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8. Post-marketing study (PMS)

8. Post-marketing study (PMS)

Post-marketing study (PMS): A study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or measuring the effectiveness of risk management measures. 

PMS studies are conducted to assure the quality, efficacy and safety of drugs after they go on the market.

Systematic PMS of drugs began in the early 1970s and has increased substantially since then. PMS is conducted by various types of organizations and agencies, including pharmaceutical manufacturers, universities, government agencies, private companies, and consumer advocacy groups. 

PMS study Objectives: 

  • to quantify potential or identified risks
  • to evaluate risks of a medicinal product used in patient populations for which safety information is limited or missing (i.e. pregnant women, specific age groups, patients with renal or hepatic impairment)
  • to provide evidence about the absence of a risk
  • to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product (i.e. indications, dosage, co-medication, medication errors)
  • to measure the effectiveness of a risk minimisation activity.

Why is it important to have PMS studies: 

The monitoring of drugs after their approval has become necessary for many reasons. The Benefit/Risk balance of a medicinal product cannot be fully identified until after a drug is on the market and has been used by a large, diverse group of patients over time.

Clinical trials conducted before approval may be too small, too short, based on surrogate endpoints to detect all possible risk (and efficacy).

Limitations of Pre-Approval Clinical Trials:

Trial population 

  • Size
        – Trial population vs. treated population 
  • Narrow
        – Very young or very old usually not enrolled 
  • Co-morbidities
        – Hepatic or renal failure
        – Other serious medical conditions 

       – Use of concomitant medications 

  • Indications for use
         – Proposed indication for use 

        – Patients at complex disease stages often not enrolled

  • Duration of trial 

        – Typical chronic use (years) vs.trial (several weeks to months) 

Types of post marketing studies:

Case control study: Case-control studies are retrospective. They clearly define two groups at the start: one with the outcome/disease and one without the outcome/disease. They look back to assess whether there is a statistically significant difference in the rates of exposure to a defined risk factor between the groups. This can suggest associations between the risk factor and development of the disease in question, although no definitive causality can be drawn.

Cohort studies: Cohort studies can be retrospective or prospective. Retrospective cohort studies are NOT the same as case-control studies.

  1. In retrospective cohort studies, the exposure and outcomes have already happened. They are usually conducted on data that already exists (from prospective studies) and the exposures are defined before looking at the existing outcome data to see whether exposure to a risk factor is associated with a statistically significant difference in the outcome development rate.
  2. Prospective cohort studies are more common. People are recruited into cohort studies regardless of their exposure or outcome status. This is one of their important strengths. People are often recruited because of their geographical area or occupation, for example, and researchers can then measure and analyse a range of exposures and outcomes.

Randomised clinical trial: 

The randomised control trial (RCT) is a trial in which subjects are randomly assigned to one of two groups: one (the experimental group) receiving the intervention that is being tested, and the other (the comparison group or control) receiving an alternative (conventional) treatment.

Non Interventional trial: 

  • A study where the medicinal product(s) is (are) prescribed in the usual manner in accordance with the terms of the marketing authorisation. 
  • The assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within the current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study. 
  • No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of the collected data 

Safety Monitoring during the Post-Approval Phase of a Drug Product’s Life Cycle: 

  • Less frequent adverse drug experiences (ADEs) 
  • Patients with higher risk for ADEs 
  • Chronic and long term use 
  • Drug-drug interactions 
  • Drug-food interactions 
  • ExpectedADEs
    – Increased severity or frequency 
  • Misuse or abuse of drug product 
  • Medication errors
  • Product packaging, labeling, other characteristics 

Case study to know how PMS studies impact drug marketing status: 

The Sibutramine experience:

  • ✓1997 sibutramine approved for weight loss by FDA labelled warning re BP and heart rate increases
  • ✓2002 EMA requires sibutramine cardiovascular outcomes trial (SCOUT)
  • ✓10,744 overweight/obese with CV disease and/or diabetes over 3.4 years.
  • ✓Analysis found 16% increased risk of CV events such as MI and stroke compared with placebo-treated patients
  • ✓6.7% patients had non fatal myocardial infraction and stroke, 4.5% patients had died due to cardiovascular arrest.
  • ✓Drug withdrawn by FDA, EMA etc. soon after
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