Summarising a Phase I trial in healthy volunteers
The EU regulation's demand for a lay summary of every trial's results reaches Phase I trials in healthy volunteers, whose results mean less to a lay reader than those of later-phase trials. Such a summary is hard to make useful, but its wording can be standardised across Phase I designs, each of its sections carries set content, and the effort it costs weighs against what the reader gains.
Why a Phase I summary is hard to make useful
The EU Clinical Trials Regulation 536/2014 requires a lay summary of results for every clinical trial, whatever its phase, therapeutic area or outcome, so a Phase I trial in healthy volunteers needs one.
A Phase I trial answers questions that are only indirectly relevant to patients. It usually evaluates the pharmacokinetics, pharmacodynamics and initial tolerability of a new compound, and no clinical endpoints. A later-phase summary, by contrast, can report something relevant to patients, such as a new therapeutic principle or efficacy confirmed in a large group.
To help readers understand a Phase I trial, the summary has to show where the trial sits in the development process. Evaluation in humans usually runs from single and multiple rising-dose trials through drug–drug interaction, food-effect, and bioavailability and bioequivalence trials, until the pharmacokinetic and pharmacodynamic properties are established. Occasionally a Phase I trial comes late in development, such as a bioequivalence trial for a fixed-dose combination.
Four features of Phase I trials make such a summary a challenge to write.
The endpoints mean little to the reader. They concern uptake, metabolism and excretion, and consist of series of blood concentrations of the substance and its metabolites: maximal concentration (Cmax), exposure (area under the curve), half-life and concentration at steady state. These endpoints are complex, often mathematically derived and generally interpretable only in combination, and usually none of them corresponds to a physical or psychological experience of the participants. So the summary aggregates them at a level that aids understanding, because details may impede rather than enable comprehension, so the result is better stated qualitatively. Tolerability is always preliminary, because participants do not have the target disease and small numbers cannot detect infrequent adverse events, and the safety signals seen in Phase I need to be confirmed in later-phase trials. So the safety results of one Phase I trial may be of limited value to a reader interested in the side effects of an eventual marketed medicine.
The indication may not be known. Some substances acting on the immune system, such as antibodies to interleukins, affect pathways relevant to many diseases, so the target disease may not yet be established when the substance is tested in Phase I. If the disease area is unknown when the summary is written, or the one it names changes later in development, the summary's usefulness to the public is limited.
Most substances never reach patients. Phase I trials are hard to count, because trials in healthy volunteers need no registration on ClinicalTrials.gov and are visible only to authorities in EudraCT. They are nonetheless likely to far outnumber trials in every other phase, while only 13.8% of drug development programmes across therapeutic areas lead to approval, and most substances evaluated in Phase I never become available to patients. So these summaries are likely to be of limited or no value to the public, while their workload and cost are considerable for commercial and academic sponsors alike.
The results arrive late. Details of a substance first tested in humans are kept confidential to protect the sponsor's intellectual property. Unlike later-phase results, Phase I results are usually not made available within a year of the trial's completion, and major registries require Phase I results only once a drug is approved, usually many years later. Once the regulation came into effect, sponsors were to be able to defer publication of Phase I results for 30 months, an option they were expected to use. Participants are therefore not told the results in a timely manner.
Standard wording across Phase I designs
Phase I summaries leave considerable scope for harmonising wording, structure and overall appearance, because Phase I trials tend to have similar designs and endpoints whatever the therapeutic area or intended indication. So standard lay wording for each design could describe the background, methods and results for any investigational substance.
One template rests on the recommendations an expert group of stakeholders developed on the structure and content of lay summaries, and on a standard for later-phase summaries. It gives the structure, annotated guidance for the writer, and standard text the writer selects according to the trial design. The template aids the writing, harmonises summaries in structure, level of detail and lay language, and aims at an efficient, lean and cost-saving writing process.
The template pairs five issues with their solutions, in this order:
- Readers must not conclude that the trial was curative or done in patients: state in the lay title that participants were healthy, add a statement emphasising that they were healthy volunteers, and visually distinguish Phase I summaries from later-phase ones.
- Readers may lack the knowledge to understand the trial's purpose: explain why it is done in healthy volunteers, as in "When we develop a new medicine, we need to understand how the body processes it. Studies in healthy people help us answer this question."
- Pharmacokinetic endpoints are the focus but unlikely to be of immediate relevance to a lay reader: describe the underlying design in lay words, as in "This study tested whether there is a difference in how the body processes medicine A and medicine B when they are taken as 1 single tablet or as 2 separate tablets", and avoid terms such as bioequivalence.
- The indication may be unknown at the time of writing: name the target organ or group of diseases instead, "diseases of the brain" rather than "Alzheimer's disease".
- Designs may be complicated, with details that may confuse readers, and numerical data for the usual Phase I endpoints may not be meaningful to them: give design and procedure details sparingly, as in "We measured the amount of medicine A and medicine B in the blood when the participants took them as separate tablets and combined in a single tablet. The doctors took blood samples at different times during the study. The doctors also collected information about the participants' health.", avoid terms such as two-sequence crossover study, and describe results qualitatively, as in "the amount of medicine in the blood was about the same, no matter whether it was taken as formulation 1 or formulation 2".
The sections of a Phase I summary
Title. A lay title is developed for every study from its full scientific title, and a good one lets a reader judge quickly whether the trial is relevant to them. The same title is used on other trial documents, such as informed consent forms, and in the ClinicalTrials.gov posting. For Phase I the title always says that the participants were healthy, so that readers understand the trial was not done in patients with a disease, and a statement directly below the title highlights it.
Background. The section gives the reader enough to understand what the trial was about and why it was needed. It opens with a purpose statement and then explains why the trial was done in healthy volunteers. The rationale stays high-level, omitting scientific details irrelevant to lay readers, with standardised text for different trial types, such as dose escalation, drug–drug interaction, and bioavailability or bioequivalence trials. The investigational product's code number or international nonproprietary name belongs here, because it is tied to the rationale, and the intended indication gets only a general statement. To help readers understand the trial, and for transparency, the section also gives some detail on procedures: dose groups and dosing intervals, whether some participants received placebo and what placebo is, how the medicine was given, blood or other sampling, and any special procedures such as imaging. It states that participants' overall health was regularly monitored during the trial.
Participants. The section gives the total number with the breakdown by age and sex, key inclusion or exclusion criteria where relevant, such as a body-mass-index range, and the country. Participant is used rather than subject, as the most appropriate factual description.
Results. Following the expert recommendations, the summary reports the primary endpoint. Pharmacokinetic endpoints resist lay translation and numeracy in the general population is low to medium, so the summary gives the result as a qualitative statement addressing the purpose of the trial and tries to limit numerical information. A drug–drug interaction example reads: "This study showed that taking medicine A did not affect the removal of medicine B from the blood. When the participants took medicine B with medicine A, the amount of medicine B in the blood was about the same as when they took medicine B alone." Where the primary endpoint is itself a safety endpoint, such as the frequency of drug-related adverse events, the results and adverse reactions sections can be combined.
Adverse reactions. These are called unwanted effects, which is more lay-friendly than adverse reactions. The most frequent are usually listed by treatment group in a table, though if very few are reported a sentence or bulleted list may suffice. MedDRA preferred terms are often not lay-friendly, so each is given with a lay term, and the MedDRA term is kept for consistency with registry postings, publications and the clinical study report synopsis. The number of serious adverse reactions in each group is added if any occurred.
The burden against the reader's gain
The Multi-Regional Clinical Trial guideline on returning results to participants suggests that summaries of certain types of study may not be warranted, because the results may not be informative or the benefit may not justify the administrative burden and expense. The European Federation of Exploratory Medicine (EUFEMED), an association of organisations involved in early clinical development, proposed in a comment on the regulation that Phase I summaries be published only once the trial information has ceased to be commercially confidential. The summaries nonetheless remain mandated by the regulation and serve its driving principle of making the whole clinical research process transparent, so sponsors need efficient ways to provide them. The challenge is to balance meaningful information on design and results, accessibility without over-simplification, protection of commercially sensitive information and efficient production. The template provides standards for the structure, content and wording of each type of Phase I trial, aimed at maximising the summaries' value to the public.