Use of surrogate end points in healthcare policy: a proposal for adoption of a validation framework

Ciani, Oriana; Buyse, Marc; Drummond, Mike; Rasi, Guido; Saad, Everardo D.; Taylor, Rod S

doi:10.1038/nrd.2016.81

Cited by 39 publications

(49 citation statements)

References 11 publications

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“…While there are successful examples of approved drugs based on established surrogate markers (i.e., HIV RNA for AIDS drugs), the role of surrogate markers in guiding patient care and health policy remains uncertain and concerning. [35][36][37][38][39] The Accelerated Approval pathway distinguishes between established surrogate markers and those that are only 'reasonably likely' to predict clinical benefit. 3 Therapeutic agents granted accelerated approval can therefore receive marketing authorization on the basis of less established surrogates.…”

Section: Surrogate Markersmentioning

confidence: 99%

The US Food and Drug Administration’s expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements

Wallach¹,

Ross

Naci

2018

Clinical Trials

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The US Food and Drug Administration has several regulatory programs and pathways to expedite the development and approval of therapeutic agents aimed at treating serious or life-debilitating conditions. A common feature of these programs is the regulatory flexibility, which allows for a customized approval approach that enables market authorization on the basis of less rigorous evidence, in exchange for requiring postmarket evidence generation. An increasing share of therapeutic agents approved by the Food and Drug Administration in recent years are associated with expedited programs. In this article, we provide an overview of the evidentiary standards required by the Food and Drug Administration's expedited development and review programs, summarize the findings of the recent academic literature demonstrating some of the limitations of these programs, and outline potential opportunities to address these limitations. Recent evidence suggests that therapeutic agents in the Food and Drug Administration's expedited programs are approved on the basis of fewer and smaller studies that may lack comparator groups and random allocation, and rather than focusing on clinical outcomes for study endpoints, rely instead on surrogate markers of disease. Once on the market, agents receiving expedited approvals are often quickly incorporated into clinical practice, and evidence generated in the postmarket period may not necessarily address the evidentiary limitations at the time of market entry. Furthermore, not all pathways require additional postmarket studies. Evidence suggests that drugs in expedited approval programs are associated with a greater likelihood that the Food and Drug Administration will take a safety action following market entry. There are several opportunities to improve the timeliness, information value, and validity of the pre- and postmarket studies of therapeutic agents receiving expedited approvals. When use of nonrandomized and uncontrolled studies cannot be avoided prior to market entry, randomized trials should be mandatory in the postmarket period, unless there are strong justifications for not carrying out such studies. In the premarket period, validity of the surrogate markers can be improved by more rigorously evaluating their correlation with patient-relevant clinical outcomes. Opportunities to reduce the duration, complexity, and cost of postmarket randomized trials should not compromise their validity and instead incorporate pragmatic "real-world" design elements. Despite recent enthusiasm for widely using real-world evidence, adaptive designs, and pragmatic trials in the regulatory setting, caution is warranted until large-scale empirical evaluations demonstrate their validity compared to more traditional trial designs.

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Section: Surrogate Markersmentioning

confidence: 99%

The US Food and Drug Administration’s expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements

Wallach¹,

Ross

Naci

2018

Clinical Trials

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“…Ciani et al (58) highlight three further conditions. First, the strength of the association between the surrogate end point and the final outcome should be measured through approaches such as regression and meta-analysis.…”

Section: Discussionmentioning

confidence: 99%

Challenges and Methodologies in Using Progression Free Survival as a Surrogate for Overall Survival in Oncology

Hernández-Villafuerte¹,

Fischer

Latimer

2018

Int J Technol Assess Health Care

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Objectives: A primary outcome in oncology trials is overall survival (OS). However, to estimate OS accurately requires a sufficient number of patients to have died, which may take a long time. If an alternative endpoint is sufficiently highly correlated with OS, it can be used as a surrogate. Progression-free survival (PFS) is the surrogate most often used in oncology, but does not always satisfy the correlation conditions for surrogacy.We analyse the methodologies used when extrapolating from PFS to OS. Methods: A wide range of methods has been used to determine the appropriateness of surrogates.While usually adhering to reporting standards, the standard of scholarship appears sometimes to be questionable and the reporting of results often haphazard. Conclusion:Standards of analysis and reporting PFS to OS surrogate studies should be improved by increasing the rigour of statistical reporting and by agreeing to a minimum set of reporting guidelines. Moreover, the use of IPD to assess surrogacy should increase.

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“…MRD measurement could fulfill this role. To make MRD eligible for surrogacy, several requirements have to be met such as the qualification of the assay, clinical validation of the relationship for surrogacy and survival benefit ( 129 ) ( Figure 3 ).…”

Section: Employment Of Measurable Residual Disease In the Clinicmentioning

confidence: 99%

MRD Tailored Therapy in AML: What We Have Learned So Far

et al. 2021

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Acute myeloid leukemia (AML) is a heterogeneous clonal disease associated with a dismal survival, partly due to the frequent occurrence of relapse. Many patient- and leukemia-specific characteristics, such as age, cytogenetics, mutations, and measurable residual disease (MRD) after intensive chemotherapy, have shown to be valuable prognostic factors. MRD has become a rich field of research where many advances have been made regarding technical, biological, and clinical aspects, which will be the topic of this review. Since many laboratories involved in AML diagnostics have experience in immunophenotyping, multiparameter flow cytometry (MFC) based MRD is currently the most commonly used method. Although molecular, quantitative PCR based techniques may be more sensitive, their disadvantage is that they can only be applied in a subset of patients harboring the genetic aberration. Next-generation sequencing can assess and quantify mutations in many genes but currently does not offer highly sensitive MRD measurements on a routine basis. In order to provide reliable MRD results, MRD assay optimization and standardization is essential. Different techniques for MRD assessment are being evaluated, and combinations of the methods have shown promising results for improving its prognostic value. In this regard, the load of leukemic stem cells (LSC) has also been shown to add to the prognostic value of MFC-MRD. At this moment, MRD after intensive chemotherapy is most often used as a prognostic factor to help stratify patients, but also to select the most appropriate consolidation therapy. For example, to guide post-remission treatment for intermediate-risk patients where MRD positive patients receive allogeneic stem cell transplantation and MRD negative receive autologous stem cell transplantation. Other upcoming uses of MRD that are being investigated include: selecting the type of allogeneic stem cell transplantation therapy (donor, conditioning), monitoring after stem cell transplantation (to allow intervention), and determining drug efficacy for the use of a surrogate endpoint in clinical trials.

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Use of surrogate end points in healthcare policy: a proposal for adoption of a validation framework

Cited by 39 publications

References 11 publications

The US Food and Drug Administration’s expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements

The US Food and Drug Administration’s expedited approval programs: Evidentiary standards, regulatory trade-offs, and potential improvements

Challenges and Methodologies in Using Progression Free Survival as a Surrogate for Overall Survival in Oncology

MRD Tailored Therapy in AML: What We Have Learned So Far

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