Janne Mewes, Anne Voermans, Bert Vrijhoef.
Call for new policies to ensure added benefit of newly approved drugs
How many of the newly approved drugs provide a substantial benefit to patients? When asking people from the general public their answer would probably be “all of them” or “the majority”.
A recently published analysis conducted by researchers of the German health technology assessment agency IQWiG (Wieseler et al. 2019) shows that, of the newly approved drugs in Germany between 2011 and 2017, only 25% has an added benefit that was evaluated to be considerable or major. Within the field of psychiatry and neurology this percentage was as low as 6%. Moreover, of the 125 evaluated drugs, 64 (51%) were not compared to standard of care in the trial analysing their effectiveness, and for 42 (33.6%) the comparators used in the trial were described as inappropriate. As the authors point out, this should be considered unacceptable for any health care system (Wieseler et al. 2019).
It is, however, impossible to provide high quality care when new therapies enter the market of which no one knows how they compare to other drugs or treatments. Also, funding drugs with unclear added benefits contributes to low sustainability of health care systems. In addition, it seems an ethical obligation to ensure that patients and health care providers have a chance to find out how effective a newly available drug is compared to the standard of care.
Part of this issue is the ongoing effort to speed up patient access to new drugs. Still, with the low percentage of drugs showing added value and promised post-approval studies not taking place, the researchers of IQWiG speak of a “policy failure” (Wieseler 2019, p. 3) and call for changes of the regulations. Their ideas are to demand evidence from longer and larger trials in which data are collected that serves the purpose of conducting Health Technology Assessments (HTA), as well as to require active controlled trials, possibly also conducted after approval. Further, the researchers suggest grounding the decisions on reimbursement and pricing on outcomes that are truly relevant. Patients need to be part of the process in which it is defined what a relevant outcome is. And finally, the decision of which drugs are to be developed in the future should lie more within a consortium of stakeholders (incl. patients and health policy makers) and be grounded on actual needs and societal interest rather than being dictated by pharmaceutical companies.
As stricter policies and evidence requirements regarding drug approval are called to be developed, pharmaceutical companies should get prepared to being able to demonstrate the patient-relevant value of their drugs as well as the wider impact on the health system in terms of costs and benefits. It is thus important to identify what the patient-relevant outcomes are before starting a trial, and to collect all information required for conducting an HTA, such as data on quality of life and all relevant costs of the health system, patients, and carers.
When applying for approval, expertise of HTA would be needed to conduct the (economic) analysis that can show the (added) value and benefit, also in relation to costs, of the drug. Early and very-early HTAs can be conducted, as this helps to identify the variables that impact the outcomes the most early in the development process. While “normal” HTA is directed at the decisions made by the government and regulators, early HTA is conducted during early stages of research and directed on the decisions that the industry takes itself while developing a drug or product. Very early HTA is conducted during the basic research stage (IJzerman & Steuten, 2011).
Regulators would likely be most strict on demanding robust evidence (and be less likely to accept data gaps in areas) underlying the parameters having the largest impact on the outcomes.
An HTA conducted by Panaxea on Oncotype DX® (Kip et al., 2015), a diagnostic test to support the decision to start adjuvant chemotherapy in breast cancer patients, enabled to guide the decision which type of future research would be needed to decide on the adoption of the test. It could be shown that although some of the data used originated from other countries than the analysis was conducted for, changes in those were unlikely to impact the results regarding the cost-effectiveness. Thus, when considering factors such as costs of research and patient burden, it could be recommended to focus on head-to-head studies with similar diagnostic tests, rather than to conduct long-term studies on the Oncotype DX´® effectiveness. Additionally, it could be demonstrated that the ability of a test to prevent future healthcare costs was not yet reflected in the pricing (Kip et al., 2015).
In a system where drug approval is more conditional on added benefits, it is wise to, in the development of new drugs, focus on those drugs who target yet unmet patient needs or have sufficiently large added benefits, in relation to the drugs costs. By using HTA very early in the research process it can be identified early on which drugs are likely to provide a sufficiently large patient benefit given its price. Regulators will increasingly use horizon scanning systems (HSS) to enable pro-active decision-making, by prioritizing those drugs who are expected to fill unmet patient needs and by proactively responding to new challenges that the regulators expect to arise with the drugs coming, for example by starting dialogues with the pharmaceutical companies and other stakeholders (Lepage-Nefkens et al., 2017).
During the whole process, more emphasis needs to be placed on the patients’ perspective. As described by the European Patients Forum (2018), patient involvement is needed in the HTA process to ensure that HTA is conducted taking the interests of patient into account. Thus, R&D needs to focus more on what patients expect of new drugs and what information it is that they require when deciding which drug to take.
For regulators, the analysis provided by Wieseler and colleagues (2019) clearly shows that it is time for higher hurdles when not being satisfied with the outcome of this analysis. From a societal point of view, it is viable to only provide public funding for drugs that can show evidence of drugs really benefitting patients at acceptable costs. Still, ways have to be found to balance the interest of pharmaceutical companies for return of investment of drug development, patients and society having the right to ask for drugs that increase quality and/or length of life, and acceptable costs of care to keep the health care system sustainable in the future.
European Patients Forum. EPF Position on the European Commission’s Proposal for a Regulation on Health Technology Assessment. Brussels: EPF, 2018. Available at: http://www.eu-patient.eu/globalassets/policy/hta/epf-position-statement-on-hta.pdf.
IJzerman MJ and Steuten LM. Early assessment of medical technologies to inform product development and market access: a review of methods and applications. Appl Health Econ Health Policy 2011; 9(5):331-47. doi: 10.2165/11593380-000000000-00000.
Kip M, Monteban H, Steuten L. Long-term cost-effectiveness of Oncotype DX® versus current clinical practice from a Dutch cost perspective. Journal of Comparative Effectiveness Research 2015; 4.5: p433+. Doi: http://dx.doi.org.offcampus.lib.washington.edu/10.2217/cer.15.18.
Lepage-Nefkens I, Douw K, Mantjes G, de Graaf G, Leroy R, Cleemput I. Horizon scanning for pharmaceuticals: proposal for the BeNeLuxA collaboration. Health Services Research (HSR) Brussels: Belgian Health Care Knowledge Centre (KCE). 2017. KCE Reports 283. D/2017/10.273/15.
Wieseler B, McGauran N, Kaiser T. New drugs: where did we go wrong and what can we do better? BMJ 2019; 366: l4340. doi: 10.1136/bmj.l4340.