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Precision medicine: the increasing complexity of decision-making within market access


Precision medicine is rapidly evolving, and manufacturers are considering more factors than ever before to achieve market access success. This update, available to read in full in the free report, “Precision medicine: positioning for market access success,” explores some of the factors impacting decision-making for precision medicines.

PRMA Consulting is now Avalere Health


How the status of molecular biomarkers is impacting decision-making for precision medicines

The increase in the number of recommended precision medicines means decision-making is no longer driven mainly by histology, but now also heavily dependent on the status of molecular biomarkers, as well as considering other patient and disease characteristics.


Precision medicine: positioning for market access success.Source: “Precision medicine: positioning for market access success.”


This becomes progressively more complex as increasing numbers of biomarkers become clinically relevant for a certain tumor type and which biomarker to target first becomes important, ie, the optimal treatment strategy or sequence/combination of treatments needs to be considered. For example, trials such as SECOMBIT and DREAMseq in BRAF V600-mutated metastatic melanoma indicated that immunotherapy (nivolumab plus ipilimumab) should be used before BRAF-targeted therapies; this is now considered best practice.

Additionally, acquired resistance should also be considered in the treatment strategy. What is the chance a patient may become resistant and when should further biomarker testing occur to ensure biomarker expression has not changed?


New treatment guidelines indicate that we may be shifting towards histology-independent practice

While guidelines largely still focus on specific histologies, there are some recent publications focusing on molecularly defined tumor types which represent steps towards biomarker-driven decision-making.

For example, in 2017, the NSCLC expert panel of the American Society for Clinical Oncology and the Ontario Health-Cancer Care Ontario published guidelines with recommendations for systemic therapy in patients with stage IV NSCLC.

After this, clinicians urged authors for another update due to the fast pace of discovery of new immunotherapies and targets. The standard of care was changing so rapidly that “it left clinicians in a lurch about how to incorporate these, in what order, and in what patient population.” (Bryan J Schneider, MD, Clinical Professor of Internal

Medicine in the Division of Hematology/Oncology, University of Michigan, in an interview with Targeted Therapies in Oncology.)

The topic became so broad and deep, with different subsets of NSCLC, that the committee divided the guidelines into two: one for NSCLC with driver gene alterations and one without.

Tools such as the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) have been developed to help clinicians navigate all this. ESCAT articulates a range of tiers defining levels of evidence supporting a molecular alteration–based drug match. However, as more evidence comes to light, distinguishing between treatments based on grade of evidence will become more challenging.

ESMO and other bodies have developed specific EGFR-mutant NSCLC guidelines and there are specific TRK fusion cancer guidelines in Canada.
Guidance is likely to become more and more complex as evidence increases for each biomarker, the number of biomarkers increases and the expansion beyond the simple focus of discreet variant detection to biomarker signatures including a range of different types of markers derived not only from genomics, but also epigenomics and metabolomics.


Evidence generation challenges at HTA for histology-independent therapies boil down to two overarching themes

The growing number of product launches and development of complex guidelines supports the move towards tumor-agnostic or histology-independent drugs, but even before the approval of these, it was obvious that assessing the clinical benefit and value of such products would be challenging.


Biomarker/companion diagnostic validation Drug
Scientific rationale – established histology; independent MOA; clinical utility
  • Lack of robust comparative data (RCT)
  • Multiplicity issues, statistical strength, chance findings due to small baskets
Evidence demonstrating lack of effect in biomarker-negative patients (clinical utility)
  • Extrapolating surrogates to patient-relevant outcomes
  • Lack of statistical methodology to assess relative effectiveness
  • Lack of experience
Homogeneity of effects across different tumor types / absence of histology-specific mechanisms of resistance
  • Characterization of subgroup heterogeneity
  • Lack of patient-reported outcomes
  • Heterogeneity in costs and health utilities
  • Lack of generalizability of the study population to clinical practice
Source: “Precision medicine: positioning for market access success.”


HTA bodies from key countries in Europe (the EU5, Norway, the Netherlands), together with CADTH (Canada) and PBAC (Australia), suggest that the challenges boil down to two overarching themes:

  1. The validity of the biomarker
  2. Basket and umbrella trials not providing the evidence required for HTA based on established assessment methodology


1. The validity of the biomarker

Key aspects of this are shown in this table, such as evidence demonstrating a lack of effect in biomarker negative patients. It is also important to understand if the biomarker is prognostic, or merely predictive of treatment effect from the drug it is paired with.


2. Basket and umbrella trials do not provide the evidence required for HTA based on established assessment methodology

For platform, basket, and umbrella trials—where no, or only limited direct head-to-head data are available—indirect comparisons are theoretically possible, but the limited number of patients in some of the tumor types in both the trial and the real world makes it difficult.

Economic evaluations require a separate analysis for each potential treatment and indication. Usually estimated survival curves are representative of the population’s survival trajectory over the entire time frame estimated. Survival analysis on basket trials violates these core assumptions in numerous ways as the sample enrolled is heterogeneous. This also affects the assumed health state transitions.


While HTA agencies have discussed changes to methods to accommodate basket trials, to date there have been few changes

The next question for market access professionals to consider is how HTA agencies are handling these new paradigms. We examine this is in our free report “Precision medicine: positioning for market access success”.

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