Tumor-Agnostic Therapy Assessment: Following Regulatory Approval, What Challenges Exist for HTAs?
By Xcenda |
HTA QUARTERLY | SUMMER 2019
Tumor-Agnostic Therapy Assessment: Following Regulatory Approval, What Challenges Exist for HTAs?
Date last updated: August 8, 2019
Novel Therapies Bring New Terminology
Tumor-Agnostic Therapy Trials Differ From “Traditional” Anti-Cancer Trials
How Are Regulatory and HTA Agencies Approaching Decisions on Tumor-Agnostic Therapies?
Table 1. Select Tumor-Agnostic Therapies in Development (Adapted From Garber 2018 and Clinicaltrials.gov)
Key: ALK – anaplastic lymphoma kinase; DNA – deoxyribonuclease acid; MSI-H – microsatellite instability high; NTRK – Neurotrophic tropomyosin receptor tyrosine kinase; PDL1 – programmed death ligand 1; RET – rearranged during transfection proto-oncogene; TRK – tyrosine receptor kinase.
With a growing pipeline of tumor-agnostic therapies, it is also important to consider how HTA agencies may evaluate the value of these therapies as they reach the global markets. Across various markets, each HTA places a differing emphasis on the relative consideration of clinical effectiveness, safety, and cost-effectiveness for new therapies. A particular consideration for the evaluation of new tumor-agnostic therapies is that current HTA systems still apply an organ-specific evaluation approach in the field of cancer drugs. The existing process for HTA evaluation will likely need to evolve further; in a tumor-agnostic scenario, new “rare” diseases are essentially created out of many individual conditions by combining biomarker or genomic subsets into 1 larger population (eg, TRK fusion cancer for larotrectinib). HTA bodies are still relatively early on in preparing for the appraisal process, though there are developments in hand (eg, the National Institute for Health and Care Excellence [NICE] in the United Kingdom [UK] is prioritizing the determination and evaluation of genetic testing for tumor-agnostic therapies). However, as no formal evaluations of tumor-agnostic therapies have been carried out, no precedents have been set. As more tumor-agnostic therapies receive regulatory approval, it is possible that disparate HTA requirements across key markets could emerge and add intricacies to an already complex scenario. In this section, we provide some further potential challenges likely to be faced by HTA bodies evaluating tumor-agnostic therapies.
Evaluation of Clinical Trial Data
Regulatory bodies still require that tumor-agnostic trial data be separated by tumor site in the product’s label, to identify tumors where the therapy may work best. This type of reporting can create challenges in the evidence package for HTAs, since there can be many clinical and economic differences for each individual tumor. For example, a 2-month improvement in progression-free survival has a different meaning in pancreatic cancer vs prostate cancer.
Additionally, determining the optimal approach to evaluating the clinical effectiveness and cost-effectiveness for reimbursement purposes of tumor-agnostic therapies is going to be challenging, especially when the conventional model of HTA is based on assessing value for single-indication cancer patient populations. Given how clinical data obtained from basket trials are reported, it may be difficult for HTAs to assess the overall economic value. As a fundamental example, in a basket trial, confidence intervals may differ for key outcomes across tumor sites, which may subsequently make estimates around quality-adjusted life-years (QALYs) and the resulting incremental cost-effectiveness ratio less precise. This issue could be even further compounded by the small trial subpopulations often seen in rare individual tumor sites. Moreover, HTA bodies are additionally challenged to identify the appropriate comparators for use in their evaluations given that, thus far, basket trials are single-arm and further complicated by the wide range of relevant interventions, comparators, and populations for multiple diseases that may be concurrently included in a single assessment of a tumor-agnostic therapy. Additionally, within current HTA frameworks, the basket trial efficacy data by which regulators may be willing to accept for approval or marketing authorization are unlikely to fit the purpose of assessing drugs for site-specific indication reimbursement.
Diagnostic Testing Is Still in Early Development
Though there are companion diagnostic tests that have been evaluated by several HTAs (eg, the Canadian Agency for Drugs and Technologies in Health [CADTH], the Centers for Medicare & Medicaid Services [CMS], and NICE) alongside therapies indicated for populations with a specific genetic mutation, the genetic testing landscape remains convoluted. The availability of multiple molecular diagnostic tests from hospital and commercial labs makes it difficult for clinicians to identify an appropriate test for their patients in a timely fashion. Moreover, there is uncertainty around the best methodology to test for these genetic and molecular targets. Providers may be left with an abundance of unnecessary information, as some genetic tests may include extra biomarker information, or the chosen test may lack information on a key molecular target, making it difficult to interpret test results. Furthermore, the coverage for multigene panel testing is limited. Payers are more likely to cover a test if it is clearly linked to a drug response or is a regulatory agency-approved companion diagnostic. In a multinational survey, 895 clinicians from Argentina, Brazil, China, France, Germany, Italy, Japan, Russia, Saudi Arabia, Spain, Turkey, and the UK were queried about their use of genomic testing, and results identified cost and lack of insurance reimbursement as the primary reasons for avoiding genomic testing. Uncertainties around appropriate use of diagnostics for tumor-agnostic therapies may make it difficult for HTAs to effectively evaluate these treatments.
Key Considerations for Manufacturers Around Strategies to Overcome HTA Challenges With Tumor-Agnostic Therapies
As evidenced above, these novel therapies will require a departure from the traditional mindset and a shift in perspective when it comes to HTA agency consideration. Below, we outline further considerations for manufacturers developing tumor-agnostic therapies.
Obtain Early Scientific Advice
Given the complexity of the trial design used for tumor-agnostic therapies, early scientific advice from regulatory agencies (eg, FDA), HTAs (eg, NICE in the UK or the Institute for Quality and Efficiency in Health Care [IQWiG] in Germany), and payers will facilitate early alignment and appropriate evidence generation to assist in gaining approval for relevant markets. Specifically, manufacturers would be well served to collaborate with both regulatory and HTA bodies on trial designs that will ultimately meet evidence generation needs both within and supplemental to the clinical development program. Earlier engagement than what is considered typical may prove beneficial as innovative therapies differ substantially from traditional medicines (eg, a novel mechanism of action, indicated for rare conditions, etc) and will require additional dialog to reach a place of consensus.
Improve Genetic Testing
Given that tumor-agnostic therapies are based on tumor biomarkers, genetic testing plays a key role. However, there is a lack of direction around coverage of genetic testing. For example, in the US, CMS recently made a National Coverage Decision for a next-generation sequencing test, which may minimize prior authorization requirements for Medicare beneficiaries. However, few other HTA agencies have made decisions in this space. Manufacturers are encouraged to meet with regulatory agencies to facilitate companion diagnostic test development to accompany tumor-agnostic therapies.
Establish Innovative Payment Models
As is the case with many of the new therapies coming to market, economic impact is a significant consideration. Tumor-agnostic therapies can show a significant clinical benefit across numerous unique tumor types but may be accompanied by a hefty price tag; the expected price considerations with these therapies will be an issue for HTA bodies. Thus, it may be helpful for manufacturers to initiate conversations about the economic challenges with new therapies and work with agencies to come up with solutions around coverage. For example, through the Vitrakvi® Commitment Program™ in the US, patients who do not show clinical benefit within the first 90 days after initiating treatment will be refunded the cost of larotrectinib. Additionally, NICE has an updated appraisal process where therapies under review are available to patients through the Cancer Drugs Fund while additional evidence to address clinical uncertainty is generated. In consideration of the need for additional data and innovative payment models for tumor-agnostic therapies, real-world evidence (eg, post-approval prospective studies) might be used to provide additional support for reimbursement. A high level of collaboration between payers and manufacturers will likely be required to develop innovative, market-specific payment models that incorporate cost-effectiveness and successfully ensure all patients can obtain these life-saving therapies.
Conduct Frequent Landscape Assessments
Since this is a new, complex landscape and things will continue to rapidly evolve, manufacturers with an interest in tumor-agnostic therapies should monitor new drug approvals and HTA evaluations in this field in key markets in order to learn from early entrants about evidence generation and innovative pricing agreements. It would be prudent to consider tracking approvals, reimbursement, and market share of products approved across a broad range of tumor types and evaluate the need for additional services like personalized genetic marker maps and decision support tools. It is likely that a multistakeholder approach with global representation will be needed to determine meaningful HTA evaluation frameworks for tumor-agnostic therapies so that appropriate value assessments and reimbursements can be determined.
The article should be referenced as follows:
Kang I, Hennenfent K, Campbell C, Tolley K, Shields K. Tumor-Agnostic Therapy Assessment: Following Regulatory Approval, What Challenges Exist for HTAs? HTA Quarterly. Summer 2019. August 27, 2019.
- Bayer Global. Bayer submits European marketing authorization application for larotrectinib for the treatment of TRK fusion cancer. https://www.investor.bayer.de/en/nc/news/investor-news/investor-news/bayer-submits-european-marketing-authorization-application-for-larotrectinib-for-the-treatment-of-tr/. August 27, 2018. Accessed June 7, 2019.
- Centers for Medicare & Medicaid Services (CMS). CMS finalizes coverage of next generation sequencing tests, ensuring enhanced access for cancer patients. [Press release]. March 16, 2018.
- Ciardiello F, Adams R, Tabernero J, et al. Awareness, understanding, and adoption of precision medicine to deliver personalized treatment for patients with cancer: a multinational survey comparison of physicians and patients. Oncologist. 2016;21(3):292-300.
- Flaherty KT, Le DT, Lemery S. Tissue-agnostic drug development. ASCO Educational Book. 2018;37:222-230.
- Garber K. Tissue-agnostic cancer drug pipeline grows, despite doubts. Nat Rev Drug Discov. 2018;17(4):227-229.
- Godfrey Scaife J. What health execs need to know about tissue-agnostic cancer drug trials. Managed Healthcare Executive. https://www.managedhealthcareexecutive.com/mhe-articles/what-health-execs-need-know-about-tissue-agnostic-cancer-drug-trials. August 17, 2018. Accessed May 21, 2019.
- Hong DS, Bauer TM, Lee JJ, et al. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol. 2019;30(2):325-331.
- Keytruda® (pembrolizumab). European Public Assessment Report—Product Information. European Medicines Agency. https://www.ema.europa.eu/en/documents/product-information/keytruda-epar-product-information_en.pdf. May 30, 2019. Accessed July 22, 2019.
- Keytruda® (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2019.
- Kogan JN, Empey P, Kanter J, Donna DJ, Shrank WH. Delivering on the value proposition of precision medicine: the view from healthcare payers. Am J Manag Care. 2018;24(4):177-179.
- Laetsch TW, Dubois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705-714.
- Levit LA, Kim ES, McAneny BL, et al. Implementing precision medicine in community-based oncology-programs: three models. J Oncol Pract. 2019;15:1-6.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer, V4.2019. 2019. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed June 1, 2019.
- NHS England. NHS prepares to fast-track “game changing” cancer drugs that target genetic mutations. https://www.england.nhs.uk/2019/06/fast-track-game-changing-cancer-drugs/. June 19, 2019. Accessed June 25, 2019.
- Offin M, Liu D, Drilon A. Tumor-agnostic drug development. ASCO Educational Book. 2018;38:184-187.
- Roche. FDA grants Priority Review to Roche’s personalised medicine entrectinib. https://www.roche.com/investors/updates/inv-update-2019-02-19b.htm. February 19, 2019. Accessed July 9, 2019.
- Roche. Japan becomes the first country to approve Roche’s personalised medicine Rozlytrek. https://www.roche.com/media/releases/med-cor-2019-06-18.htm. June 18, 2019. Accessed July 9, 2019.
- Sammon C, Mbanya Z, Sen Nikitas F. Tissue/site agnostic regulatory approval of oncology drugs: are HTAs ready for a new era in personalised medicine? Value Health. 2017;20(9):A705.
- US Food and Drug Administration. FDA approves first treatment for certain patients with Erdheim-Chester disease, a rare blood cancer. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-certain-patients-erdheim-chester-disease-rare-blood-cancer. November 6, 2017. Accessed June 1, 2019.
- US Food and Drug Administration. FDA approves larotrectinib for solid tumors with NTRK gene fusions. https://www.fda.gov/drugs/fda-approves-larotrectinib-solid-tumors-ntrk-gene-fusions-0. December 14, 2018. Accessed June 7, 2019.
- Vitrakvi® Commitment Program™ fact sheet. https://www.multivu.com/players/English/8404651-bayer-loxo-vitrakvi/docs/Vitrakvifactsheet_1540853611431-879007142.PDF. Accessed August 8, 2019.
- Vitrakvi® (larotrectinib) [package insert]. Stamford, CT: Loxo Oncology, Inc.; 2018.
- Yan L, Zhang W. Precision medicine becomes reality-tumor type-agnostic therapy. Cancer Commun (Lond). 2018;38(1):6.
- Yates LR, Seoane J, Le Tourneau C, et al. The European Society for Medical Oncology (ESMO) Precision Medicine Glossary. Ann Oncol. 2018;29(1):30-35.