Integrated Scientific Advice: Helping to Optimize RWE Planning for Market Access

Real-world evidence (RWE) – what is its true value in health technology assessment?  This is a question continually faced by biotech and pharmaceutical companies. High-quality practice guidelines on how to develop robust RWE continue to be developed though organizations such as the Innovative Medicines Initiative’s (IMI) GetReal project and the Joint ISPOR-ISPE Special Task Force on Real-World Evidence in Health Care Decision Making,^1,2 submissions of real-world data or evidence are often not given the consideration that manufacturers had hoped or anticipated. 

In this article, we review the current use of real-world data and evidence in health technology assessment (HTA) and payer appraisals, its potential role in lifecycle management, and how the early dialogue provided by Integrated Scientific Advice (ISA) engagement can be used as a key tool in the planning and generation of RWE.

What role does RWE play now and what do we expect to see in the future?

With RWE obtained from sources in the ‘real world’ and seemingly less controlled than clinical trial data, there is obvious concern about the potential for greater bias in real‐world data (RWD). Additionally, RWE affects a multitude of internal stakeholders, including clinical, regulatory, health economics and outcomes research (HEOR), market access, etc. Effective RWE planning and generation requires internal stakeholders to work collaboratively across teams – an often-formidable task. As a result of these challenges, implementation of robust RWE plans can be almost as work-intensive as planning for a randomized clinical trial (RCT) while the return on investment may not be as transparent. 

One may wonder, then, if developing RWE is truly worth the effort. But given its prominence in healthcare publications and discussions on decision making by HTA bodies and payers and by regulators on a global level, it seems safe to say that RWE is here to stay. While there is clearly a place for RWE in HTA and regulatory decision making today, the predominant use – and most favourable response – is seen mainly in cost-effectiveness markets. We have observed that markets that do not utilize cost-effectiveness analyses in their HTA appraisal procedures also do not seem to utilize RWE for decision making to a large extent. This observation might merit further investigation, as it might suggest that markets not using cost-effectiveness data are still establishing appraisal processes for RWE. However, these markets may need to begin considering RWE in their drug appraisals given the challenges brought by new medicines with long-term effects, such as CAR-T and other gene therapies, which can be extremely expensive and often come with a great deal of uncertainty in terms of their long-term impact, putting increasing pressure on healthcare systems. In response, many systems are starting to look at lifecycle management of drugs. For example, EUnetHTA is dedicating a whole workstream in a Joint Action to lifecycle management, implying a continuous need for data on every asset launched.³

Lifecycle management of drugs that incorporates the use of RWE is an increasingly discussed topic. An example from the 2019 HTAi conference was CAR-T-cell therapies. Long-term evidence and RWE that have emerged since launch suggest that CAR-T may not be as effective in the long term as initially hoped or projected. Similar results may become reality with regards to other gene-therapies. This constitutes a “perfect storm” for healthcare systems with robust pipelines of promising technologies, with increased demand for early and equitable access likely resulting in a deepening of the affordability crisis. We are seeing activity in two key areas that address this challenge. First is the removal of low-value technology, as evidenced in the UK with a 2017 guidance listing 18 items that should no longer be routinely prescribed in routine care a 2019 update, showing active management of care pathways.⁴ Second is the shift of pricing, reimbursement, and market access (PRMA) decision-making to a proactive approach throughout the lifecycle. An example of this can be seen in the recent ratification of the GSAV (Gesetz für mehr Sicherheit in der Arzneimittelversorgung) law in Germany this year which outlined the potential for frequent reassessment throughout products’ lifecycles to ensure continued delivery of relative value in a shifting landscape.⁵

With the infusion of RWE into HTA and market access in general, the need for data on treatments throughout the product lifecycle will increase.  What does that mean for manufacturers? It means RWE strategies need to be established as early as possible across all stakeholders to optimize efficiencies.

Where does Integrated Scientific Advice fit into RWE planning? 

Integrated Scientific Advice is a multi-stakeholder advice process which brings together regulatory and HTA advice. Early engagement with Integrated Scientific Advice is a valuable strategy to refine and evaluate evidence generation plans and align them with regulators’ and HTA bodies’ needs. (See Figure 1.) However, a vital question emerges: Do regulatory agencies and HTA bodies require a discussion on the plans for developing real-world evidence during scientific advice and to what level are they willing to discuss it?

Figure 1. Timeline for Inclusion of RWE Generation Strategy and Integrated Scientific Advice

Historically, regulatory agencies have often requested RWD and RWE as mandatory post-launch evidence commitments to enhance existing safety and efficacy data in the long-term and satisfy approval requirements. Alternatively, HTA bodies did not often request or consider this data, having a more conservative philosophy about the use of RWE and RWD in initial PRMA assessments. We are seeing a shift in this thinking and a new trend is emerging; in the past two years, we have seen an increase in requests for and clarifications on RWE and RWD generation. In particular, the EU parallel advice program has included more requests for RWE planning – such as observational trials and registries - in the feedback given to manufacturers. It seems requests for RWE and the willingness to discuss its inclusion now come equally from HTA bodies and regulators during EMA-HTA Parallel Consultation.

As with most changes, there are also challenges that come with these new demands. Given the newness of RWE consideration by HTA bodies, the impact of its use is still to be determined.  Manufacturers will need to understand the requirements in the exact context of their product. From the scientific advice feedback being seen, general themes are emerging that indicate RWE should provide:

• Collection of long-term effectiveness and safety outcomes

• Assurance that manufacturers are prepared to support their therapies throughout the lifecycle

• Preparation by the manufacturer to actively contribute to the development and improvement of overall disease area outcomes

• Generation of data that applies to different healthcare systems and treatment patterns as an acknowledgement that variation inside a randomized clinical trial, and thus local applicability of trial data, is limited

• Demonstration that therapies provide satisfactory relative value in a clinical landscape that is continually evolving, particularly in some disease areas such as cancer 

Clarity also emerged that indicated HTA bodies do not want RWE or RWD to replace or circumvent the gathering of sufficient clinical trial evidence or as a tool targeted at collection of evidence on a therapy in isolation from the system, for example, product registry planning versus integration into a disease registry.

The value of RWE can be improved with global collaboration

We know RWE is an important and necessary part of a treatment’s evidence generation plan. What is not as clear is the exact use and design of RWE to make an impact on regulatory and HTA decision making. Markets not currently using cost-effectiveness data should be key areas of interest for manufacturers, as the role of RWE in these markets seems less defined and hold opportunities to help shape developing processes.   

Discussions are occurring among and across organizations, countries, and healthcare systems regarding RWE and its use, relevance, and impact in decision making. A team at HTAi proposed key focus areas to be developed in order to further the importance and place of RWE in market access, including global collaboration to provide leadership in the form of an accreditation body and establishment of common legal and methodological frameworks.⁶At the HTAi Global Policy Forum conference in January 2019, there was clear indication that progress is already underway in the form of EUnetHTA’s Work Package 5, titled “Life Cycle Approach to Improve Evidence Generation”³ which is focused on helping generate robust evidence for health technologies (pharmaceuticals or others) all along the technology lifecycle, including early dialogues (initial evidence generation) and post-launch evidence generation and registries. 

The continually evolving dynamics of drug development and the evidence being considered and required by both regulators and payers means that manufacturers must take a more collaborative, cross-functional approach in their planning. A siloed approach equates to less robust and effective evidence generation with almost guaranteed time and cost increases. Scientific advice and early dialogues with HTA bodies and regulatory agencies offer an optimal approach for early development of evidence generation plans that include all stakeholders and are particularly applicable to areas like RWE for several reasons.

1.    Early cross-functional alignment on requirements helps develop a clear path forward, reducing the chance of last-minute shifts in evidence planning that can be very costly; a side benefit of needing to write a briefing book.

2.    Participating in scientific advice generates alignment, both internally and with the external entities, and marks a willingness to communicate with regulators and HTA bodies, which equates to evidence plans that are less likely to be dismissed than those without official consultation.

3.    Advice provided will be situational and applicable to the exact asset in question, essentially removing the chance of ambiguity in evidence planning due to interpretation of general guidelines without dialogue.

4.    Manufacturers have the ability to actively participate in the conversation on the role of RWE in evidence generation plans outside of political discussions, providing further input into shaping the current and future landscape.

The global PRMA landscape is seemingly shifting towards demands for iterative demonstration of value in real-world populations for therapies to earn and maintain their place in clinical pathways. Early alignment of goals and expectations, and a clearer understanding of potential challenges which can then be addressed during evidence planning, can help ensure RWE that demonstrates that value.  

Andrea Schmetz, MBA, is Senior Consultant, Value and Access Consulting; Stephanie Wise, MPharm, is Consultant, Value and Access Consulting; Matthew Bending, Ph.D, is Executive Director of HTA Strategy and UK Practice Lead, Value and Access Consulting; and Patricia Hurley, Ph.D, is Senior Director, Strategic Regulatory Consulting, all at Evidera.

References

1 Berger, ML, Sox H, Willke, RJ, Brixner, DL, Eichler, HG, Goettsch, W., Madigan, D., Makady, A., Schneeweiss,  S., Tarricone, R., Wang, SV, Watkins, J., Mullins CD, "Good Practices for Real-World Data Studies of Treatment and/or Comparative Effectiveness: Recommendations from the Joint ISPOR-ISPE Special Task Force on Real-World Evidence in Health Care Decision Making," Value Health. 2017 Sep;20(8):1003-1008. doi: 10.1016/j.jval.2017.08.3019. Epub 2017 Sep 15.

2 Miksad, RA, Abernethy, AP, "Harnessing the Power of Real-World Evidence (RWE): A Checklist to Ensure Regulatory-Grade Data Quality," Clin Pharmacol Ther. 2018 Feb;103(2):202-205. doi: 10.1002/cpt.946. Epub 2017 Dec 6.

3 EUnetHTA | European Network for Health Technology Assessment. JA3 Work Package 5 - Lifecycle Approach to Improve Evidence Generation. Available at: https://www.eunethta.eu/ja3-archive/work-package-5-life-cycle-approach-to-improve-evidence-generation/. Accessed August 29, 2019.

4 NHS Clinical Commissioners, Items Which Should Not Routinely be Prescribed in Primary Care: Guidance for CCGs. Version 2, June 2019. Available at: https://www.england.nhs.uk/wp-content/uploads/2019/08/items-which-should-not-routinely-be-prescribed-in-primary-care-v2.1.pdf. Accessed September 4, 2019.

5 Bundesministerium fur Gesundheit, Gesetz fur Mehr Sicherheit in der Arzneimittelversorgung. Available at: https://offenegesetze.de/veroeffentlichung/bgbl1/2019/30. Accessed September 4, 2019.

6 HTAi. Tunis, S, Sampietro-Colom, L, "Real-World Evidence in the Context of Health Technology Assessment Processes – from Theory to Action," HTAi Policy Forum Series Newsletter, February 2019. Available at: https://htai.org/wp-content/uploads/2019/03/HTAi_Global-Policy-Forum_newsletter_20190222.pdf. Accessed September 4, 2019.