Janssen’s EMEA market access head Martin Price outlines the regulatory changes that need to be made for patients across Europe to better access cutting-edge cancer medicines.
Recent advances in medical science are the driving force behind the research and successful development of innovative cancer treatments in Europe. By targeting the specific characteristics of the underlying disease, deep and durable responses to treatment are now within reach. It is highly probable that in the future, cancer may be viewed as a chronic condition, where patients remain stable for prolonged periods of time and, in some cases, may be cured.
Despite the paradigm shift in how regulatory agencies have adapted their traditional drug approval and scientific advice procedures to accelerate the approval of innovative cancer medicines – granting approval based on surrogate or intermediate endpoints – the path to securing reimbursement across Europe remains fraught with difficulty. This is because Health Technology Assessment (HTA) agencies prefer to base their decisions (whether to reimburse a given treatment) on the availability of overall survival data, which in the case of innovative cancer treatments is incomplete at the time of assessment due to patients living longer and beyond the usual timeframes of clinical trials, due to the effectiveness of newer treatments.
The consequences of this situation are often lengthy discussions between the HTA agency and manufacturer, whilst eligible patients who could potentially benefit from the innovative treatment need to wait and will likely receive clinically inferior treatments or, in some cases, palliative (end-of-life) care (Figure 1).
The average time between regulatory approval and patient access varies considerably between countries – from 67 days in Denmark, for example, to 968 days in Estonia (Figure 2) – and inter-country variation in the HTA recommendation has also been observed. Both of these variances are of great concern (Adkins et al 2017; Nicod & Kanavos 2012; Hughes-Wilson et al 2012; Simoens 2011).
In summary, HTA agency rules regarding evidence quality and data uncertainty have not evolved to accommodate the types of benefit/risk data used to support these early marketing authorizations and is an issue that needs to be urgently addressed.
How has this situation arisen?
Rather than waiting for overall survival data to read out in full, the FDA and EMA are granting marketing authorizations for highly promising cancer medicines based on compelling data from trials with surrogate endpoints with some select examples below:
|Surrogate endpoint||Product and indication||Relevant links|
|Overall response rates (ORR)||Darzalex in multiple myeloma patients who have received at least 3 prior lines of therapy (incl. PI and IMiD) or double refractory to PI and ImiD MMY2002 study||EMA
|Erdafitinib in metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt) – more specific FGFR3 or FGFR2 genetic alterations||Janssen|
|Major molecular response (MMR)
|Bosulif (bosutinib) in newly diagnosed patients with chronic-phase Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML).||PrimeOncology|
|Invasive disease-free survival
|Neratinib after trastuzumab-based adjuvant therapy in HER2-positive early stage breast cancer.||PrimeOncology|
|Disease-free Survival||Adjuvant Sunitinib in high-risk renal-cell carcinoma after nephrectomy.||NEJM|
|Event-free Survival (EFS)||Dasatinib in pediatric patients with newly diagnosed philadelphia chromosome positive acute lymphoblastic leukemia.||AscoPost
|Gemtuzumab in adult patients with de-novo acute CD33 positive myeloid leukaemia (ALFA-0701).||TheOncologist|
|Progression-free Survival (PFS)||Dacomitinib in patients with first-line advanced non-small cell lung cancer (NSCLC) who carry EGFR activating mutations.||NCBI|
|Osimertinib in untreated patients with EGFR-Mutated Advanced Non–Small-Cell Lung Cancer||AstraZeneca|
|Caprelsa (conditional approval) in medullary thyroid cancer||EMA|
Mature data on overall survival is not typically available at the time of registration, which is a growing problem in large phase III trials – comparing two very effective treatment options or evaluating treatments very early in the disease trajectory – where subsequent therapies and long survival times can make measurement of overall survival extremely difficult.
In the case of single arm trials (SATs), the lack of comparative evidence (missing from the SATs) creates further uncertainty for the HTA agencies because the extent to which the new treatments extend survival and improve health-related quality of life compared to usual standards of care is not known. There is also a lack of clarity on what comparative evidence is needed to reduce uncertainty around the quantification of relative efficacy and safety from the SATs (Figure 3).
The extent to which qualitative insights from patients who have first-hand experience of the treatment are considered in the HTA process is also variable and inconsistent across agencies.
The key access hurdles facing innovative cancer therapies can be summarised as follows:
- HTA agency value assessment criteria relying on endpoints such as overall survival and reward data certainty have not evolved to reflect the recent scientific advances that have led to a wave of highly effective treatments being available for some cancers.
- Delays in reaching a decision (whether to recommend reimbursement) leave eligible patients who could potentially benefit from the innovative treatment receiving clinically inferior treatments or, in some cases, palliative (end-of-life) care.
- Considerable inter-country variation in the HTA recommendation has also been observed.
Increased awareness of these challenges is needed to evoke a call to action.
What potential solutions could we bring forward to optimise the value assessment process and speed up access to transformational cancer therapies?
The proposed solutions focus on 5 key areas:
- An aligned and consistent position between the EMA and HTA agencies on the acceptance of surrogate / intermediate endpoints (by tumor type) to bridge the evidence gap, whilst the overall survival data are pending, for decision-making purposes and faster patient access.
- Greater clarity on the types of comparative (real world or other) evidence (by tumor type), acceptable to both EMA and the HTA agencies, that can accompany data from single arm trials and inform estimates of relative efficacy and safety.
- Broader consideration of the longer-term economic (e.g. costs avoided through ineffective alternative treatments and/or need for subsequent treatments, as well as productivity gains through patients’ ability to return to work) and humanistic (e.g. health-related quality of life and patient preferences) benefits of treatment should be factored into the appraisal and valuation process, including appropriate consideration of the patients’ experience of the innovative treatment.
- An openness by payers to exercise greater flexibility into pricing & payment approaches that factor in the long-term value proposition at the start of treatment.
- A list of accepted registries at national or European level that can be used to demonstrate the value of innovative cancer therapies over time and, potentially, support outcomes-based approaches that link reimbursement to the outcomes achieved for the patient and national health care systems, as well as improvements compared to the existing standard of care.
Solving these problems would mean improved patient outcomes – as time to reimbursement may be accelerated – and a more sustainable life sciences industry, with greater recognition of the value of innovation.
Key stakeholders need to come together to figure out how HTA appraisal and valuation methodologies should evolve for these types of treatments. At Janssen, we remain committed to engaging with key stakeholders to address these challenges and find sustainable solutions to achieving timely patient access.
Adkins EM, Nicholson L, Floyd D, Ratcliffe M, Chevrou-Severac H. Orphan drugs for orphan indications: how are HTA processes evolving for this specific drug category. Clinicoecon Outcomes Res 2017; 9:327.342.
Hughes-Wilson W, Palma A, Schuurman A, Simoens S. Paying for the orphan drug system: break or bend? Is it time for a new evaluation system for payers in Europe to take account of new rare disease treatments? Orphanet J Rare Dis. 2012;7:74.
Nicod E, Kanavos P. Commonalities and differences in HTA outcomes: A comparative analysis of five countries and implications for coverage decisions. Health Policy 2012: 108:167-177.
Simoens S. Pricing and reimbursement of orphan drugs: the need for more transparency. Orphanet J Rare Dis. 2011;6:42.