Regulatory Intelligence (RI) is a practice that has been used in highly regulated sectors, such as energy, health insurance and the pharmaceutical industry.
It is a systematic process of collecting information and analyzing it, which aims to support, based on health principles, the development of strategies and decision-making so that the company can obtain competitive advantages or avoid losses.
In other words, within what is permitted, the fastest way to register a product is sought, to prove its safety and efficacy, since health legislation is quite complex, with several layers, and to understand this tangle, what is allowed and what is not, it is necessary to have in-depth knowledge of the health framework.
But how will RI help clinical research?
First, it is important to clarify that there are two types of clinical research: (i) clinical research for scientific purposes, which answers the researcher's question, and (ii) clinical research aimed at product registration, which has very specific standards and answers the question “is the treatment or health product safe, effective and can be marketed in the country?”.
IR applies to research for registration purposes, because for this type of research, in addition to ethical approval, prior approval from Anvisa is also required.
For this reason, it is crucial that the research project is designed within Anvisa's regulatory scope. Deviating from the legislation is not an option. Furthermore, regulatory intelligence only makes sense when combined with clinical intelligence.
Therefore, the medical, research and development and regulatory areas must work together, exchanging a lot of experience, because the knowledge of each area is complementary to that of the other. When we talk about RI in clinical research, this integration is essential.
Working in this way, the RI process will guide the surveys that must be carried out by the medical field, such as researching information about the disease, its pathophysiology, symptoms, understanding the drug's mechanism of action, pharmacological effects, pharmacokinetics, identifying which drugs are already available for the same indication, the designs of competitors' clinical studies, and also identifying the information that is present and missing to complement the safety and efficacy data.
On the other hand, the regulatory area must specify the classification of the product. This is essential and is one of the first things to be defined within the RI process, because each type of drug or health product registration has a different classification, a different, specific way of proving safety and efficacy. Therefore, knowing the correct classification and the clinical data collected, the clinical development rationale is assertively developed, focusing on obtaining product registration.
For example, for a new biological product, it will be necessary to conduct complete studies, including all non-clinical studies, phase 1, phase 2, phase 3, pharmacodynamics, pharmacokinetics and other complementary studies to prove safety and efficacy. For a biosimilar, for example, it is possible to significantly reduce the number of non-clinical studies and conduct a non-inferiority study complemented by obtaining immunogenicity data.
For a synthetic drug, it is important to identify the development pathway that will be used. A new molecule, for example, will certainly be developed through the complete pathway, whereas for an innovative drug, it will be developed through the abbreviated pathway.
The IR process also assesses whether there is a way in the legislation that allows for a reduction in the number of studies for product registration in order to speed up its launch. For example, is a phase one, phase two, phase three clinical study really necessary if the drug is already known? Will a new pharmaceutical form actually require a clinical study, or would a relative bioavailability or pharmacodynamics study be enough?
Another very relevant issue is to think about the comparator drug focusing on the strategy of proving safety and efficacy, but taking into account the issue of price, since the price definition will be based on the price of the comparator.
All of these connections will be made in this stage of classification, choice of development route, choice of comparator and data collected to develop the most appropriate clinical development rationale for the product and register it as quickly and at the lowest cost possible.
The way to present the rationale to Anvisa should also be discussed by the team, since the presentation of data to the Agency must be done in a way that convinces it that the strategy adopted in the clinical development dossier is the best to prove the safety and efficacy of that product.
In addition, the possibility of obtaining analysis priority for the process is assessed, since reducing the analysis time by Anvisa can be very significant, given the long queue of products submitted for approval of the DDCM and registration. So, for example, if the indication is for a rare disease, or a pediatric disease, or one without treatment, or if the drug has the potential to be much better or to provide a much longer survival rate, it is up to the analysis to be prioritized.
After collecting all this data, the next step is to organize and analyze everything that is already available to identify what is still missing, what data needs to be generated to prove safety and efficacy. The important thing at this stage is to understand what is already known about the drug and what needs to be completed, and then outline the strategy that will be adopted, as well as to point out alternatives for registration, always seeking to register the product in the shortest time, at the lowest cost and in compliance with health requirements.
In short, this analysis phase should extract more than information; in fact, it should provide elements that serve as a basis for decision-making by the team and the company.
Note that the RI process involves outlining the main strategy and alternatives to it, because during the meeting to validate the development project with Anvisa, it is possible that, although the main strategy is well-founded and demonstrates that it contains all the necessary data, the Agency may understand it differently and, with the alternatives in hand, in the same meeting it is possible to obtain the Agency's acceptance to proceed with the project.
It is worth noting that the validation meeting with Anvisa, before submission, is not mandatory, but it brings substantial advantages. Since the Agency is not a development consultancy, if asked about what should be done to demonstrate the safety and efficacy of a product, it will request all the tests. However, at the validation meeting, there is an opportunity to present a structured strategy and discuss and argue with the Agency the validity of the proposed project, capturing its guidelines.
Since during the RI process everything was built together, the registration strategy already includes the rationale for clinical development. Therefore, immediately after the strategy is validated with Anvisa, it is possible to proceed with the finalization of the clinical development dossier and, thus, submit it for ethical approval. After ethical approval, the research can then be submitted for approval by the Agency. Finally, only after approval by the Agency can the clinical study be initiated.
It is important to note that clinical research is not an end, it is a means to register the product.
Another stage of the process that deserves to be highlighted is monitoring the execution of the approved strategy. Since it is a long-term project, several situations may change during the course of the study, such as changes in legislation, the entry of new competitors or other market changes, and these changes may require adjustments to the protocol or different decision-making.
In conclusion, when we talk about registering a product with Anvisa, we are talking about applied science, which must follow the rules in order to register the product. A development design, a clinical protocol for registration purposes, must respond to all safety and efficacy issues and be constructed in such a way that Anvisa understands that the product is fit to reach the market.
Clinical research for registration purposes presents challenges that go beyond finding a cure for diseases and saving lives. It must be developed in a strategic and focused manner, respecting the legislation, considering what is happening in the surrounding area and being planned assertively, so that the “cure” found can be registered, approved and made available to the market.
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