Clinical trial designs and study designs

Most errors and technical failures in clinical trials arise due to the improper selection of clinical trial designs. The clinical trial design selection will have a strong impact on the cost and time associated with clinical trials. The expected outcomes shall be thought out and carefully addressed while designing a clinical trial. 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.

Clinical trial designs and study designs

In any clinical research, a researcher aims to design a study to derive a valid and meaningful scientific conclusion using appropriate statistical methods which can translate 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 select an appropriate target population that is most representative of the real-world population. These avoid unnecessary expenses, and time delays and improve the chances of approvals.

There are several types of clinical trial designs below.

  • Treatment studies
    • Randomized controlled trial
      • Blind trial
      • Non-blind trial
    • Adaptive clinical trial
    • Nonrandomized trial (quasi-experiment)
  • Observational studies
    • Descriptive
      • Case report
      • Case series
      • Population study
    • Analytical
      • 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.

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 often consists of five phases ( (Phase 0 to IV). Clinical trials happen in these phases to answer different questions and each phase builds on the results of previous phases.

PhaseStudy goalDose
Phase 0Pharmacokinetics, particularly oral bioavailability and half-life of the drugSmall, subtherapeutic
Phase IDose-ranging on healthy volunteers for safetyOften subtherapeutic, but with ascending doses
Phase IITesting the drug on participants to assess the efficacy and side effectsTherapeutic dose
Phase IIITesting the drug on participants to assess efficacy, effectiveness, and safetyTherapeutic dose
Phase IVPostmarketing surveillance in publicTherapeutic dose

The phase of the study and clinical trial designs

Drug development is ideally a strategical, step-wise procedure in which researchers use information from previous studies 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 the trial with some suitable trial designs.

Phase 0 trials and clinical trial designs

Phase 0 is a designation for optional exploratory trials to conduct in accordance with the United States Food and Drug Administration’s (USFDA)

  • Researchers conduct these studies, also known as human micro-dosing studies, to expedite the development of promising drugs or imaging agents. The studies aim to determine at an early stage if the drug or agent behaves in human subjects as expected based on preclinical studies.
  • Phase 0 studies generally use only a few small doses of a new drug in a few people.
  • These studies give no data on safety or efficacy, as the dose is too low to cause any therapeutic effect.

Researchers use Phase 0 trials to  

  • Determine drug pharmacokinetics.
  • Pharmacologically significant doses of the drug.
  • Understand the drug 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 includes the studies that test whether the drug reaches the tumor in case of cancer clinical trials. Another example is studying how the drug acts in the human body. Additionally, researchers examine 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 the evaluation of a new drug under phase 0 investigation can be

  • Pharmacodynamic activity of the drug.
  • The broad therapeutic window of a drug.
  • The drug candidate should be non-toxic at a dose level and should expose for a short duration, that is, about a week, on a limited number of volunteers (like 10 to 15).

Phase I trials and clinical trial designs

The primary aims of phase I clinical trials are to determine the safety, tolerability, pharmacokinetics (PK), and 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). Perform close safety monitoring and usually PK assessments for a predetermined time. Subjects are usually randomly assigned to treatment using computer-generated randomization codes to minimize the effect of bias.
  • Multiple ascending doses (Phase Ib): These studies elucidate the PK and PD of multiple doses of the compound.

Phase II trials and clinical trial designs

Phase II trials usually 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 dose-escalation designs to provide an early estimate of dose response. Later studies may confirm the dose-response relationship for the indication in question by employing recognized parallel dose-response designs.
  • Researchers may perform confirmatory dose-response studies in phase II or leave for phase III.
  • Doses in phase II are usually but not always less than the highest doses used in phase I.

Phase II studies sometimes consist of 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

Researchers can design Phase II trials either as case series, demonstrating drug safety and activity in a selected group of participants, or as randomized controlled trials. In the latter design, researchers administer the drug/device to some patients while assigning a placebo or the standard treatment to others. Randomized phase II trials generally have fewer patients than randomized phase III trials.

Adaptive trial designs

The adaptive clinical trial design is a new design that helps 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.

Click here for more details about the adaptive trial designs.

Phase III trials and clinical trial designs

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 intend 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 wide populations, in different stages of the disease, or combined with another drug.
  • For drugs for long-period administration, trials involving extended exposure to the drug are ordinarily conducted in phase III, although researchers may start in phase II.
  • These studies carried out in phase III complete the information needed to support adequate instructions for the use of the drug.
  • In this stage of drug assessment, a larger and often more diverse target population is involved to demonstrate and/or confirm efficacy. Additionally, researchers aim 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.

Phase IV trials and clinical trial designs

Phase IV trials are conducted generally after the drug approval. Therapeutic use studies go beyond the prior demonstration of drug 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 studies help to detect any rare or long-term adverse effects over a much larger patient population and longer periods than was possible during the Phase I-III clinical trials.

Clinical trial designs in Phase IV studies

  • Pharmacovigilance studies can include observational or intervention studies. Common designs in these phases 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 the bioavailability and/or establish the bioequivalence of a compound which are important elements in support of regulatory submissions.

  • For orally administered compounds, bioavailability studies elucidate the drug release process from the oral dosage form and move to the site of action within the body.
  • Bioavailability data may provide an estimate of the fraction of the drug absorbed, as well as its subsequent distribution and elimination.
  • This can be either absolute bioavailability, comparing the compound to IV administration (assumed to be 100% bioavailable), or relative bioavailability, comparing the compound to another formulation or non-intravenous route of administration.
  • Researchers also perform bioequivalence studies for generic drugs which contain the same active ingredients as the original formulation, which is no longer under patent protection.
  • Bioavailability and bioequivalence studies usually have a small number of subjects in phase I.

Clinical trial designs in bioavailability and bioequivalence studies studies

  • The common design in these studies includes 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 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.

Data analysis gives the stored RWE in 

  • Electronic Health Records (EHR),
  • Medical claims,
  • Billing activities databases, 
  • Registries, 
  • Patient-generated data including in-home-use settings, 
  • Data is gathered from other sources that can inform on health status, such as mobile devices, etc. 

Retrospective or prospective observational studies and observational registries derive the RWE data.

RWE provides answers to the problems and also analyzes 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 

  • Submit new protocols to an existing IND, 
  • Submit a final study report to an NDA or BLA supplement, or 
  • A meeting package that discusses the use of RWE.

Sponsors can include RWE as part of the regulatory submissions in the following cases

  • To provide evidence in support of the effectiveness or safety of new product approval,
  • 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.

Clinical study designs 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 represent 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.

Expanded access

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, 
  • Named-patient access,
  • Compassionate 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 before regulatory approval.
  • EA studies may serve as a way to provide patients with continued access to treatment following a pivotal trial.
  • Provide pharmaceutical companies with 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. 

Clinical 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,
  • Meeting operational and technical needs,
  • Setting financial expectations, 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 represents the real-world population 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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