HEOR Articles

Lieven J.P. Annemans, PhD, Ghent University; Ghent, Belgium

In this supplement to Value & Outcomes Spotlight, a very nice overview is provided about the challenges in improving patient access to next-generation sequencing (NGS) and a Plan of Action is proposed with several solutions to improve access.¹ As clearly explained by the authors, NGS is a form of DNA sequencing that can examine millions of DNA molecules simultaneously. Through NGS, the genomic and genetic profile of a patient with cancer can be assessed, which can then be used to help guide patients to the most suitable targeted therapies.

At first sight, NGS entails benefits for all stakeholders. With one single test, multiple gene mutations can be assessed, allowing patients to receive a cancer therapy with increased likelihood of success and enabling better informed decisions. Clinicians will be more confident in the therapy choices they offer and make, since the appropriate treatments will be identified faster. The health industry will receive more credibility for having better and more appropriate treatments available, and payers and policy makers will avoid having to spend money on empiric “trial-and- error” treatments that often prove ineffective.

"Patient access requires that the available and reimbursed technology is endorsed by clinicians and actually used in real practice so that patients can benefit from it."

 

Given those benefits, it is logical that a Plan of Action focuses on improving patient access. Of note, it is thereby important to distinguish between market access and patient access. Market access is obtained after regulatory approval and reimbursement by the healthcare system. It is essential that, in a universal healthcare system, all eligible patients who can benefit from a health technology do not face financial barriers for access to that technology. This is a human right as stipulated in article 25 of the Universal Declaration of Human Rights.² In addition, patient access requires that the available and reimbursed technology is endorsed by clinicians and actually used in real practice so that patients can benefit from it. Patient access requires the necessary infrastructure, awareness, and education of health professionals, which appears to be suboptimal in many geographical areas. Taking a step back to market access, clear procedures for decision making about price and reimbursement of NGS and the associated cancer treatments are required. Unfortunately, large geographical differences in procedures exist and need to be addressed, as correctly stipulated in the Plan of Action.

Even more important for market access, and not overtly stressed in the Plan, is the clinical and health economic evidence that is required for a positive reimbursement decision. Indeed, with NGS, besides the described benefits, false-positive and false-negative results can occur. The consequence of a false-positive result—which happens very rarely with NGS—is that the payer pays twice: once for the test and once for a treatment that afterwards does not seem to work (the test was false-positive). The psychological consequences for the patients are also likely to be major, since all hope was set on the treatment that was predicted to work but eventually did not. The consequences of a false-negative test might even be more concerning from a health and ethical perspective. It means that patients will be denied a treatment from which they could have benefited. Moreover, even if mutations are correctly identified by true positive results (which fortunately occurs in the large majority of cases) and guide towards the right therapeutic choice, it is not a guarantee that this treatment will work in 100% of the patients with that mutation.

In light of the above considerations and the substantial price of the related therapies, the assessment for reimbursement of NGS and especially those related therapies requires evidence on effectiveness and cost-effectiveness. This means that although NGS clearly represents a new paradigm, evidence about the benefits to patients and society is still required. The authors of the Plan of Action admittedly point to this as one of the key issues with NGS-based therapies: there is still a lack of studies showing the benefits in terms of quality-adjusted life years (QALYs) and therefore, the knowledge about their cost- effectiveness is rather scarce. Although it could be argued that the technology is likely to be cost-effective because a lot of money can be saved by avoiding ineffective treatment, the reality might be different, and this needs to be assessed. For instance, an Australian study by Doble and colleagues found very poor cost-effectiveness results of multiplex targeted sequencing in fourth-line treatment of lung cancer when compared to no further testing with chemotherapy or no further testing with best supportive care.³

"Although NGS clearly represents a new paradigm, evidence about the benefits to patients and society is still required."

The authors of the Plan of Action correctly argue that due to the fact that the outcome of a NGS test provides multiple theoretic treatment pathways, there is no one-to-one relationship between the NGS test and the value of one single therapy. This means that the broad benefits of NGS testing need to be accounted for when assessing the value and value for money of NGS and its related therapies. Given the specificities of the technology, the Plan of Action proposes to establish a separate funding and reimbursement pathway for NGS testing “that provides the required flexibility and can account for changes in the value of the NGS test across time.”

"The broad benefits of NGS testing need to be accounted for when assessing the value and value for money of NGS and its related therapies."

What is more urgently needed, however, is to be clearer about which type and level of evidence is required. According to Faulkner and colleagues, the ability to broadly leverage biomarkers has enabled novel trial designs that cut across disease areas or enable unique enrichment scenarios: “Adaptive and so-called ‘umbrella,’ ‘basket,’ or ‘bucket’ trials create the potential to determine treatment effectiveness in multiple diseases simultaneously.”⁴ Some HTA bodies actually have provided guidance on the evaluation of precision medicine but it is not clear to what extent these designs are sufficiently convincing for HTA bodies, some of whom are still focusing too much on the traditional randomized clinical trial paradigm.⁵ Adopting new designs and acknowledging the additional value of real-world evidence alongside outcomes-based agreements is needed.

To make progress in this field on what evidence is required, the diagnostics and pharmaceutical industry needs to start dialogues with payers and HTA bodies in order to arrive at a clear and broadly applied consensus about how much and which type of evidence is enough to allow market access to the benefit of the patients.

References

1. Wilsdon T, Horgan D, Akkermans M. Accelerating patient access to next-generation sequencing in oncology: a plan of action. Value & Outcomes Spotlight. 2022;8(S1):S5-S11.
2. Universal Declaration of Human Rights. United Nations. Accessed August 25, 2022. https://www.un.org/en/about-us/universal-declaration- of-human-rights
3. Doble B, John T, Thomas D, Fellowes A, Fox S, Lorgelly P. Cost- effectiveness of precision medicine in the fourth-line treatment of metastatic lung adenocarcinoma: an early decision analytic model of multiplex targeted sequencing. Lung Cancer. 2017;107:22-35.
4. Faulkner E, Holtorf AP, Walton S, et al. Being precise about precision medicine: what should value frameworks incorporate to address precision medicine? a report of the Personalized Precision Medicine Special Interest Group. Value Health. 2020;23(5):529-539.
5. Annemans LJP. Solutions for rapid and sustained patient access to precision medicine. European Federation of Pharmaceutical Industries and Associations. Published May 12, 2022. Accessed August 25, 2022. https://www.efpia.eu/news-events/the-efpia-view/blog-articles/solutions- for-rapid-and-sustained-patient-access-to-precision-medicine/