Understanding the different clinical trial phases

Introduction
Chapter 1
Preclinical research
Chapter 2
Phase 1: First-in-human trials
Chapter 3
Phase 2: Efficacy and dose-finding
Chapter 4
Phase 3: Confirmation of efficacy and adverse effects profile
Chapter 5
Phase 4: Post-marketing surveillance
Chapter 6
Different clinical trial phases for medical devices
Conclusion

Introduction

Medical breakthroughs like vaccines, cancer therapies, and innovative treatments for chronic diseases have transformed healthcare, saving countless lives and improving the quality of life for millions. For instance, the rapid vaccine development and deployment for COVID-19 was pivotal in mitigating the global pandemic, demonstrating the profound impact that well-conducted clinical trials can have on public health. However, extensive research comprising multiple clinical trial phases is mandatory before these interventions can be released into the consumer marketplace or used in clinical practice.

Each clinical trial phase is designed to answer specific questions about novel therapies, such as their safety, optimal dosing, efficacy, and potential side effects. This guide will walk you through the intricacies of each phase to give you a clear understanding of the journey a new treatment undergoes—from the lab to the pharmacy shelf.

Clinical trial phases flowchart

Preclinical research is the foundational step in developing a new medical treatment. Before a new treatment can be tested in humans, it must undergo rigorous safety and efficacy assessments in other species. These assessments aim to identify any potential risks and ensure that the treatment is likely to be effective.

This phase involves laboratory studies and animal testing to assess the safety and efficacy of a potential therapy before it is tested in humans.

In vitro and in vivo studies

In vitro studies: These are laboratory experiments conducted in controlled environments outside of a living organism, such as in Petri dishes or test tubes. They allow researchers to study the biological and chemical properties of a drug.
In vivo studies: These involve testing the drug on living organisms, typically animals, to evaluate its effects in a complex biological system.

Regulatory requirements for preclinical testing across the globe

Preclinical research is heavily regulated to ensure that treatments entering clinical trials are as safe and effective as possible. Each region has its own regulatory requirements that must be met.

Australia

In Australia, preclinical research must comply with the Australian Code for the Care and Use of Animals for Scientific Purposes. This code establishes guidelines for the ethical treatment of animals in research, emphasizing the need to justify the use of animals with the potential benefits of the research. It mandates that procedures are designed to minimize pain and distress and requires researchers to ensure the welfare of animals through proper housing, care, and veterinary oversight. As part of the approval process for clinical trials, researchers must submit detailed preclinical data to the Therapeutic Goods Administration (TGA).

United States of America

In the United States, the Food and Drug Administration (FDA) requires comprehensive preclinical testing before human trials can commence. Researchers must submit an Investigational New Drug (IND) application, which includes all preclinical data, to the FDA for review. This application process ensures that the preclinical studies adhere to Good Laboratory Practice (GLP) regulations to guarantee the quality and integrity of the data. Compliance with GLP regulations is essential to prevent any discrepancies that could affect the outcomes of subsequent clinical trials.

Canada

Canada's regulatory framework, overseen by Health Canada, mandates rigorous preclinical testing similar to the FDA's requirements. When moving to the clinical stage, researchers are required to submit a Clinical Trial Application (CTA) that includes comprehensive preclinical data for review. This preclinical data must prove that the intervention has been thoroughly evaluated for safety and efficacy before it is tested in humans, while also adhering to ethical standards for the treatment of animals.

Europe

In Europe, the European Medicines Agency (EMA) oversees preclinical testing requirements. Researchers must submit an Investigational Medicinal Product Dossier (IMPD) that includes detailed preclinical data for approval before initiating clinical trials. Compliance with Directive 2010/63/EU, which sets forth guidelines for the ethical use of animals in research, is mandatory. This directive ensures that animal testing is conducted responsibly, focusing on minimizing harm and ensuring high animal welfare standards.

Phase 1 trials represent the initial step in the clinical testing of new drugs in humans. At this stage, trials typically involve a small group of healthy volunteers ranging from 12–100 participants. The primary objectives of these trials are to assess the safety, tolerability, pharmacokinetics (PK) (how the drug is absorbed, distributed, metabolized, and excreted), and pharmacodynamics (PD) (the drug's effects on the body) of the investigational drug. This phase is crucial because it lays the groundwork for subsequent phases of clinical development by showing that your drug doesn’t pose undue risks to patients at certain doses and provides insights into its behavior in the human body.

Safety and tolerability: The foremost goal is to determine if the drug is safe for human use. Researchers closely monitor participants for any adverse effects and work to establish the maximum tolerated dose (MTD). This process involves identifying any dose-limiting toxicities (DLTs) and ensuring that the drug’s side effects are manageable.
Pharmacokinetics (PK): Understanding the pharmacokinetics of a drug involves studying how it is absorbed, distributed, metabolized, and excreted by the body. PK studies help determine the appropriate dosage and frequency of administration by providing data on the drug’s half-life, peak plasma concentrations, and bioavailability.
Pharmacodynamics (PD): Pharmacodynamics focuses on the biochemical and physiological effects of the drug, including its mechanism of action. PD studies help you understand the relationship between the drug concentration and its therapeutic effects, which is critical for determining the optimal dosing regimen.

Healthy volunteers vs. patients

While healthy volunteers are commonly used in phase 1 trials, there are exceptions, particularly in oncology and other serious conditions where the drug's effects need to be evaluated directly in patients who have the disease. Oncology trials often begin with patients because the cytotoxic nature of many cancer therapies necessitates understanding their effects on cancer cells directly. These patients, often lacking effective treatment options, may benefit from early access to new therapies, and their participation can provide valuable data on the drug's therapeutic value.

Dose escalation designs

Dose escalation is the increase of the drug dose administered to participants to determine the MTD and observe the onset of any adverse effects. The common designs include:

Single Ascending Dose (SAD) Studies: Participants receive a single dose of the drug, and if no severe adverse effects are observed, you can gradually increase the dose in subsequent participant groups.
Multiple Ascending Dose (MAD) Studies: Participants receive multiple doses of the drug over a period while increasing dose levels in subsequent groups if no significant adverse effects are observed at lower doses.
Accelerated titration designs: These designs allow for rapid dose escalation until moderate toxicity is observed, followed by more cautious increases. This approach can reduce the time required to reach the MTD.

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Phase 2 clinical trials are a critical juncture in the development of new therapeutic interventions. This phase builds on the safety data gathered in phase 1, targeting specific patient groups to assess the efficacy of the drug, determine optimal dosing, and continue to monitor safety. These trials are more extensive and involve larger patient pools, reflecting the prevalence of the disease or condition being treated.

Target specific patient groups

Phase 2 trials are designed to target specific patient populations likely to benefit from your intervention. This helps you accurately assess the drug's efficacy and safety in a relevant context. So, you need to identify target patient groups based on the disease pathology, genetic markers, and previous clinical data. Then, to obtain clear and interpretable results, you can use inclusion and exclusion criteria to carefully define and ensure the selection of a homogeneous patient population.

For example, a phase 2 trial for a new diabetes medication might specifically include patients with type 2 diabetes who are not adequately controlled by existing treatments. Focusing on this group can help you better understand how the new medication performs in a real-world scenario where it is most needed.

Evaluate efficacy

Unlike phase 1, which focuses primarily on safety and tolerability, phase 2 trials aim to answer questions about whether the drug works and to what extent it works.

Efficacy endpoints are pre-defined and can include clinical outcomes such as symptom relief, disease progression, or biomarker changes. For instance, in a cancer trial, the primary endpoint might be tumor size reduction or progression-free survival. Secondary endpoints might include overall survival, quality of life, and additional biomarker assessments.

Determine optimal dosing

Another crucial aspect of phase 2 trials is determining the optimal dose of the drug for the target indication. This involves identifying a dose that provides the maximum therapeutic benefit with the minimum adverse effects. A high dose might increase efficacy but also the risk of adverse effects, while a low dose might be safer but less effective. Dose-ranging studies, which test multiple doses of the drug, are often conducted to find this balance.

Build the safety profile

Finding the balance between efficacy and safety is a delicate task. While phase 1 trials provide initial safety data, phase 2 trials continue to build the safety profile of the drug. As the patient population is larger and more representative of the real-world scenario, new safety information often emerges. This is where you analyze adverse events (AEs) and closely monitor and record their frequency, severity, and relationship to the drug.

As your patient pool expands, the likelihood of encountering rare or unexpected adverse events increases. Rigorous safety monitoring protocols are essential here to promptly identify and address any safety concerns. Data Safety Monitoring Boards (DSMBs) often oversee phase 2 trials to ensure patient safety and data integrity.

Sample size and statistical considerations

Phase 2 trials typically involve more patients, with sample sizes determined by the selected primary endpoint. The sample size must be sufficient to detect a statistically significant difference between the treatment and control groups. Statistical power, which is the probability of detecting a true effect, can help you determine your trial’s sample size.

Phase 3 trials typically involve large-scale, randomized controlled trials (RCTs) with participant numbers ranging from 300 to over 3,000, depending on various factors, including the rarity of the condition and the anticipated duration of treatment. The primary objectives of phase 3 trials are to establish whether the new treatment is more effective than current standard treatments, to continue monitoring for adverse effects, and to provide data that will support regulatory approval.

Establishing treatment efficacy

Efficacy is assessed through well-designed, large-scale RCTs, which are considered the gold standard for clinical research due to their ability to minimize bias and provide high-quality evidence.

Large-scale randomized controlled trials

RCTs in phase 3 typically enroll a large number of participants to ensure that your study has sufficient statistical power to detect meaningful differences between your new treatment and the control group. The sample size can vary widely, for example, for diseases that affect large populations, your trial might enroll thousands of participants. This ensures a robust dataset that can detect even slight differences in efficacy and safety.

However, for rare diseases, it might be challenging to enroll large numbers of participants. In such cases, trials may include several hundred participants, but the data must still be compelling and show a significant benefit for the new intervention.

Multi-country studies

To enhance the generalizability of the results, phase 3 trials often involve multiple sites across different countries. This approach ensures that the treatment is effective across various populations with different genetic backgrounds and lifestyle factors. This also facilitates acceptance by regulatory bodies in different regions, as the data will reflect a broader demographic.

A doctor takes a woman's blood pressure.

Monitoring adverse effects

An equally important objective of phase 3 trials is the comprehensive monitoring of adverse effects. It is important to collect data on adverse effects by conducting regular check-ups and reporting any side effects your participants experience. This data is then analyzed to identify any patterns or concerning trends. This ensures that your treatment is not only effective but also safe for widespread use. What’s more, the duration of the trial can vary depending on the treatment regimen:

Short-term treatments: For treatments that are administered over a short period, such as a 10-day medication course, monitoring might focus on immediate and short-term adverse effects.
Long-term treatments: For treatments intended for long-term use, monitoring extends over a longer period, sometimes spanning years, to identify any delayed adverse effects and ensure long-term safety.

Comparing with the standard of care

A critical aspect of phase 3 trials is the comparison between your novel treatment and the existing standard of care. This evaluation is crucial for determining whether your new treatment provides substantial improvements in efficacy, safety, or both.

Superiority trials are designed to demonstrate that your therapeutic intervention is superior to the current standard. They aim to show that your product achieves better outcomes, whether in terms of disease management, patient outcomes, or other critical metrics.

On the other hand, non-inferiority trials are conducted to establish that your new treatment is not inferior to the standard care. These trials are particularly relevant if your therapeutic intervention offers advantages such as reduced side effects, improved patient adherence, or lower costs, even if it does not surpass the standard treatment in all aspects.

Sub-phases: 3a and 3b Clinical Trials

Phase 3 trials can be further divided into sub-phases, often referred to as phase 3a and phase 3b, which serve different purposes in the drug development process.

Phase 3a trials

Phase 3a trials are conducted once the product developer believes they have enough data to target specific conditions and confirm the treatment is effective. These trials focus on gathering sufficient evidence to support initial regulatory product registration:

Safety and efficacy data generation: Confirm efficacy and monitor safety in a controlled setting.
Regulatory submission: Data from phase 3a trials is used to file for initial regulatory approval.

Phase 3b trials

Phase 3b trials may commence either during or after phase 3a trials. These trials often run in parallel with the initial regulatory review process:

Broader safety and efficacy data: Phase 3b trials aim to provide additional data on the treatment’s safety and efficacy, sometimes in different populations or for extended durations.
Post-marketing commitments: The data from phase 3b trials can also fulfill post-marketing requirements set by regulatory agencies.

In the lifecycle of a novel medical treatment, phase 4, or post-marketing surveillance, plays a pivotal role in maintaining public health by continuously monitoring your therapeutic treatment’s effectiveness and safety in real-world settings. These trials are conducted after a treatment receives regulatory approval for a specific indication.

Unlike earlier phases, which primarily focus on establishing efficacy and safety in controlled environments, phase 4 studies extend this assessment in approved indications to broader populations over extended periods. The primary goals include:

Monitoring effectiveness: Assessing how well your treatment works in routine clinical practice compared to controlled trials.
Safety surveillance: Identifying and evaluating rare or long-term adverse effects that may not have been evident during earlier phases of your trial.
Health outcomes research: Exploring your treatment's impact on patient outcomes and quality of life beyond the initial efficacy measures.

Tools and methods of surveillance

Observational studies and registries

Observational studies within phase 4 use real-world data from routine clinical practice. These studies are crucial for:

Real-world effectiveness: Providing insights into how your treatment performs in diverse patient populations and clinical settings.
Longitudinal analysis: Tracking patient outcomes over time to detect trends or patterns that may emerge post-approval.

Registries complement observational studies by systematically collecting data on patient demographics, treatment protocols, and outcomes. These databases are valuable for:

Long-term safety monitoring: Identifying rare adverse events that may occur in specific patient subgroups or with prolonged use.
Comparative effectiveness: Evaluating how your treatment compares to alternatives in terms of safety, efficacy, and patient satisfaction.
Determining the need for further RCTs: Addressing specific unanswered questions that arise post-approval, such as your treatment's efficacy and safety in populations not well-represented in earlier trials.

Adverse event reporting and regulatory obligations

Beyond generating data on safety and effectiveness, you have regulatory obligations during the post-marketing phase. These include adherence to pharmacovigilance requirements set forth by regulatory agencies, timely submission of periodic safety update reports, and maintaining communication channels for reporting adverse events.

Compliance ensures that all your stakeholders - patients, healthcare providers, and regulatory bodies - are informed and can proactively manage potential risks associated with the treatment. This continuous cycle of monitoring and feedback is essential for maintaining trust in the safety profile of your pharmaceutical innovation.

Medical devices encompass a wide array of products ranging from simple bandages to complex robotic surgical systems and implantable devices. Clinical trials for these devices are essential to validate their performance, safety, and usability. Unlike pharmaceuticals, medical devices often require iterative testing and refinement throughout their life-cycle, influencing the structure of their clinical trials.

1. Proof of concept and pilot studies

Proof of concept or feasibility studies and pilot trials represent the initial stages in the clinical evaluation of medical devices. These studies involve a small number of subjects to assess preliminary safety and functionality of a medical device. The focus is on refining device design and identifying potential issues early in development. Regulatory requirements during this phase emphasize proof of concept and initial safety assurances before advancing to larger-scale studies.

2. Pivotal trials

Pivotal trials establish definitive evidence of safety and efficacy required for regulatory approval. These trials are designed with stringent investigational plans and controlled conditions to generate statistically significant data. They involve larger patient populations and are essential for demonstrating clinical performance in comparison to existing standards of care. Regulatory agencies, such as the TGA in Australia or the FDA in the United States, set specific requirements for pivotal trials to ensure robust validation of device safety and effectiveness.

Considerations for drug-device combination products

Drug-device combination products integrate pharmaceutical agents with medical devices, presenting distinct challenges and regulatory considerations compared to standalone drugs or devices. These products are categorized based on their primary mode of action - whether the therapeutic effect primarily arises from the drug, the device, or a combination of both. It’s important to note that regulatory pathways and considerations vary accordingly, influencing the clinical trial phases and approval process and often requiring interdisciplinary collaboration.

To streamline this complex process, many medical innovators turn to Contract Research Organizations (CROs). CROs have expertise in managing the multifaceted requirements of drug-device combination trials, from study design to regulatory submissions. By leveraging the capabilities of CROs, companies can more effectively manage the intricacies of clinical development, navigate diverse regulatory landscapes, and move their innovative products towards approval and market entry.

Regulatory guidelines for Medical Device trials

Regulatory oversight for medical device trials differs significantly from that of pharmaceuticals. Authorities such as the TGA, FDA and the European Medicines Agency (EMA) enforce guidelines that emphasize safety, performance, and usability. These guidelines incorporate principles from ISO 14155:2020, which are internationally recognized standards for the conduct of clinical investigations of medical devices involving human subjects. These standards outline principles for study design, conduct, monitoring, and reporting. Adherence to ISO principles is crucial for maintaining consistency in clinical trial practices across different regions and ensuring the reliability and validity of study results submitted for regulatory approval.

Conclusion

From early discovery to post-market surveillance, clinical research is a rigorous and intricate process designed to ensure that new treatments are safe, effective, and beneficial for patients. Each clinical trial phase - preclinical research, phase 1, phase 2, phase 3, and phase 4 - plays a critical role in this journey. By thoroughly assessing safety, efficacy, optimal dosing, and potential side effects, data from these phases collectively build a robust body of evidence that supports the approval and successful implementation of your novel therapy in a real-world setting.

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