Where a protocol's content requirements come from

29 min read

No single guidance sets what a clinical trial protocol must contain. The SPIRIT statement, the ICH E6 guideline on good clinical practice, Annex I of the EU's clinical trials legislation and the US rules for review boards each set part of it, and common protocol templates fill the space they leave.

The guidances that set the content

Protocol regulations and guidance are not held in a single location but spread across several. The SPIRIT 2013 statement and ICH E6 carry the two highest-level statements of core content, and which further guidance applies depends on the nature of the trial and what it sets out to achieve. As of 2014, the topics a protocol includes were described in Section 6 of ICH E6, in the SPIRIT initiative and in Annex I, Section D of the EU's 2014 clinical trials legislation, No. 536, and the last two gave a more extensive list than E6 did. One experienced protocol writer does not expect a single unified source of truth on protocol content and structure to appear.

ICH E6, first published in 1996 and updated in 2016, gave a general overview of what a protocol and its amendments should contain, but its guidance for protocol development was minimal, lacked detail and was open to interpretation. It suggested no format and did not map directly to the data presentation that E3 sets out for the report, and following E6 alone is rarely sufficient to write a protocol.

ICH E9 and E9(R1) are the statistically focused guidelines that apply depending on the trial. Two further ICH guidelines are relevant: M11, and E17 on multiregional clinical trials, whose section 2.2 addresses clinical trial design and protocol issues and is worth checking when a protocol is multiregional.

In Europe, Annex I, Section D of the Clinical Trials Regulation relates to protocols. It stipulates what is needed, and its associated question-and-answer document is worth checking too, as it is updated quite frequently and can give more information.

As of 2023, regulations and guidance were changing significantly, with some changes already out, such as E8(R1), and others expected soon, and they were expected to change not only what is done but also how it is done and for whom.

The SPIRIT statement

The SPIRIT 2013 checklist sets out the items a protocol should address, and it is strongly recommended that the checklist be read with the SPIRIT 2013 explanation and elaboration paper, which clarifies the items. The items are:

Title (item 1): a descriptive title identifying the study design, population and interventions and, if applicable, the trial acronym.
Trial registration (2a and 2b): the trial identifier and registry name, or the intended registry if the trial is not yet registered, and all items of the World Health Organization Trial Registration Data Set.
Protocol version (3): the date and version identifier.
Funding (4): the sources and types of financial, material and other support.
Roles and responsibilities (5a to 5d): the names, affiliations and roles of the protocol contributors; the name and contact information of the sponsor; the role of the sponsor and funders, if any, in study design, in collecting, managing, analysing and interpreting the data, in writing the report and in the decision to submit it for publication, including whether they will have ultimate authority over any of these; and the composition, roles and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team and other individuals or groups overseeing the trial, if applicable.
Background and rationale (6a and 6b): the research question and the justification for the trial, including a summary of relevant published and unpublished studies examining the benefits and harms of each intervention, and an explanation of the choice of comparators.
Objectives (7): specific objectives or hypotheses.
Trial design (8): the type of trial, such as parallel-group, crossover, factorial or single group, the allocation ratio, and the framework, such as superiority, equivalence, noninferiority or exploratory.
Study setting (9): the settings, such as a community clinic or an academic hospital, the countries where data will be collected, and where the list of study sites can be obtained.
Eligibility criteria (10): the inclusion and exclusion criteria for participants and, if applicable, the eligibility criteria for study centres and for the individuals who will perform the interventions, such as surgeons or psychotherapists.
Interventions (11a to 11d): the interventions for each group, in enough detail to allow replication, including how and when they will be administered; the criteria for discontinuing or modifying a participant's allocated intervention, such as a dose change in response to harms, at the participant's request, or with improving or worsening disease; strategies to improve adherence and any procedures for monitoring it, such as tablet return or laboratory tests; and the concomitant care and interventions permitted or prohibited during the trial.
Outcomes (12): the primary, secondary and other outcomes, each with its measurement variable, such as systolic blood pressure, its analysis metric, such as change from baseline, final value or time to event, its method of aggregation, such as median or proportion, and its time point; an explanation of the clinical relevance of the chosen efficacy and harm outcomes is strongly recommended.
Participant timeline (13): the schedule of enrolment, interventions, including any run-ins and washouts, assessments and visits, for which a schematic diagram is highly recommended.
Sample size (14): the estimated number of participants needed to achieve the study objectives and how it was determined, including the clinical and statistical assumptions supporting any sample size calculation.
Recruitment (15): the strategies for achieving enough enrolment to reach the target sample size.
Sequence generation (16a): the method of generating the allocation sequence, such as computer-generated random numbers, and any factors for stratification; to reduce the predictability of a random sequence, details of any planned restriction, such as blocking, should be given in a separate document that is unavailable to those who enrol participants or assign interventions.
Allocation concealment and implementation (16b and 16c): the mechanism for implementing the allocation sequence, such as a central telephone or sequentially numbered, opaque, sealed envelopes, with any steps to conceal the sequence until interventions are assigned; and who will generate the sequence, who will enrol participants and who will assign them to interventions.
Blinding (17a and 17b): who will be blinded after assignment, such as participants, care providers, outcome assessors or data analysts, and how; and, if the trial is blinded, the circumstances under which unblinding is permissible and the procedure for revealing a participant's allocated intervention during the trial.
Data collection methods (18a and 18b): the plans for assessing and collecting outcome, baseline and other trial data, including any processes to promote data quality, such as duplicate measurements or training of assessors, a description of the study instruments, such as questionnaires or laboratory tests, with their reliability and validity if known, and where the data collection forms can be found if not in the protocol; and the plans to promote participant retention and complete follow-up, including any outcome data to be collected for participants who discontinue or deviate from the intervention protocols.
Data management (19): the plans for data entry, coding, security and storage, including any processes to promote data quality, such as double data entry or range checks, and where the details of the procedures can be found if not in the protocol.
Statistical methods (20a to 20c): the methods for analysing the primary and secondary outcomes, and where the other details of the statistical analysis plan can be found if not in the protocol; the methods for any additional analyses, such as subgroup and adjusted analyses; and the definition of the analysis population relating to protocol nonadherence, such as an as-randomised analysis, and any statistical methods for handling missing data, such as multiple imputation.
Data monitoring (21a and 21b): the composition of the data monitoring committee, a summary of its role and reporting structure, a statement of whether it is independent of the sponsor and of competing interests, and where further details of its charter can be found if not in the protocol, or else an explanation of why no such committee is needed; and any interim analyses and stopping guidelines, including who will have access to the interim results and make the final decision to terminate the trial.
Harms (22): the plans for collecting, assessing, reporting and managing solicited and spontaneously reported adverse events and other unintended effects of the trial interventions or of trial conduct.
Auditing (23): the frequency and procedures for auditing trial conduct, if any, and whether the process will be independent of the investigators and the sponsor.
Research ethics approval (24): the plans for seeking approval from a research ethics committee or institutional review board.
Protocol amendments (25): the plans for communicating important protocol modifications, such as changes to eligibility criteria, outcomes or analyses, to relevant parties, such as investigators, ethics committees and review boards, participants, trial registries, journals and regulators.
Consent or assent (26a and 26b): who will obtain informed consent or assent from potential participants or authorised surrogates, and how; and additional consent provisions for collecting and using participant data and biological specimens in ancillary studies, if applicable.
Confidentiality (27): how personal information about potential and enrolled participants will be collected, shared and maintained to protect confidentiality before, during and after the trial.
Declaration of interests (28): the financial and other competing interests of the principal investigators for the overall trial and for each study site.
Access to data (29): who will have access to the final trial dataset, and any contractual agreements that limit such access for investigators.
Ancillary and post-trial care (30): the provisions, if any, for ancillary and post-trial care and for compensating those who suffer harm from taking part.
Dissemination policy (31a to 31c): the plans for investigators and sponsor to communicate the results to participants, health-care professionals, the public and other relevant groups, such as through publication, reporting in results databases or other data-sharing arrangements, including any publication restrictions; the authorship eligibility guidelines and any intended use of professional writers; and the plans, if any, for granting public access to the full protocol, the participant-level dataset and the statistical code.
Informed-consent materials (32): the model consent form and other related documentation given to participants and authorised surrogates.
Biological specimens (33): the plans for collecting, evaluating in the laboratory and storing biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable.

Amendments to the protocol should be tracked and dated.

One experienced writer finds SPIRIT structured much like CONSORT, its counterpart for reporting randomised trials, but notes that a protocol has to describe in more detail the ethical requirements, the review board's approval and how study material was managed, all of which a good-quality clinical study needs.

The SPIRIT statement was revised as SPIRIT 2025, which changes the minimum requirements for interventional trials. In the revision some items of the 2013 statement were revised, some merged and some removed.

SPIRIT extensions cover further ground, such as the outcomes extension, which one experienced protocol writer finds quite useful, and extensions on patient-reported outcomes and artificial intelligence. That writer finds them very helpful guidance for protocol authors, especially when a study team has no clear idea of the content it needs to provide.

The ICH E6(R3) contents list

ICH E6(R3) defines a protocol as a document that describes the objectives, design, methodology, statistical considerations and organisation of a trial, and that usually also gives the background and rationale, although these could be provided in other documents the protocol references. Throughout the guideline, "protocol" refers to the protocol and its amendments. A protocol amendment is a documented description of a change to a protocol.

Appendix B of the guideline states that a trial should be described in a clear, concise and operationally feasible protocol, designed to minimise unnecessary complexity and to mitigate or eliminate important risks to the rights, safety and well-being of participants and to the reliability of the data. Protocol development should incorporate input from relevant interested parties, where appropriate. Building adaptability into the protocol, for example by including acceptable ranges for specific provisions, can reduce the number of deviations or in some instances the need for an amendment, but such adaptability should not adversely affect participant safety or the scientific validity of the trial. For further information the appendix refers to ICH E8(R1), E9 and E9(R1).

The appendix lists the topics a protocol should generally include, which may vary with the trial design; investigator site-specific information may be given on separate protocol pages or in a separate agreement, and some of the information may be contained in other documents the protocol references, such as the investigator's brochure.

The general information is the protocol title, a unique identifying number and a date, with any amendments bearing their own numbers and dates; the name and address of the sponsor; and the name and title of the people authorised to sign the protocol and its amendments for the sponsor.

The background information is the name and description of the investigational products; a summary of the findings from nonclinical studies that potentially have clinical significance and from clinical trials relevant to the trial; a summary of the known and potential risks and benefits, if any, to participants; a description of and justification for the route of administration, dosage, dosage regimen and treatment periods; a statement that the trial will be conducted in compliance with the protocol, good clinical practice and the applicable regulatory requirements; a description of the population to be studied; and references to the literature and data relevant to the trial that provide its background.

The objectives and purpose are a clear description of the scientific objectives and the purpose of the trial, with information on estimands where they have been defined.

The scientific integrity of the trial and the reliability of its results substantially depend on its design, and the description of the trial design includes:

a specific statement of the primary endpoints and any secondary endpoints to be measured
a description of the type and design of the trial, such as double-blind, placebo-controlled, parallel, adaptive, platform, umbrella or basket, or with decentralised elements, and a schematic diagram of the design, procedures and stages
a description of the measures taken to minimise or avoid bias, including randomisation and blinding
a description of the investigational products and their dosage and dosage regimen, including the dosage form, packaging and labelling
preparation, such as reconstitution, and administration instructions where applicable, unless described elsewhere
a description of the schedule of events, such as trial visits, interventions and assessments
the expected duration of the participant's involvement and a description of the sequence and duration of all trial periods, including any follow-up
a description of the stopping rules or discontinuation criteria and the dose adjustment or dose interruption, for individual participants, for parts of the trial or for the entire trial
the accountability procedures for the investigational products, including any placebos and other comparators
the maintenance of treatment randomisation codes and the procedures for breaking them

The selection of participants is the inclusion criteria, the exclusion criteria, and the mechanism for pre-screening, where appropriate, and for screening.

The investigator may discontinue a participant from the trial, and the participant may decide to withdraw from the trial or to stop treatment with the investigational product. The protocol should specify when and how participants are discontinued from the trial or from treatment; the type and timing of the data to be collected for withdrawn or discontinued participants, including how those data are handled in accordance with applicable regulatory requirements; whether and how participants are to be replaced; and the follow-up for participants who have stopped using the investigational product.

The treatment and interventions are the treatments to be administered, with the names of all the products, the doses, the dosing schedules, the criteria for dose adjustment, the routes or modes of administration and the treatment periods, including the follow-up periods, for each treatment group or arm; the medications and treatments permitted, including concomitant and rescue medication, and those not permitted before or during the trial; and the strategies to monitor the participant's adherence to treatment.

The assessment of efficacy is the specification of the efficacy parameters, where applicable, and the methods and timing for assessing, recording and analysing them. Where a trial-related committee, such as an independent data monitoring committee or an adjudication committee, assesses efficacy data, its procedures, timing and activities should be described in the protocol or a separate document.

The statistical considerations are a description of the statistical methods, including the timing and purpose of any planned interim analysis and the statistical criteria for stopping the trial; the number of participants planned and the reason for that sample size, including reflections on or calculations of the power of the trial and a clinical justification; the level of significance to be used, or the threshold for success on the posterior probability in a Bayesian design; the selection of participants to be included in the planned analyses, the statistical methods and the procedures for handling intercurrent events and accounting for missing, unused and spurious data, aligned with the target estimands where they are defined; and a statement that any deviation from the statistical analysis plan will be described and justified in the clinical trial report.

The sponsor should ensure that the protocol or another documented agreement specifies that the investigators, institutions and service providers will permit trial-related monitoring, audits, regulatory inspections and, in accordance with applicable regulatory requirements, review by the institutional review board or independent ethics committee, providing direct access to source records.

Quality control and quality assurance are a description of the identified critical to quality factors, the associated risks and the risk mitigation strategies, unless documented elsewhere; a summary of the monitoring approaches that are part of the quality control process; and a description of the process for handling noncompliance with the protocol or good clinical practice.

The ethics section is a description of the ethical considerations relating to the trial.

Data handling and record keeping are the specification of the data to be collected and the method of collection, with additional detail in a trial-related document where necessary; the identification of data to be recorded directly into the data acquisition tools, with no prior written or electronic record, and so considered the source record; and a statement that records should be retained in accordance with applicable regulatory requirements.

Financing and insurance, and the publication policy, are each covered in the protocol if they are not addressed in a separate agreement.

What a US review board expects the protocol to address

A protocol under US federal rules must be what the dictionary defines a protocol as, "a detailed plan of a scientific or medical experiment, treatment, or procedure", and more. Under 21 CFR 56.111(a)(2), 56.115(a)(1) and 312.55 the protocol must also address:

the title of the study
the purpose of the study, with the expected benefits of doing it
the sponsor
the results of previous related research that justify the purpose and phase of the study
the inclusion and exclusion criteria
a justification for using any vulnerable population, such as children, prisoners or pregnant women and fetuses
the study design, a description of the procedures to be performed, and the provisions for managing adverse reactions
the circumstances of the consent procedure, including its setting, concerns about participants' autonomy, language difficulties and the special treatment of vulnerable populations
the procedures for documenting informed consent, including any procedures for obtaining assent from minors, using witnesses and translators, and storing the documents
compensation for participation, and compensation available to participants who are injured
the provisions for protecting participants' privacy
the extra costs to participants of taking part, and the extra costs to third-party payers

The protocol must give the research justification and plans in enough detail for the reviewers to assess the risks against the benefits and decide whether the project can be approved, in language accessible to every member of the board. Too much detail can be unnecessary, but the protocol must disclose, for example, that blood will be drawn, the number of visits planned and any planned compensation. Commonly omitted details might include the volume of blood drawn, the length of visits and the lack of a prorated compensation plan for partly completed procedures.

Common protocol templates

ICH E3 and M4E describe structure and content in enough detail to serve as templates for clinical study reports and Module 2 summaries, but no parallel template-like guidance existed for protocols, and hardly any formal guidance on their document structure was available. The resulting lack of consistency across protocols presented challenges, especially as trials grew more complex.

Multi-investigator trials, multinational trials and increased public scrutiny create pressure to produce succinct, unambiguous, high-quality and readable protocols, and the burden a protocol creates for participants and investigators is a further consideration of complexity, yet authoring protocols remains a challenge for many sponsors. The need for template-driven protocol development is well established in the clinical literature. Advocates for specific diseases and conditions encourage standardised trial design, so that data can be compared across trials and safety signals understood earlier and more thoroughly.

To those who work in clinical research, a protocol template seemed long overdue. For investigator-sponsored research a well-written template can make protocols consistent within institutions, lessen the chance of misinterpretation by colleagues, institutional review boards or government bodies, and facilitate compliance with section 801 of the FDA Amendments Act. For industry a consistent template can aid submissions, ensure the mapping between the protocol and the data presentation expected in the clinical study report, and make protocols more readable and consistent for agency reviewers.

Early in 2016 TransCelerate BioPharma launched its common protocol template, which provides a heading structure and common text expected to be used across protocols and is accompanied by a set of text libraries for specific areas, such as diabetes and asthma. A few weeks later the US National Institutes of Health and the Food and Drug Administration jointly released their own draft protocol template for public comment, with instructional and sample text and a heading structure that differs from TransCelerate's. The two authoritative initiatives thus released protocol templates in parallel. Such parallel work by two major initiatives on the same complex topic was unexpected, and a medical writer interested in protocol structure should keep an eye on both.

Disease-specific protocol templates have been published for vaccines and for alopecia areata and used to align researchers across organisations such as the National Institute of Allergy and Infectious Diseases, although one group of researchers has suggested that a single template for all trials may not adequately serve the investigator community, and the quest to develop a single standard protocol template continues.

The NIH-FDA template

The National Institutes of Health and the FDA jointly developed the template to give primarily researchers and, to a lesser degree, industry more structured guidance for designing studies and their protocols, and potentially to streamline their review, for NIH-funded investigators writing protocols for phase 2 and 3 trials that need an investigational new drug or investigational device exemption application. It is a Microsoft Word document with a heading for each required protocol section and both instructional and sample text where appropriate, it provides structure and formatting suggestions with definitions, and in part it attempts to align standards from the Centers for Medicare & Medicaid Services, the Code of Federal Regulations, the FDA, the Department of Health and Human Services, ICH, the International Organization for Standardization, the National Institutes of Health and the Office for Human Research Protections, among others. The accounts of the draft's release differ: one gives the period in which feedback was solicited as 17 March to 17 April 2016, and another dates the release to 18 March and the close of comments to 17 April 2016. The National Institutes of Health reported more than 200 comments from more than 60 respondents, and the final template was released for public use in May 2017. The National Institutes of Health also introduced the e-Protocol Writing Tool, which uses an identical version of the template: an online interface that collects the protocol's content through questions and fields for each heading and subheading, with word-processing features and export to Word, which is meant to allow collaborative writing and review by investigators and other study team members.

The template hews closely to the requirements of ICH E6. Its sections map onto E6's protocol headings, with the compliance statement against 6.2.5, the protocol summary against 6.1.1 to 6.1.6, the objectives and endpoints against 6.3 and 6.4.1, the inclusion and exclusion criteria against 6.5.1 and 6.5.2, the statistical sections against 6.9 and its subsections, and the regulatory, ethical and study oversight considerations against 6.10 to 6.14. Seven sections have no E6 counterpart: lifestyle considerations, screen failures, strategies for recruitment and retention, lost to follow-up, unanticipated problems, abbreviations and references. In some cases aspects of the template may reflect a contributing body's interpretation of a requirement, as unanticipated problems may reflect the Office for Human Research Protections' interpretation of 45 CFR part 46, or lessons learned by the contributing authors, as lost to follow-up may. In industry practice the information on screen failures, recruitment and retention, and loss to follow-up is typically part of a study manual or another training document outside the protocol, such as a site training manual. A writer applying the template for industry use should consider how it conforms to the evolving transparency landscape, which may influence the level of detail in a protocol.

The template maps onto ICH E3 section by section: the compliance statement to the title page, the protocol summary to the synopsis, the rationale, background and risk–benefit assessment to section 7, the objectives and endpoints to section 8, the overall design and the scientific rationale for it to 9.1, 9.2 and 9.5.2, the statistical sections to 9.7 and 11, the regulatory, ethical and study oversight considerations to sections 5 and 9.6, the additional considerations, which no E3 section directly matches, to section 5, since the template places institutional or review-board requirements there, and the amendment history to 9.8. A writer using the data the template generates, or applying its details to the clinical study report, needs to be aware that some of its sections, such as lifestyle considerations and unanticipated problems, do not clearly map to E3.

The template provides a robust framework for detailing the definitions, procedures, endpoints and adverse events of a trial, and it has the potential to be widely applied in other investigator-initiated studies and in studies sponsored by life science companies, particularly newer biotech companies that may not yet have standard templates for their regulatory documents. For investigators and sponsors with no in-house template or resources to develop one, it is a solid introduction to writing a thorough protocol, and it is an improvement over the broader protocol guidance of ICH E6. It is mostly, but not entirely, aligned with E3 and E6, and because it attempts to incorporate guidance from many bodies, aspects of it may differ from the goals of an industry user. Aligning protocol writing in academia and industry is a worthwhile goal.

The template was designed for phase 2 and 3 studies and may not suit other types of study, although the National Institutes of Health stated that it planned to extend the instructional and sample text to studies that fit poorly, such as phase 1 or behavioural studies. Its instructional text is in italics but can sometimes be hard to tell from the sample text, and it offers no structure or instructional text for protocol amendments. Its font, Calibri, and its formatting, such as shading and colour, do not comply with the FDA's guidance on PDF specifications. So before an eCTD submission the writer should change the protocol to standard, unshaded serif fonts in all headings and paragraphs, and use appropriate styles to insert caption headings and create active cross-references throughout.

TransCelerate's common protocol template

TransCelerate BioPharma, a non-profit organisation formed in 2012 to collaborate across biopharmaceutical research and development, issued release 5 of its common protocol template in December 2017, with the stated goals of aligning with good clinical practice, ICH and European Union requirements and of following clinical data standards. It is a Microsoft Word template with headings, instructions for authors and sample text, and it specifies three components: core backbone headings, which are level 1 headings intended always to be used; libraries, which hold specific content; and appendices, which are headings for information that may be deleted if not used. It also provides terminology, formatting and text conventions. Its e-protocol writing tool populates the template through a series of questions and can produce a Word document or an XML deliverable, in anticipation of the FDA's electronic submission gateway requirements. TransCelerate views the template as a foundational element in a longer-term movement towards an electronic protocol, and recommendations for modifications in future releases could be submitted at any time and would be reviewed on a routine basis. Its implementation toolkit, for use with therapeutic area–specific libraries, is meant to foster common wording that eases review, and it is consistent with the Clinical Data Interchange Standards Consortium's therapeutic area standards.

The sections of release 5 are a protocol summary with a synopsis, schema and schedule of activities; an introduction; objectives and endpoints; study design; study population; study intervention; discontinuation of study intervention and participant discontinuation or withdrawal; study assessments and procedures; statistical considerations; supporting documentation and operational considerations, which hold the appendices; and references. The appendices cover regulatory, ethical and study oversight considerations; clinical laboratory tests; adverse events; contraceptive guidance and collection of pregnancy information; genetics; liver safety; medical device incidents; country-specific requirements; abbreviations; and the protocol amendment history.

The template is intended for all phases of drug development. Its core backbone establishes a common heading structure and recommends content applicable to all protocols. Many of its redefined headings map to E6, E3 and more recent guidance, several new headings encourage more detailed and updated information in the protocol, and subheadings may be added when needed. Its detailed instructional text attempts to reduce misinterpretation by study sites and regulatory authorities while enabling downstream automation. TransCelerate stated in release 5 that the template is intended to support the requirement to upload disclosure data to clinical trial registries.

For the most part, the body of the template fits well within the framework of E3 and E6. The template's headings map onto E6 and E3 in pairs that include the inclusion and exclusion criteria against E6 sections 6.5.1 and 6.5.2 and E3 sections 9.3.1 and 9.3.2; the statistical hypotheses and sample size determination against E6 sections 6.9.1 and 6.9.2 and E3 sections 9.7.1 and 9.7.2; the populations for analyses against E6 section 6.9.7 and E3 sections 9.7.1 and 11.1; the regulatory, ethical and study oversight appendix against E6 sections 6.10 to 6.14 and E3 sections 5 and 9.6; the abbreviations against E3 section 4 alone; the protocol amendment history against E6 section 6.1.1 and E3 section 9.8; and the references against E3 section 15 alone.

The template aligns most closely with E3, perhaps because E3 is the more detailed guidance. Where E6 lacks specificity and leaves interpretation open, the template gives its own direction. Sections 1 to 4, the introduction, overall design, objectives and rationale, are well defined in both E3 and E6. Most of section 5, the study population, maps to both, but subsections on lifestyle considerations were added to encourage reporting the restrictions on lifestyle or diet recommended during a trial. The sample text includes a statement on exposure to sunlight for interventions with a potential for photosensitivity. E3 has a section on the selection and timing of doses for each patient (9.4.5), and the template also sets out food and drink restrictions and encourages more detail on the timing of meals relative to dosing. In a departure from the ICH guidances, it also specifies restrictions on water, alcohol, tobacco, caffeine and xanthine-containing products. Limits on physical activity, especially strenuous exertion, are a new consideration.

Section 6, the study intervention, is largely consistent with E3 and E6, but it adds an optional subsection on medical devices, which covers companion diagnostic tests used to stratify participants and sponsor-provided devices used for dosing and administration. The wording of that subsection can be adapted to regional definitions of medical devices, since not every country follows the FDA in defining diagnostics as medical devices. Intervention after the end of the study, the template's section 6.7, is specified in section 6.4.5 of E6 and implied but not specified in E3.

Section 7 hews closely to guidance, but section 8, on study assessments and procedures, has several subsections specific to the template that likely reflect the development programmes of TransCelerate's members. Many of the subsections of section 8 have no E6 heading and only occasionally an E3 one. Monitoring of suicidal ideation and behaviour for compounds known to be active in the human central nervous system (section 8.2.5) is unique to the template, and medical device incidents, including malfunctions (section 8.3.8), appear in neither guidance. Optional subsections on immunogenicity, RNA transcriptome research, RNA expression research, proteomics research and metabolomics research may reflect advances in the clinical analysis of novel treatment modalities. Several sections, such as 5.3.2, 8.3.5 and 8.9, are represented in neither guideline and may reflect changes in clinical trial development since E3 and E6 were written in the 1990s, or the interests of TransCelerate's members.

The template's most notable exceptions to E3 and E6 lie in its appendices. Appendix 4 (contraceptive guidance and collection of pregnancy information), appendix 5 (genetics), appendix 6 (liver safety: suggested actions and follow-up assessments and study intervention rechallenge guidelines), appendix 7 (medical device incidents: definition and procedures for recording, evaluating, follow-up and reporting) and appendix 8 (country-specific requirements) map directly to neither guidance. Some of them correspond to newer guidance or to region-specific position statements, and appendix 6, for example, aligns closely with the FDA's guidance on drug-induced liver injury in premarketing clinical evaluation. Appendix 8 acknowledges that clinical development is global, and it helps reduce the country-specific amendments that bog a study down and confound the statistical analysis and the clinical study report, because one global protocol can carry a subsection of the appendix for each country that requires special procedures.

The appendices most likely depart from the guidances to make the template more accessible across the life science industry, to address emerging therapeutics, to recognise newer guidance and to lead in an evolving landscape. International regulators may not agree on standards for birth control, so there are no specific, harmonised international guidelines on birth control requirements and pregnancy prevention in trials, and appendix 4 may be how the industry acknowledges the need to clarify these data considerations and their complexity. Contraceptive use is outlined in the US-specific 1993 guideline for the study and evaluation of gender differences in the clinical evaluation of drugs. Appendix 5, on genetics, speaks to the emerging technologies of biopharmaceutical development and the more recent guidance on pharmacogenomics, genomic biomarkers, genomic sampling and data management, guidance that reflects trends encouraging genetic profiling in trials and gives direction on managing and reporting these data.

Some core backbone sections do not fit the needs of every user. Like E6, the template is aligned with pharmaceutical development, and its use for medical devices is likely limited and would leave much of the core backbone marked not applicable, while its subsection on medical devices would have to be deleted for interventions that need no device. The sections on contraception and genetics may not apply to every trial. A consortium of global pharmaceutical companies developed the template to suit their needs, and it may not be broadly applicable to smaller companies, to newer modalities such as gene therapy and RNA modulation, or to medical device firms. It has no language specific to paediatric or geriatric studies, and it supports food-effect studies well although they are not universally required, particularly for therapies given by a non-oral route. As of 2018, its terminology and adoption had not yet been broadly established.

One experienced writer sees the template as another option for preparing protocols: more general than SPIRIT, without the guidelines' structure, and closer to ICH in giving instructions on how to write each topic. It can be used together with SPIRIT for a randomised trial, or together with the guidelines available for other types of protocol, with others under development.

The template offers a common structure, common text and regulation-oriented definitions for use across a clinical development programme, while leaving their use to the user's discretion. It supports the Clinical Data Interchange Standards Consortium's therapeutic area standards for unifying data representation and statistical endpoints for specific diseases, and its section headings mark a shift in pharmaceutical development towards precision medicine. As TransCelerate's member companies implement it, it may become a new standard in protocol development, familiar across the pharmaceutical industry and to health authorities, ultimately helping speed new therapeutics to the patients who need them. Standardising protocol development will facilitate collaboration and encourage information sharing and disclosure, and, it is hoped, increase efficiency in clinical development.

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