Generating the right evidence at the right time Principles of a new class of flexible augmented clinical trial design s C Dunger -Baldaufa1 R Hemmingsb1 F Bretzac B Jonesd A Schiele C Holmesf

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Generating the right evidence at the right time: Principles of a new class of flexible

augmented clinical trial designs

C Dunger-Baldaufa,

, R Hemmingsb,1, F Bretza,c, B Jonesd, A Schiele, C Holmesf

aStatistical Methodology, Novartis Pharma AG, Basel, Switzerland

bConsilium Salmonson & Hemmings

cSection for Medical Statistics, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical

University of Vienna, Vienna, Austria

dNovartis UK

eNorwegian Medicines Agency

fUniversity of Oxford, and The Alan Turing Institute

Correspondence: Chris Holmes (cholmes@stats.ox.ac.uk)

ABSTRACT: The past few years have seen an increasing number of initiatives aimed at integrating

information generated outside of confirmatory randomised clinical trials (RCTs) into drug development.

However, data generated non-concurrently and through observational studies can provide results that are

difficult to compare with randomised trial data. Moreover, the scientific questions these data can serve to

answer often remain vague. Our starting point is to use clearly defined objectives for evidence generation,

which are formulated towards early discussion with health technology assessment (HTA) bodies and are

additional to regulatory requirements for authorisation of a new treatment. We propose FACTIVE (Flexible

Augmented Clinical Trial for Improved eVidencE generation), a new class of study designs enabling flexible

augmentation of confirmatory randomised controlled trials with concurrent and close-to-real-world

elements. These enabling designs facilitate estimation of certain treatment effects in the confirmatory

part and other, complementary treatment effects in a concurrent real-world part. Each stakeholder should

use the evidence that is relevant within their own decision-making framework. High quality data are

generated under one single protocol and the use of randomisation ensures rigorous statistical inference

and interpretation within and between the different parts of the experiment. Evidence for the decision-

making of HTA bodies could be available earlier than is currently the case.

These authors contributed equally to this article

INTRODUCTION

To support informed decision making by pharmaceutical companies, regulators, health

technology assessment (HTA) bodies, payers, patients and physicians, clear descriptions of the

benefits and risks of a treatment for a given medical condition should be made available in a

timely fashion. The current paradigm is to generate evidence in a sequential manner where at

each stage the focus is on one stakeholder and the information they need in order to progress to

the next stage. This is inefficient. In this paper we present FACTIVE, a new paradigm where

information for regulatory agencies and HTA bodies is generated concurrently via a new class of

augmented clinical trial designs. FACTIVE designs study not only patients who are suitable for

entry into a conventional Phase 3 randomized controlled trial (RCT) that is conducted under well-

controlled conditions but bridges to a broader population, or different experimental conditions,

that can be tailored to address a particular HTA question or reflect a particular healthcare system.

The proposed framework is different from existing approaches (as we explain later) and allows

the generation of the right evidence at the right time, such that key decisions made after

Marketing Authorisation (MA) can be made sooner than would otherwise be the case.

CURRENT STATUS

Figure 1 (upper panel) summarizes the current evidence generation and decision-making

process: Following confirmatory Phase 3 trials, an application for MA of a new treatment is

submitted to a regulatory agency. MA is accompanied by a period of discussion and agreement

with payers (e.g., HTA bodies, government agencies, medical insurance companies), who will

reimburse the cost of the treatment and influence the price at which the treatment should be

marketed. The treatment is then placed on the market (❶ in Figure 1). Physicians, health care

providers and patients are subsequently informed how the new treatment is positioned in the

landscape of already available treatment options (❷) and at some time later (❸) the maximum

uptake of its use is achieved. Alongside this, post-authorization trials are conducted to learn more

about how the treatment performs in normal clinical practice.

[Insert Figure 1 around here]

The sequential nature of generating the evidence for different stakeholders is immediately visible.

The current main driver when designing confirmatory RCTs is to provide sufficient evidence to

regulatory agencies of the efficacy and safety of a new treatment in order that it may be granted

MA. Additional post-authorization trials provide further evidence of the treatment’s effectiveness

in a broader patient population under clinical practice conditions. Evidence from such trials, in

addition to that provided by the confirmatory trials, is then used to inform further market access

and pricing discussions with HTA bodies, taking into account the therapeutic landscape. The post-

authorization trials can be RCTs, or open-label extension phases to RCTs, but are commonly

undertaken as observational studies. The pre- and post-authorisation experiments are conducted

independently of each other, such that if estimates of a particular treatment effect differ between

experiments, the reasons for that difference cannot be determined with certainty.

Multiple initiatives have attempted to streamline the evidence generation that will support

regulator, HT assessor, payer, prescriber, and patient decision-making [Eichler et al. 2016; Califf

et al. 2016; Ray et al. 2022]. Efforts in this direction must address the fact that different

stakeholders have different questions to address, including the benefit-risk of an intervention

within a specific target population vs the cost-effectiveness of an intervention including societal

perspectives and a specific healthcare budget. Decision-making by the European Medicines

Agency (EMA) is centralised on behalf of the European Union (EU) whereas decisions made by

one or more country specific HTA bodies are national or local. Different stakeholders will also

identify different sources of uncertainty and evidence gaps they want to see addressed,

preferably during the clinical evidence generation phase, or at least post-authorisation. This paper

focuses on evidence generation to meet the needs of regulatory agencies and HTA bodies, as they

make the two initial and most critical public-sector decisions to determine patient access to

medicinal products. The EU is taken as a jurisdiction for illustration, though the benefits of the

approach described can be realised more generally.

A point of particular focus for discussions on streamlining evidence generation has been the

design and conduct of RCTs. All stakeholders recognise the high internal validity of this

experimental design: the fact that reliable treatment effect estimates for well-defined research

questions can be provided through a design where experimental conditions are controlled and

well-understood. Indeed, deriving a reliable estimate and being able to interpret the magnitude

of treatment effects in the context of experimental conditions that are documented and

understood are the attributes of the RCT that make it the “gold-standard”. In addition, all

stakeholders understand that there can be a scientific basis to generalise, or extrapolate,

inferences from a clinical trial dataset to a broader patient population or clinical context, though

the basis for extrapolation (e.g., other clinical trial data, pharmacological understanding of the

mechanism of action, pharmacological modelling), the extent of the extrapolation (to what

proportion of the target population does the extrapolation apply) and the type and strength of

evidence needed to support extrapolation is not documented and hence not unified for benefit-

risk vs cost-effectiveness decisions. Importantly, an RCT design in which the experimental

conditions are controlled too tightly can leave all stakeholders questioning its external validity,

i.e., the applicability of the trial results to the intended patient population and therapeutic use in

clinical practice.

External validity of a trial is assessed in relation to its inclusion and exclusion criteria (vs the

population indicated for clinical practice) and its experimental conditions (vs the therapeutic use

expected in clinical practice) such as the outcome variable or comparator, permitted concomitant

medications or combinations of treatments. The different mandates for regulators and HT

assessors can also lead to different clinical outcomes being prioritised for the assessment of

efficacy or effectiveness with a consequence for the periods of treatment and follow-up that are

of interest, and potentially different treatment effects of interest (i.e., estimands) [ICH, 2019;

Remiro-Azócar, 2022]. Importantly, whereas a given clinical development programme will be

targeted towards a centralised regulatory approval, each HT assessment of the applicability of the

trial results to their specific national or local jurisdiction might differ, for example, in relation to

other products that are/are not reimbursed and used locally, or the precise target population for

which cost-effectiveness can be justified. Concerns over the external validity of a particular RCT

does not represent a fundamental flaw in that study design and conduct, only that the specific

trial design cannot directly address the needs of a specific HTA body. Section 1 of the

Supplementary Material gives additional discussion on external validity and extrapolation.

The result of these dynamics is that a regulator might authorise a product, perhaps with post-

authorisation evidence generation to address identified uncertainties, whilst an HT assessor

might not feel fully informed about how the product will impact their specific healthcare system

and budget, and whether a positive decision on cost-effectiveness can be justified. To address a

broader set of stakeholder needs, RCTs might be made larger and/or longer and/or less well

controlled in respect of patient population and experimental conditions. In addition, different

endpoints or multiple comparators might be used. In reality, however, complementary sources

of evidence generation are more efficiently used to provide answers to general and specific

questions from HTA bodies. An often-overlooked fact is that the information required to

strengthen the external validity can be generated concurrently with the trial data. Additional

evidence is not necessarily generated to replicate trial results, rather additional data can explore

the effects of treatment beyond the patient population and experimental conditions of the RCT.

This paper discusses an experimental design that provides these additional data and seeks to

deliver information to all stakeholders in a timely manner, preserving efficient evidence

generation for each stakeholder and promoting a methodologically robust approach in an

experimental design where different parts are no longer independent.

FLEXIBLE AUGMENTION TO GATHER THE RIGHT EVIDENCE AT THE RIGHT TIME

We argue that the understanding of the relative effectiveness and time to peak uptake of a new

treatment can be enhanced, without compromising safety, by generating additional rigorous

evidence throughout the confirmatory development process. To do so we propose FACTIVE, a

new class of augmented RCT designs aimed at widening the evidence base of traditional RCTs.

The lower panel of Figure 1 summarizes the potential impacts of using such an augmented RCT

design (which we describe below): Discussions with HTA bodies are better informed and

shortened, along with a potentially greater maximum uptake of treatment use.

A key feature of the new paradigm is that augmentation is wrapped around a conventional RCT

that is designed in the usual manner to focus on treatment efficacy and safety in a controlled

experimental environment. The consequence is that the core RCT, or RCTs, which form the pivotal

evidence for a regulatory approval, is ring-fenced. A cross-disciplinary team can consider the

specific objectives, subsequent design criteria and the timing for augmentation with real-world

elements, including consideration of market value and patient heterogeneity as well as early

evidence of efficacy and safety in the core RCT. The augmentation can resolve uncertainties that

could not be achieved by simple improvements to the RCT. For example, providing some insights

into multiple, different combinations of active comparators are classic examples of HTA

requirements that might dramatically increase the size, duration and cost of a confirmatory RCT.

We set no limitations to the scope of research questions that can be addressed through

augmentation. The questions to be answered by augmentation may be general: to provide

estimates of treatment effects in the target population reflecting routine clinical care and under

conditions reflecting clinical practice; to facilitate data integration with an existing external data

source, by augmenting the RCT with subject eligibility criteria and conditions matched to the

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Generatingtherightevidenceattherighttime:PrinciplesofanewclassofflexibleaugmentedclinicaltrialdesignsCDunger-Baldaufa,1,RHemmingsb,1,FBretza,c,BJonesd,ASchiele,CHolmesfaStatisticalMethodology,NovartisPharmaAG,Basel,SwitzerlandbConsiliumSalmonson&HemmingscSectionforMedicalStatistics,CenterforMedicalS...

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Generating the right evidence at the right time Principles of a new class of flexible augmented clinical trial design s C Dunger -Baldaufa1 R Hemmingsb1 F Bretzac B Jonesd A Schiele C Holmesf

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