Just imagine the following situation: You have an appointment with your family physician because of some recurring pains that have concerned you for some time now. It has taken (only) two weeks to get this appointment, and the doctors, after a brief bodily check and some questioning, ask whether you would be interested and willing to take part in a test for a new drug “under development” for your pains, and, after some discussion, explains that you may have a 50% chance to be in the true drug group or to receive a placebo.
Would you be willing to participate, and, if so, for what reason? To eventually get rid of your pains, to please your doctor, to help improve the situation of other patients with similar symptoms, or as a matter of curiosity whether the new pill may work better that all the other ones that you have tried in the past? Or would you just ask the doctor to have another prescription of the medicine that he gave you the last time, which relieved your symptoms quite effectively, at least for some weeks before you stopped taking the pills to see whether you got along without it?
This is exactly the situation the World Medical Association (WMA) expert panel on ethics had foreseen when outlining the latest revision of the Declaration of Helsinki (DoH) of 1964 (1): Patients, when asked participate in drug testing, are not free to make a decision about such request, because they are in need of medical help and might agree to accept such an invitation because they are dependent on the doctor to help them. And doctors adhere tightly to their Oath of Hippocrates that requires them to provide help to patients in need, and while the support of novel therapy development may be a legitimate interest of them, it is not part of their professional (medical) duties.
Not so much with the use of placebos, but rather the fact that drug trials in the early phases of systematic drug development (2) were done even without explicit ethical review and approval, and often even without appropriate patient information and informed consent – there are horrible stories about drug testing in prisons, with minors and dependent people in psychiatric hospitals, with minorities and other groups, in foreign countries and secluded conditions, in war and peace. And while we have discussed this also with respect to forerunners of placebo research such as Henry K Beecher, we have to admit that, at the same time, he was among the first to foster and promote the establishment of proper ethical review and approval of medical research (3). The ethics of placebo use was but one of the topics in medicine that needed this review.
With respect to the use of placebos, the DoH therefore took — and still takes — a strong position on the use of placebos in medical care. When a patient consults a doctor for medical help, he/she has the right to receive the best treatment available (BTA) for his/her condition, and this definitively excludes the use of a placebo pill not containing any active component, irrespective of whether it may or may not improve symptoms, as has been shown in placebo research (4). Even matching this request, BTA already steers many discussions: Is BTA the best therapy on a global market, is it the best therapy a medical care system can provide in a given country or region, or is it the best therapy the patient can afford or the doctor knows and believes in? This is why medicine has developed the concept of “medical evidence,” which says that all medicines must meet standards of solid scientific proof of their efficacy and can reliable be distinguished from quackery, snake oil, and wishful thinking. Placebo pills are tools to make this distinction, but they are not (or should not be) part of medical care.
While the WMA DoH committee accepts the need for medical research to develop new therapies including drugs, and also accepts a role placebo pills may play in this development, at the same time, they separate drug development from medical therapy for the benefit of the patients. This standpoint has some quite important practical implications as we will see, but before that we would like to explore two exceptions that the DoH allowed in their rules: a) there is no treatment available, and b) the medical condition to be treated is of minor severity.
The first seems to be a condition that may not be simple to imaging — there are, overall, many drugs for many conditions already available, and the need for development of a new one may not easily be seen. However, the necessary question is not whether there is a drug available somewhere on the planet, but whether it is available for a specific patient in a specific country — and here the problem starts. Different countries have different legal systems for drug approval, different health care systems for prescription and reimbursement, and different access to therapy that depends on more than just the existence of a drug somewhere that has been found to be effective for a medical condition.
Furthermore, there are in fact medical conditions for which drugs are not available, or are no longer available, or are not yet available, and one such example is irritable bowel syndrome (IBS). Over the past 35 years that we have observed medical management of IBS patients, many drugs have seen the market that have subsequently disappeared and are no longer available, for quite different reasons: adverse events, selling of the compound to another company, shift of interests, and poor post-marketing data etc.
All this would permit a placebo-controlled trial of a novel compound, provided that the other condition is fulfilled: the disease tested by a placebo-controlled trial should be of minor severity. Now, this is even more difficult to assess: certainly, the view pf patients, e.g. those affected by IBS, would be entirely different and maybe opposite to the view of a doctor used to treats patients with cancer. Therefore, the WMA has defined this request in a bit more detail, saying that this is the case when — without effective treatment, e.g. by providing a placebo — the disease does not worsen the situation of the patient, and the symptoms overall are not so bad that they would affect the life of the patient afflicted in a considerable manner. While this still leaves some ambiguity, it excludes, on the other hand, most acute diseases, even if minor (because they require treatment to not become chronic), and it would include many chronic conditions that have reached a stable burden of disease status irrespective of treatments applied.
Getting back to the initially described situation, a patient consulting a doctor for symptoms that need treatment — how can, given all the restrictions ethics puts onto doctors and the health care system, drug evaluation comply and promote new drug development at the same time under these limiting conditions? There are two principally different ways to do so: either develop new drug testing methods (designs, trials) that would minimize or even completely dismiss the use of placebos in RCT and replace it by other means and methods. The other alternative is to move away from RCT and test drugs under “real world” conditions of medicine, where placebos do not exist, but the placebo effect may still be alive and effective. We will discuss these alternative in the two final postings of this series.
This is part 16 of a series covering “placebo” provided by Paul Enck and Sibylle Klosterhalfen from the Tübingen University Hospital. Continuous updates on placebo research can be found at www.jips.online.