Post-Approval Frequently Asked Questions (FAQ)

Although there are no specific regulatory guidance documents for post-approval research, all randomized clinical trials should be conducted within the framework of the ICH Guidelines and Good Clinical Practice (GCP) Guidelines. Observational studies should be conducted within the framework of Good Pharmacoepidemiology Practices (GPP) and EudraVigilance Volume 9A Pharmacovigilance for studies conducted in the EU. In addition, post-approval studies in the U. S. will also operate under the guidance of the Office of the Inspector General (OIG) for compliance with the Anti-Kickback Statute and the False Claims Act.

Under the Food and Drug Administration Amendments Act of 2007 (FDAAA), a Risk Evaluation and Mitigation Strategy (REMS) is the new legal framework for risk management plans, specifying timelines and procedures for submission and review. REMS are tailored to fit the safety profile of each new drug. For example, depending on a product's risk profile, the strategy could include special requirements for labeling, post-approval studies and limitations on direct-to-consumer marketing.

FDAAA identifies a RiskMAP as a tool of REMS. RiskMAPs have a variety of categories and components, such as safety studies, targeted education and outreach, reminder systems and performance-linked access systems.

The FDA can require a REMS during clinical development or post-approval if determined that specific interventions are needed to ensure that benefits outweighs the risks. For products in clinical development, items of consideration include:

  • Estimated size of likely patient population
  • Seriousness of disease or condition
  • Expected benefit of the drug
  • Expected duration of treatment
  • Seriousness of known or potential AEs
  • Whether the drug is an NCE

The REMS must be submitted with the NDA/BLA application.

For approved products, criteria include new safety information that emerges after approval. This includes clinical trial data, adverse event reports, post-approval studies, peer-reviewed literature, risk identification and analysis system, or other means about:

  • A serious risk or unexpected serious risk that arises after drug approval, REMS required, or last REMS assessment; or
  • Effectiveness of the approved REMS (since last assessment)

The REMS proposal must be submitted within 120 days of notification of FDA's determination.

While the FDA has not provided a template for risk management plans, the EMEA has provided a template based on ICH E2E guidelines. PPD recommends using the EMEA format as a foundation to develop a REMS, modifying where necessary.

A clinical trial is an experimental study that involves a therapeutic intervention intended to change a subject's outcome. Participants are randomized to ensure that known and unknown extraneous factors are evenly distributed between treatment groups. The protocol describes inclusion and exclusion criteria that are used to select the participants. Procedures follow a strict schedule of visits and treatments.

An observational study is similar to a clinical trial, but the methodology is different. Observational studies do not include randomization and do not define the treatment plan to be followed. They are conducted as part of routine clinical practice, for the purpose of assessing physician practice patterns and examining patient outcomes for each treatment plan, without influencing the outcome. In order to make the results generalizable to broad patient populations, there are typically fewer inclusion and exclusion criteria than randomized clinical trials.

Post-approval study designs can vary significantly due to the wide range of objectives beyond traditional safety and efficacy. The scope is dependent upon whether an IND or non-IND post-approval protocol is involved. Key differences include:

Protocol: Non-IND post-approval protocols tend to be shorter and more streamlined, often with simpler inclusion/exclusion criteria, fewer procedural requirements and simpler drug management requirements.

Regulatory documents: Non-IND studies tend to feature limited regulatory collection (CVs, confidentiality disclosures, study agreement, ethical review board approval letter with informed consent and medical license).

Case report form/data collection: CRFs used in non-IND post-approval studies tend to be streamlined and shorter than those used in clinical trials. Study objectives will drive the scope of content. Non-IND trials often contain abbreviated medical histories, concomitant medications and lab data.

Adverse event collection: Adverse event collection can range from full collection (as in a Phase III trial) to reporting through typical post-approval mechanisms (such as FDA MedWatch forms). Typical collection only includes adverse events of special interest.

Monitoring approach: As an alternative to routine onsite monitoring, targeted monitoring can be used for post-approval studies. A limited number of select sites may receive on-site monitoring*, while all sites receive telephone-based monitoring on a pre-determined basis.

Source document verification: Post-approval studies may include less than 100% source document verification. However, post-approval source data verification should include:

  • Presence of the correct version(s) of a signed and dated IRB-approved Informed Consent for each subject
  • 100% of the first two (chronological or randomized) CRFs
  • Basic demographic data in all CRFs
  • Inclusion/Exclusion criteria for each subject
  • All safety and efficacy data
  • All CRFs for subjects experiencing a SAE
  • Data consistency within and across CRF sections
  • CRFs randomly selected at periodic intervals

 

 

 

 

 

 

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