During the public meeting of the Collegiate Board (DICOL) on 3/19/24, ANVISA approved the normative instruction (IN No. 289, OF MARCH 20, 2024) that establishes on a permanent basis, in accordance with the Resolution of the Collegiate Board - RDC No. 741 of August 10, 2022, the criteria and procedures for registration and post-registration of medicines, vaccines, biological products and their active substances, and for issuing an adequacy letter for an active pharmaceutical ingredient dossier (CADIFA) through the use of analyzes carried out by the Equivalent Foreign Regulatory Authority (AREE - acronym coming from Portuguese). The IN came into force on April 1, 2024.
Its publication was already awaited by the sector, as this regulatory advance was the result of a process planned and executed in different stages, involving interested parties from the beginning with the pilot phase, conducted through the publications of RDCs 750 and 741 /2022, until the publication of Public Consultation 1,108, held between October 15 and December 29, 2022. Furthermore, throughout this process, Anvisa promoted a series of interaction activities with the parties and established dialogues with various foreign regulatory authorities.
According to specialist Cláudia Cilento, the new regulations did not bring significant changes to administrative procedures. However, the inclusion of registration and post-registration of vaccines through the optimized analysis route and the admission of the Australian agency (Therapeutic Goods Administration - TGA) as AREE, are relevant changes that were contemplated.
Other important deliberations were: (i) allowing requests rejected by RDC No. 750 to be resubmitted and reevaluated based on the requirements established by the new Instruction; (ii) establish that requests that were pending decision, on the date the Regulation came into force, will already be evaluated according to the rules established in the aforementioned Resolution.
ANVISA has been taking this direction lately, so much so that now at the beginning of April it published OFFICE No. 35/2024/SEI/DIRE2/ANVISA where it communicates that it has chosen as one of its strategic projects, to qualify in order to meet the requirements of the World Health Organization - WHO, so that the Agency is recognized as an international reference, being included among the Organization's Listed Authorities. If you successfully complete this qualification, the drug evaluations carried out by Anvisa could positively impact the marketing authorization of products regularized with ANVISA in countries that choose to adopt regulatory trust measures, as well as having easier access to the agencies' purchasing mechanisms. connected to the United Nations. This ends, with a flourish, the cycle of reliance.
After all, what is "Reliance" in the Regulated Sector?
Reliance – which in this article means “trust” – is the term adopted by the regulated sector to refer to the simplified analysis procedure that is based on regulatory trust. In other words, it involves regularizing the product using analyzes previously carried out by foreign regulators recognized by ANVISA.
Equivalent Foreign Regulatory Authority (AREE)
The Normative Instruction lists, in its Annex I, the AREEs that it considers having regulatory practices aligned with those of Anvisa and whose registrations issued by them may be considered for the types of products specified. Check the table below:
When can it be used and how to prove it?
To be eligible for reliance, the product must be registered, solely and exclusively, with one of the agencies (AREEs) listed in the Instruction. It is up to the petitioner to indicate the AREE that will be used as a reference.
Another essential requirement is proof that the product that will be submitted for evaluation by Anvisa is essentially identical to that approved by the foreign reference agency. To do this, it must have the same essential characteristics.
As defined by the standard, “essential characteristics are attributes of the medicine, vaccine and biological product that include their manufacturers, qualitative and quantitative composition, concentration, pharmaceutical form, therapeutic indications, contraindications, dosage, target population, route of administration, mode of use, specifications, manufacturing process and respective production plants involved, API manufacturers and quality grades of APIs and excipients.”
Therefore, the product to be submitted in Brazil may only presents very small differences in relation to the product registered abroad.
The instructional documentation to support the request for regularization of the product with Anvisa through the use of analyzes carried out by the AREE must, in turn, (i) contain updated data and information that ensure that the product has essential characteristics identical to those approved by the AREE , including its quality aspects; (ii) be sufficient to identify the level of quality of the API, when it is a DMF; and (iii) be submitted in its complete form, without any information relevant to the agency's assessment being marked or omitted, including questions and guidance that were made during the analysis by the foreign agency.
Furthermore, as expected, the product must not have failed any of the AREEs listed; it must not have been subject to recall, cancellation of registration or regularization; Manufacturers must not have a history of being banned within the last three years due to non-compliance with health requirements by their country's health authority, Anvisa or AREE.
Reliance is not automatic; it must be requested!
Although ANVISA may request a comparison through a requirement during the course of an analysis process (and this has been done before), reliance must be required when submitting the request and must have already been foreseen by the applicant from the beginning of preparation. of the petition, applying their specific codes.
The request for regularization via the optimized analysis procedure must be accompanied by all the documents and information established by the specific regulations in force and the instruction must be made in a specific addition to the process or part(s) of the process requested. optimization, by completing and signing the checklist available in Annexes II or III of the Regulation. Proof of Regularization granted by AREE, in force at the time of the petition, must be attached; attach regulatory documentation issued by the AREE, with the mandatory information mentioned above; list all documents submitted in the initial claim and in the specific addition, differentiating those that were previously evaluated by the AREE from those that were produced for the Brazilian context; and, finally, complete the report containing the evaluation of the documentation issued by the AREE and, additionally, demonstrate that the product has essential characteristics equivalent to those approved by the foreign authority.
Despite Anvisa's openness to the regulatory trust process, it maintained its autonomy in the decision. Upon evaluation of the instructional documentation, the agency will decide whether to accept the optimized analysis route, using it as a sole or complementary reference, or whether the regularization request should be submitted, in part or in full, to the ordinary analysis route.
Furthermore, Anvisa's decision-making autonomy applies at any time, given that, during the course of the optimized analysis process or even after registration has been granted, if the agency has doubts regarding safety and effectiveness, it may request complementary documents or complete documentation applicable to the ordinary registration route.
Isonomy
Reliance is a facilitating process, but adopting the optimized procedure does not imply changing the chronological order of the petitions. This measure ensures that companies are treated equally, as otherwise imported products would have an advantage in the registration queue.
Impact
Considering all this, Cilento assesses that the optimized analysis procedure has the potential to reduce the time spent by the technician analyzing the process. Therefore, it would have a positive, but small, impact on reducing registration time.
The optimized route can also be considered safer, since Anvisa will be based on the AREE's assessment, which can reduce the chance of demands or rejection of the process.
However, the expert considers that the admission of the optimized route through the use of analyzes carried out by foreign regulators will not bring many gains in terms of number of registered products or registration time, since one of the biggest difficulties that the agency faces is the deficit of human resources.
Final considerations
According to Claudia Cilento, the optimized analysis procedure is a very laborious process that requires a lot of support from the holder of the registration issued by the foreign agency; therefore, being advantageous depending on each case.
Before opting for the optimized route, one must consider how easy it is to access the documentation issued by the AREE. If it is easily accessible, the reliance route will always be a good option. Otherwise, if there is not much cooperation from the foreign registration holder, it must be carefully assessed whether the regulatory trust route will indeed be the most advantageous.
Furthermore, strengthening international cooperation, with the exchange of information, with interoperability mechanisms and standardization of processes, maximizes the benefits for patients by ensuring greater safety and effectiveness for products regulated by health agencies around the world.
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