Analysing recent preliminary research on the ‘placebome’ – a set of genes that trigger some placebo responders to respond to the placebo effect, Dr Joseph Kamalesh, Associate Vice President, Quest Life Sciences concludes that this could lead to a possible revolution in clinical trial design. This is because with the incorporation of genetic screening at the clinical trial design stage, placebo responders could be excluded, resulting in more accurate and precise clinical trials. However, there are certain ethical issues which will need to be first sorted out
A small change made today can become history to be reckoned with someday. Just to prove the statement to be true, the study of Kathryn Hall a researcher at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, is on the cusp of unearthing data that can in future change the design of clinical trial studies as we see it today.
Clinical trials have always been a basis for the approval of pharmaceutical products to be marketed on a commercial scale. It is an extremely sensitive field of study since it also carries an element of risk for the human volunteers participating in the trials. Before any drug can make its way into the market, safety and efficacy studies should be performed and have to be proved beyond debate. Human volunteers play a very crucial role by rendering their co-operation in the clinical trials conducted.
As stated by a clinical trial researcher, “The first object of a therapeutic trial is to discover whether the patients who receive the treatment under investigation are cured more rapidly, more completely or more frequently, than they would have been without it”. Keeping this in mind, over time the field of clinical trials has faced many revolutionary changes, of which a major one was the formation of the placebo controlled clinical study.
Placebos in clinical trials
Placebos can be considered as a therapeutically inert substance given to the human volunteers, thereby giving them the perception that they are being treated while in reality, there is no therapeutic treatment. On the other hand, studies now suggest that random patients do exhibit responses when administered with a placebo formulation, which in turn has spurred the debate amongst the scientific community, that the body has genes responsive to placebo molecules, and this reaction of the body has been termed as placebo eesponse. Common placebos include inert tablets, vehicle infusions, sham surgery etc.In technical terms, placebo-controlled studies are a way of testing a medical therapy whereby, in addition to a group of volunteers subjected to the treatment to be evaluated, a separate control group receives a placebo treatment which is specifically designed to have no real effect. Placebos are most commonly used in blinded trials, where subjects do not know whether they are receiving real or placebo treatment. The aim of incorporating a placebo arm in the study is to determine the treatment effects in the study which are not related to the treatment itself.
In different phases of clinical trials, placebos, either inactive drug or sugar pills, are used as controls for the comparison against the effectiveness of active substances. The placebo effect makes it difficult for the evaluation of clinical studies conducted. Placebo responders who are basically human volunteers with a genetic makeup that makes them susceptible to the effects of the placebo formulation, as they participate in the trial and when administered with the placebo, will tend to have a misconception of it, where the person comes to a conclusion that the betterment of their health had occurred due to the uptake of it. This placebo effect might be the outcome of the genetic programming of the placebo responders which eventually makes them conclude that the placebo had really worked wonders by eliminating their physical abnormalities.
Hall states, “Our findings strongly support the idea that genetic signatures for placebo responses exist, but our findings are preliminary.” The findings stated by her indicate the finding of the ‘placebome’ a set of genes that trigger some placebo responders, to respond to the placebo effect. Previous studies prove that certain signaling pathways like the dopamine, opioid, endocannabinoid, and serotonin pathways in the brain can play a mediatory role in the variations seen in the placebo responses. Taking the dopamine pathway as an example, Hall and her team have gained more evidence from their work that some small variation in the dopamine pathway can extract favourable outcomes from patients subjected to placebos that might overcome the placebo effect, since the dopamine pathway seems to be responsible for all the pain and pleasure responses of a person. In her study the variations instilled in the COMT (catechol-O-methyltransferase) gene which influences the dopamine pathway eventually alters the placebo responses of a person since the placebo effect is mediated by the dopamine. This variation is believed to bring about a revolution in the clinical trial design by the incorporation of genetic screening where the placebo responders can be excluded and the trial can be conducted with placebo non-responders and concluded accurately with more precision. The refined acceptance of the subjects for the trial would be made possible by the study of Hall and there are possibilities of great noticeable changes occurring in the trial design.
Impact of ‘placebomes’ on clinical trials
A general hypothesis states that, the pathways that influence the placebo response, can also produce the same outcome, in the responses of the human volunteers to drugs that target these pathways. Again these responses are said to vary from person to person based on their genetic makeup. If this hypothesis is proven, then it can further help in cutting the costs of clinical trial studies, by the incorporation of a no treatment arm in addition to the placebo controlled arm. All the above mentioned findings, if and when proven, will take the researchers another step closer to making the concept of personalised medicine more accurate and viable. Personalised medicine in a nutshell, it is the mode of treatment, whereby a patient is subjected to their genetic analysis as well as the molecular and cellular data are collected, and this data is used as a template to provide personalised singular treatment to the patient, and this includes prescription drugs, medical decisions and therapeutic procedures.
Ethical aspects
There are also certain other ethical issues which need to be answered like, whether a person would be psychologically disturbed when becoming aware of their placebo response effects. Another point to be debated upon will relate to the labeling of drugs, as to whether a drug clinically tested only on placebo non-responders can be prescribed for use on patients who are genetically prone to show a placebo response.
Another probing issue is on whether the physician during disease diagnosis, should be allowed to carry out patient profiling based on their response/ non-response to placebos, and if allowed to do so, then are the patients to be given the right to accept or decline such a type of profiling. If the physicians are allowed access to this information, then what are the measures to be taken to ensure that this patient information will be used by the physicians without any compromise on the ethical norms.
“If there is indeed a biological element and you can actually find a genetic basis for it, you would absolutely be causing a revolution in clinical trial design,” says Arthur Caplan, an ethics researcher at New York University Langone Medical Center. On the same note, if the studies of Hall managed to be scientifically proved with proper evidences, clarifying all the ethical issues, would become a great breakthrough in clinical trial designing. The acceptance of the new design of the clinical trial which can be more constructive and cost effective is a big question to be answered in the near future by the CRO’s.
Reference:
http://www.worldpharmanews.com/research/3065-certain-genes-might-make-some-people-more-prone-to-experience-the-placebo-effect
http://www.reuters.com/article/2015/04/15/us-placebo-effect-genes-idUSKBN0N62L220150415
http://www.dispatch.com/content/stories/local/2015/04/26/health/placebo-effect-might-be-genetic.html
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