Before enrolling real patients, clinical trials can be “test-flown” on a computer, running thousands of virtual versions to assess how reliable, fast, and safe the chosen design will be.
The law today does not require trial simulations: neither Regulation (EU) 536/2014 on clinical trials nor the forthcoming Pharma Package obliges sponsors to simulate a study’s design, although the latter mentions in silico methods as a way to replace animal testing. Meanwhile, the intellectual property status of simulation tools, algorithms, and resulting data remains largely uncharted in EU regulatory discourse.
Looking ahead, a “risk-based” simulation requirement for more complex trial designs could make trials safer, faster, and cheaper, provided it does not penalize academic and noncommercial research and IP frameworks offer adequate incentives and protections for innovators and data generators alike.
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What are clinical trial simulations?
A recent paper titled “Design, simulate, refine: simulation-guided clinical trials for accelerated drug development”, published in Nature Reviews Drug Discovery, explores the use of simulation to guide trial design. The core idea: before enrolling a single real patient, thousands of virtual versions of the same study can be “flown” on a computer to understand how the design will behave, how likely it is to reach a correct answer, how long it will take, and how many subjects will end up on ineffective arms. The authors call this a “test flight” that lets teams anticipate risks and choose, transparently and with documented justification, among several designs.
In practice, teams must choose among many designs (sample sizes, allocation ratios, adaptations) under uncertain assumptions (treatment effect, recruitment rate). Each design–assumption pairing is a scenario, which simulations replay across many replications to produce anticipated decisions and performance metrics. These outputs inform discussions among sponsors, investigators, regulators, and patients, and may trigger a new cycle.
Beware: “simulation” does not mean just one thing
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- Trial design simulation, in which the patients remain real. What is simulated is the behavior of the study design, to measure its “operating characteristics,” e.g., statistical power, false-positive risk, expected duration, and exposure to ineffective doses.
- In silico trials, in which virtual patients replace or supplement real data.
- In silico methods as an alternative to animal testing (New Approach Methodologies), using computational models at the preclinical stage.
The distinction matters: obligations, evidentiary standards, and ethical implications differ radically across the three. Whether the law should require simulation before a trial starts concerns mainly the first.
Does the Pharma Package require trials to be simulated before they start?
The short answer is: no.
The Pharma Package concerns marketing authorization, post-market obligations, the EMA’s role, and the incentive system; it does not govern clinical trials, which are and will remain governed by Regulation (EU) No 536/2014 (the Clinical Trials Regulation, CTR).
Where it refers to in silico methods, it does so as an alternative to animal testing (preclinical stage), not as an obligation to simulate trial design.
Simulating a trial’s design thus remains an optional methodological tool, not a general legal obligation under current or imminent legislation.
What EU law provides today
The CTR requires a study to be scientifically sound (Article 25) and subjects’ rights, safety, and well-being to be protected (Article 3). It also calls for a description of the statistical methodology in the protocol (Annex I, Section D), but does not expressly require design simulations. Simulation, however, enters “through the window” via soft law and regulatory practice, especially for complex and innovative designs:
- The joint EC/EMA/HMA document Complex Clinical Trials – Questions and Answers, which requires validation of the design methodology and, for Bayesian settings, expressly calls for validation “including via simulation.”
- The EMA Reflection Paper on adaptive designs and the draft ICH E20 on adaptive clinical trials, the latter devoting a section to the simulation plan and report.
If a preventive simulation avoids needlessly exposing dozens of patients to an ineffective arm, it is not merely “good statistics”: it is consistent with legal and ethical obligations already in force in the EU.
Would it be appropriate to introduce an obligation?
The central question is whether trial legislation should require simulations to make trials safer, faster, cheaper, and more reliable. The arguments in favor are serious:
- Ethicality: fewer patients exposed to futile arms, thanks to well-calibrated early-stopping rules.
- Efficiency: faster and cheaper studies, with fewer protocol amendments.
- Reliability: more robust designs, tested under many scenarios before launch.
- Systemic consistency: better assessment of the adaptive, Bayesian, and platform designs agencies are moving toward.
Yet equally real counter-considerations argue against an indiscriminate obligation:
- “Garbage in, garbage out”: a simulation is only as good as its assumptions. “Biased comparisons,” where a seemingly rigorous analysis is built (even unintentionally) to favor the preferred design, mean a poorly conceived obligation could produce false scientific rigor.
- Proportionality and access to research: quality simulations require expertise and resources. A general obligation would weigh above all on academic, nonprofit, and SME sponsors, favoring large groups and conflicting with the CTR’s goal of facilitating noncommercial research.
- Regulators’ assessment capacity: assessors often cannot re-run all the simulations. An obligation would make sense only with “good simulation practice” standards, reproducibility, and code transparency.
- Not all trials need it: for a simple fixed design, classical statistical formulae suffice, and requiring simulation everywhere would be disproportionate and costly.
The reasonable synthesis is a risk- and complexity-based obligation, not a blanket one: simulation reports mandatory only for adaptive, Bayesian, seamless, and platform designs, and strongly encouraged for others. This should come with a codified good-simulation-practice standard inspired by the paper’s five principles (validity, transparency and reproducibility, thoroughness, efficiency, comparability) and a strengthened EMA qualification pathway.
Finally, one boundary must be kept firm: requiring the design to be simulated is not the same as accepting in silico evidence that replaces patients.
Trade secrets and know-how
The algorithms, assumptions, calibration parameters and source code underlying simulation models are paradigmatic examples of trade secrets under Directive (EU) 2016/943 (Trade Secrets Directive).
A tension may arise between transparency and reproducibility of simulations and the holder’s interest in keeping proprietary algorithms undisclosed. Regulators could require submission of simulation reports and results while allowing the underlying code to remain confidential, subject to inspection under secure conditions, as is already done in the pharmaceutical sector for manufacturing process data.
Looking ahead
Simulations do not replace human judgment: they inform it, making transparent what would otherwise remain a “black box.” EU law does not require them today; but a proportionate embrace, in the right legislative vehicle, with clear methodological standards, and without crushing noncommercial research, could make trials safer, faster, cheaper, and more reliable, without sacrificing rigor.
At the same time, as simulation tools become more commercially valuable, the IP framework must keep pace: patent applicants, trade-secret holders, data generators, and regulators need clarity on how the EPC, the Trade Secrets Directive, data exclusivity rules, and the Data Act interact. The goal should be an ecosystem that incentivizes innovation and openness in equal measure, while ensuring the resulting insights benefit patients, science, and the public interest.
It is a direction worth discussing now, as Europe’s regulatory framework enters a phase of profound renewal.
Credit: sinonimas, Getty Images
Marco Blei, partner at McDermott Will & Schulte, focuses his practice on industrial and intellectual property, information technology and contracts, with specific focus in the life sciences and high technology sectors. He also handles disputes in patent and know-how matters, as well as in relation to trademarks, designs, copyrights, unfair competition and misleading advertising.
Marco has significant experience in the drafting and negotiation of agreements for the licensing, exploitation, valorization and acquisition of intellectual property rights, R&D and collaboration agreements as well as IT related contracts, also in the context of extraordinary corporate transactions and technology transactions. Marco is regularly involved in drafting and negotiating agreements for the manufacturing, supply, distribution and co-marketing of pharmaceutical products and medical devices as well as of clinical trials agreements. Marco also serves as an adjunct professor at several universities, teaching courses on intellectual property law and pharmaceuticals and medical devices regulation.
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