What has become of controlled drug trials

Some have even called the controlled drug trial the most important discovery of the last century in the field of medical research. Let us assume there is a series of observations suggesting that a newly developed drug might be effective for a disease. The most definitive way to determine how and to what extent these observations reflect reality is to conduct a controlled drug trial. 

For this purpose, and to ensure that the statistical analysis to be performed at the end of the study is sound, let us assume that about 200 subjects with disease B are found who will volunteer to participate in such a study. The volunteers are first told the main purpose of the study, the potential side effects of the drug to be tested, and, in summary, the various burdens of participating. Throughout the study, the volunteers will receive either drug A, which is designed to be beneficial to them, or an ineffective substance that looks exactly like it (such as sugar)—in other words, a placebo—or a drug that is already on the market and effective for the same disease. The progression of their illness will be monitored at specific intervals. Among the 200 patients in question, who will receive the new drug and who will receive the placebo or the old drug will be determined by lottery, and neither the patients nor the physicians conducting the study will know the result of this lottery during the study period. 

During the study period, which is often 3-12 months, patients are monitored meticulously at regular intervals. As I emphasized, once the study is over, it is revealed which patient received what—information that was kept secret from both the patients and the doctors monitoring them—and whether the new drug has any superiority over the old drug or the placebo is revealed through a meticulous statistical analysis. In this analysis, comparisons are naturally made in terms of both the curative effects and the harmful side effects of the new drug being tested. 

The invariable prerequisite for any new drug to be released to the market is that it has undergone such scientifically high-value, controlled—or to use the exact term, double-blind randomized controlled drug trials. Today, both the FDA in the USA and the EMA in the EU primarily grant licenses to new drugs based on such studies. 

In these studies, the primary focus is the curative effect of the new drug being tested. Undoubtedly, any drug-related side effects or adverse events that may arise during the study are also carefully monitored and are naturally taken into account when the drug is licensed. On the other hand, the investigation of the potential side effects of a new drug is first carried out through animal experiments and then on a small number of healthy and/or patient volunteers. Only after these stages, and if the new drugs do not show serious and significant adverse side effects, are their potential curative effects investigated through such randomized controlled trials. Let me add immediately: in some cases, the adverse effects of a newly released drug may only emerge after the drug has been licensed and entered widespread use. For this reason, the potential side effects of new drugs that may emerge later are meticulously monitored by national and international organizations. 

In short, a randomized controlled drug trial is a full-fledged scientific experiment conducted on patients, with the main goal of offering a new drug to the service of humanity. The first example in the history of science was the famous MRC (Medical Research Council) study conducted in England in 1948, which proved the effect of streptomycin in the treatment of tuberculosis. In our country, apart from a few unethical studies conducted by foreign companies on psychiatric patients before that, the first example was the research conducted by the Cerrahpaşa Behçet's Disease Research Group, which proved that a drug called colchicine was effective for certain symptoms of this disease. Such studies require great ethical rigor because they are, by definition, experiments conducted on patients. Volunteers first read an informed consent form, which should explain the benefits and harmful aspects of the study they will participate in as simply as possible, ask the researchers questions about it, and if they are satisfied, they give their consent to enter the study. What must be emphasized here is that if the effect of the drug to be tested on the disease is proven at the end of the study, some of the patients will not have benefited from the drug at all due to the lottery conducted at the beginning of the study. Therefore, the volunteer patient who consents to participate in the study is participating primarily for the benefit of society.  

A distressing development is that randomized controlled drug trials have begun to be used in recent years to test the side effects or harms of a relatively new drug rather than its efficacy. The scenario is more or less as follows: Some time after a drug, whose efficacy has been proven by traditional methods and licensed, has been in widespread use—often within a few years—potential side effects are reported to drug monitoring agencies, or isolated scientific articles begin to appear. In some cases, these potential side effects are not relatively trivial issues like itching or mild diarrhea, but very serious health problems such as an increasing number of heart attacks, cancer, strokes, and even death. In this case, the correct path to follow is not to conduct experimental studies, but to investigate the reality of these potential side effect reports using purely observational methods, even stopping the sale of the drug in question if necessary. I admit that such observational studies were very difficult to conduct 20-30 years ago. However, today, with the support of artificial intelligence, collecting observational data has become easier and more reliable.

Let me state with continuing sadness: Today, in some cases, the randomized controlled trial method—which I underlined above is essentially an experiment on sick people—is also applied to test the connection between these later-emerging side effects and the drug in question. The sample scenario is as follows: Let us say we have a drug that has been proven to lower blood sugar and is licensed for use in diabetics. However, some time after the drug is widely used, reports begin to emerge that the same drug might increase the risk of heart attacks in diabetics. Upon this, the company producing the drug, sometimes with the support—or even the mandate—of the state, initiates a controlled study to test these potential side effects. To make matters worse, the volunteer patients who will participate in the study are specifically selected from among patients with an increased tendency for heart attacks, such as those with high blood lipid levels, etc.

My anger grows as I explain this. Look, one of the outcomes of the Nuremberg trials, where the Nazis were judged after World War II, is the famous Nuremberg Code of Medical Research Ethics. The 5th article of this short, 10-point code, prepared as a natural reaction to the inhumane medical research conducted by the Nazis, says exactly this: No experiment should be designed where death or permanent disability is foreseen as a result, except in cases where the doctors conducting the experiment are the subjects themselves. 

Recently, on the CNN Int. channel, experienced host Amanpour hosted a British historian and asked him the following question: “You are known as a scientist who usually makes moderate comments about what is happening. However, I read one of your recent articles with some surprise. You were making very harsh comments about the authoritarian regimes currently ruling the world. What I want to ask you is this: To which place or phase of the thousands of years of human history, which I know you know very well, do you liken what is happening now?”

The historian gave an immediate, very short, and definitive answer: “Berlin, 1932.”