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Which points generate the most rejections and demands in innovative drug processes?




On 06/17/19, the Sectorial Dialogue of the Incremental Innovation Coordination (COINC) took place, where Dr. Isabela Gomes presented the main reasons for demands and rejections in the registration processes for innovative medicines.


The rejection rates are alarming and need to be better understood in order to be avoided as they reach an unbelievable 53%. The main reasons are:

· Relative bioavailability outside the recommended confidence intervals without substantiated justification that these deviations do not compromise the safety and effectiveness of the proposed innovation.

· Deficiency in EC management: inadequate comparator, inadequate margin of inferiority, primary outcome without statistical significance, inclusion of patients who violated the protocol and problems in the sample calculation.

· Lack of clinical rationality

· Presentation of a process based only on literature without a clinical study to support the proposed innovation, mainly for new associations in fixed dose and kits.

The importance of having a discussion with COINC prior to the submission of the DDCM on the clinical development rationale intended with the product was stressed in order to ensure that the study design drawing (number of patients, outcome, etc.) can support the future record. This discussion can be carried out through a face-to-face meeting or through the development rationale analysis protocol.

Of the processes analyzed since the creation of COINC 09/2017 (09/2017), 130 requirements were generated, totaling 1453 items whose main reasons were:

1. Correction of information in the package insert text and grammatical/orthographic correction: consistency between the results of the clinical study's effectiveness vs. indications, does not include adverse reactions during the conduct of the clinical study (EC), does not include the results of clinical studies with monodrugs in associations, inappropriate language in the patient's package insert, absence of bibliographic references, grammatical corrections, (51% of requirements)


2. Clarifications of information presented in the process: presentation of the clinical rationale for the registration, absence of bibliographic references to support the results and the claim, sending justification for the suggested doses / presentations, presentations and dosages without basis on the CE results, requests clarifications due to inconsistency of information within the process. (12%)


3. Doubts in conducting the study: prevalence of the disease treated, study conducted with a placebo without due justification for existing treatments, inadequate bibliographic references to support the absence of CE. (6%)


4. Request for additional documents or information: Sending study protocol in addition to the final study report, absence of justification for items (for example, use of placebo), not sending the mentioned bibliographic references. (7%)


5. Update on the international regulatory situation and request for post- marketing data (for products already registered abroad). (4%)


6. Request for amendments to CETER and GFARMA in the cases required by regulation. (3%)


7. Information items (17%)

A point frequently addressed in all ANVISA presentations and raised again was the importance of having consistency in the information within the dossier.




From all the items raised for both requirements and rejections, the need to rely on literature for design, sample calculation, selected outcomes, clinical rationale, comparator and dosage, as well as for all the justifications provided in the process, stands out. It is quite evident that ANVISA wants to see in all innovation processes a strong scientific basis and not just presentation of data without insertion in the clinical context of the disease and treatment.

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