Health Technology Assessment in a Multi-Indication Era

Overview of Multi-Indication Therapies

In recent years, multi-indication (MI) therapies have emerged as transformative assets within the healthcare landscape, particularly in biologic fields like antibodies and cell therapies. These innovative treatments are designed to address multiple conditions by leveraging shared mechanistic pathways across diseases, offering substantial efficiency gains for patients and manufacturers. Unlike traditional drug development, which entails extensive research and testing efforts per indication, MI therapies streamline these processes, consolidating efforts and resources into a single drug development pathway.¹ Notably, over the past 25 years, targeted immunology products have averaged approximately four indications each.²

MI therapies can be categorized into three types³:

• Therapies spanning distinct therapeutic areas, such as a drug effective in oncology and immunology. For example, rituximab is approved for the treatment of certain types of cancer, such as non-Hodgkin's lymphoma and chronic lymphocytic leukemia. It later received approval for use in various autoimmune conditions, including rheumatoid arthritis and granulomatosis with polyangiitis.

• Therapies within specific therapeutic areas but across different diseases, such as an oncology treatment used for both melanoma and lung cancer. For example, pembrolizumab is approved for multiple types of cancers, including melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, classical Hodgkin lymphoma, gastric cancer, renal cell carcinoma, and other indications.

• Therapies covering different lines of treatment within a particular disease, such as a drug that could be used in various stages of prostate cancer treatment. For example, enzalutamide is used in both first-line and second-line settings for metastatic castration-resistant prostate cancer.

Overview of the HTA Process

Health Technology Assessment (HTA) is the process of evaluating new technologies and treatments to ensure their efficacy, safety, and cost-effectiveness. HTAs are carried out by designated regulatory bodies. HTAs have emerged as a critical process in this context, bridging the gap between research and health policies. By providing detailed information, HTA helps policymakers make informed decisions to maximize health benefits for the population.⁴

In countries with national health systems, HTA aids in allocating limited healthcare funds effectively among different technologies and ensures optimal use of resources. HTA offers evidence-based guidance to policymakers, helping them prioritize technologies that benefit patients and society the most.^5,6 HTA evaluates the economic value of technologies for sustainable healthcare and supports evidence-based decision-making with robust, systematic evidence.⁷

Each HTA body employs unique valuation criteria, such as clinical effectiveness, cost-effectiveness, ethical, legal, and social implications, organizational impact, safety, and technical properties. Recognizing these distinctions helps stakeholders navigate HTA processes and informs best practices for presenting new therapies for evaluation.

Table 1: Types of evidence accepted and value frameworks preferred by a sample of key HTA bodies. Source: Axtria Inc.
Abbreviations: Canada's Drug and Health Technology Agency, CADTH; Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde, CONITEC; Haute Autorité de santé, HAS; Health technology assessment, HTA;  Incremental cost utility ratio, Institute for Clinical and Economic Review, ICER; Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG; Indirect treatment comparison, ITC; National Institute for Health and Care Excellence, NICE; Randomized controlled trial, RCT; Real-world evidence, RWE; Systematic literature review, SLR; Scottish Medicines Consortium, SMC; Swedish Dental and Pharmaceuticals Benefits Agency, TLV..

Although HTA bodies publish guidance for those seeking reimbursement recommendations, there are no guidelines specific to MI therapies, which face distinct challenges. Without formal guidance, HTA bodies and pharmaceutical manufacturers are left to evaluate MI therapies as they do single-indication therapies despite their unique benefits and challenges. These challenges include:

• Increased Administrative Burden and Delays in Access: Each indication requires individual assessments, increasing workload for HTA agencies and potentially delaying patient access.⁸

• Aligning Prices with Different Values: Different indications may require different comparators and endpoints, leading to varying clinical and cost-effectiveness outcomes.⁸

• Managing Clinical Uncertainty at Launch: New indications often enter the market with clinical uncertainties, posing challenges for HTA agencies that rely on robust data.⁸

• Managing Budget Impact and Uncertainty: Expanding indications increases the potential patient population, introducing budget uncertainties for payers.⁸

• Scarcity of Well-Designed Randomized Controlled Trials (RCTs): MI therapies often target diverse patient populations, posing challenges for conducting RCTs that adequately cover all indications. The limited data from these trials can impede robust HTAs.⁹

• Inconsistent Real-World Evidence (RWE) Data Sources and Methods: Collecting reliable RWE for MI is complex due to inconsistencies in data quality, study designs, and patient characteristics. Harmonizing RWE sources is essential for comprehensive evaluations.⁹

Case Study: HTA Assessment Review of Multi-Indication Therapies

Axtria's RWE, HEOR, and Evidence Synthesis practice recently conducted an HTA review assessing the challenges faced by MI therapies during the HTA evaluations and whether later indications experience delays in their evaluations. The study supported a pharmaceutical client's initiative to understand the current HTA landscape and better position future indications of its MI therapy.

Figure 1: Days between HTA evaluation submission and reimbursement decisions for four immunology MI therapies across three HTA bodies

Methodology

Four therapies were selected based on the existence of multiple indications and overall presence in the global market. The therapies were all under the immunology therapeutic area, limiting the findings to those assessments. Three HTA bodies were then chosen based on publicly accessible assessments and variations of value frameworks: The United Kingdom's (UK) National Institute for Health and Care Excellence (NICE), France's National Authority of Health (HAS), and Germany's Institute for Quality and Efficiency in Health Care (IQWiG)/Gemeinsamer Bundesausschuss (G-BA).

Following data extraction of the collected assessments, several analyses were performed to find trends in the mentions of multiple indications, criticism of submissions, time taken for evaluation with additional indications, as well as the number of reports reimbursed, non-reimbursed, or terminated, and the types of evidence used for reimbursement decisions for each HTA body.

Learnings

• New indications often experience delays or inconsistent evaluation by HTA bodies after European Medicines Agency (EMA) approval.
  New indications experienced reimbursement delays in the UK, inconsistent reimbursement in France, and consistent reimbursement in Germany. As seen in Figure 1, new indications for NICE experienced increasing delays with each submission, specifically for drugs #1 and #3. A rise in terminations was also observed, posing a greater challenge in the UK. There were inconsistent reimbursement periods after EMA approval for HAS, with new indications experiencing delays or fast reimbursement. Consistent reimbursement periods were seen for IQWiG/G-BA. Overall, reimbursement by NICE became more challenging for additional indication submissions, while for HAS and IQWiG/G-BA, it was less challenging.
  A lack of accelerated reimbursement periods can provide challenges in patient access, specifically for a market where there are delays for new indications, as seen in the UK and occasionally in France. This further suggests shortcomings in attributing the whole value of multi-indication therapies in these markets, as faster reimbursement could be expected based on previous reimbursement.
  
  

• HTA reports do not mention the benefits of multi-indication status.
  Despite a thorough review of reimbursement reports for multi-indication therapies, indications other than the one being evaluated were only occasionally mentioned, and the use of other indications' data was scarce. These results suggest that HTA bodies may not currently attribute the total value of multi-indication therapies. It was also unclear whether this contributed to the positive reimbursements that these assessments received.
  Specifically, one NICE assessment mentioned the manufacturer's survey submission and clinical evidence from another indication; the committee concluded that this could not be applied to other indications. For HAS, seven assessments mentioned using safety and tolerance or efficacy data for indications other than the one under evaluation. Although these assessments received positive reimbursement, it was unclear whether this contributed to the decision. IQWiG/G-BA did not mention the multi-indication status of therapies other than the product information. The reviewed reports reflect limited information on the multi-indication status of therapies, suggesting that HTA bodies may not be evaluating the therapy holistically and are instead focusing on the indication submitted for evaluation.

• In the UK, the negotiated price of each drug is adopted for all indications.
  The UK's current pricing scheme was adopted after the Medicines and Healthcare products Regulatory Agency (MHRA) was established as the UK's main regulator of pharmaceutical law. It forces the use of a single unique price that is cost-effective for the lowest-priced indication, as well as all other indications^.10 This typically undervalues higher-costing indications, pricing them lower to match lower-costing indications. With higher-valued indications not receiving a comparable price, manufacturers often refrain from submitting these indications, which has led to a rise in terminated appraisals in the UK. Reasons for termination included a lack of evidence within the submission, wherein the manufacturer considered the evidence insufficient to prove cost-effectiveness, or because a manufacturer did not intend to launch a given indication in the UK.

Conclusion

MI therapies are gaining prevalence in many markets. However, capturing and evaluating their full value remains an ongoing challenge for manufacturers and HTA bodies alike.

Regulatory changes happen frequently to take advantage of the evidence generated from real-world data (RWD) on therapies already on the market. For example, Axtria's recent whitepaper "The Inflation Reduction Act (IRA) and Its Implications on Real-World Evidence” highlights that unlike a traditional HTA, IRA evaluations in the US will consider RWE for both active treatments and comparators, accommodating complex treatment combinations and novel therapeutic sequences. This approach is essential for understanding the benefits across various indications and treatment lines, and leverages RWE to robustly assess MI therapies.

Moving forward, adopting RWE and emulating target trials using claims-linked electronic health record data present promising avenues for evaluating the long-term effectiveness and safety of MI therapies. This shift addresses the inherent challenges of traditional randomized controlled trials and underscores how evidence-based medicine optimizes patient outcomes and healthcare efficiency.

Pharmaceutical companies should be prepared for changes in HTA assessments of MI as RWD becomes more widely accepted and a holistic value of MI therapies becomes more apparent in real-world populations. In the future, RWE will play a central role in the value assessment of MI therapies.

Based on the findings of the HTA review described herein, Axtria's RWE, HEOR, and Evidence Synthesis team has developed several recommendations for pharmaceutical companies conducting reimbursement submissions for MI therapies:

• Consider the HTA landscape when determining the proper sequencing of their indication launches. In countries like the UK, indications with a greater cost-effectiveness should be targeted first, so that MI drugs can be assigned a high initial reimbursement price.
• Include cross-indication RWE as part of their submission packages.
• Submit economic models that consider MI patients as a subgroup or scenario analysis to encourage HTA bodies to evaluate this population, where MI therapies are likely to excel in cost-effectiveness.
• Finally, manufacturers should regularly conduct thorough reviews of existing HTA reports relevant to their markets of interest to be better prepared for their own reimbursement submissions.

References

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