This article first appeared as a contribution to the 'Key Opinion Leader' series produced by Panacee Conseil.
All physicians and pharmacists involved in the prescribing and dispensing of medicines know that adopting a positive attitude when providing patients with a medicine can markedly enhance its therapeutic effect. If a patient has positive expectations, it is more likely the drug will have a beneficial effect than if the patient is skeptical about the drug. In this way healthcare professionals can significantly enhance the effect of a drug, which is why the double blind placebo-controlled trial was invented, to eliminate this influence in drug efficacy studies. So, what do we see in such trials? The placebo has beneficial effects, but can also generate a variety of side effects about which the patient was told in the informed consent procedure.
Since the 1970s, we know that the reverse can also be true: If a patient has the impression that a medicine may be less effective or is inferior in quality (sometimes perceived as such, due to a lower price) then its pharmacological efficacy may be compromised and there is a chance the patient will experience decreased benefits and possibly also increased side effects. This phenomenon was first studied extensively when generic medicines with exactly the same composition, even those from the same manufacturer, induced unwanted effects in patients. Could it possibly be something like a reverse-placebo effect? The answer is yes. Patients who are told that their medicine may not be exactly the same (similar but not identical) or that it could cause side effects (not necessarily different from the original) may have a different therapeutic outcome.
Understanding the Nocebo Effect
In the early 2000s I became interested in this therapeutic phenomenon. When patients were switched from an originator anti-epileptic drug to a generic version with exactly the same composition, some of them experienced an increase in seizure frequency. How could this be possible? The question puzzled researchers, and numerous real-world studies were conducted to try and figure it out. They all tended to show the same answer: changing treatment can induce harmful effects.
It was a fascinating puzzle that was resolved by the Kesselheim and Avorn team at Harvard Medical School (for a systematic analysis, see Kesselheim et al. Drugs 70(2010)605). They examined large databases to determine which factors were influencing seizures in patients, and they observed that after visiting a doctor’s office for a check-up and a new prescription, a certain proportion of patients always experienced an increase in seizure frequency, irrespective of the drug they were prescribed. This was clearly a non-pharmacological effect of the prescribing and treatment process. In a recent review by an international team of experts (Kristensen et al., BioDrugs 2018) an entire table of “nocebo effects” is described, ranging from pain, biased oral provocation tests in allergology, impact on morbidity in cardiovascular disease, and even motor performance in Parkinson’s disease. The nocebo effect is now clearly a scientifically defined and proven clinical entity.
Biosimilars and the Nocebo Effect
Patients who are treated with biological drugs for chronic conditions have usually undergone a whole host of trial and error treatments before they are more or less stabilized. And now their doctor is proposing to switch them to an alternative version—a biosimilar—of the drug they are dependent on. A biowhat, you say? In this age of shared decision making, patients are fully informed of all the pros and cons of the alternative version of the drug responsible for their relatively stable condition.
This happened, for instance, in the landmark Nor-Switch trial. It was a double-blind controlled trial comparing originator infliximab (Remicade) with the biosimilar CT-P13 (Inflectra or Remsima) in a variety of inflammatory diseases (including rheumatoid arthritis and inflammatory bowel disease). Almost 500 patients were randomized and followed up for a year by a highly experienced clinical trial team. To make a long story short, based on objective disease parameters as measured by the medical team, there was no relevant difference between the originator drug and the biosimilar.
Remarkably, the subjective experience of patients was different: between 25% and 30% of the patients experienced an increase in global disease activity. This increase in disease activity was not corroborated by the physician’s score of global disease activity. What was even more remarkable was that the patients on the reference treatment also reported a similar worsening of disease activity, proving that a factor other than the drug treatment was at play. Apparently, the expectation that under blind conditions a patient might receive an alternative drug, one not exactly the same but similar, caused in all patients, feelings of anxiety that they might get worse, and so they did. Not pharmacology, but psychology, or what we know as a “nocebo response.”
The way we communicate with patients: a critical factor
The assumption that the way patients had been informed was a critical factor in this response was tested in two open trials in which RA patients were switched from an originator to a biosimilar. In the first trial, infliximab originator was switched to the biosimilar CT P13 with extensive information and education of patients. In a second trial, patients were transitioned from originator etanercept to a biosimilar SB4 with the message that the new drug was just a different brand, and that it had been shown in previous trials to be less painful on injection. In the first trial the discontinuation rate after 6 months was around 25%, with many patients feeling less comfortable after the switch. In the second trial, which included a structured communication strategy, around 10% of patients stopped treatment, a figure consistent across almost all trials where drug treatment is changed. The authors attribute the discrepancy to the difference in the way the patients had been informed about the possible consequences of the switch.
In the literature, many transition studies have reported on discontinuation rates. Several registry studies (including DanBio) have also examined the persistence of drug treatment. As most of these studies are open and single arm (no proper controls), the way patients have been informed is extremely critical as we know now. In almost none of the studies is this critical detail reported adequately, making data on drug persistence almost impossible to interpret. Innovator companies are quick to claim: see, the biosimilar doesn’t perform as well… But what we actually see is the methodological weakness of these studies. In properly controlled trials there is no overall clinically relevant difference in efficacy, side effects, and persistence between innovator drugs and biosimilars.
What conclusions should we draw for daily practice?
Healthcare professionals should always express their confidence in the results from properly executed research: biosimilars are as good as the originator product, otherwise they would not be approved by national drug agencies. We should all convey this confidence in a consistent and positive matter to patients, i.e., we will continue your treatment with a different brand of the medicine than you are used to, one with the same proven efficacy and safety. The advantage is its lower cost, and in this way, together, we help keep our healthcare system affordable. We generate headroom for new expensive medicines, and more patients can be treated for the same amount of money.
There are now more than 170 transition studies published on the switch from originator to biosimilar, and the great majority of these trials confirm that efficacy and patient safety were not compromised by the transition.
As healthcare professionals we need to be aware of the nocebo effect and train our teams to speak with one voice and avoid negative language when dispensing all medicines, including biosimilars. In doing so we maximize the beneficial potency of those medicines, possibly far beyond their pharmacological effect. And the cherry on the sundae is that it’s at absolutely no extra cost!
