The primary aims of Phase 1 clinical trials are to determine the safety, tolerability and pharmacokinetics (PK) of a compound. These are often performed on healthy volunteers, rather than participants who would benefit from the treatment, unless it is a therapeutic area where exposure in healthy volunteers would be inappropriate, such as cancer or HIV. Trials have historically been conducted in the logical sequence of single ascending dose (SAD), multiple ascending dose (MAD), examination of preliminary effect of food on exposure, and potential drug-drug interaction, with assessments to determine the effect of gender, age, bioavailability and bioequivalence performed as necessary.
Depending on the compound and therapeutic area, Phase 1 trials may also assess pharmacodynamics (PD), biomarkers, target engagement, or preliminary evidence of activity.
Additional studies may be performed, including definitive electrocardiogram (ECG) investigations to thoroughly evaluate the QT/QTc prolongation potential of a compound, which can increase the risk of potentially fatal proarrhythmias. This blog will describe the different designs commonly used in Phase 1 clinical trials.
Single ascending dose (SAD) studies are often described as Phase 1a, although terminology can vary between development programmes.
These are studies in which a small group of subjects receive a single dose of the compound in a clinical setting, usually a Clinical Research Unit (CRU). The first participant or participants at a dose level may be dosed and assessed before the remainder of the cohort, depending on the protocol and level of uncertainty.
Close safety monitoring and usually PK assessments are performed for a predetermined time. If the compound is deemed to be well tolerated, and the PK data are broadly as expected, dose escalation occurs, either within the same group or in a further group of healthy subjects, according to the approved protocol.
Dose escalation usually continues until the maximum dose has been attained per the protocol unless a predefined maximum exposure is reached, intolerable side effects become apparent, or another protocol-defined stopping criterion is met. Additionally, dose escalation may be discontinued (or may proceed more cautiously than planned) if there is evidence of a supra-proportional relationship between dose and exposure, such that exposures at higher dose levels become difficult to predict.
The conventional 3+3 method has historically been used in oncology dose-escalation studies, rather than as a standard design for all healthy-volunteer SAD studies.
However, new methods, such as the Bayesian Optimal Interval (BOIN) method, allow for more flexible investigations, such as allowing for de-escalation and then re-escalating back to a level, or evaluating different dose-limiting toxicity (DLT) rates.
BOIN is one example of a model-assisted design. Other approaches include interval-based and model-based methods, such as the Continual Reassessment Method (CRM). Each uses accumulating safety data differently and carries its own statistical and operational requirements.
The appropriate method depends on factors such as the study population, target toxicity rate, number and spacing of dose levels, available prior evidence, and the statistical support available during the trial. Candidate designs may be compared through simulation to assess how they perform under plausible dose-toxicity scenarios.
Multiple ascending dose (MAD) studies are often included in Phase 1a or Phase 1b programmes, but the terms are not universally interchangeable.
These studies are conducted to investigate the PK and PD of multiple doses of the compound, again usually in a CRU. The dose levels and dosing intervals (i.e. the time between consecutive doses) are selected as those that are predicted to be safe from single dose data.
Samples are collected and analysed to allow the determination of PK profiles and a better understanding of how the drug is processed by the body; with multiple dosing, a key part of the PK analysis is to identify whether accumulation of the drug occurs. The study may also assess when steady-state exposure is reached and whether exposure changes after repeat dosing.
As for SAD studies, dose escalation proceeds according to the protocol assuming strict safety and PK criteria are met. It is usual for several dose levels to be studied, at and above the expected therapeutic dose level(s) to determine the ‘safety margin’ for repeat dose administration. The number and range of doses will depend on the compound, emerging data, and study objectives.
Phase 1a and Phase 1b components are increasingly included within the same multipart protocol. For example, the protocol may contain separate SAD and MAD parts, with prespecified criteria for using findings from the SAD component to inform progression into MAD. This can reduce the time and duplication involved in preparing separate studies.
However, a combined SAD and MAD protocol is not necessarily the same as a dose-escalation and dose-expansion study. Dose expansion usually involves enrolling additional participants at one or more selected doses to collect further safety, PK, PD, biomarker, or preliminary activity data.
There is also the option to conduct a phase 1b/2a trial, where the objectives and progression criteria for each part are clearly defined.
Both Phase 1a and 1b studies have a high emphasis on safety. In both cases, it is likely to be the first time participants will be exposed to a particular dose level or repeat-dose regimen. They are normally both conducted in similar settings to allow close monitoring for any potential reactions.
A SAD study gives participants a single dose, whereas a MAD study involves repeated doses over a longer period. Phase 1a and Phase 1b should not be used as fixed substitutes for these design terms because their meaning can vary between programmes.
This allows for multiple measurements/assessments to be conducted in a MAD study to see how the treatment works over a longer period, for example, whether absorption changes after multiple doses or cycles in a drug trial.
Regardless of the escalation method, the protocol should define when emerging data will be reviewed and which findings allow the next dose level or cohort to proceed. Decisions may consider adverse events, laboratory findings, clinical observations, ECG results, drug exposure, and any protocol-defined dose-limiting toxicities.
Dose-limiting toxicity is an adverse event that is sufficiently severe or clinically significant to restrict further dose escalation under the protocol’s definition. It is commonly used in oncology dose-finding, although the relevant safety criteria and assessment period depend on the treatment and study.
The protocol should also set out the applicable pausing and stopping rules, who reviews the data and how incomplete or late-arriving safety information will be handled. A safety review committee may assess the accumulated evidence before the next dose level or study component begins.
Food effect studies are conducted to allow a preliminary assessment of how absorption of the compound is affected when administered after a specifically designed and standardised test meal, usually a high fat breakfast in the first instance.
Such studies are usually conducted following a crossover design such that the same subjects receive doses of the study drug on different occasions under fasted and fed conditions. In such studies, each subject acts as his or her own control such that the impact of intersubject variability is reduced.
These studies are important as the results are likely to contribute to the wording on the label as to when drugs should be administered relative to food in order to increase, or indeed decrease, absorption. Please see the table below as an example of potential wording and grouping.
|
|
Period 1 |
Period 2 |
|
Group A |
Take dose after consuming standardised test meal |
Take dose while fasted |
|
Group B |
Take dose while fasted |
Take dose after consuming standardised test meal |
To reduce the costs of drug development and time to market, the designs above have more recently been combined into single flexible protocols that include adequate dosing intervals to allow for the review of safety and/or PK data prior to study progression.
Although multipart protocols can provide efficiencies, the decision to combine components should be based primarily on whether the scientific objectives, progression criteria, and safety review process can be defined clearly.
These studies form an extension of the in vitro and in vivo preclinical studies in which the routes of metabolism are identified. Correlation of the results allows the identification of enzymes which may be subject to inhibition or induction by the test drug, or which are responsible for its metabolism.
The treatments selected for drug–drug interaction studies should reflect the metabolic or transport pathway under investigation, the likely clinical setting and current regulatory guidance. Studies may assess the investigational treatment alongside a recognised inhibitor or inducer of the relevant pathway.
The route of administration should be based upon that planned for the marketed compound, assuming this is known, and studies should use doses and intervals that provide an interpretable assessment of interaction potential, unless this is precluded for safety reasons.
There should be a particular emphasis on monitoring for adverse events (AEs) that occur at a greater frequency or severity during combination treatment than during treatment with either drug alone. In addition, there should be extensive PK sampling to allow for full characterization of the parent drug and important metabolites, if applicable, and any potential temporal relationship to AEs.
Studies to measure bioavailability and/or establish bioequivalence of a compound are important elements in support of regulatory submissions.
For orally administered compounds, bioavailability studies elucidate the process by which a drug is released from the oral dosage form and moves to the site of action within the body. Bioavailability data provide an estimate of the fraction of drug absorbed, as well as its subsequent distribution and elimination.
This can either be absolute bioavailability, the compound is compared to intravenous administration, as the reference, or relative bioavailability (the compound is compared to another formulation or non-intravenous route of administration).
In bioequivalence studies, the systemic exposure profile of a test compound is compared to that of a reference drug product. To be considered bioequivalent (or statistically ‘non-different’), the active drug ingredient or active moiety in the test compound must exhibit a rate and extent of absorption that is comparable to the reference drug product, according to strict statistical rules.
For many conventional bioequivalence assessments, the 90% confidence interval for the ratio of selected log-transformed exposure measures is compared with an acceptance range of 80% to 125%. The applicable measures and limits depend on the product and regulatory context, so this should not be treated as a universal rule.
Bioequivalence studies are performed if there is a change in dose form, structure, manufacturing process, or excipients to ensure the ‘new’ form is equivalent to the previous version. Bioequivalence studies are also performed when generic drugs are developed which contain the same active ingredients as the original formulation, which is no longer under patent protection.
Bioavailability and bioequivalence studies are routinely conducted in a small number of subjects in Phase 1 CRUs and reported according to strict regulations.
The absorption, distribution, metabolism and/or excretion (ADME) of a compound or its metabolites may be influenced by many factors including age, sex, genetics or social factors, such as smoking status. Phase 1 studies are not only conducted at the initial stages of drug development in humans; whilst such studies are undoubtedly more common, additional Phase 1 studies are often conducted later in the development of a compound, alongside large Phase 3 studies in the target population/indication.
The aim of these studies is to obtain data to support the wording for the label and may be the result of requests from regulatory authorities to further substantiate claims or address perceived weaknesses in a drug submission.
Phase 1 studies have historically been less common in paediatric populations. Paediatric development requires population-specific scientific, ethical, and regulatory planning, with requirements varying by jurisdiction and development programme.
For therapeutic areas such as oncology, Phase 1 studies are an important step in the evaluation of novel compounds. Such studies must include a potentially active treatment and must not be performed solely to evaluate toxicity.
Where paediatric Phase 1 oncology trials are conducted, the starting dose, escalation increments and use of adult data should be determined from the available evidence and current regulatory guidance rather than assumed from a fixed convention. The design should limit unnecessary exposure while collecting sufficient evidence to support a development programme.
From a cost perspective, the design of a Phase 1 study can be positively influenced with proper planning, appropriate design, and standardisation of CRF design and statistical programming.
Where a protocol contains multiple parts, it should specify which data must be received before each part opens, who will make the decision, and which criteria permit progression. Apart from combination studies, statistical design can support Phase I studies or other clinical pharmacology studies in other ways.
For example, the use of incomplete block designs (where each subject receives a subset of the treatments under study) can enable more treatments to be tested within a cross-over study than might otherwise be thought practical. This may arise in situations where different formulations of the same compound are to be evaluated.
Factorial designs can also be used to help explore several factors simultaneously in one study (e.g. for ascertaining the optimal dose levels for a combination product).
For compounds where the expected variability of the pharmacokinetic parameters is high, resulting in a large sample size, the use of interim analysis or sequential designs can offer the opportunity to complete the study more quickly with fewer subjects, if the primary objective has been reached or the study looks as if it will fail to achieve it.
Any interim or sequential approach should be prespecified and assessed for its effect on estimation and decision-making.
Phase 1 trials usually involve relatively small samples, so they provide limited information about uncommon adverse events or differences between participant subgroups. Early assumptions about the relationship between dose, exposure, toxicity and pharmacological activity may also be uncertain.
Dose-escalation designs can expose some participants to doses that are too low to produce the intended biological effect or high enough to cause unacceptable toxicity. Statistical methods can inform these decisions, but they cannot remove the underlying uncertainty.
Model-assisted and model-based designs also depend on timely data, appropriate statistical programming and consistent implementation. Delayed observations, incomplete toxicity assessment or departures from the planned decision rules can affect how the design performs in practice.
In the UK, Phase 1 clinical trials of investigational medicinal products are subject to regulatory and ethics review. Sponsors should also consider the applicable requirements for trial registration, research transparency and participant protection.
Healthy-volunteer studies should include controls intended to prevent participants from enrolling in trials too frequently. As requirements and submission processes can change, study teams should refer to current Health Research Authority and Medicines and Healthcare products Regulatory Agency guidance during protocol and submission planning.
Phase 1 clinical trial design should reflect the treatment, study population, and evidence needed to support the next development decision. Whether a study uses SAD, MAD, or a more adaptive dose-escalation method, clear progression criteria and timely safety review are essential. Careful planning can help protect participants while ensuring the study generates useful evidence for later development.
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