CASRAI Dictionary

Tag: clinical trials

  • ICH E6(R3) Good Clinical Practice: GCP Modernised

    ICH E6(R3) is the revised version of the international Good Clinical Practice (GCP) guideline, developed through the International Council for Harmonisation (ICH). GCP is the ethical and scientific quality standard for designing, conducting, recording and reporting clinical trials that involve human participants. The R3 revision modernises the guideline around quality-by-design, risk-based approaches and flexibility for contemporary trial designs and data sources. This article is a neutral explainer and not clinical, regulatory or legal advice.

    What Good Clinical Practice is

    GCP exists to protect the rights, safety and wellbeing of trial participants and to ensure that trial data are credible and reliable. It sets expectations for ethics oversight, informed consent, the responsibilities of sponsors and investigators, documentation, and data integrity. Regulators around the world reference ICH GCP, which is why a revision to the core guideline matters internationally. For the wider context, see our overview of clinical-trials regulation and the focused explainer on Good Clinical Practice.

    Why GCP needed modernising

    The previous version, E6(R2), added an addendum to a guideline whose structure dated to the 1990s. Since then, clinical research has changed: trials use electronic data systems, decentralised and remote elements, real-world and diverse data sources, and increasingly complex designs. The earlier text, written for a more uniform model of site-based trials, did not always map cleanly onto these newer approaches. E6(R3) was developed to be more principles-based and adaptable, so that the same quality expectations can apply across a wider range of trial types.

    Quality-by-design: building quality in

    A central theme of E6(R3) is quality-by-design (QbD): the idea that quality should be designed into a trial from the start rather than inspected in afterwards. Under this thinking, sponsors identify the factors that are truly critical to quality — the aspects of a trial that, if compromised, would undermine participant safety or the reliability of the results — and focus attention and resources there.

    • Critical-to-quality factors: the elements that genuinely matter for safety and reliability.
    • Proportionate effort: attention concentrated where the risk to those factors is greatest.
    • Avoiding low-value activity: not treating every data point and process as equally important.

    The practical implication is fewer one-size-fits-all checklists and more deliberate judgement about where rigour adds value.

    Risk-based and proportionate

    Closely related is the risk-based orientation that runs through the guideline. Rather than prescribing identical, exhaustive procedures for every trial, E6(R3) emphasises identifying, assessing and managing risks in proportion to their importance. This extends to monitoring: risk-based monitoring focuses oversight on the data and processes most likely to affect participant safety and result credibility, which may combine on-site and centralised approaches.

    This proportionality is intended to make trials both more efficient and more robust, by concentrating effort where it protects participants and data integrity most.

    Flexibility for modern trials and data

    E6(R3) is written to accommodate a broader range of trial designs and data sources, including the use of varied technologies and the realities of decentralised elements. By framing requirements in terms of underlying principles and outcomes rather than rigid prescriptions, the guideline aims to remain relevant as methods evolve. Throughout, the emphasis on data integrity and a clear, reliable record remains central — modern tools do not relax the expectation that data be attributable, legible, contemporaneous, original and accurate.

    Participant protection stays at the heart of the guideline. Informed consent, ethics oversight and the duty of care to participants are reaffirmed, not diluted, by the modernisation. For neutral definitions of related terms, see our standards dictionary.

    Roles, responsibilities and the structure of the guideline

    E6(R3) restates the responsibilities of the main parties in a trial. Sponsors are responsible for the overall quality system, trial design, risk management and oversight, including oversight of any parties to whom activities are delegated. Investigators are responsible for the conduct of the trial at their site, the care of participants, informed consent and the integrity of the data they generate. The guideline is structured around principles supported by more detailed expectations, with the intent that the principles guide judgement when specific situations are not spelled out.

    This principles-first structure is a deliberate response to the pace of change in clinical research. By anchoring expectations in durable principles — participant protection and reliable results — rather than in an exhaustive list of procedures, the guideline is intended to remain applicable as trial methods and technologies continue to evolve.

    What it means in practice

    For sponsors, investigators and clinical-operations teams, E6(R3) signals a shift in mindset: from procedure-led compliance toward thoughtful, risk-proportionate quality management tailored to each trial. Organisations generally review their quality systems, monitoring strategies and standard operating procedures to align with the principles-based approach. Teams often revisit how they document critical-to-quality factors, how they justify monitoring intensity, and how they evidence oversight of delegated activities. Regulators, in turn, adopt the revised guideline into their own frameworks, so the practical timing of when E6(R3) applies in a given country depends on that jurisdiction’s adoption process. Sponsors operating across multiple regions therefore track adoption status region by region, since the same global guideline may take legal effect at different times in different jurisdictions, and transitional arrangements may govern trials already underway when a region adopts the revised text.

    The essence of E6(R3) is that good clinical practice is achieved by designing quality in, focusing on what is critical, and managing risk proportionately — applied flexibly across the diverse trials of today. The authoritative text is published by ICH, and readers should consult the official guideline and adopting regulators for binding detail. Our EU Clinical Trials Regulation explainer describes how one major jurisdiction frames trial conduct alongside these GCP principles.

  • EU CTR and CTIS Now Mandatory: Harmonised Trials

    The EU Clinical Trials Regulation (Regulation (EU) No 536/2014, the CTR) is now in full effect, and the Clinical Trials Information System (CTIS) is the single, mandatory entry point for clinical-trial applications across the European Union and the European Economic Area. The CTR replaced the earlier Clinical Trials Directive, moving from a country-by-country model to a harmonised one. This article is a neutral explainer of how the system works following the end of the transition period; it is not legal or regulatory advice.

    From directive to regulation

    The previous framework, the Clinical Trials Directive, was a directive — meaning each EU member state transposed it into national law, producing variation in how trials were authorised and overseen. Sponsors running multinational trials had to submit separately to each country, with differing requirements and timelines. The CTR is a regulation, applying directly and uniformly across member states, and was designed specifically to harmonise the assessment and supervision of clinical trials. For the focused overview, see our explainer on the EU Clinical Trials Regulation.

    What CTIS does

    CTIS is the IT backbone of the regulation. It provides a single online portal and database through which sponsors submit one application to run a trial in one or several EU/EEA countries, and through which regulators and ethics bodies coordinate their assessment. It also includes a public-facing component that improves transparency about authorised trials.

    • Single submission: one dossier for a trial spanning multiple member states.
    • Coordinated assessment: a reporting member state leads the scientific assessment shared across the countries concerned.
    • Two-part evaluation: a jointly assessed scientific part and a national part covering country-specific and ethical aspects.
    • Transparency: a public portal with information on authorised trials.

    The coordinated model means sponsors no longer duplicate a full application in every country; instead, a shared assessment is combined with country-specific evaluation.

    The transition period has ended

    The regulation became applicable in January 2022, but it included a phased transition to give the system and its users time to adapt. During that window, sponsors could in some cases still start trials under the old directive, and existing trials had a defined period to transition to the regulation and into CTIS. That transition has now concluded: CTIS is the mandatory route, and trials that were approved under the old directive were required to be brought under the CTR framework within the transition timeline.

    The end of the transition is significant because it means there is now a single regime in operation. New trials are authorised exclusively through CTIS under the CTR, and the legacy directive pathway is closed.

    How an application flows

    At a high level, a sponsor compiles a single application dossier and submits it through CTIS, indicating the member states in which the trial is to run. A reporting member state coordinates the scientific assessment (Part I), which is shared across the participating countries, while each member state evaluates the national and ethical aspects relevant to its territory (Part II). Defined timelines structure the process, and the outcome is a single decision per member state delivered through the system. Substantial changes and safety reporting during the trial are also managed within the same platform.

    This single-platform approach is intended to make multinational trials more predictable and to reduce duplicative administration, while maintaining rigorous scientific and ethical assessment in each country.

    Transparency and public access to trial information

    A notable feature of the CTR and CTIS is the emphasis on transparency. The system includes a public component through which information about authorised trials is made available, and the regulation sets expectations around the publication of trial information and, in time, results. This responds to long-standing calls to reduce so-called publication bias — the under-reporting of trials whose findings are inconvenient or negative — by making the existence and outcomes of trials more visible. Certain commercially confidential information and personal data are protected, so transparency operates within defined limits rather than as unrestricted disclosure.

    For the research community, this public visibility supports independent scrutiny and helps ensure the evidence base reflects the trials that were actually conducted, not only those that reported favourable results. It connects clinical-trials regulation to the broader open-science direction seen elsewhere in research policy.

    How it fits with GCP and global standards

    The CTR governs authorisation and oversight within the EU, while the conduct of trials continues to follow Good Clinical Practice. The modernised international GCP guideline is described in our explainer on ICH E6(R3) Good Clinical Practice, and the two operate together: the regulation defines how trials are approved and supervised in Europe, and GCP defines the quality and ethical standards for running them.

    The transparency dimension also connects to broader open-science expectations, since CTIS publishes information about authorised trials, supporting public visibility of clinical research. For neutral definitions of related terms, see our standards dictionary.

    What it means for sponsors and sites

    For sponsors, the end of the transition removes the option of the legacy pathway and concentrates all trial activity in one system, which favours organisations that have built familiarity with CTIS and its document and timeline requirements. For sites and investigators, the harmonised model means the ethical and national assessment of a trial in their country proceeds within a coordinated EU process rather than in isolation. Sponsors running trials in several member states benefit most from the single submission, but even single-country trials in the EU now flow through CTIS. As with any large system, users continued to adapt their internal processes — document preparation, role management within the portal, and response to assessment questions — to work efficiently within the platform.

    The takeaway

    The EU has moved decisively to a single, harmonised system for clinical trials: one regulation applying directly across member states, one mandatory portal in CTIS, and a coordinated assessment that replaces country-by-country duplication. With the transition period over, CTIS is the only route for trial applications in the EU and EEA. Authoritative detail is published by the European Medicines Agency and the European Commission at ema.europa.eu, which sponsors and investigators consult for binding requirements.

  • The Pharmaceutical Research and Development Pipeline Explained

    The pharmaceutical research and development pipeline is the structured, multi-stage process through which a candidate medicine progresses from initial discovery to an approved, monitored product. It moves through discovery, preclinical evaluation, phased clinical trials, regulatory review and post-market surveillance, with rigorous standards and accumulating data governing the decision to advance or halt at every step.

    The pipeline is best understood not as a guaranteed route but as a sequence of evidentiary gates. Most candidates that enter discovery never reach patients, and attrition is a designed feature rather than a failure: each stage is intended to identify safety or efficacy problems before more participants and resources are committed.

    Discovery and target identification

    Discovery begins with understanding the biology of a disease and identifying a molecular target — a protein, receptor or pathway whose modulation might produce a therapeutic effect. Researchers then screen large libraries of compounds to find “hits”, refine them into “leads” through medicinal chemistry, and characterise how they behave. This stage is heavily data-driven, relying on reproducible assays and well-documented methods. Clear, standardised reporting of these early findings — the kind of metadata discipline catalogued in the CASRAI dictionary — makes downstream reuse and verification possible.

    Preclinical evaluation

    Before any human exposure, candidates undergo preclinical testing in laboratory and animal models to assess pharmacology, toxicology and how the body absorbs, distributes, metabolises and excretes the compound. The aim is to establish a plausible safety margin and a rationale for a starting human dose. Good Laboratory Practice frameworks govern how these studies are conducted and recorded, and the resulting data package supports the application a sponsor must file before clinical testing may begin.

    Clinical phases

    Human testing proceeds through sequential phases, each answering a different question. The structure and oversight of these phases are explored in detail in our guide to clinical trial phases I to IV.

    Phase Primary question Typical focus
    Phase I Is it safe in humans? Safety, tolerability, dose range, pharmacokinetics
    Phase II Does it work, and at what dose? Preliminary efficacy, dose-finding, further safety
    Phase III Is it effective and safe at scale? Confirmatory efficacy versus a comparator, broader safety
    Phase IV How does it perform in routine use? Post-approval surveillance, rare effects, long-term outcomes

    Confirmatory phases typically rely on the randomised controlled trial design, which provides the most robust basis for causal claims about benefit and harm. Comparator arms frequently use a placebo, whose role and ethics are discussed in our piece on the placebo effect.

    Regulatory review

    Once clinical data are assembled, the sponsor submits a marketing authorisation application to a regulator, which assesses quality, safety and efficacy. Reviewers scrutinise the trial designs, statistical analyses and manufacturing controls. Approval is conditional on the totality of evidence supporting a favourable benefit–risk balance for a defined indication and population — not on any single trial in isolation. Regulators may also attach post-approval commitments, such as further studies or restricted use, where uncertainty remains. Because the review weighs an entire evidence package, the credibility of each underlying study — its design, its pre-specified outcomes and its transparent reporting — directly shapes the decision. Weak or selectively reported evidence at any earlier stage can undermine an otherwise promising candidate at this gate.

    Post-market surveillance

    Approval is not the end of the pipeline. Pharmacovigilance systems continuously monitor real-world safety once a medicine reaches large, diverse populations, capturing rare or delayed effects that controlled trials cannot detect. Findings can lead to label changes, restrictions or, occasionally, withdrawal. This continuous-evidence model reflects the wider research lifecycle, in which knowledge is provisional and updated as data accumulate. Phase IV studies, spontaneous adverse-event reporting and large observational databases all feed this stage, and the same standards of structured data and transparent methods that governed the clinical phases continue to determine how reliably real-world signals can be interpreted and acted upon.

    Why the pipeline takes so long and stays uncertain

    The pipeline is long and uncertain because biology is difficult to predict and because each stage deliberately raises the evidential bar. A candidate that looks promising in a laboratory model may behave differently in human physiology; one that is safe at a low dose may show toxicity at a therapeutic one; and an effect seen in a small early study may evaporate in a large confirmatory trial. Rather than treat these surprises as setbacks, the staged design exists precisely to surface them while exposure is still limited.

    Uncertainty also compounds across stages. Because so few discovery candidates survive to preclinical work, and only a fraction of those entering human testing reach approval, the pipeline is best modelled as a funnel of conditional probabilities. This is why sponsors run programmes as portfolios rather than single bets, and why transparent reporting of failures — not only successes — is so valuable to the wider field. We avoid quoting specific cost or duration figures here precisely because they vary enormously by therapeutic area and are frequently misreported; the structural point stands regardless of the numbers.

    Data and standards at each stage

    Each stage produces a distinct evidence package, and the value of that package depends on how well it is structured and documented. Discovery generates assay data and compound characterisation; preclinical work produces toxicology and pharmacokinetic datasets; clinical phases yield protocol-bound outcome data; and post-market surveillance accumulates real-world safety signals. When these are recorded with consistent terminology, persistent identifiers and version-controlled protocols, evidence can be audited, pooled across studies and reused — strengthening regulatory decisions and reproducibility alike.

    Stage Key data produced Standards focus
    Discovery Screening hits, assay and structure data Reproducible methods, metadata
    Preclinical Toxicology, pharmacokinetics Good Laboratory Practice records
    Clinical Protocol-bound outcome data Preregistration, trial governance
    Post-market Real-world safety signals Pharmacovigilance reporting

    The role of standards and data discipline

    At every stage, structured data, consistent terminology and transparent methods determine whether results can be trusted and reused. Persistent identifiers, version-controlled protocols and clear documentation of contributions allow regulators, replicators and downstream researchers to interpret findings correctly. The discipline of specifying analyses in advance — explored in our guide to preregistration and Registered Reports — is increasingly applied to clinical work to keep confirmatory claims honest. Guidance for documenting one’s own contributions to such work is set out in our resources for authors.

    Frequently asked questions

    Why do so few candidates reach approval?

    Attrition is intentional. Each gate is designed to stop unsafe or ineffective candidates early, before larger populations are exposed. The high failure rate reflects the difficulty of predicting human biology from early models, not a flaw in the process.

    What distinguishes preclinical from clinical work?

    Preclinical work occurs in laboratory and animal models to establish a plausible safety case, whereas clinical work involves human participants under regulatory oversight and ethical review.

    Does approval mean a medicine is fully understood?

    No. Approval reflects a favourable benefit–risk judgement on the evidence available at the time. Post-market surveillance continues to refine that picture, sometimes for many years.

    How do standards improve the pipeline?

    Consistent terminology, structured metadata and transparent protocols make data verifiable, reusable and comparable across studies, strengthening regulatory decisions and reproducibility throughout the lifecycle.