Post-Authorisation Safety Studies (PASS) – Categories and Considerations

You are a CRO and (1) you’ve been asked to submit a proposal to conduct a client’s post-authorisation safety study (PASS), or (2) you’ve won the work and now need to deliver the goods.

Key Consideration #1 = Is the proposed study a Category 1, 2 or 3 PASS?

• Why is this important? o Category 1 and 2 PASS are imposed by the EMA as a condition of the marketing authorisation for the medicinal product. This ‘imposition’ comes with

additional and specific regulatory requirements, compared to Category 3/ voluntary PASS (refer to Figure 1 and Table 1)• How do I find out?

o The quickest way is to head to the EMAs website and search for the products European Public Assessment Report (EPAR). Check Annex II.D (Category 1 PASS) and Annex II.E (Category 2 PASS) of the Marketing Authorisation/ European Public Assessment Report (for centrally authorized products), If the PASS isn’t listed there then it’s a Category 3 PASS (refer to Table 2)

Key Consideration #2 = What are the country-specific regulatory requirements for your PASS?

• The country-specific requirements will (usually) depend on the Category of the PASS and the study design (e.g., secondary or primary data, +/- biosamples, collection of genetic data etc) (refer to Figure 1)

• Some companies have consolidated this information and provide access for a fee (e.g., CHCUK). Otherwise, it’s a case ofassessing and consolidating the applicable regulations, guidelines and best practices for each country

• For Category 1 and 2 PASS, these country-specific requirements are ADDITIONAL to the regulatory requirements imposed by the EMA through Regulation EC/726/2004, Regulation EC/520/2012 and Directive 2001/83/EC

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Non-Interventional Post-Authorisation Safety Study (PASS)

General Requirements: Category 1 and 2 PASS (Requirements for Centrally Authorised Products)

• Must use EMA PASS protocol and report templates• Protocol must be endorsed by PRAC• Study details must be uploaded to the EU PAS Register• Substantial amendments must be approved by PRAC• PASS Study report and abstract must be submitted to

PRAC (in English^) for assessment of impact on product’s risk-benefit profile (^ as per Article 36.2 of Regulation EC/520/2012)

Send copy of protocol and PRAC endorsement to National Competent Authority of each country where the study will be conducted (as per Article 107(m)(5) of Directive 2001/83/EC)

Per Country Requirements: Category 1 and 2 PASS(Requirements for Centrally Authorised Products)

Requirements Applicable to ALL PASS

• Assess country-specific regulatory requirements based on PASS Category and study (e.g., secondary or primary data, +/- biosamples etc)

NO = Category 3/ Voluntary PASS

How do I know what Category my PASS fits in to?

Check Annex II of the MA/EPAR –See Table 2 for examples

Category 1 or 2 PASS?

Addi

tiona

lReq

uire

men

ts fo

r Ca

tego

ry 1

and

2 P

ASS

YES

Study Assumptions (for the purposes of the examples below):• Category 3 PASS• Primary data collection• No biosamplesEx

ampl

es

SSARs(Serious Suspected Adverse Reactions)

15 Days

SARs(Suspected Adverse Reactions)

90 Days

EMA(Eudrvigilance)

Spain

• Study classification by AEMPs = EPA-SP

• LEC Approval• Autonomous Community

Approval

Germany

• LEC approval• Notify BfArM, KBV, GKV and PKV• Register study online

France

• CPP approval• CNIL approval (or MR-003

compliance)• ANSM notification

PASS definition as per Article 1(15) of Directive 2001/83/EC

Required under Article 107.3 of Directive 2001/83/EC

Figure 1: Schematic of Regulatory Requirements for Non-Interventional PASS

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Supervised Under Directive 2001/83/EC*

Category of PASS^ the Requirements are 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):

o Study shall not promote the use of a medicinal producto Payments to HCP restricted to compensation for time and expenses

incurredo Final study report to be submitted to NCA of country where study

conducted within 12 months of the end of data collectedo Implications of study results on risk-benefit of medicinal product to be

assessed and any new information which may impact the risk-benefit profile to be communicated to NCAs where the medicinal product is authorised

• Guidance on Post-Authorisation Safety Studies: EMA GVP Module VIII• Guidance of Safety Reporting Requirements for Prospective NIS: EMA GVP

Module VI

107n 1 & 2 (Imposed PASS) Process for the Pharmacovigilance Risk Assessment Committee (PRAC) endorsement of the PASS protocol

• Chapter VIII (Articles 36 – 38) and Annex III of Regulation EC/520/2012• EMA Guidance on Imposed Non-Interventional Post-Authorisation Safety Studies:

o What is a non-interventional imposed PASS?o Under which procedure should I submit my non-interventional imposed PASS?o What if the results of a non-interventional imposed PASS make a variation necessary?o How shall I present my non-interventional imposed PASS and in which format?o To whom should I submit my non-interventional imposed PASS?o How do I submit a joint PASS?o How ill my non-interventional imposed PASS protocol be handled?o How ill my non-interventional imposed PASS study report be handled?o How is the CHMP/ CMDh position structured and which annexes need to be translated?o How shall I implement the outcome of a non-interventional imposed PASS final study

report procedure?o When should I register my studies in the EU PAS Register?o Are outcomes of imposed non-interventional PASS published?o What fee do I have to pay?o Who should I contact if I have questions about my submission?o Scientific advice for safety studies

107o 1 & 2 (Imposed PASS) Process for review and approval of substantial amendments

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

107q 1 & 2 (Imposed PASS) Process for recommendations for the variation, suspension or revocation of the marketing authorisation (where applicable)

* Directive 2001/83/EC (as amended): https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf^ As described in Section V.B.6.3 of GVP Module V: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-v-risk-management-systems-rev-2_en.pdf

Table 1: Regulatory Requirements and Conditions for Non-Interventional PASS

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Post-Authorisation Safety Study (PASS) Category*

Details Example Reference/ Link

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.

EPAR: https://www.ema.europa.eu/en/medicines/human/EPAR/yescartaEU PAS Register Entry: http://www.encepp.eu/encepp/viewResource.htm?id=32540

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)

https://www.ema.europa.eu/en/documents/product-information/yescarta-epar-product-information_en.pdf

2 Specific obligation in the context of a marketing authorisation under exceptional circumstances^

• Comprehensive data cannot be provided (Specific reasons foreseen in the legislation)• Reviewed annually to re-assess the risk-benefit balance, in an annual re-assessment

procedure• Will normally not lead to the completion of a full dossier and become a “normal” marketing

authorisation

Brineura - Non-interventional post-authorisation safety study (PASS):Study 190-501. In order to evaluate the long-term safety of cerliponase alfa, including the occurrence of serious hypersensitivity reactions and anaphylaxis, the MAH should submit the results of a study based on adequate source of data deriving from a registry of patients with neuronalceroid lipfuscinosis Type 2 (CLN2)

EPAR: https://www.ema.europa.eu/en/medicines/human/EPAR/brineuraEU PAS Register Entry:

See specific obligations listed on page 19 (Annex II.E of the MA/EPAR):

https://www.ema.europa.eu/en/documents/product-information/brineura-epar-product-information_en.pdf

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-termeffectiveness, the MAH should submit the results of a study based on data deriving from a registry of patients with high risk neuroblastoma.

EPAR: https://www.ema.europa.eu/en/medicines/human/EPAR/qarzibaEU PAS Register Entry: http://www.encepp.eu/encepp/viewResource.htm?id=31974

See specific obligations listed on page 18 (Annex II.E of the MA/EPAR):

https://www.ema.europa.eu/en/documents/product-information/qarziba-epar-product-information_en.pdf

2 Specific obligation in the context of a conditional marketing authorisation^

• Demonstrate positive risk-benefit balance, based on scientific data, pending confirmation• Authorisation valid for one year, on a renewable basis• Once the pending studies are provided, it can become a “normal” marketing authorisation

Adcetris - Non-Interventional Post-Authorization Safety Study (PASS) conducted in HL and sALCL patient populations (Study MA25101)

EPAR: https://www.ema.europa.eu/en/medicines/human/EPAR/adcetrisEU PAS Register Entry:

See specific obligations listed on page 40 (Annex II.E of the MA/EPAR):

https://www.ema.europa.eu/en/documents/product-information/adcetris-epar-product-information_en.pdf

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

EPAR: https://www.ema.europa.eu/en/medicines/human/EPAR/yervoyEU PAS Register Entry: http://www.encepp.eu/encepp/viewResource.htm?id=30051

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

https://www.ema.europa.eu/en/documents/product-information/yervoy-epar-product-information_en.pdf

* As described in Section V.B.6.3 of GVP Module V: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-module-v-risk-management-systems-rev-2_en.pdf^ Refer to EMA Pre-Authorisation Guidance on ‘Types of Applications’: https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/pre-authorisation-guidance#1.-types-of-applications-and-applicants-section

Table 2: Examples of Imposed (Category 1 & 2) and Category 3/ Voluntary Non-Interventional PASS

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