Most errors and technical failures in clinical trials arise due to the improper selection of clinical trial designs. The clinical trial design selection will also have a strong impact on the cost and time associated with clinical trials. The expected outcomes shall be thoughtfully addressed while designing a clinical trial and the selection of clinical trial designs varies with the phase of the trial, stage of drug development, expected outcome, patient population factors, disease type, and many other such factors.
In any clinical research, the aim of a researcher is to design a study, which would be able to derive a valid and meaningful scientific conclusion using appropriate statistical methods that can be translated to the “real world” setting.
Clinical trial designs
The clinical study design is the formulation of experiments, trials, and studies (observational) in medical, clinical, and other types of research involving human beings.
The goal of any clinical study is to assess the safety, efficacy, and/or the mechanism of action of an Investigational Medicinal Product (IMP) or procedure, or new drug or device that is in development, but potentially not yet approved by a health authority (for example FDA, TGA, EMA, PMDA, etc).
Choosing the right design is essential for any clinical trial and before choosing a study design, one must establish the aims and objectives of the study, and choose an appropriate target population that is most representative of the population being studied. This avoids unnecessary expenses, time delays, and improve the chances of approvals.
There are several types of clinical trial designs used in clinical trial industry as below
- Treatment studies
- Randomized controlled trial
- Blind trial
- Non-blind trial
- Adaptive clinical trial
- Nonrandomized trial (quasi-experiment)
- Randomized controlled trial
- Observational studies
- Case report
- Case series
- Population study
- Cohort study
- Prospective cohort
- Retrospective cohort
- Time-series study
- Case-control study
- Nested case-control study
- Cross-sectional study
- Community survey (a type of cross-sectional study)
- Ecological study.
- Cohort study
In this article, we will be discussing some of the most commonly used trial designs based on the phase of the study.
Phases of clinical trials
Clinical drug development is often described as consisting of five phases ( (Phase 0 to IV). Clinical trials happen in these phases during which different questions are answered and each phase builds on the results of previous phases.
|Phase 0||Pharmacokinetics, particularly oral bioavailability and half-life of the drug||Small, subtherapeutic|
|Phase I||Dose-ranging on healthy volunteers for safety||Often subtherapeutic, but with ascending doses|
|Phase II||Testing of drug on participants to assess efficacy and side effects||Therapeutic dose|
|Phase III||Testing of drug on participants to assess efficacy, effectiveness and safety||Therapeutic dose|
|Phase IV||Post marketing surveillance in public||Therapeutic dose|
The phase of the study and clinical trial designs
Drug development is ideally a strategical, step-wise procedure in which information from executed early studies is used to support and plan later larger, more definitive studies. To develop new drugs efficiently, it is essential to identify characteristics of the investigational medicine or treatment or device in the early stages of development and to plan an appropriate development based on this profile.
The initial phase of trials provides an early evaluation of short-term safety and tolerability and may provide pharmacodynamic and pharmacokinetic information required to choose a suitable dosage range and administration schedule for initial exploratory therapeutic trials.
Later confirmatory studies are generally larger and longer and include a more diverse patient population.
Now let’s discuss each phase of trial with some suitable trial designs
Phase 0 trials
Phase 0 is a designation for optional exploratory trials conducted in accordance with the United States Food and Drug Administration’s (USFDA).
- Phase 0 studies generally use only a few small doses of a new drug in a few people.
- These studies are also known as human micro-dosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies.
- Phase 0 studies give no data on safety or efficacy, as the dose is too low to cause any therapeutic effect.
Phase 0 trials are commonly used for
- Determination of drug pharmacokinetics.
- Determination of pharmacologically significant doses of the drug.
- Determination of drugs mechanism of action.
- They help in making go/no-go decisions on relevant human models instead of relying completely on animal data.
An example of these studies include the studies that test whether the drug reaches the tumor, in case of cancer clinical trials, how the drug acts in the human body, and how cancer cells in the human body respond to the drug
Distinctive features of phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (like 10 to 15) to gather preliminary data.
The ideal requirements for evaluation of a new drug under phase 0 investigation can be
- Pharmacodynamic activity of the drug.
- The broad therapeutic window of a drug.
- The selected drug candidate should be non-toxic at a dose level and should be exposed for a short duration, that is, about a week on a limited number of volunteers (like 10 to 15).
Phase I trials
The primary aims of phase I clinical trials are to determine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) of a compound, and early measurement of drug activity.
Designs used in Phase I trials
- Single ascending dose (Phase Ia): These are the studies in which a small group of subjects receives a single dose of the compound in a clinical setting, usually a Clinical Research Unit (CR0U). Close safety monitoring and usually PK assessments are performed for a predetermined time. To minimize the effect of bias, subjects are usually randomly assigned to treatment using computer-generated randomization codes.
- Multiple ascending doses (Phase Ib): These studies are conducted to elucidate the PK and PD of multiple doses of the compound.
Phase II trials
Phase II trials are usually considered to start with the initiation of studies in which the primary objective is to explore therapeutic efficacy in patients. An important goal for this phase is to determine the dose and regimen for phase III trials.
Initial therapeutic exploratory studies may use a variety of clinical study designs, including concurrent controls and comparisons with baseline status. Subsequent trials are usually randomized and concurrently controlled to evaluate the efficacy of the drug and its safety for a particular therapeutic indication.
- Early studies in this phase usually utilize the dose-escalation designs to give an early estimate of dose-response and later studies may confirm the dose-response relationship for the indication in question by using recognized parallel dose-response designs.
- Confirmatory dose-response studies may be conducted in phase II or left for phase III. Doses used in phase II are usually but not always less than the highest doses used in phase I.
Phase II studies are sometimes divided into Phase IIa and Phase IIb. However, there is no formal definition for these two sub-categories, but
- Phase IIa studies are usually pilot studies designed to demonstrate clinical efficacy or biological activity (also known as proof of concept’ studies)
- Phase IIb studies determine the optimal dose at which the drug shows biological activity with minimal side-effects (definite dose-finding studies).
Trial designs in Phase II studies
Some phase II trials are designed as case series, demonstrating a drug’s safety and activity in a selected group of participants. Other phases II trials are designed as randomized controlled trials, where some patients receive the drug/device and others receive a placebo or the standard treatment. Randomized phase II trials generally have fewer patients than randomized phase III trials.
Adaptive trial designs
Adaptive clinical trial design has been Introduced as a way to reduce the costs of phase II testing by providing an earlier determination of futility and prediction of phase III success, reducing overall phase II and III trial participant sizes, and shortening overall drug development time.
Phase III trials
Phase III usually is considered, to begin with, the initiation of studies in which the primary objective is to demonstrate or confirm the therapeutic benefit of a treatment/drug/device, etc.
- Studies usually in phase III are designed to confirm the preliminary evidence accumulated in phase II that a drug is safe and effective for use in the intended indication and recipient population.
- These studies are intended to provide an adequate basis for obtaining regulatory and marketing approval.
- Studies in phase III may also further explore the dose-response relationship, or explore the drug’s use in wider populations, in different stages of the disease, or in combination with another drug.
- For drugs intended to be administered for long periods, trials involving extended exposure to the drug are ordinarily conducted in phase III, although they may be started in phase II.
- These studies carried out in phase III complete the information needed to support adequate instructions for use of the drug.
- This stage of drug assessment is conducted in a larger and often more diverse target population in order to demonstrate and/or confirm the efficacy and to identify and estimate the incidence of common adverse reactions.
Trial designs in Phase III studies
Comparative efficacy trials (referred to as “superiority” or “placebo-controlled trials”) that compare the intervention of interest with either standard therapy or placebo are common Phase III designs used.
Phase IV trials
Phase IV trials are conducted generally after the drug approval. Therapeutic use studies go beyond the prior demonstration of the drugís safety, efficacy, and dose definition. These studies are also called pharmacovigilance studies.
These studies are not considered necessary for approval but are often important for optimizing the drug’s use.
Commonly conducted studies include
- Additional drug-drug interaction,
- Dose-response or safety studies, and
- Studies designed to support use under the approved indication, e.g. mortality/morbidity studies, epidemiological studies.
These are designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials.
Trial designs in Phase IV studies
- Pharmacovigilance studies can include observational or intervention studies. Common designs used in this phase include case-control studies, cohort studies (cohort event monitoring), and spontaneous (passive) reporting schemes.
- In some circumstances, RCTs might also be possible.
Bioavailability and bioequivalence studies
These are 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 may 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 IV administration, assumed to be 100% bioavailable) or relative bioavailability such as the compound is compared to another formulation or non-intravenous route of administration.
- 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 I.
Trial designs in bioavailability and bioequivalence studies studies
- The common design in these studies include randomized, two-period, two-sequence, single dose cross-over design, parallel design and replicate designs.
- Pharmacokinetics and Pharmacodynamics of the study designs make an important role.
RWE – Real-World Evidence (RWE)
The use of Real World Evidence (RWE) comes into play when clinical trials cannot really account for the entire patient population of a particular disease. Real-world evidence (RWE) in medicine is the evidence obtained from real-world data (RWD) and is the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of Real World Data – RWD.
RWE is generated by analysing data which is stored in
- Electronic Health Records (EHR),
- Medical claims,
- Billing activities databases,
- Patient-generated data including in home-use settings,
- Data gathered from other sources that can inform on health status, such as mobile devices, etc.
These RWE data are derived from retrospective or prospective observational studies and observational registries.
RWE provides answers to the problems and also analyze the effects of drugs over a longer period of time such as,
- The patients suffering from comorbidities or
- Belonging to a distant geographic region or
- Age limit who did not participate in any clinical trial may not respond to the treatment in question as expected.
Submissions using RWD/RWE
The submissions can be in different forms such as a
- New protocols submitted to an existing IND,
- A final study report submitted to an NDA or BLA supplement, or
- A meeting package that discusses the use of RWE.
RWE can be used as part of the regulatory submissions in the following cases
- To provide evidence in support of the effectiveness or safety of new product approval,
- To provide evidence in support of labeling changes for an approved product,
- To be used as part of a postmarketing requirement to support a regulatory decision.
Study design using RWE
Creating a study protocol is crucial in determining the success of the research effort as it is the fundamental document that drives the study, providing pre-defined, standardized procedural methods to effectively communicate plans for study conduct and implementation to all stakeholders and involved parties.
Real-world evidence studies differ from clinical trials in nature as they are devoid of any form of intervention. As patient data are gathered and collected during routine clinical care, specific considerations have to be accounted for when developing non-interventional study protocols.
A real-world study protocol addresses the same principal elements as a clinical trial protocol, however, there are fundamental differences based on the nature and design of non-interventional studies.
Trial designs using RWD represents a logical, much‐needed step in the development and future‐proofing of the regulatory approval system, but will require regulators, pharmaceutical companies, and RWE experts to collaborate early on to unlock the scientific potential of RWD through innovative study designs generating solid and dependable RWE, as well as to address privacy concerns that often accompany linking primary and secondary data.
Observational studies for RWE is well accepted for satisfying post-approval safety monitoring requirements, it has not commonly been used to demonstrate drug effectiveness for regulatory purposes.
Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug applications (IND) or IDE application outside of a clinical trial, by people with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress.
Various names for Expanded access are
- Early access,
- Special access, or managed access program,
- Compassionate use,
- Compassionate access,
- Named-patient access,
- Temporary authorization for use,
- Cohort access, and
- Pre-approval access.
Objectives of Expanded Access studies
- The primary object of EA studies is to provide patients early access to potentially life-improving or saving treatments prior to regulatory approval.
- EA studies may serve as a way to provide patients continued access to treatment following a pivotal trial.
- Provide pharmaceutical companies a way to collect additional safety data and expand the safety profile of the therapy.
For conducting the EA studies, the regulatory agencies need to agree that the risks and possible benefits of the drug or device are understood well enough to determine if putting the person at risk has sufficient potential benefit.
The limitations of EAP studies are the data collection is often limited to safety data and EA studies do not have a research rationale.
Most of the countries like the USA, UK, Japan, China Canada have developed a regulatory framework for regulating access to unapproved medicines.
Study designs for Expanded Access studies
There are several logistical questions that sponsors must address to ensure the proper and smooth administration of the Expanded Access study program.
- Setting exclusive inclusion/exclusion criteria for RCTs and EAPs,
- Setting financial expectations,
- Meeting operational and technical needs, and
- Meeting regulatory demands.
While choosing a study design, one must identify the aims and objectives of the study, and choose an appropriate target population that is most representative of the population being studied for efficiency. For this to happen requires a well‐designed clinical research study.
Cohort Expanded Access
Cohort (or ‘Group’) Expanded Access (also known as Expanded Access Programs)
In the process of developing new investigational medicine for a serious or life-threatening condition, the clinical information about that investigational medicine is used to identify a population of patients for whom expanded access may be appropriate. An expanded access program may be established for a cohort, or group, of patients who meet specific eligibility criteria.
Individual Patient Expanded Access
In the absence of a Cohort Expanded Access Program and in rare cases, Individual patient expanded access is utilized provided this study design is acceptable by the regulatory authorities. This study is usually managed by the patient’s physician.
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