On innovation, patient-centricity and added value
18.09.19
From time to time we see an article or a headline on the theme that "so and so many new drugs have no added value". The latest example was an article published in the BMJ in July, looking at assessments done by the German agency IQWiG between 2011 and 2017. It says that more than half of the new drugs that have entered the German health system lacks proof of an added value.
It sounds outrageous, and when you start to think about it also rather mysterious, almost baffling. Who approved all these drugs that have no added value? Why were they developed? What kind of doctor prescribes them, and what kind of patient takes them? Or are they all sitting on a shelf somewhere, produced en masse by a soon to be bankrupt pharmaceutical company who made a bad investment decision?
Let's take a look at one of these drugs with “no added value” referenced in the BMJ article: teriflunomide which was approved by the EMA in 2013 for the treatment of relapsing-remitting Multiple Sclerosis, a serious disease of the central nervous system. The same year, IQWiG performed an assessment of this drug compared to interferon beta-1a, which is considered to be an appropriate comparative therapy. These therapies were directly compared in the TENERE randomised clinical trial, which is the basis for IQWiG's assessment.
On the primary endpoint and most secondary endpoints - time to failure, Annual Relapse Rate and quality of life (fatigue), teriflunomide scores more or less the same as interferon with no statistical significant differences. The adverse events are different in nature – diarrhea and hair thinning for teriflunomide compared to flu like symptoms and headaches for interferon - but IQWiG assesses that they are comparable in terms of severity (mild to moderate). Increase of ALT in the blood stream, which can indicate liver problems, were more often reported in the interferon arm, but the difference in treatment discontinuation caused by changed lab results was not statistically significant between the two arms.
So far, teriflunomide is up to par with what was then the standard therapy, with some minor differences here and there.
On one metric however, teriflunomide is clearly superior to interferon: patient satisfaction. If you know anything about these drugs then you'll understand why. Interferon is administered by injections, whereas teriflunomide is an oral tablet that is taken daily. For many patients this makes a big difference – for many decades MS patients have had to inject the treatment, for many a less pleasant way of taking a drug, with associated skin rashes and other side effects, but continuous innovation in the field is now resulting in new drugs that you can swallow with a glass of water.
This point is very summarily dealt with in the IQWiG assessment. "Die Patientenzufriedenheit ist kein patientenrelevanter Endpunkt gemäß AM-NutzenV und wird deshalb nicht in der Nutzenbewertung berücksichtigt." In English: Patient satisfaction is not a patient relevant endpoint according to AM-NutzenV [the applicable legislation] and is therefore not included in the benefit assessment.
That's quite interesting. Patient satisfaction is not a patient relevant endpoint. In other words, it's considered to be fluff, a nice-to-have, but not a real, hard endpoint. Why would it be?
Well, even if we don't care about what patients think but confine ourselves to an ivory tower of statistics, patient satisfaction can play into a system level impact: adherence. Lack of adherence is a major problem in our health systems, and becomes more and more important to tackle as chronic diseases become a larger and larger part of the disease burden and health system cost. According to Health at a Glance: Europe 2018, poor adherence is believed to cost European health systems around EUR 125 bn every year in avoidable hospitalisations, outpatient visits and emergency care. Lack of adherence also means that the clinical outcomes that were proven in the near perfect world of the clinical trial are actually not achieved to the same extent in the real world.
Relevant for this case, needle phobia is a common phenomenon among the population at large, and according to one study, affects around 12% of MS patients. According to this study, among MS patients with injection concerns, 40% in the EU5 (30% in the US) were currently not on treatment, compared to 29% of patients (20% in the US) who did not have such concerns.
So, arguably one of the most important aspects of the innovation with teriflunomide - that an MS treatment could now be taken in the form of a tablet, instead of through injection - was not even part of the assessment. In the language of US crime dramas, it was not admissible as evidence. Is that reasonable? That seems to depend on who you ask. Now, was this drug a seismic breakthrough in treating MS? Clearly not. But “no added value”?
In an article about the TENERE trial, Patricia K. Coyle, MD, director of the Multiple Sclerosis Comprehensive Care Center at Stony Brook University, says that patient satisfaction with treatment is a very important aspect of how a patient is doing while on a given therapy.
“With multiple options, you do not want a patient suffering,” Coyle said. “It can have great efficacy, but if a patient’s report is that they’re unhappy with the treatment, I believe that’s a valid reason to switch.”
Indeed, not all patients are created equal - some treatments do work better for some patients than for others, and the perception and severity of the side effects can vary. For patients with hard to treat chronic diseases - like MS - it is therefore a value in itself to have choice, to have a range of therapies with different profiles (benefits, side-effects and administration modes) from which to choose, or switch between, in dialogue with the treating physician. (This is sometimes dismissively referred to as "me too" drugs.) In this case, the value of teriflunomide as one of several treatment options for MS is further confirmed by its inclusion in the European guidelines adopted by the European Academy for Neurology (EAN) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Again, the snappy headline "no added benefit" conceals a much more complex reality.
There is a lot of talk about patient-centred healthcare these days. Everyone says it's important. What does it mean beyond the buzzwords? In recent years, the pharmaceutical industry has made real progress in engaging patients, their experience, insight and expertise across the life cycle of a medicine. Patients are more and more often involved from the beginning of R&D, to help the researchers understand what the patients' needs actually are, and how products and services should be designed to best cater to those needs. There is increasing attention given to Patient Reported Outcomes to measure what's actually important for patients, both as endpoints in clinical trials and to measure real world performance of treatments, healthcare providers and entire health systems. But no chain is stronger than its weakest link. If these dimensions are not valued by all parts of the system, including the regulators and payers, then they will never go from buzzwords to the real world. No added value indeed.
References
- Hoffman, Matt. "Teriflunomide Improves Patient Satisfaction In Teri-PRO, TENERE Trials". Neurology Live, 2018, https://www.neurologylive.com/conferences/aan-2018/teriflunomide-improves-patient-satisfaction-in-teripro-tenere-trials.
- Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen. Teriflunomid – Nutzenbewertung Gemäß § 35A SGB V. 2013.
- OECD/EU. Health At A Glance: Europe 2018: State Of Health In The EU Cycle. OECD Publishing, Paris, 2018, https://doi.org/10.1787/health_glance_eur-2018-en.
- Montalban, Xavier et al. "ECTRIMS/EAN Guideline On The Pharmacological Treatment Of People With Multiple Sclerosis". Multiple Sclerosis Journal, vol 24, no. 2, 2018, pp. 96-120. SAGE Publications, doi:10.1177/1352458517751049.
- Narayanan, S. et al. "Needle Phobia And Associated Clinical Practice Patterns Among Patients With Multiple Sclerosis (Ms) In Europe And The United States". Value In Health, vol 17, no. 3, 2014, p. A63. Elsevier BV, doi:10.1016/j.jval.2014.03.371.
- Vermersch, Patrick et al. "Teriflunomide Versus Subcutaneous Interferon Beta-1A In Patients With Relapsing Multiple Sclerosis: A Randomised, Controlled Phase 3 Trial". Multiple Sclerosis Journal, vol 20, no. 6, 2013, pp. 705-716. SAGE Publications, doi:10.1177/1352458513507821.
- Wieseler, Beate et al. "New Drugs: Where Did We Go Wrong And What Can We Do Better?". BMJ, 2019, p. l4340. BMJ, doi:10.1136/bmj.l4340.
