Phase 4 Clinical Trials Explained

Phase 4 Clinical Trials – Overview

Phase 4 clinical trials, also known as post-marketing surveillance (PMS) studies, are conducted primarily to monitor the safety and effectiveness of medicines under real-world conditions.

These trials improve scientific knowledge about the drug’s long-term effects, safety, and optimal dosing in a broader patient population.

While these studies can have economic implications, they are primarily designed to ensure ongoing safety and efficacy monitoring rather than facilitating product promotion.

Phase IV trials focus on safety monitoring, real-world effectiveness, and exploring new indications or dosage adjustments post-approval.

These trials aim to ensure drug safety and efficacy in diverse real-world settings beyond the controlled conditions of earlier trial phases. The ultimate goal of phase 4 clinical trials is to explore new indications, formulations, and patentable innovations.

Phase 4 Clinical Trials – Introduction

Phase 1, phase 2, and phase 3 of clinical trials are essential steps for developing and approving a drug.

For certain drugs, phase 4 clinical trials begin as soon as drug approval is obtained; however, for others, they start after marketing has started and continue throughout the drug’s commercial life.

Phase 4 clinical trials are undertaken to study a drug under the broader conditions of its approved indications and dosages, including variations in patient populations. These trials are intended to offer a better knowledge of the benefits of the drug for the patient and society.

Phase 4 trials provide further insights into the drug’s performance by gathering additional epidemiologic data and understanding its impact on routine clinical practice.

These studies can further evaluate the drug, resulting in greater utility and efficacy, enhanced quality of life, and improvements in the cost-benefit ratio.

Continuous observation and evaluation are required to improve the medical services and assess the therapeutic needs of the drug.

Based on real-world data, the drug is observed in its ordinary environment to refine the understanding of its indications and precautions for use. The drug can be judged in terms of its role in everyday circumstances.

The results of phase 4 trials may inform further phase 2 and 3 studies to explore expanded indications, dosage modifications, and new formulations.

Phase 4 Clinical Trials – Why are they Conducted?

Phase 4 trials are conducted once the drug is marketed and available to the general public. The objective is to check the drug’s performance in a real-life scenario while studying its benefits, long-term risks, and side effects.

If serious concerns about the drug are revealed during phase 4 trials, it may lead to a review and potentially a withdrawal from the market, making it unavailable for prescription.

Reasons for Conducting Phase 4 Clinical Trials

Let us check out the essential reasons for undertaking phase 4 clinical trials.

1. Scientific Knowledge

The drug’s knowledge is considered incomplete until the phase 3 trials, where untoward effects may have been missed. This is because the patients selected for these trials were carefully selected within protocols that were too rigorous for routine medical practice.

The information gathered during phase 3 trials is also limited in time and space where the treatment period is short or intermediary evaluation criteria are used.

Phase 4 trials are conducted in varied populations, eliminating bias or unfair influences that could affect the research’s results.

Diseases occur within a non-uniform genetic inheritance and environment. Therefore, the dosage and indication must be adapted.

Studies in subpopulations are necessary to define the safest conditions for application and ensure the plausibleness of the trials.

Subpopulations in phase 4 trials include the function of age, sex, origin, and morphology. Age can modify the pharmacodynamic and pharmacokinetic constants of a drug. The pharmacokinetic behavior can differ significantly for different sexes of the same age. It can also vary depending on race, and additionally, it can be modified by obesity or associated pathology.

2. Redefine Drug Dosage

The proposed dosage of a drug during registration can be adjusted to the needs of different patients, so it is gradually redefined.

It is based on the pathology of a severely afflicted patient; however, the ambulatory patient has a less threatening and often different condition that requires adjustment of the dosage.

Large Streamlined Trials (LSTs) or practical trials study the drug’s effectiveness and safety in real-world settings with minimal study-imposed interventions.

3. Study Drug Interactions

The physician often prescribes two or more medicines depending on the patient’s condition. Infinite combinations have to be determined in advance, which makes phase 4 clinical trials mandatory. These trials search for the optimal conditions of drug use.

Phase 4 is therefore considered as the opportunity to study drug interactions. Phase 4 trials also check the side effects induced by pathology or through drug-treating illness.

4. Economic Purpose – Facilitating Product Promotion

After the registration and approval of the drug, the new drug begins its commercial life, which will probably change the environment in sociocultural, economic, and scientific terms.

Introducing new drugs improves the knowledge of pathologies and develops prescription strategies.

The reliable information based on rigorous trials assists physicians in making correct therapeutic decisions, reducing the frequency of adverse events.

The pharmaceutical firm collects the maximum quantitative and qualitative information about the new products, which is beneficial for a practitioner in prescribing the drug. The practitioner improves and develops as much knowledge as possible to maintain therapeutic potential.

Phase 4 Clinical Trials – Types

Phase 4 trials involve the medical and marketing departments as well as pharmacovigilance. Thus, they are defined as three different types of activities.

  • Clinical Research

Manufacturers develop a research plan based on the queries and recruit investigators.

A trial may also be requested by a physician who feels that improvements are required due to the drug’s difficulties, failures, or limitations.

The group of physicians, public authorities, state health insurance offices, or patient associations may be the promoters of these studies.

Health research is the best option for accessing real-world data. It includes collecting health outcomes and comparative effectiveness research, which is catalyzed by adopting electronic health records and integrating clinical and biological information.

  • Seeding Trials

Phase 4 clinical trials promote the commercial development of a drug by communicating concepts and knowledge of a drug.

Seeding trials serve this purpose by familiarizing physicians with the drug. It allows physicians to become accustomed to a newly approved drug.

  • Prescription Studies for Commercial Purposes

The pharmaceutical firm conducts prescription studies or pseudo-trials to ensure physicians prescribe the new drug.

It is accomplished by compensating physicians or investigators for treating patients. The Social Security system reimburses drug purchases made on patients’ prescriptions.

Investigators are compensated in the form of fees proportional to the number of packages of the products.

Phase 4 Clinical Trials – Types of Studies

The drug’s performance in real-world conditions tests its effectiveness. Once approved, all these studies are conducted under phase 4 clinical trials.

  • Non-Interventional Studies (NIS)

NIS studies assess approved and marketed medicines’ safety, tolerance, and effectiveness. It includes laboratory investigations, clinical examinations, and other invasive and non-invasive procedures at the study site.

NIS does not need regulatory approval; however, it is a good practice to register it on

NIS allows for collecting information on the actual use of a specific drug where no diagnostic or additional monitoring procedures are applied to the patients. It provides greater knowledge about drug effects and is a good way to map risks further in the real world.

  • Large Simple Trial (LST)

It combines a randomized clinical trial (RCT) and an observational study. A large number of participants are randomly assigned to treatment groups, and their follow-up is taken as per routine practice.

These trials involve enrolling physicians and participants in ways that interfere with routine practice as little as possible, maximizing validity and generalizability.

  • Post-Marketing Surveillance (PMS) Studies

There might be certain adverse reactions that are unlikely to be detected in Phase 1, phase 2, and Phase 3 clinical trials. These reactions will likely be detected when a large population is exposed to a drug after its approval.

Safety monitoring and planned collection of clinical data is a form of PMS. In these studies, the patients are not strictly defined by inclusion and exclusion criteria. However, it is governed by the contra-indications and permissible indications of the drug.

PMS studies are non-interventional studies requested by regulatory authorities to verify the marketed drug’s safety, tolerability, and effectiveness in a particular population.

The outcomes of PMS studies could be signals or warnings, pharmacoepidemiological information, labeling changes, the need for controlled studies, indications and dosing schedules, or regulatory action.

  • Adverse Event Monitoring

Adverse event monitoring is only possible once the drug has been marketed and is used by patients at a given incidence where the reaction has been gauged.

Safety monitoring continues throughout the life of a drug. Pharmaceutical companies continuously track, investigate, and evaluate adverse drug events (AER) for their products and report them to regulatory authorities.

Drug companies change prescribing information, and under certain circumstances, the drug may be withdrawn from the market.

  • Case-Control Studies

Phase 4 studies may be retrospective case-control evaluations. They are performed to study the rarely suspected side effects of the drug. It also involves cross-sectional and cohort studies for comparative observational in pharmacovigilance planning.

  • Drug Utilization Studies (DUS)

DUS studies elaborate on how the drug is marketed, prescribed, and used in varied populations. Further, it determines how these factors influence clinical, social, and economic outcomes.

DUS provides data on varied populations, including the elderly, children, or patients, often stratified by age, gender, sex, and other characteristics.

These studies can be used to determine rates of adverse drug reactions. Besides, DUS has been used to develop estimates of the economic burden of the cost of drugs.


Clinical trials assess the efficacy and safety of new medicines. However, because they are conducted in standardized conditions, discrepancies in patient selection or treatment conditions may alter both the effectiveness and risks.

Although all drugs contain animal reproduction data, these are usually not predictive of human risk.

Sufficient observational data is collected in phase 4 clinical trials after the drug is approved and marketed. These trials help gain additional information, including the risks, benefits, and optimal drug use.

Properly designed real-world phase 4 clinical trials enrich understanding of the effectiveness of new health care interventions, thereby informing patients and health care providers in a better way.

See Also

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Current Version
April 24, 2021
Written By
Victoria Abigail Friedland
April 25, 2024
Updated By
Franco Cuevas, MD

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