Post-Authorisation Safety Studies (PASS)
Quick Reference Guide
PASS Definition
Post-authorisation safety studies (PASS) can be interventional (clinical trials) and non-interventional. At Phoenix, we’re only interested in the non-interventional PASS.
A PASS is non-interventional if…
The medicinal product is 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 current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study; and
No additional diagnostic or monitoring procedures are applied to the patients and epidemiological methods are used for the analysis of collected data.
In these studies, interviews, questionnaires, blood samples and patient follow-up may be performed as part of normal clinical practice^
[^ as per Section VIII.A of GVP Module VIII]
When Should a Non-Interventional Study (NIS) be Considered a Post-Authorisation Safety Study (PASS)?
A post-authorisation study should be classified as a post-authorisation safety study when the main aim for initiating the study includes any of the following objectives:
- to quantify potential or identified risks, e.g. to characterise the incidence rate, estimate the rate ratio or rate difference in comparison to a non-exposed population or a population exposed to another medicinal product or class of medicinal products as appropriate, and investigate risk factors, including effect modifiers;
- to evaluate the risks of a medicinal product used in a patient population for which safety information is limited or missing (e.g. pregnant women, specific age groups, patients with renal or hepatic impairment or other relevant comorbidity or co-medication);
- to evaluate the risks of a medicinal product after long-term use;
- to provide evidence about the absence of risks;
- to assess patterns of drug utilisation that add knowledge regarding the safety of the medicinal product or the effectiveness of a risk management measure (e.g. collection of information on indication, off-label use, dosage, co-medication or medication errors in clinical practice that may influence safety, as well as studies that provide an estimate of the public health impact of any safety concern);
- to measure the effectiveness of a risk management measures.
[Reference: Section VIII.B.1 of GVP Module VIII]
Key GVPs Applicable to PASS
References
- GVP MODULE V – Refer to Section V.B.6.3 for PASS categories
- GVP MODULE VI – Refer to Sectionj VI.C.1.2 for guidance of safety reporting requirements for non-interventional studies
- GVP MODULE VIII – EMA Post-Authorisation Safety Study (PASS) Guideline
GVP Module VIII – PASS Guidelines
GVP Module VIII is usually your first point of reference if you are planning to run a non-interventional PASS in Europe.
Why? GVP Module VIII provides guidance on the legal framework and best practice guidelines for PASS, as well as the format for PASS protocols and reports.
A word of warning though…YOU STILL NEED TO COMPLY WITH THE PER COUNTRY REGULATORY REQUIREMENTS FOR NON-INTERVENTIONAL STUDIES.
This is mentioned in Section VIII.A of GVP Module VIII, but you would be forgiven for missing it, as it’s a ‘small’ reference that reads as an after-thought:
“National and Union requirements for ensuring the well-being and rights of participants in non-interventional PASS shall also apply”
Scientific Guidance Relevant to PASS
Relevant scientific guidance should be considered by marketing authorisation holders and investigators for the development of study protocols, the conduct of studies and the writing of study reports, and by the Pharmacovigilance Risk Assessment Committee (PRAC) and national competent authorities for the evaluation of study protocols and study reports. Relevant scientific guidance includes, amongst others:
- ENCePP Guide on Methodological Standards in Pharmacoepidemiology
- ENCePP Checklist for Study Protocols
- Guideline on Conduct of Pharmacovigilance for Medicines Used by the Paediatric Population
- Guidelines for Good Pharmacoepidemiology Practices of the International Society of Pharmacoepidemiology (ISPE GPP)
PASS Categories
Post-Authorisation Safety Study (PASS) categories are defined inSection V.B.6.3 of GVP Module V
| PASS Category*^ | Details |
|---|---|
| 1 | Imposed as a condition to the marketing authorisation because they are key to the risk-benefit profile of the product |
| 2 | Specific obligation in the context of a marketing authorisation under exceptional circumstances^
|
| 2 | Specific obligation in the context of a conditional marketing authorisation^
|
| 3 | Other studies might be required in the Risk Management Plan (RMP) to investigate a safety concern or to evaluate the effectiveness of risk minimisation activities. Such studies included in the pharmacovigilance plan are also legally enforceable – refer to the regulatory requirements and conditions laid down in Article 107m of Directive 2001/83/EC and applicable guidelines (e.g., GVP Modules VI and VIII) |
*^ As described in Section V.B.6.3 of GVP Module V; ^ Refer to EMA Pre-Authorisation Guidance on ‘Types of Applications‘
Examples of Imposed PASS (Category 1 & 2) and Category 3/ Voluntary Non-Interventional PASS
| PASS Category | Details | Example(s) | References and Links |
|---|---|---|---|
| 1 | Imposed as a condition to the marketing authorisation because they are key to the risk-benefit profile of the product | Yescarta – Non-interventional post-authorisation safety study (PASS):In order to assess the safety profile including long term safety in patients with B-lymphocyte malignancies treated with axicabtagene ciloleucel in the post marketing setting, the applicant should conduct and submit a study based on a registry. | See “Conditions or restrictions with regard to the safe and effective use of the medicinal product” listed on page 22 (Annex II.D of the MA/EPAR) |
| 2 | Specific obligation in the context of a marketing authorisation under exceptional circumstances^
|
Qarziba – Non-interventional post-authorisation safety study (PASS): In order to collect data on pain and its management, effect on peripheral and central nervous system, including visual impairment, long-term safety and long-term effectiveness, the MAH should submit the results of a study based on data deriving from a registry of patients with high risk neuroblastoma. | See specific obligations listed on page 18 (Annex II.E of the MA/EPAR) |
| 2 | Specific obligation in the context of a conditional marketing authorisation^
|
Adcetris – Non-Interventional Post-Authorization Safety Study (PASS) conducted in HL and sALCL patient populations (Study MA25101)
|
See specific obligations listed on page 40 (Annex II.E of the MA/EPAR) |
| 3 | Other studies might be required in the Risk Management Plan (RMP) to investigate a safety concern or to evaluate the effectiveness of risk minimisation activities. Such studies included in the pharmacovigilance plan are also legally enforceable – refer to the regulatory requirements and conditions laid down in Article 107m of Directive 2001/83/EC and applicable guidelines (e.g., GVP Modules VI and VIII) | Yervoy – A Multi-National, Prospective, Observational Study in Patients with Unresectable or Metastatic Melanoma | Note that the study is NOT listed in Annex II.D (Conditions) or Annex II.E (Specific Obligations), indicating that this is a Category 3/ voluntary PASS |
Regulatory Requirements and Conditions for Non-Interventional PASS
| Directive 2001/83/EC Reference | Category of PASS Requirements Applicable to | Regulatory Requirements/ Conditions | Further Information and Guidance |
|---|---|---|---|
| Article 107m | 1, 2 & 3 (Imposed and Voluntary PASS) | General requirements when conducting Post-Authorisation Safety Studies (PASS):
|
|
| Article 107n | 1 & 2 (Imposed PASS) | Process for the Pharmacovigilance Risk Assessment Committee (PRAC) endorsement of the PASS protocol |
|
| Article 107o | 1 & 2 (Imposed PASS) | Process for review and approval of substantial amendments |
|
| Article 107p | 1 & 2 (Imposed PASS) | Process for submitting the final study report and abstract and providing an assessment (if any) on the impact to the benefit-risk assessment of the medicinal product |
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| Article 107q | 1 & 2 (Imposed PASS) | Process for recommendations for the variation, suspension or revocation of the marketing authorisation (where applicable) |
|
Study Start-Up Requirements for PASS
Safety Reporting Requirements for Non-Interventional Studies
SERIOUS SUSPECTED ADVERSE REACTIONS (SSARS)
Marketing authorisation holders shall submit electronically to the database and data-processing network referred to in Article 24 of Regulation (EC) No 726/2004 (hereinafter referred to as the ‘Eudravigilance database’) information on all serious suspected adverse reactions that occur in the Union and in third countries within 15 days following the day on which the marketing authorisation holder concerned gained knowledge of the event (as per Article 107.3 of Directive 2001/83/EC as amended).
NON-SERIOUS SUSPECTED ADVERSE REACTIONS (SSARS)
Marketing authorisation holders shall submit electronically to the Eudravigilance database information on all non-serious suspected adverse reactions that occur in the Union, within 90 days following the day on which the marketing authorisation holder concerned gained knowledge of the event (as per Article 107.3 of Directive 2001/83/EC as amended).
Management of Adverse Events for Non-Interventional Post-Authorisation Studies with a Design Based on Primary Data Collection
