Scope

This WHO pilot procedure for prequalification of biotherapeutic products (BTPs) or their corresponding similar biotherapeutic products (SBPs) is specifically focused on Rituximab and Trastuzumab and is carried out using either full assessment or abridged assessment pathways. Full assessment includes, among other requirements WHO inspection of the relevant manufacturing facilities and clinical research sites, based on information submitted by the manufacturer of such products. Evaluation and inspection is based on WHO-recommended technical standards and guidance including those mentioned above. The WHO pilot procedure for prequalification of Rituximab and Trastuzumab addresses technical, communication, policy and other aspects of  the prequalification of Rituximab and Trastuzumab BTPs and corresponding SBPs. Based on the experience gained during the pilot process, WHO reserves the right to revise the prequalification procedure accordingly.

Steps of the pilot procedure

WHO will undertake a full assessment of the quality, non-clinical and clinical aspects of the candidate Rituximab and Trastuzumab SBPs (based on a reference biotherapeutic product (RBP) approved by a stringent regulatory authority), that have not been registered by SRAs. Full assessment will include an evaluation of data, to be submitted by the applicant, demonstrating similarity of the SBP to a suitable RBP in terms of quality characteristics, biological activity, and clinical aspects.

 Alternatively, WHO will undertake an abridged assessment of Rituximab and Trastuzumab BTPs, or corresponding SBPs, as applicable, if the products have been approved by SRAs and marketed in the country of registration.

 Any products, whether BTPs or SBPs, that are prequalified by WHO under this pilot procedure must still be approved for use by the national regulatory authorities (NRAs) of the countries for which market entry is sought.

 The prequalification of a product pursuant to this pilot procedure is not a substitute for any NRA evaluation and market approval, according to applicable local regulatory and other requirements. NRAs, using reliance and collaborative principles, may leverage prequalification reports to facilitate their evaluation and approval. The flowcharts in Appendices 1 and 2 of the document WHO Pilot Procedure for Prequalification of Biotherapeutic Products: rituximab and trastuzumab, describe the steps for full assessment and abridged assessment, respectively.

The steps of the full assessment pathway include, but are not limited to:

• The publication of an invitation to submit an expression of interest (EOI) for product evaluation by WHO.
• A presubmission meeting with WHO before the submission by the applicant of an EOI.
• Submission by the applicant to WHO of an EOI to participate in this pilot procedure.
• A screening procedure to ensure that the dossier(s) submitted by the applicant as part of its EOI is complete.
• Assessment of product dossier, which must include product data and information as specified in the applicable guidelines for submission.
• Inspection of manufacturing sites of drug substances and drug products, if applicable, to assess compliance with current good manufacturing practices and current good distribution practices.
• Inspection of clinical sites (if applicable) to assess compliance with current good clinical practice and current good laboratory practice, as appropriate.

The steps of the abridged assessment pathway include, but are not limited to:

• The publication of an EOI by WHO.
• Submission by the applicant to WHO of an EOI to participate in this pilot procedure.
• A screening procedure to ensure that the dossier(s) submitted by the applicant as part of its EOI is complete.
• Assessment of prequalification-specific data and information as specified in the applicable guidelines for submission.

Reliance on the assessment of the product dossier, inspection of manufacturing sites and/or clinical sites conducted by the SRAs. However, WHO reserves the right to conduct inspections of manufacturing sites and/or clinical sites in connection with an abridged assessment if, in WHO’s discretion, such inspections are necessary or required.

Note: By submitting an EOI, the applicant undertakes to share information with WHO on all relevant aspects of manufacture and control of the specified products along with changes made and/or planned. Applicants must provide the necessary information to WHO by submitting a product dossier, in the prescribed format, and other information as requested by WHO.

WHO reserves the right to terminate the prequalification assessment of a specific product if the applicant is not able or not willing to provide the required information or to implement corrective actions which WHO may require within a specified time period, or if the information supplied is inadequate to conduct this procedure.

Applicant's responsibilites – abridged and/or full assessment pathway

• It is the applicant's responsibility to source and purchase the RBP, used to conduct the similarity exercise (quality characteristics, non-clinical and clinical data set), from an SRA market.
• It is the applicant's responsibility to promptly communicate to WHO any safety concerns arising from the RBP on which its prequalification application is based, in the case of similar biotherapeutic products (SBPs).
• WHO relies on information supplied by or originated from SRAs, which may result in WHO determining (in its sole discretion) to waive one or more of the requirements listed below.
• It is the applicant's responsibility to demonstrate that the selected RBP has been licensed and approved by an SRA based on a product dossier containing comprehensive data on nonclinical and clinical studies / full quality, safety and efficacy data.
• It is the applicant's responsibility to conduct a similarity exercise(s), starting with comparison of quality characteristics, of the SBP and RBP that represents the prerequisite for the reduction of the non-clinical and clinical data set required for licensure of the SBP and prequalification.
• It is the applicant’s responsibility to provide evidence of the similarity of the SBP with a suitable RBP based on evaluation of the whole data package for each of the quality, nonclinical, and clinical parameters, i.e. the totality of evidence.

Applicant's responsibilites – full assessment pathway

• This consists of WHO assessment of the required product dossier submitted by the applicant, which must include product data and information on quality, non-clinical and clinical aspects, including product formulation, manufacture and test data and results. Product data and information should meet the requirements described in the WHO guidelines on the evaluation of BTPs or of SBPs.
• It is the applicant's responsibility to source and purchase the comparator used for clinical studies from an SRA market.
• It is the applicant's responsibility to provide WHO with all results of pharmaceutical (physico-chemical, biological andmicrobiological) tests, pre-clinical (toxicological and pharmacological) tests and clinical trials related to the product to be prequalified.
• It is the applicant's responsibility to document that the manufacturer is authorized in their country to produce medicinal products for human use.
• It is the applicant's responsibility to provide WHO with the details of any decision to refuse authorization in any country and the reasons for such a decision.
• It is the applicant's responsibility — after the product has been listed in the prequalification list and with respect to the methods of manufacture and control provided in the prequalified dossier — to take into account technical progress and introduce any changes that may be required to enable the prequalified product to be manufactured and checked by means of generally accepted scientific methods. Those changes shall be subject to WHO evaluation.
• It is the applicant's responsibility to ensure that the product information is kept up to date with the current scientific knowledge. The proposed changes shall be subject to WHO evaluation the applicant is encouraged, if a product has been prequalified by WHO via the full assessment route, to apply for the collaborative procedure which facilitates the assessment and accelerated national registration of a WHO-prequalified product.

Furthermore, WHO may collaborate with NRAs regarding the product dossier assessments and site inspections. Subject to the terms described in the section below (Steps of the pilot procedure), WHO's prequalification of Rituximab and Trastuzumab BTPs, or corresponding SBPs as applicable, may also be based on approval of such products by SRAs. WHO recommends that applicants expressing interest in participating in the prequalification procedure:

• inform the NRAs in the country of manufacture and/or the country where an application for registration has been submitted of their intention to do so
• request such NRAs to collaborate with WHO in the prequalification process including, in particular, the quality assessment process.

Applicants should provide the NRAs with the necessary authorization to discuss the relevant product files with WHO representatives during the product dossier assessment and site inspections (subject to appropriate confidentiality provisions, if necessary).

Invitation for submission of expressions of interest

The products listed in any invitation for submission of EOIs are considered by WHO to be vital for the effective diagnostic, treatment or prevention of specified diseases. Invitations are open and transparent, inviting all relevant parties to submit an EOI for the products listed.

Such invitations are published on this WHO website and possibly also through other media, such as the international press.

For each product for which prequalification under this pilot procedure is sought, the applicant should send a product dossier in the common technical document (CTD) format, together with the other data required, as per the relevant guidelines, to the WHO Team Lead for Medicine Assessment.