This column is a translation of the Dutch version.

The current drug evaluation and reimbursement system provides little incentive for the development of personalised treatments. Nor does it encourage well-integrated biomarker research that can lead to a clear delineation of the patient group that will benefit most from treatment. It is time for a policy review at all levels.

Developing personalised treatments often requires significant investment in research because they target smaller subgroups of patients. These studies are more complex and expensive, as it is difficult to recruit enough patients. In addition, it is sometimes difficult to generate robust data for very small subgroups, which adds complexity to the process of registration, market access and reimbursement. All in all, the high costs and limited target population make personalised treatments less profitable and less interesting for pharmaceutical companies, especially if the drug is already on the market for a broader indication.

‘State of Science and Practice’ leaves a lot of room for overtreatment
According to the Health Insurance Act, all insurable care must comply with the ‘state of science and practice’ (SWP). This means that care must be sufficiently proven effective at the population level. However, no statement is made about the level of effectiveness required. For example, is it acceptable to treat 29 patients with no effect to achieve a possible positive outcome in only 1 patient? What is a reasonable ‘number needed to treat’?
At the population level, statistical significance can often be achieved by study size. A large study with many patients may detect smaller effects that are statistically significant but possibly less clinically relevant. These large studies, often labelled ‘practice-changing’, can lead to much overtreatment in practice. There is also another problem: nowadays, a second, confirmatory study is often not required. This can carry the risk that the observed effect is the result of study bias, such as selection bias or bias in the analysis, or of an accidental imbalance between the two study arms.

How can we prevent overtreatment? After all, overtreatment harms the sustainability of the healthcare system by wasting resources and time. In addition, how can we better encourage the development of personalised medicine? Here are a few suggestions:

1. The criterion ‘state of science and practice’ should provide more room for customisation.
In recent years, we at the Add-on Medicines Committee (CieBAG) of Zorgverzekeraars Nederland have tried to create more room within our SWP assessments for customisation and specific patient needs. This is because robust data at population level are not always available. To enable the development of personalised treatments for small groups of patients, we have introduced individualised reimbursement.1 This means that if it can be shown, based on objective criteria, that a patient with a severe disease will benefit from treatment, the follow-up treatment will be taken over from the basic insurance. At the same time, data are collected for the entire population. This is done within the DRUG-Access Protocol (DAP)2 and the Orphan Drug Access Pilot (ODAP)3 for registered indications, but also within the Drug Rediscovery Protocol (DRUP),1,4 a national platform investigating ‘repurposing’ of anti-cancer drugs. This encourages both the development of personalised treatments and the advancement of therapies for patients with rare diseases for which no treatments are being developed.

2. Individualised reimbursement can be used more often, not only for rapid access to innovations as with DAP, ODAP and DRUP, but also when drugs are effective only in a small group of patients and no biomarkers are available to identify this group in advance. In such a case, it makes much more sense to pay for a drug only when it is actually effective in an individual patient. In practice, this means that the first period of treatment can be considered a trial period, with the costs borne by the manufacturer.

3. The ‘state of science and practice’ criterion should set limits on the ‘number needed to treat’. For drugs developed for larger groups, HTA organisations, such as the Health Care Institute, should set a reasonable limit on the NNT to prevent overtreatment and waste of resources and encourage manufacturers to better define the groups that will benefit most from treatment.

4. Studies evaluating personalised treatments should receive more support and funding. For example, studies with an adaptive trial design. These studies often offer the flexibility to adjust treatments based on interim results and to investigate more specific patient groups.

5. Drug manufacturers who have integrated good biomarker studies into their trials to better stratify and target patients should be rewarded. Currently, it is often the other way round: manufacturers who conduct good biomarker studies often receive a narrower label from registration authorities, while those who conduct no or less good biomarker studies receive a broader label for similar indications. Regulatory policy should provide more incentives for conducting good biomarker research.

A change in policy at various levels is needed to make investment in the sustainable development of personalised treatments more attractive.

Dr S. Barjesteh van Waalwijk van Doorn-Khosrovani is pharmacist Drug & Society at health insurer CZ. She is a member of the Commissie Beoordeling Add-on Geneesmiddelen en Moleculaire Diagnostiek (CieBAG) of Zorgverzekeraar Nederland and affiliated with the Department of Medical Oncology at Leiden University Medical Centre. She is also a member of the Horizon Scan Working Group on Haematology and Oncology of the Dutch Health Care Institute and a committee member of the KWF’s Long-term Biomarkers Programme.

References:

1 van Waalwijk van Doorn-Khosrovani SB, Pisters-van Roy A, van Saase L, et al. Personalised reimbursement: a risk-sharing model for biomarker-driven treatment of rare subgroups of cancer patients. Annals of Oncology 2019; 30: 663-5.
2 van Waalwijk van Doorn-Khosrovani SB, Zeverijn LJ, Voest EE. The DRUG Access Protocol: access inequality and European harmonisation – Authors’ reply. Lancet Oncol 2022; 23: e203.
3 Pisters-van Roy AB van W van D-KS, Reparon-Schuijt CV der FS. Promising non-oncology orphan drugs reach patients faster: Medication controlled availability with Orphan Drug Access Protocol. Pharm Weekbl 2024; 27-28.
4 van der Velden DL, Hoes LR, van der Wijngaart H, et al. The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs. Nature 2019; 574: 127-31.