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Clinical trials are crucial in medical research, helping to determine the safety and efficacy of new treatments. The designs of these trials vary based on their objectives and the phase of the trial. In this note, we’ll explore some of the most popular and impactful clinical trial designs, from the classic randomized controlled trials to innovative adaptive designs.

Clinical Trial Phases

Let’s start with a quick review of trial phases, looking at their specific objectives and characteristics. These phases are designed to answer different research questions and ensure the safety and efficacy of new treatments before they become widely available.

  1. Phase 0:

    • Objective: To assess the toxicity and pharmacokinetics (PK) of a drug following a small subtherapeutic dose, usually administered for a short amount of time (no more than a week).
    • Participants: Very small number, typically around 10-15.
    • Purpose: To decide if it is safe for a drug to move on to testing at therapeutic doses. First introduced by the FDA in 2006, Phase 0 trials are a fairly new addition to the scheme. They usually follow fairly straightforward designs, with a single pre-defined dose and administration schedule. As such, we will not consider this phase in our further discussions.
  2. Phase I:

    • Objective: To determine a drug’s safety profile, including the safe dosage range, and to identify side effects.
    • Participants: Small group of 20-100 volunteers, usually healthy participants but sometimes includes patients.
    • Purpose: The main focus is on a drug’s safety and side effects at different doses and how it is metabolized and excreted. The key output of a Phase I trial is the Recommended Phase 2 Dose (RP2D).
  3. Phase II:

    • Objective: To assess the drug’s efficacy and further evaluate its safety.
    • Participants: Larger group, typically 100-300 patients who have the condition the drug is meant to treat.
    • Purpose: This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition.
  4. Phase III:

    • Objective: To confirm the drug’s effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug to be used safely.
    • Participants: Large number of patients, ranging from several hundred to several thousand.
    • Purpose: These trials are pivotal for the approval process and often involve a randomized and blind testing in several hundred to several thousand patients.
  5. Phase IV:

    • Objective: To monitor the long-term effectiveness and impact of a treatment after it has been approved and is on the market.
    • Participants: Varies widely depending on the drug’s widespread use and the specific aspects being studied.
    • Purpose: Phase IV trials can result in a drug being withdrawn from the market or restrictions on its use being placed based on the findings.

Phase I Designs

Phase I clinical trials are primarily designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often the first step in testing new drugs in humans, and they use several common designs to meet their objectives effectively. Here are some of the most frequently used Phase I trial designs:

  1. Single Ascending Dose (SAD): Participants receive a single dose of the drug, with each new group receiving a higher dose. Used to assess the safety profile and identify any side effects at increasing dose levels. Often, not a very efficient approach, both in terms of time and the number of subjects required.

  2. Multiple Ascending Dose (MAD): Participants receive multiple low doses of the drug, with the dose being escalated in subsequent groups over a period. Used to study the pharmacokinetics and pharmacodynamics when the drug is administered multiple times and to identify any cumulative toxicity.

  3. 3+3 Dose-Escalation: This design involves starting with a cohort of three patients at a low dose and observing them for toxicity. If no significant toxicities are observed in all three patients, the dose is escalated to a higher level in a new cohort. If one of the three patients experiences toxicity, three additional patients are treated at the same dose. If two or more patients (including the additional set of 3) experience significant toxicity, the dose escalation is halted, and this dose may be considered above tolerable levels. This method is especially prevalent in oncology trials, where establishing the Maximum Tolerated Dose (MTD) of a new cancer therapy is crucial.

  4. Accelerated Titration: Similar to the 3+3 design but includes fewer dose levels and allows for faster dose escalation. This is meant to ensure that fewer patients are treated at subtherapeutic dose levels, and the valuable results are determined faster. This is typically done by doubling doses until grade 2 toxicity (moderate toxicity) is observed. Early phases of the trial often involve single-patient cohorts, allowing for dose escalation without waiting for responses from multiple patients. Once any Dose-Limiting Toxicity (DLT) is observed, the design switches to a more traditional approach with larger patient cohorts and smaller dose increments (often ~40% increases). Special provisions are typically included to reduce patient risk, such as de-escalation options if the initial dose escalations prove too aggressive. Generally used to speed up the identification of the MTD, particularly useful when there is prior knowledge suggesting high toxicity of the compound.

  5. Continuous Reassessment Method (CRM): Another approach for efficient determination of MTD in oncology trials. CRM relies on statistical models to estimate the relationship between dose levels and the probability of DLT, and continuously updates the probability based on the collected data as the trial progresses. CRM typically requires fewer subjects, can adapt to new data in real-time, making it highly responsive to patient outcomes. However, the effectiveness of CRM is heavily reliant on the fitness of the model and the accuracy of the initial dose-toxicity estimates. Poor estimates can lead to an inefficient dose exploration. Used to more accurately estimate the MTD with fewer patients than the traditional 3+3 design.

  6. Adaptive Design: Allows for modifications to the trial procedures (like dosages, cohort sizes, patient selection criteria, etc.) based on interim results. This design can incorporate various statistical strategies (often relying on Bayesian methods), to adaptively find the optimal dose. To ensure the integrity of a trial, all potential changes to the trial must be planned a priori and specified in the protocol before the trial begins. This pre-planning helps to prevent biases that often occur with post hoc decisions. The interim analyses are conducted at predefined points in the trial, and help to inform decisions about trial modifications. Adaptive designs often feature combined phases, such as Phase I/II or Phase II/III, to reduce the downtime and gain in efficiency. On the downside, the exhaustive planning and analysis of adaptive trials tends to make them more complex and costly than traditional trials, and requires sophisticated statistical expertise. Used to make the trial more flexible and efficient by using emerging data to inform ongoing decisions.

Phase II Designs

Phase II clinical trials are designed to evaluate the efficacy of a drug or treatment and continue the safety assessment from Phase I. These trials often involve patients who have the disease or condition that the drug is intended to treat. Various designs can be utilized in Phase II to achieve the necessary balance between understanding the treatment effect and ensuring patient safety. Here are some of the most popular Phase II trial designs:

  1. Single-Arm Trials: All participants receive the same treatment. Often used when historical control data are available or when it’s difficult to recruit participants for a control group due to the severity or rarity of the condition. Advantages include the simplicity and faster setup; disadvantages include the lack of a control group, which can make it difficult to discern whether observed effects are due to the treatment or other factors.

  2. Randomized Controlled Trials (RCTs): Participants are randomly assigned to either the treatment group or a control group, which may receive a placebo or a standard treatment. Used to provide a clear comparison between the new treatment and an existing standard or placebo. Advantages include the higher scientific rigor and reduced bias; disadvantages include the requirement for blinding, which makes them more complex and costly to administer.

  3. Crossover Trials: Each participant receives both the treatment and placebo at different times, separated by a washout period. Used to allow each participant to serve as their own control, improving the efficiency of the trial by reducing the variability between subjects. This design encourages the effective use of patient data and reduced sample size requirements. However, it is not suitable for treatments with long-lasting effects or diseases with variable natural histories.

  4. Factorial Design: Participants are randomized into a trial that tests more than one intervention simultaneously. Used to study the effects of each treatment, as well as any interaction between them. Allow efficient assessment of multiple treatments, but the has high complexity in analysis and potential for higher participant burden.

  5. Adaptive Design: Same as in Phase I, the trial design allows for modifications based on interim data. These changes might involve stopping for futility, adjusting dose levels, or reallocating patients to different arms.

Phase III Designs

The pivotal phase III trials are usually large-scale, involving several hundred to several thousand participants, and are often the final step before a drug seeks regulatory approval for market entry. Many designs used in earlier phases are also used in phase III, including RCTs, Crossover, Factorial, and Adaptive designs. Some of the more phase III-specific designs include:

  1. Parallel Group Design: Participants are randomly divided into two or more groups, each receiving a different treatment or the control (which could be a placebo or a standard treatment). Proper group randomization plays an especially important role in reducing bias and confounding variables. Participants remain in their assigned groups throughout the study. Importantly, each group receives the designated treatments during the same time period. This design is used to evaluate the effect of the treatment over time compared with a control or another treatment. Allows for simplicity in understanding and analyzing outcomes, but usually requires a larger sample size to ensure power to detect differences.

  2. Equivalence Trials (or Non-inferiority): These trials are designed to show that the new treatment is not worse than the comparator by more than a pre-specified margin (non-inferiority) or that it is statistically equivalent (equivalence). Often used when the new treatment is expected to have similar efficacy but other benefits (e.g., fewer side effects, lower cost). They are suitable for niche situations where surpassing the standard treatment in terms of efficacy is unlikely or unnecessary. Usually involves complex statistical analysis and interpretation.

Phase IV Designs

Phase IV post-marketing surveillance trials are conducted after a drug has been approved for use by regulatory authorities and marketed to the public. These studies are designed to monitor the drug’s performance in real-world settings, assess long-term effects, and detect any rare or long-term adverse events that might not have been apparent in the earlier phases of clinical trials. Here’s an overview of some common Phase IV trial designs:

  1. Observational Studies: In these studies, patients are observed under normal clinical practice conditions without any experimental intervention by the researchers. Typically involving large populations, observational studies are used to gather data on how a drug performs in a diverse patient population over a longer period, helping to assess effectiveness and safety in a real-world setting.

  2. Registry Studies: These studies collect data about patients who have a particular disease or condition, or who are receiving a particular treatment. Registry studies aim to understand the long-term impact of a treatment and to evaluate factors influencing the effectiveness and safety in various subgroups by tracking outcomes and identifying patterns over time.

  3. Case-Control Studies: These retrospective studies compare patients who have experienced a specific outcome (such as an adverse effect) to those who have not, to identify potential causes or contributing factors. They are particularly useful for analyzing rare adverse effects or outcomes that may be related to the drug usage.

  4. Cohort Studies: A cohort of individuals is followed prospectively, and data on various outcomes are collected. Outcomes of cohorts using the drug are compared to those not using the drug over time, studying multiple outcomes, including efficacy and adverse reactions, and understanding how effectively the drug works in different population segments.

  5. Cross-Sectional Studies: These studies collect data at a single point in time from a population using the drug. This snapshot helps to assess the current status and health outcomes of the population, quickly gathering data on how a drug is being used and its effects in the general population.

  6. Pharmacovigilance Studies: These studies involve continuous monitoring for adverse events in drugs that are already on the market, often as a regulatory requirement. They involve collecting and analyzing reports of adverse effects to ensure ongoing evaluation of the drug’s risk-benefit balance and to detect any issues that occur when the drug is used widely.

Wrap up

Clinical trials play an indispensable role in the development and approval of new medical treatments, progressing through carefully structured phases that focus on safety, efficacy, and long-term effects. From the initial explorations in Phase 0 to the rigorous testing of Phase III, and the ongoing surveillance of Phase IV, each phase is designed to address specific research questions using various trial designs tailored to achieve these goals. As we’ve explored, the selection of trial designs is critical in maximizing the effectiveness and safety of new treatments. Understanding these designs not only aids in the proper execution of trials but also ensures that the results are reliable and meaningful, ultimately leading to better and safer healthcare solutions for patients worldwide.