Brief · Use case · Market Access

Evidence Generation Strategy.

LiveDecision Memo

Choose between a randomized trial, a single-arm study with an external control and real-world evidence, scored on payer credibility, cost, time and the risk of an inconclusive result.

DecidersChief medical officer with the head of market access

Needed by31 May 2027

Designs scored3

Criteria5

ExpertGlobal Real-World Evidence Lead

LengthComprehensive

Evidence Generation Strategy is a ready-made use case for Market Access. It ships under the Decision Memo template.

For evidence and medical leads committing to a study design. The memo scores each design against what payers and regulators will accept, shows the cost and time trade-off, and states the assumptions that must hold. Claims about acceptance are cited or marked as gaps.

Add it to your library to reuse from New → From template. Edit the saved copy in your library on the service form.

The decision

How should a new digital therapeutic generate the evidence a payer will accept: a randomized controlled trial, a single-arm study with an external control, or a real-world evidence study on an existing registry? The memo also scores delaying evidence generation.

The three designs on the table

Each design answers the payer’s question with a different amount of control, cost and time. The memo scores them, and the option of delay, on the same five criteria.

Route	What it asks of you	It fits when	What payers and regulators will test
Randomized controlled trial	Assign participants at random to the digital therapeutic or a control. ICH E10 sets out what each type of control can show, and EU regulators treat randomized evidence as the standard for confirmatory efficacy.^{1European Medicines Agency. ICH E10: Choice of control group in clinical trials (Step 5), CPMP/ICH/364/96. Date of effect 1 January 2001.,2European Medicines Agency. Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation, EMA/CHMP/430688/2024. First published 16 September 2024.}	Payers or regulators will not accept less, a credible comparator exists, and you can carry the cost and time.	The choice of control and whether blinding is possible
Single-arm study with an external control	Treat everyone in the study and compare the results with an outside group that did not receive the treatment. FDA’s draft guidance covers the design and analysis, and the threats to validity. EU regulators say a single-arm trial shows only outcomes under the treatment and must be justified.^{2European Medicines Agency. Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation, EMA/CHMP/430688/2024. First published 16 September 2024.,3U.S. Food and Drug Administration. Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products. Draft guidance, February 2023. Docket FDA-2022-D-2983.}	Randomization is not feasible or not ethical, and a closely comparable external group exists.	How well the outside group matches yours, and the risk of bias
Real-world evidence study on a registry	Analyze data already collected in a registry. Write the protocol on a harmonized template so that reviewers can judge the risk of bias and repeat the analysis.^{4Wang, S. V. et al. HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: a good practices report of a joint ISPE/ISPOR task force. Value in Health, 2022;25(10):1663–1672.}	The registry holds the outcomes and the patient characteristics you need for the target population, and speed and cost matter more than control of the design.	Where the data come from, confounding, and whether the study can be reproduced

What the memo does with them

The control group decides credibility. A result is only as believable as its comparison. The memo sets out what each type of control can and cannot show, using ICH E10, and names the design flaw a skeptical payer would go to first.^{1European Medicines Agency. ICH E10: Choice of control group in clinical trials (Step 5), CPMP/ICH/364/96. Date of effect 1 January 2001.}

Every statement about acceptance has a source, or is a gap. Most of the guidance in this field was written for medicines, not digital therapeutics. The memo says where a digital therapeutic follows different rules and marks any claim about what a payer or regulator will accept as a gap when it cannot be sourced.^{2European Medicines Agency. Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation, EMA/CHMP/430688/2024. First published 16 September 2024.,3U.S. Food and Drug Administration. Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products. Draft guidance, February 2023. Docket FDA-2022-D-2983.}

Confidence rated in a common language. For each design the memo says how much confidence its result would support, in the four GRADE levels of high, moderate, low and very low, and what would raise or lower it.^{5Guyatt, G. H. et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ, 2008;336(7650):924–926. DOI 10.1136/bmj.39489.470347.AD.}

Five criteria, scored the same way. Credibility with payers and regulators, cost, time to results, the risk of an inconclusive result, and how well the result applies to your target population. Delay is scored too. The scores are analyst judgment, labeled as such.

How it could fail. The pre-mortem probes the failures this decision invites: a study that ends inconclusive, an external control a payer rejects, a registry that lacks the outcome you need, or results that arrive after the payer submission. Each gets an early warning and an owner.

Recommended length

Comprehensive

The study design locks in cost and time, and the decision rests on an assumption about what payers will accept. Comprehensive adds the table that tests each assumption.

You can pick another length on the form. The other two stay available.

Assumptions the memo tests

A Comprehensive memo lists the assumptions that carry the answer, each with a test and a date. A Standard memo carries the main ones in its section on what would change the answer. Examples for this decision:

A comparator that payers accept exists, such as sham, active or usual care.
The external group or registry matches your target population on the factors that drive the outcome.
The study can report in time for the first payer submission.
One study can serve both the regulator and the payer, or the memo budgets for two.

Standards, guidance and sources

Choosing the comparison

ICH E10, choice of control group in clinical trials: the general principles for selecting a control group and what each design can demonstrate. In effect in the EU since 1 January 2001.^{1European Medicines Agency. ICH E10: Choice of control group in clinical trials (Step 5), CPMP/ICH/364/96. Date of effect 1 January 2001.}
EMA reflection paper on establishing efficacy from single-arm trials, final, first published 16 September 2024: randomized evidence remains the standard, and a single-arm pivotal trial must be justified.^{2European Medicines Agency. Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation, EMA/CHMP/430688/2024. First published 16 September 2024.}
FDA draft guidance on externally controlled trials, February 2023, docket FDA-2022-D-2983. It is a draft with non-binding recommendations.^{3U.S. Food and Drug Administration. Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products. Draft guidance, February 2023. Docket FDA-2022-D-2983.}

Real-world evidence

The HARPER protocol template from ISPE and ISPOR for real-world evidence studies of treatment effects, so that design choices are documented and the risk of bias can be judged.^{4Wang, S. V. et al. HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: a good practices report of a joint ISPE/ISPOR task force. Value in Health, 2022;25(10):1663–1672.}

Rating confidence

GRADE, for rating the quality of a body of evidence and the strength of a recommendation.^{5Guyatt, G. H. et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ, 2008;336(7650):924–926. DOI 10.1136/bmj.39489.470347.AD.}

The decision practice behind the memo itself is on the template page.

What gets flagged

Every statement about what a payer or regulator will accept that has no source, the design most likely to end inconclusive, the assumption about the target population that carries the result, and the guidance cited that was written for medicines and not for digital therapeutics.

What arrives

Decision requested
Recommendation
Context and framing
Options considered
Why this option wins
What must be true
What would change the answer
Risks and the pre-mortem
Path and what we do not know

What it will not do

It does not design the study. It chooses between designs and says what the chosen design would have to get right.

It does not predict what a payer or regulator will decide, and it does not replace scientific advice from the regulator or a conversation with the payer.

It does not make the decision. The named decider does.

Scores and weights are analyst judgment from an AI specialist, not measurements. They show how the options compare on the criteria you chose; change the weights and the ranking can change.

It is one specialist’s answer. When you need several specialists to disagree in the open, run a Panel.

Facts the specialist could not source appear as gaps. Regulatory fees, review goals, reference prices and probabilities are cited to their sources or left open. Check any figure you will act on against its primary source.

References

[1] European Medicines Agency. ICH E10: Choice of control group in clinical trials (Step 5), CPMP/ICH/364/96. Date of effect 1 January 2001.
[2] European Medicines Agency. Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation, EMA/CHMP/430688/2024. First published 16 September 2024. Written for medicines.
[3] U.S. Food and Drug Administration. Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products. Draft guidance, February 2023. Docket FDA-2022-D-2983. Draft, for medicines. Check whether it has been finalized.
[4] Wang, S. V. et al. HARmonized Protocol Template to Enhance Reproducibility of hypothesis evaluating real-world evidence studies on treatment effects: a good practices report of a joint ISPE/ISPOR task force. Value in Health, 2022;25(10):1663–1672. Summarized from ISPOR’s page and search excerpts; the full text is behind a paywall.
[5] Guyatt, G. H. et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ, 2008;336(7650):924–926. DOI 10.1136/bmj.39489.470347.AD.

Links checked 9 October 2026

These are the sources the template drew on. None of their authors or issuers has reviewed it.

About the Brief service

A Brief is a written answer from one specialist, at the depth you asked for. It arrives with its sources, and it closes by saying plainly what would change the conclusion. Nothing is hidden behind a summary, and anything the expert could not source is marked as a gap rather than filled in.

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