Phase 4 Clinical Trials – Overview
Phase 4 clinical trials, also known as real-world trials or post-marketing surveillance (PMS) studies, are conducted to understand the true efficacy of medicines. These trials improve the scientific knowledge regarding the use of the drug in special conditions, side-effects, and better precision of the dosage. Also, there are some studies that are designed for economic purposes, facilitating product promotion.
Phase IV trials include the range of medical endeavors to fully develop and exploit the therapeutic potential of the drug on its approval. The aim of these trials is to deliver the maximum benefit to patients while reaping the investments during development. 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 the development and approval of a drug. For certain drugs, phase 4 clinical trials begin as soon as the drug approval is obtained; however, for others, it comes after marketing has started and continues throughout the commercial life of the drug.
Phase 4 clinical trials are undertaken to study a drug under the strict context of the indications and dosage approved while registration. These trials are intended to offer a better knowledge of the benefits of the drug for the patient and society. Phase 4 trials indicate the advantages of the drug after the complete collection of epidemiologic data and strategical pathology. 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. The drug can best be observed in its ordinary environment and can be improved with respect to indications and precautions for use. The drug can be judged in terms of its role in everyday circumstances.
The results of phase 4 trials give rise to new phase 2 and 3 studies to expand the indications, modify the dosage, and elaborate new galenic forms.
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 any concerns about the drug are revealed during phase 4 trials, the drug may be withdrawn from the market, where it is no more available on prescription.
Reasons for Conducting Phase 4 Clinical trials
Let us check out the essential reasons for undertaking phase 4 clinical trials.
Till the phase 3 trials, the knowledge of the drug is considered incomplete where untoward effects may have been missed. It is because the patients selected for these trials were carefully selected, within the 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 result of the research. Diseases occur within a non-uniform genetic inheritance and environment. Therefore, the dosage and indication are required to be adapted. It is necessary to carry out studies in subpopulations to define the safest conditions for application and ensure that the trials are plausible.
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 greatly for different sex of the same age. It can also differ depending on race, and additionally, it can be modified by obesity or associated pathology.
Redefine Drug Dosage
The proposed dosage of a drug while registration can be adjusted to the needs of different patients, and hence 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 are used to study the effectiveness and safety of the drug in real-world settings with minimal study-imposed interventions.
Study Drug Interactions
The physician often prescribes two or more medicine as per the condition of the patient. There are infinite combinations that have to be determined in advance that 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.
Economic Purpose – Facilitating Product Promotion
After the registration and approval of the drug, the new drug begins its commercial life that will probably change the environment in sociocultural, economical, and scientific terms. The introduction of new drugs improves the knowledge of pathologies and develops prescription strategies. The reliable information based on the 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 to maintain therapeutic potential.
Phase 4 Clinical Trials – Types
Phase 4 trials involve the medical and marketing department as well as pharmacovigilance. Thus, these are defined as three different types of activities in the phase 4 trial.
Manufacturers develop a research plan based on the queries and recruits investigators. A trial may also be requested by a physician who feels that improvements are required due to the confronted difficulties, failures, or limitations concerning the drug.
The group of physicians, public authorities, state health insurance offices, or patient associations may be the promoters of these studies.
To access the real-world data, health research is conducted as the best option. It includes collecting health outcomes and comparative effectiveness research catalyzed by adopting electronic health records and integrating clinical and biological information.
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 the 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 are prescribing the new drug. It is accomplished by compensating physicians or investigators for the treatment of patients. The drug purchases on the prescription of patients are reimbursed by the social security system.
Investigators are compensated in the form of fees that is proportional to the number of packages of the products.
Phase 4 Clinical Trials – Types of Studies
The performance of the drug in real-world conditions tests the effectiveness of that particular drug. All these studies are conducted under phase 4 clinical trials once they have been approved.
Non-Interventional Studies (NIS)
NIS studies assess the safety, tolerance, and effectiveness of approved and marketed medicines. 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 ClinicalTrials.gov.
NIS allows 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 further map risks in the real world.
Large Simple Trial (LST)
It is a combination of a randomized clinical trial (RCT) and an observational study. A large number of participants are randomly involved in treatment groups. Their follow-up is taken as per routine practice. These trials are the efforts of enrolling physicians and participants with an objective to 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 are likely to 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, 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, need for controlled studies, indications and dosing schedules, or regulatory action.
Adverse Event Monitoring
The 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 track, investigate, and evaluate adverse drug events (AER) for their products continuously and report them to regulatory authorities.
Drug companies make changes in prescribing information. Under certain circumstances, the drug may be withdrawn from the market.
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 being marketed, prescribed, and used in the varied population. Further, it also determines that how these factors influence outcomes, including 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 are helpful in gaining additional information, including the risks, benefits, and optimal use of a drug.
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.