Contents of a Dossier

Different regulatory requirements apply to different international markets for MCDsmale circumcision devices. Manufacturers who supply an MCD in multiple countries often alter some aspects of a single product to comply with such varying regulatory requirements (for example, the information within the instructions for use (IFU), the intended purpose statements, batch release procedures, or information on the labels).

If the product submitted for prequalification has multiple regulatory versions, the manufacturer should provide information regarding these different regulatory versions. This information should cover all aspects that differ between these product regulatory versions, including (but not limited to) differences in design, manufacturing, quality control, labeling, release for supply, and post-market practices.

Device description

The dossier should include the following device descriptive information:

• A general description including its intended use/purpose.
• The intended patient population and medical condition to be treated or prevented and other considerations such as patient selection criteria.
• Principles of operation.
• An explanation of any novel features.
• A description of the accessories, other medical devices and other products that are not medical devices, which are intended to be used in combination with it.
• A description or complete list of the various configurations/variants of the device that will be made available.
• A general description of the key functional elements, e.g. its parts/components, its formulation, its composition, its functionality. Where appropriate, this will include: labelled pictorial representations (e.g. diagrams, photographs, and drawings), clearly indicating key parts/components, including sufficient explanation to understand the drawings and diagrams.
• A description of the materials incorporated into key functional elements and those making either direct contact with a human body or indirect contact with the body.

The IFU may be used to provide some of this information on the condition that a cross-reference to the different requirements is supplied in conjunction with the IFU.

Product specification

The dossier should contain a list of the features, dimensions and performance attributes of the MCD, its variants and accessories (if such are within the scope of the dossier), that would typically appear in the product specification made available to the end user, e.g. in brochures, catalogues and the like.

Reference to similar and previous generations of the device

Where relevant to demonstrating conformity to the Essential Principles, and to the provision of general background information, the dossier should contain an overview of the manufacturer's previous generation(s) of the device, if such exist and/or similar devices available on the local and international markets.

Essential Principles (EP) checklist

The product dossier should include an EP checklist that identifies:

• the Essential Principles of Safety and Performance
• whether each Essential Principle applies to the male circumcision device and if not, why not
• the method used to demonstrate conformity with each Essential Principle that applies
• a reference for the method(s) employed (e.g. standard)
• the precise identity of the controlled document(s) that offers evidence of conformity with each method used.

The method used to demonstrate conformity may include one or more of the following:

• conformity with recognized or other standards; where the manufacturer demonstrates conformity with particular EP by claiming compliance with available standards, these standards should be identified
• conformity with a commonly accepted industry test method (reference method)
• conformity with appropriate in-house test methods that have been validated and verified
• the evaluation of pre-clinical and clinical evidence
• comparison to an MCD already available on the market.

The EP checklist should include a cross-reference to the location of such evidence both within the full technical documentation held by the manufacturer and within the dossier (when such documentation is specifically required for inclusion in the dossier as outlined in this guidance).

Note: The identity of the MCD must be clearly identified on the EP checklist and should include the product name and product code(s). This information must be aligned with the information provided in the dossier section on regulatory versions of the product.

Risk analysis and control summary

A risk analysis should be undertaken to identify and address all known or foreseeable hazards for the product, taking into account such aspects as the user/s of the device, the patients on whom the device will be used and the technology involved. The dossier should contain a summary of the risks identified during the risk analysis process and a description of how these risks have been controlled to an acceptable level. Furthermore, the risk analysis should be part of the manufacturer's risk management plan. Where specific standards or guidelines are recommended by WHO, these should be followed. The information provided in the dossier should address possible hazards for the MCD. The results of the risk analysis should provide a conclusion with evidence that remaining risks are acceptable when compared to the benefits.

Note: The risk analysis and the instructions for use should be controlled by the manufacturer in full consistency with one another. All residual risks that could not be mitigated through design or protection measures should be addressed in the instructions for use as warnings and precautions and vice versa, all warnings and precautions mentioned in the instructions for use should originate from the risk analysis.

The product dossier should summarize the results of verification and validation studies undertaken to demonstrate conformity of the MCD with the Essential Principles that apply to it. Such information would typically cover:

• engineering tests
• laboratory tests
• simulated use testing
• any animal tests for demonstrating feasibility or proof of concept of the finished device
• any published literature regarding the device or substantially similar devices.

Such summary information may include:

• declaration/certificate of conformity to a recogniZed standard(s) and summary of the data if no acceptance criteria are specified in the standard
• declaration/certificate of conformity to a published standard(s) that has not been recognized, supported by a rationale for its use, and summary of the data if no acceptance criteria are specified in the standard
• declaration/certificate of conformity to a professional guideline(s), industry method(s), or inhouse test method(s), supported by a rationale for its use, a description of the method used, and summary of the data in sufficient detail to allow assessment of its adequacy
• a review of published literature regarding the device or substantially similar devices.

A summary of outcomes should be provided that contains enough information to allow WHO to assess the validity of that information. It should include any references to relevant international or published standards or guidelines that have been applied in the production of the data. It should also include a review of relevant published literature regarding the product or substantially similar products.

In addition, where applicable to the device, the dossier should contain detailed information on:

• biocompatibility
• medicinal substances incorporated into the device, including compatibility of the device with the medicinal substance
• biological safety of devices incorporating animal or human cells, tissues or their derivatives
• sterilization
• animal studies that provide direct evidence of safety and performance of the device, especially when no clinical investigation of the device was conducted
• clinical evidence.

Detailed information on each performance claim should be provided and include:

• the complete study protocol
• the method of data analysis
• the complete study report
• the study conclusion.

Actual test result summaries with their acceptance criteria should be provided and not just pass/fail statements. Where no new testing has been undertaken, the dossier should incorporate a rationale for that decision, e.g. biocompatibility testing on the identical materials was conducted when these were incorporated in a previous, legally marketed version of the device. The rationale may be incorporated into the EP checklist.

Note: In each submitted study, the product should be clearly identified; i.e. clearly indicate the product name, product code(s) and the regulatory version of the product submitted for prequalification assessment.

Biocompatibility

The dossier should contain a list of all materials in direct or indirect contact with the patient or user.

Where biocompatibility testing has been undertaken to characterize the physical, chemical, toxicological and biological response of a material, detailed information should be included on the tests conducted, standards applied, test protocols, the analysis of data and the summary of results. At a minimum, tests should be conducted on samples from the finished, sterilized (when supplied sterile) device.

Medicinal substances

Where the device incorporates, or its use requires, a medicinal substance(s), the dossier should provide detailed information concerning that medicinal substance, its identity and source, the intended reason for its presence, and its safety and performance in the intended application.

Biological safety

The dossier should contain a list of all materials of animal or human origin used in the device. For these materials, detailed information should be provided concerning the selection of sources/donors; the harvesting, processing, preservation, testing and handling of tissues, cells and substances of such origin should also be provided.

Process validation results should be included to substantiate that manufacturing procedures are in place to minimize biological risks, in particular, with regard to viruses and other transmissible agents.

The system for record-keeping to allow traceability from sources to the finished device should be fully described.

Sterilization

Where the device is supplied sterile, the dossier should contain the detailed information of the initial sterilization validation including bio burden testing, pyrogen testing, testing for sterilant residues (if applicable) and packaging validation.

Typically, the detailed validation information should include the method used, sterility assurance level attained, standards applied, the sterilization protocol developed in accordance with those standards, and a summary of results.

Evidence of the ongoing revalidation of the process should also be provided. Typically this would consist of arrangements for, or evidence of, revalidation of the packaging and sterilization processes.

Animal studies

Where studies in an animal model have been undertaken to provide evidence of conformity with the Essential Principles related to functional safety and performance, detailed information should be contained in the dossier.

The dossier should describe the study objectives, methodology, results, analysis and conclusions and document conformity with WHO Good Laboratory Practices. The rationale (and limitations) of selecting the particular animal model should be discussed.

Clinical evidence

The dossier should contain the clinical evidence that demonstrates conformity of the device with the Essential Principles that apply to it.

Clinical evidence is an important component of the technical documentation of a male circumcision device for use in public health male circumcision programmes for HIV prevention, which along with other design verification and validation documentation, device description, labelling, risk analysis and manufacturing information, is needed to allow a manufacturer to demonstrate conformity to the Essential Principles.

A clinical study (also called clinical investigation or clinical trial) is a systematic investigation or study in or on one or more human subjects, undertaken to assess the safety and/or performance of a male circumcision device. The undertaking of a clinical study is a scientific process that represents one method of generating clinical data.

The objective of a clinical investigation is to assess the safety and performance/efficacy of the device in question and evaluate whether the device is suitable for the purpose(s) and the population(s) for which it is intended.

Clinical study – manufacturer

All performance claims should be supported by well-designed studies which have been carried out or coordinated by the manufacturer. Provide information for these clinical studies which should include:

• A detailed written plan and protocol which explains the intent of the study and the way in which the study was performed.
• The date/s on which the study was performed and by which site.
• A written report on the outcome of study. This report should explain how the study results support the product clinical claims. Any anomalous results, or results that are not within predetermined specifications, should be clearly explained or justified.
• Clear identification of the product and product version that is being evaluated.
• Details of the product lots/batches used for the evaluation, including lot number, date of expiry, and the storage conditions of the product prior to and during the study.
• Details of the geographical region and the clinical status of the subjects included in the study.
• Full details of the methods used to define the clinical status of the subjects.
• Full details of statistical methods, estimations and calculations applied.
• Evidence that the outcomes of the studies have been reviewed and accepted.

Note: Actual test results and their acceptance criteria should be provided, and not just pass/fail statements. All data provided should be clearly labelled, and should be clearly linked to the study report. Furthermore, all abbreviations used in reports and on data records should be defined and spelt out in full.

Clinical study – independent study

The product dossier should contain clinical evidence that demonstrates conformity of the device with the Essential Principles that apply to it. (The Essential Principles of Safety and Performance of Medical Devices include essential safety and performance criteria for a medical device that allow the manufacturer to demonstrate that the product is suitable for its intended use. ) Clinical evidence is an important component of the technical documentation of an MCD for use in public health male circumcision programmes for HIV prevention, which along with other design verification and validation documentation, device description, labelling, risk analysis and manufacturing information, is needed to allow a manufacturer to demonstrate conformity to the Essential Principles. A clinical study (also called clinical investigation or clinical trial) is a systematic investigation or study in or on one or more human subjects, undertaken to assess the safety and/or performance of an MCD. The undertaking of a clinical study is a scientific process that represents one method of generating clinical data.

The objective of a clinical investigation is to assess the safety and performance/efficacy of the device in question and evaluate whether the device is suitable for the purpose(s) and the population(s) for which it is intended.

The WHO Technical Advisory Group on Innovations in Male Circumcision has recommended that the following pivotal clinical studies be conducted independently from the manufacturer in at least two countries representative of the intended use setting:

Clinical study: Phase 1 (randomized controlled trial): This phase includes a comparative study (at least 100 patients) that compares the performance of the device with a standard surgical procedure in a randomized controlled trial. This trial needs to be performed by surgeons skilled and equipped to offer either method.

Clinical study: Phase 2 (field study): This study phase, also called field study, is a non-comparative field trial of the device in settings of intended use, with procedures performed by trained mid-level providers (non-physicians). A cohort study of at least 500 patients in each country is enrolled and followed up.

It is anticipated that principal investigators responsible for the independent clinical trials and field studies will provide a detailed full study protocol, the method of data analysis and the full study report directly to WHO (Department of HIV/AIDS). This information will be reviewed by experts and presented to the WHO Technical Advisory Group on Innovations in Male Circumcision (TAG IMC) for their review. The recommendation from the TAG IMC will constitute the information required for this section of the dossier. Scientifically sound clinical data should include:

• the evaluation study design, study protocol, results, and conclusions
• the date/s on which the study was performed
• clear identification of the product and product version that is being evaluated
• details of the product lots/batches used for the evaluation, including lot number, date of expiry, and the storage conditions of the product prior to and during the study
• details of the geographical region and the clinical status of the subjects included in the study
• details of the methods used to define the clinical status of the subjects
• details of statistical methods, estimations and calculations applied
• details of the entity which performed the evaluation, including current contact details
• a declaration from the entity which performed the evaluation declaring any interests that could constitute a real, potential, or apparent conflict of interest with respect to their involvement in the independent study of this product or the manufacturer of the product.

Countries of supply

The information provided in this section should include: 

• A list all countries in which the product under assessment is currently supplied and the year when supply started. This includes all countries where the device has been made available, in return for payment or free-of-charge, for distribution and/or use in that country.
• Detailed information about the training and support network that is available in each country of supply. For example:
  • how the users are trained in the operation of the device
  • how the users of the product contact the supplier/manufacturer for technical support
  • if there are representatives located in each country of supply to provide technical support
  • how many representatives are available in each country of supply to provide technical support.
• The minimum and maximum price of supply for this product for the last financial year, if available. These prices should be the global minimum and maximum prices and should be quoted in US dollars.
• The number of products sold in each country of supply for the last five financial years, where applicable.

Adverse events and field safety corrective actions

This section should provide the following information:

• A list of all adverse events that have occurred (within the last five years) that did affect, or could have potentially affected, the performance of the device, safety of the patient, safety of users, or safety of any person associated with this product. Include details of the corrective and preventative action taken.
• A list of all events (within the last five years) that required field safety corrective action such as:
  • withdrawal of products from sale or distribution
  • physical return of the product to the manufacturer
  • product exchange
  • destruction of the product
  • product modification/s
  • additional advice provision to customers to ensure that the product continues to function as intended.

An effective quality management system (QMS) is a key consideration for all manufacturers of MCDs. Therefore, MCDs submitted for prequalification assessment should be manufactured under an appropriate QMS. The manufacturer’s QMS should cover all sites used to manufacture this product. The quality management standard ISO 13485:2003 Medical devices – Quality management systems – Requirements for regulatory purposes is considered to be a benchmark in quality management for manufacturers of male circumcision devices by regulatory authorities throughout the world. WHO bases its MCD prequalification assessment and inspection processes on the requirements of this internationally-recognized quality management standard.

Quality manual

Include a copy of the current version of the manufacturer's quality manual. (The manufacturer's quality manual is expected not to exceed 30 pages. However, if it does so, only the electronic copy (CD or DVD) of the document should be submitted.) The following requirements (based on  ISO/TR 10013:2001 Guidelines for quality management system documentation) should be included or covered (or referred to) in the quality manual:

• the title and scope
• the table of contents
• the review, approval and revision
• the quality policy and objectives
• the organization, responsibility and authority
• the references
• the QMS description
• the appendices.

Include the organizational chart of the manufacturer (if not already available within the quality manual) and document control information for the quality manual (such as version number, release date and approval record).

A complete list of all QMS documents, with the document title and document number, relevant to this product should be included.

Quality management system documents

It is expected that, to maintain an effective QMS management system for the manufacture of this MCD, the manufacturer will use a number of documented procedures. Provide copies of the following documented procedures applied in the manufacture of this MCD:

• The manufacturer's documented procedure/s, relevant to this product, for the control of design and development changes.
• The manufacturer’s documented procedure/s, relevant to this product, for the provision of advisory notices to customers subsequent to product delivery.
• The manufacturer’s documented procedure/s for corrective and preventative actions for nonconformities relating to the product under assessment.
• The manufacturer’s documented procedure/s for batch release.
• The manufacturer’s documented procedure/s for the evaluation of key suppliers.
• The manufacturer’s documented procedure/s for the quality control of received supplies (ingredients, components).

Quality management system certification

If the manufacturer holds ISO 13485:2003 Medical devices – Quality management systems – Requirements for regulatory purposes certification for the manufacture of the product under assessment, then provide evidence, such as certified copies of the certificates issued by the conformity assessment body. Ensure that any certificates provided clearly demonstrate that the manufacture of the product under assessment is within the scope of the certification.

WHO guidance

Instructions for compilation of a product dossier (PQMC_018 v1, 23 January 2012)

Dossier checklist (PQMC_049 v1, 6 January 2012)

Post-market surveillance of in vitro diagnostics

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Global Harmonization Task Force (GHTF)* guidance

GHTF/SG1/N70:2011 Label and instructions for use for medical devices

GHTF/SG2/N54R8:2006 Medical devices post-market surveillance: Global guidance for adverse event reporting for medical devices

GHTF/SG2/N57R8:2006 Medical devices post-market surveillance: Content of field safety notices

GHTF/SG5/N3:2010: Clinical investigations

GHTF/SG5/N2R8:2007: Clinical evaluation

* A voluntary group of representatives from regulatory authorities (United States, Canada, European Union, Japan, and Australia), as well as representatives from the medical device industry. In 2012 GHTF was replaced by a regulators-only group, the International Medical Device Regulators Forum (IMDRF), which has adopted the GHTF classification rules and other GHTF regulatory guidelines. IMDRF continues to maintain GHTF guidelines and develop more guidance that will encourage international regulatory convergence and support innovation and timely access to safe and effective medical devices globally.

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International Medical Device Regulators Forum guidance

Essential Principles of Safety and Performance of Medical Devices and IVD Medical Devices (IMDRF/GRRP WG/N47 FINAL:2018)

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International Organization for Standardization guidance

ISO 13485:2003 Medical devices – Quality management systems – Requirements for regulatory purposes

ISO/TR 10013:2001 Guidelines for quality management system documentation

ISO 14971:2017 Medical devices – Application of risk management to medical devices

ISO 14155-2011 Clinical investigation of medical devices for human subjects – Good clinical practice