Limitations of Premarketing Clinical Trials

Size of the patient population studies Narrow population often not providing for special groups Elderly, children, women Narrow indications studied Exclusion of certain disease states Short duration Not reflective of a drugs potential chronic use

Phase IV or Post marketing Surveillance

No fixed duration / patient population Starts immediately after marketing

Report all ADRs

Helps to detect

rare ADRs Drug interactions Also new uses for drugs [Sometimes called Phase V]

An Ideal Registry Design

Actively collects information STUDY POPULATION exposed and unexposed patients with the same baseline risk, identified prospectively EXPOSURE MEASUREMENT dose, duration and timing of all relevant medications OUTCOME MEASUREMENT complete ascertainment of outcome in both groups

COVARIATES complete information on all potential confounders and effect modifiers

FOLLOW-UP complete follow-up time period sufficient to observe outcomes POWER ability to detect or rule out an increased risk of X over the exposed or observed in the unexposed group

Definition of a Post Marketing Commitment As a requirement for the approval or continued marketing of medicines, US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) may require additional information on a product to be generated, in the form of post marketing commitments (PMCs). These commitments are agreed to by a company with the health authority and are used to gather additional information about a medicine's safety, efficacy, or optimal use. Post marketing commitments can be required either before or after the health authority has granted approval to a company to market a medicine.1 In the EU, PMCs are also known as Post Approval Commitments (PACs) and may take the form of follow-up measures (FUMs) or Specific Obligations (SOs).

Post Marketing Studies

Clinical Trials studies to answer specific questions about new treatments or new ways of using known treatments.

Clinical trials (also called medical research and research studies) are used to help determine the benefit/risk profile of new medicines and treatments.
Carefully conducted clinical trials are the fastest and safest way to find what medicines and treatments work, and to understand any potential limitations to their use.

Types of clinical trials include:

Randomized clinical trials (RCTs) Drug interaction studies Efficacy studies Large simple trials (LSTs) Pharmacokinetic and pharmacodynamic studies

Safety studies
Completion of ongoing study

Pediatric studies

Efficacy studies Pharmacokinetic and pharmacodynamic studies PREA studies In the United States the Pediatric Research Equity Act of 2003 requires new drug applications (and supplemental applications) to contain a pediatric assessment.6 At the time of regulatory approval, these pediatric studies may be required as a post marketing commitment.

Safety studies Safety studies may be conducted in several forms, and may be carried out to evaluate the safety of a medicinal product.

Special population studies such as pregnant women, children, geriatric (elderly) patients, patients with specific disease characteristics, such as liver (hepatic) impairment or kidney (renal) impairment, or patients with specific reactions to treatment, such as change in QT interval (heart rate measurement).
New dosage form/strength studies Studies testing different dosage forms/strengths or delivery systems.

Other types of studies can include:

Pre-clinical studies Testing of medicines in the test tube (in vitro) or in animals. This typically occurs before trials in humans may be carried out, but may be required at any time.2 These studies may examine carcinogenicity, microbiology or toxicology. Epidemiological studies Non-interventional studies of incidence, distribution and control of a disease in a given population.2 Epidemiological studies can also be designed to evaluate drug safety.

Safety registry Generally non-interventional studies, registries are repositories where data, records or laboratory samples are kept and may be made available for research or comparative study.

For example, physicians may maintain lists of patients who share a characteristic, such as a medical condition or medication regimen. Safety registries capture and document ongoing safety and outcomes data in patient populations under real-world treatment conditions. Other types of registries include disease registries, drug registries and pregnancy registries.

Other types of activities to address a specific commitment may include for example, a labelling comprehension study, a commitment to convene an expert panel, or an education program.

Development Process for Post Marketing Studies

Protocol development Investigator start-up Subject recruitment Conducting a study Reporting PMs progress

US Post Marketing Commitment Status Definitions Post marketing commitment progress is reported on this website using the following status descriptions [(consistent with the definitions used in the US by the FDA)]:1 Pending The commitment has not been initiated (i.e., no subjects have been enrolled or animals dosed), but does not meet the criterion for delayed (i.e., the original projected date for initiation of animal dosing has not passed). On-going The commitment is proceeding according to, or is ahead of, the original schedule. A study will be considered to be on-going until a final study report is submitted to the health authority, as long as the activities are proceeding according to the original study schedule. If patient accrual or animal dosing has started but is not complete, and the projected date for completion of that milestone has passed, the study should be categorized as delayed. Delayed The progression of the commitment is behind the original study schedule. Delays can occur in any phase of a study, including patient enrollment, analysis of study results or submission of the final study report to the FDA. While the original study schedule not a revised schedule serves as the basis for defining a study as delayed, each phase of the study will be considered in its own right. If the company has one delayed phase, but gets back on schedule during the next phase, the delayed status will no longer apply. Terminated The company ended the study before completion, and has not yet submitted a final study report to the FDA. Submitted The company has concluded or terminated the commitment and has submitted a final study report to the FDA, but FDA has not yet notified the applicant in writing that the study commitment has been fulfilled or that the commitment has been released. Fulfilled The company has submitted the final study report for the commitment, and upon review of the final study report, FDA is satisfied that the applicant has met the terms of the commitment. Released FDA has informed the company that it has been released from its obligation to conduct the post marketing commitment because the study is either no longer feasible or would no longer provide useful information.

EU Post Marketing Commitment Status Definitions Pending The commitment has not been initiated.

On-going The commitment is proceeding according to, or is ahead of, the original schedule.
Delayed The progression of the commitment is behind the original schedule. Terminated The commitment has been terminated. Submitted The company has submitted the required information to the Agency but has not yet been notified that the commitment has been fulfilled. Fulfilled The company has submitted the required information to the Agency and upon review of the Agency is satisfied that the applicant has met the terms of the commitment. Released The Agency has informed the company that it has been released from its obligation to conduct the post approval commitment.