Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5423_Библиотеки_им_академика_М_И_Перельмана

are provided to patients that are within the EU, which is referred to as distance sales. Chapter VI of the IVDR covers the requirements for clinical evidence, per­formance evaluation, and performance studies. Under Article 58(1) it states that a performance study application and approval is required when the study involves:

The review process for a performance study application under IVDR can range from 10days up to 80days. Once the application is submitted, the reviewing com­petent authority has 10 days, with an optional five‐day extension, to notify the sponsor (i.e. the submitter of the application) that the application is within scope of IVDR and is complete. If the competent authority does not think the applica­tion is incomplete or that the application does not fall into scope of the IVDR, the sponsor has 10days to respond. After responding, the competent authority has an additional 5 days to review the updated response and/or application with an optional five‐day extension. This first review is considered the validation of the application. Once the application has been validated, the competent authority has 45days to review and notify the sponsor of the approval status of the application, with an optional 20‐day extension for the purpose of consulting with experts. For CDx, studies using leftover samples are able to initiate the clinical trial after the application validation date assuming that they have received ethics committee approval. For CDx clinical trials not using leftover samples, the competent author­ity approval and ethics committee approval must both be received prior to initiat­ing the clinical trial.

With the newness of IVDR, both therapeutic and device manufacturers are uncertain of how the requirements should be interpreted. One area of ambiguity is around who should be the submitter of the performance study application. A majority of the elements required for a performance study application would be known by the device manufacturer; however, with the scope of IVDR being broad­ened to include any in vitro diagnostic that may influence patient management decisions and IVDR not having an option to submit an application based on risk (i.e. FDA NSR studies being exempt from an IDE application), not all invitro diag- nostic manufacturers have the capabilities to submit a performance study applica­tion. This is leading to some pharmaceutical companies taking on the role of submitting the performance study application for the invitro diagnostic.

Class C device under IVDR and therefore have two options to obtain a CE mark, a quality management system (QMS) and technical documentation according to Annex IX or a type examination according to Annex X combined with a produc­tion quality assurance according to Annex XI.

outlined in Annex I and the summary of technical documentation (STED) out­lined in Annex II.

Brexit, MHRA announced that they were intending to introduce new regulation for governing medical devices, including CDx, which were separate from those estab­lished by the EU Commission (i.e. MDR and IVDR). At the time this chapter was written, the MHRA had released transitional provisions to allow for the continued acceptance of the EU CE Mark, under both the previous directive (98/79/EC) and the current regulation (IVDR 2017/746). MHRA is aiming for core aspects of the future medical device regulations to apply in July 2025[15].

A global regulatory strategy (GRS) document looks at the device for what is cur­rently being developed and thinks wholistically about the device and its market­ing future. The document should be generated at the beginning of the device development and updated regularly throughout its lifecycle. By creating the GRS early in the device development, it ensures all parties are including country‐ specific requirements that may be needed at a future date and could potentially cause rework or delays. For example, some countries require in‐country clinical trials to be completed before authorization of the device. Knowing these require­ments early in the development process will minimize any delays or additional clinical trials that may be needed.

marketing authorization. For example, more complex CDx programs may have three or more pre‐submissions that take place with FDA prior to submission of a PMA and the rationale behind the development team’s responses should be recorded. The FDA review team may provide the manufacturer with requests for the PMA in their first pre‐submission, which will need to be addressed during the PMA submission.

When developing a CDx for a rare disease, there are constraints that need to be considered during development that may not be present for a common or promi­nent disease indication.

from similar disease indications. However, even if surrogate samples are pro­cured, the regulatory agency reviewers will still expect that true patient samples be used in the key performance studies, such as accuracy and precision. The use of surrogate samples and the number of true patient samples that are necessary for conducting nonclinical performance studies should be discussed with the FDA or EMA early in the CDx development process.

Another consideration would be the limited amount of clinical data that may be available to support the clinical validation of the CDx. Rare diseases may often receive accelerated approval on smaller patient numbers than a full approval would require. In these situations, the gene therapy manufacturer discusses this pathway with the therapeutic regulatory agency review team and seeks endorse­ment; however, this conversation also needs to occur with the device regulatory agency review team. If these conversations do not take place during the develop­ment timeline, the CDx approval may jeopardize the approval of the gene therapy.

The selection of the CDx partner by the gene therapy manufacturer is a critical process that should not be rushed and be very deliberate. Some questions that the gene therapy manufacturer should ask themselves before selecting the partner would be:

A commercialization strategy for the CDx should be prepared well before market­ing approval is obtained in order to ensure rapid deployment of the test. The strat­egy must consider matters, such as reimbursement, logistics, marketing, and regulatory approvals, in additional markets. Post‐approval the CDx may evolve as reagents and instruments are updated or changed, or laboratory facilities are moved and these changes typically require some type of regulatory action. And as a regulated product, CDx may be subject to various reporting obligations to the relevant authorities.

A common scenario is for an already approved CDx to be used in clinical develop­ment for a different drug, indication, or patient population than its original approval. For example, the FoundationOne CDx (Foundation Medicine, Inc.), cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc.), and BRACAnalysis CDx (Myriad Genetic Laboratories, Inc.) have claims for multiple drugs and indi­cations as shown on the FDA’s website, List of Cleared or Approved CDxDevices (In Vitro and Imaging Tools)[22]. The use of an already approved test during

clinical development will typically incur lower risk than development of a new test.

In the years following marketing, modification to the CDx may be required because of changes in reagent or instrumentation availability. Other potential changes that may impact a CDx include software updates and moving the site of a manufacturing or testing facility. These changes to the device typically require additional validation and reporting or submissions to regulatory agencies.