMJ Christmas issues have covered topics such as the epidemiology, treatment, and prevention of zombie epidemics; the survival time of chocolates on hospital wards; and the dynamics of disappearing teaspoons in research institutes. However, the 2003 issue also addressed a more serious problem (OK, if it should come to that, I would like to know more about the treatment of a zombie infection, but until then the following problem seems more pressing):
When leaving aircraft in the air (whether voluntarily or involuntarily), parachutes are often used to reduce the risk of orthopedic, head, and soft tissue injuries after a gravitational load. However, this use is largely based on anecdotal evidence, without the public being fully aware of that. Anecdotal evidence is particularly worrying here because there is evidence of adverse events associated with the use of parachutes, and even without an intervention, a jump from an airplane does not always have negative outcomes.
In 2003, a British group of authors set out to remedy this untenable situation and conducted the first systematic review of the prevention of death and major trauma related to gravitational challenge through parachute use. 7 And they did not find a single randomized controlled study (RCT) on the subject. Many radical advocates of evidence-based medicine demand that interventions for which there are no RCTs, especially if there is a potential for side effects, should no longer be used. It is not known whether these people changed their own health behavior after it became clear that there was no hard evidence for parachute use.
Perhaps it was simply not necessary, because a solution was on the horizon: 15 years later, again in the BMJ Christmas issue, a further, this time U.S. research group published the first RCT on the subject: 23 people were randomly assigned to a verum group that received a parachute and a placebo group that only strapped on an empty backpack. They then jumped from an airplane or helicopter. The study found no difference in the primary outcome measure, the composite of death or major traumatic injury upon impact with the ground. It should be noted that the experimental design was slightly modified for ethical reasons and that the aircraft were parked on the ground instead of flying. 8 Nevertheless, this RCT is the best evidence we have for the use of parachutes when jumping from an airplane, and we all know that clinical studies always deviate to a certain extent from the reality of care and have to make compromises.
But seriously, I think the clear conclusion from these studies is that the lack of evidence, but also negative studies, do not always refute practical experience and do not necessarily lead to changes in practice! Especially when there are centuries, if not millennia, of clinical experience with the intervention.
You may now have an idea what this long introduction has to do with integrative and complementary medicine. I will deal with this in more detail in the second part of this editorial. In the meanwhile, I would like to wish those of you who follow the Gregorian calendar a Happy New Year. Stay healthy and stay curious.
Holger Cramer, PhD
Editor-in-Chief