Achievements and Opportunities in Pan-Tumor Oncology European HTA & Access (Guest blog)

Efforts to accelerate genomic science and clinical research in Europe and beyond as envisioned by new plans and policies require health technology assessment (HTA) to keep pace in order to benefit patients.  Recent milestones from such efforts include the legislative proposal for joint HTA across the European Union (EU)1-2, Europe's new Beating Cancer Plan3-4, and a global campaign for a first United Nations (UN) Resolution on persons living with rare disease5-7, where:
  • Joint HTA legislation calls for EU-level cooperation to standardise submission and review procedures for health technologies in order to enhance transparency, efficiency, and patient access to these technologies1-2.
  • Europe’s Beating Cancer Plan outlines a multi-dimensional, patient-centric approach to addressing cancer, including specific “flagship initiatives” such as "Cancer Diagnostic and Treatment for All" featuring next generation sequencing (NGS), and "Cancer Inequalities Registry" to identify and resolve disparities among Member States and regions3-4.
  • The #Resolution4Rare global campaign co-led by EURORDIS, RDI, and NCO Committee for Rare Diseases champions for further inclusivity, empowerment, and access for those living with rare diseases at the UN level, with resolution adoption decision pending in September 20215-7.
These efforts from various organisations strive towards a common, essential goal of enhancing timely, equitable patient access to quality health technology. A measure of progress towards this goal is the EFPIA Patient W.A.I.T. (Waiting to Access Innovative Therapies) Indicator which has tracked availability of innovative medicines across EU and other European countries for over a decade8.  It is comprised of two key metrics - rate of availability as calculated by the number of medicines available (added to reimbursement list) from a 4-year rolling cohort of European Medicines Agency (EMA)-approved medicines; and time to availability as measured by average time between marketing authorisation and availability to patients. The W.A.I. T. Indicator shows that specifically for oncology medicines, both rate of and time to availability range more widely across EU countries than for medicines overall, revealing that much progress still needs to be made for timely, equitable access to innovative cancer treatments.
A poignant illustration of remaining challenges involving HTA, oncology, and rare disease is tyrosine receptor kinase (TRK) cancer. TRK fusion cancer is caused by a genomic alteration where the neurotrophic tyrosine receptor kinase (NTRK) gene fuses with another, unrelated gene, ultimately leading to growth of tumors in various parts of the body9. Genomic testing such as NGS can help identify whether tumors are positive for NTRK gene fusion and help inform physicians in determining whether patients may benefit from this form of precision medicine approach.  Until recently, there had been no standard of care for this rare cancer, with invasive treatments such as amputations or chemotherapy being the only options.
In 2018, pivotal trial results for a first-in-class TRK inhibitor were published in the New England Journal of Medicine.  Simultaneously in the same journal issue, an editorial heralded the publication as an illustration of 10:
  • The "future of drug development in rare genomic entities" and the foundation for a new "paradigm under construction".
  • Clinical trial innovation through its single-group, basket trial design.
  • Diagnostic technology advancement through integration of multigene sequencing alongside conventional methods.

These attributes and the clinical results achieved led to a rating of highest magnitude of clinical benefit under the Magnitude of Clinical Benefit Scale developed by the European Society of Medical Oncology (ESMO) for single-group trials10.
These pronouncements validate that the clinical data for TRK inhibitor meets an appropriate level of ‘evidence hierarchy’, and acknowledges the limitations of studying such therapies in conventional randomised, large-scale clinical trial (RCT) settings. Despite this, not every TRK fusion cancer patient is able to access TRK inhibitor treatment because of HTA evaluation issues, relating to:
  • Regulatory rules of what qualifies as rare disease, and in turn, which treatments are eligible for orphan drug status, a designation which may facilitate, and even expedite, HTA and access by allowing medicine appraisal under different criteria in some countries. Germany is one such example, but the TRK inhibitors approved to date, despite targeting an ultra-rare genomic alteration, nevertheless received “no evidence of additional benefit”.  
  • How HTA systems assess evidence hierarchy requirements to assign “additional medical benefit”, with a strict adherence to requiring large-scale RCTs, thereby precluding such an adjudication in case of single-group trials.
  • How HTA systems in some countries, such as France and Italy among others, maintain a conventional tumor-by-tumor approach for evaluating effectiveness, risk/benefit, and reimbursement, instead of evolving to a unified approach for pan-tumor, single biomarker-targeted therapies. In the same vein, some HTAs separately consider adult versus paediatric populations, at times leading to differential conclusions.
The above issues result in two main access challenges: (1) incomplete access across all of the indications of the pan-tumor precision medicine – in other words, access for only select tumors/populations – and (2) delays in access. To the first point, the phenomenon that some patient populations have access to TRK inhibitor treatment, while others do not, is evidence of persisting healthcare disparity that ought to be addressed by European HTA.  There needs to be allowance for more flexible HTA processes such that lower-hierarchy evidence, post-hoc analyses, and even real-world evidence, are all worthy of exploration and potential adoption with sufficient pressure-testing.  To the second point, the Patients W.A.I.T. Indicator by EFPIA for 2020 across 24 EU countries shows that for oncology medicines, the average rate of availability is just 58%.  Furthermore, there are prevalent instances of limited access i.e. to specific subpopulations, on individual patient basis, only while final decision pending, through special programs etc. Average time to availability for oncology medicines is 561 days, 2 months longer than for new medicines overall, and a critical window especially for cancer patients8.
For the first-in-class TRK inhibitor treatment, it has been 3 years since pivotal trial publication and 18 months, or approximately 549 days, since EMA approval.  As such, it dwells near the average time to availability for an oncology medicine according to the Patient W.A.I.T. Indicator. However, even now, the rate of availability remains 33%, lower than the European average of 58%. 
The recent initiatives by European and global organisations are laudable for recognising some of these remaining opportunities in HTA. However, HTA still needs to establish (alternative) assessment methodology which accounts for single-group, basket trials and alternative forms of evidence required for characterisation of additional medical benefit, over reasonable time frames, especially for rare diseases, so that patients are not kept waiting because HTA has not yet caught up with therapeutic innovation. Per above, the “tumor-by-tumor” HTA approach ought to be critically re-appraised to achieve a Patient W.A.I.T. time which better addresses the needs of those waiting for these pan-tumor precision medicines.
We look forward to continuing to support and lend expertise to ongoing initiatives, such as Europe’s Beating Cancer Plan by the European Council and official address by the UN General Assembly of  pending HTA and access challenges, as they (also) hold much relevance and promise for precision medicine especially in Oncology, and for TRK inhibitors. Bayer applauds these initiatives and is similarly committed to continuing to serve patients by developing next-generation precision medicine therapies, evidence, and resources to support patient-access. Now is the time to act. Patients are waiting.


1. "Health Technology Assessment: Informal deal between Council and European Parliament." European Council, Council of the European Union, 22 June 2021,!Bb9ngX. Accessed 20 July 2021.

2. "Deal on boosting member states’ cooperation in assessing health technologies." European Parliament, 22 June 2021, Accessed 20 July 2021.

3. "Communication from the commission to the European Parliament and the Council, Europe's Beating Cancer Plan COM/2021/44 final." EUR-Lex, 3 February 2021, Accessed 20 July 2021.

4. "EU Health Union: Europe's Beating Cancer Plan - Factsheet - Europe's Beating Cancer Plan." European Commission, 3 February 2021, Accessed 20 July 2021.

5. Ostapenko, Stanislav. "#Resolution4Rare: Global campaign for the first UN Resolution on Persons Living with a Rare Disease." EURORDIS Rare Diseases Europe, 12 May 2021. Accessed 20 July 2021.

6. "UN Resolution on Persons Living with a Rare Disease and their Families." Rare Diseases International, Accessed 20 July 2021.

7. "United Nations General Assembly Resolution on Persons Living with a Rare Disease and their Families." Rare Voices Australia, 14 May 2021, Accessed 20 July 2021.

8. "EFPIA Patients W.A.I.T. Indicator 2020 Survey." EFPIA, April 2021, Accessed 20 July 2021.

9. Amatu A, Sartore-Bianchi A, Siena S. “NTRK gene fusions as novel targets of cancer therapy across multiple tumour types.” ESMO Open 2016;1(2):e000023. DOI:

10. André, F. "Developing Anticancer Drugs in Orphan Molecular Entities — A Paradigm under Construction." N Engl J Med 2018; 378:763-765. DOI: 10.1056/NEJMe1716821.


Brian Cuffel

Brian Cuffel, Ph.D. is VP and Head of Market Access Oncology for Bayer Pharmaceuticals and part of the Oncology...
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