The regulatory regimei Classification
Some classifications are expressly defined by Federal Laws. For example, the definitions for 'medicine', 'drug' and 'pharmaceutical input' are defined by Federal Law No. 5,991/1973. Within the legal boundaries, ANVISA has the corresponding competence to issue regulations on the classification of the products subject to sanitary surveillance. Borderline cases are decided by the agency, with the issuance of a decision or a new regulation by the board of directors.
In case of new technologies that have not yet been subject to specific regulation, ANVISA's technical areas may issue orientations on the classification of products. That is the case involving software of medical devices, for example. Although health software has not been subject to a specific ANVISA Resolution so far, one of the agency's technical areas has issued guidance on how to differentiate software as a medical device, software as part of a medical device and software that is not a medical device.ii Non-clinical studies
ANVISA requires pharmacological and toxicological data derived from non-clinical studies to authorise a clinical trial. These studies must be performed according to Good Laboratory Practices (BPL). The BPL correspond to a 'quality system covering the organisational process and conditions under which non-clinical health and safety related environmental studies are planned, developed, monitored, recorded, archived, and reported'.6
ANVISA published a guide in 2013 regarding the performance of non-clinical trials of toxicology and pharmacological safety, which are necessary for the development of drugs. The guide mentions that non-clinical studies must comply with the Principles of Good Laboratory Practice from the OECD and the Handbook Good Laboratory Practices (GLP) from the World Health Organization (WHO), whenever applicable.
According to the guide, the animals must be healthy, stated as specific pathogen free (SPF), must be from known origin and possess age and weight compatible with the experiment.
Experiments with vertebrate animals (subphylum Vertebrata, phylum Chordata) are regulated by the National Council for the Control of Animal Experimentation (CONCEA). CONCEA is responsible for regulating and monitoring the humanitarian use of animals in scientific research.iii Clinical trials
There are two main authorities that regulate clinical trials in Brazil: ANVISA and the National Health Council (CNS). ANVISA regulates the clinical trials of medicines through Resolution ANVISA No. 9/2015 and the clinical trials of medical devices through Resolution ANVISA No. 548/2021. CNS regulates the ethical aspects of studies involving human beings through Resolution CNS No. 466/2012.
To be performed, a clinical trial must obtain the regulatory approvals from ANVISA and from the CEP/CONEP System. This system is composed of the local research ethics committees (CEP) and by the National Commission for Ethics in Research (CONEP), which are all linked to CNS.
The sponsor of the clinical trial must be identified before the authorities. The sponsor may be responsible for managing the clinical trial or it may hire a contract research organisation (ORPC) to assume all or some of the regulatory obligations. Hiring an ORPC may be particularly advantageous in case the sponsor is not established in Brazil through a parent company or subsidiary.
There is also the possibility of a clinical trial being initiated and fully conducted by the investigator. In this case, the investigator is called a sponsor-investigator, a physical person that develops the trial with its own financial resources and materials, as well as resources from research funding bodies, private entities and non-profit organisations.
Clinical trials in Brazil must follow harmonised guidelines for Good Clinical Practice (BPC) as set forth in PAHO's Document of the Americas and in ICH's Guideline for Good Clinical Practice (Document E6), as well as specific BPC regulation issued by ANVISA.
As determined by good clinical practices, informed consent must be obtained from the subjects or their legal representative through a written document, the Informed Consent Form (TCLE).
The investigator is responsible for communicating all adverse events to the CEP/CONEP system and to the sponsor. The sponsor, by its turn, must notify ANVISA of all unexpected serious adverse events (EAGs) identified during the study. Phase III clinical trials must be accompanied by Independent Safety Monitoring Committees whose recommendations must be presented to ANVISA by the sponsor.
According to Resolution CNS No. 466/2012, at the end of a clinical trial, the participants are entitled to free indefinite access to the best proven prophylactic, diagnostic and therapeutic methods. The absence of a time limitation to the guarantee of free access has raised the industry's concerns regarding the post-study costs, especially in the case of high-cost medicines. In 2017, CNS issued Resolution No. 563/2017 regarding the post-study access to treatment of ultra-rare diseases.7 This Resolution established a five-year term, from the date of registration, for the subject's free access to the best proven prophylactic, diagnostic and therapeutic methods, in case of ultra-rare diseases.iv Named-patient and compassionate use procedures
ANVISA regulates two different procedures through which a patient may access drugs before the marketing authorisation is granted: compassionate use and expanded access programmes.
A compassionate use programme is a programme conducted for 'a new promising drug for the personal use of patients who are non-participants of an expanded access programme or clinical trial, which has not yet obtained a marketing authorisation before ANVISA, that is in process of clinical development, intended for patients with serious debilitating or life-threatening diseases and without satisfactory therapeutic alternative registered in the country'.8
ANVISA's approval for compassionate use is personal and non-transferable. To obtain approval for the programme, there must be enough scientific evidence for the therapeutic indication. Also, the drug may be in any clinical development phase, provided that the initial information is promising, and the severity of the disease and the absence of available treatments are proven.
An expanded access programme is a programme to make available a 'promising new drug, which has not yet obtained a marketing authorisation before ANVISA or is not commercially available in the country, that is currently in or concluded a phase III of a clinical trial, directed for a group of patients suffering from severe or life-threatening debilitating diseases and without satisfactory therapeutic alternative with registered products'.9
Expanded access programmes are available to a certain group of patients who were not subjects of a clinical trial because of lack of access or because they did not meet the inclusion criteria.
The programme approval procedure begins with a request from the sponsor or the contract research organisation (ORPC) to ANVISA. In case of both programmes, the sponsor must support the patients with free access to the drug without time limitation, according to medical recommendation. The sponsor must also provide full assistance to the patient in case of complications or damages, foreseen and unforeseen, associated to the use of the programme's drug.
The responsible physician must notify the sponsor of the occurrence of EAGs. The sponsor is responsible for notifying ANVISA of such events.
Until this date, there are no similar programmes regarding medical devices. Nonetheless, in June 2021, ANVISA published Public Consultation No. 1,049/2021 with a proposal of regulation for the compassionate use of medical devices. ANVISA has already received the contributions to the proposal and should publish a new Resolution on the matter.v Pre-market clearance
To be marketed in Brazil, a product must be regularised before ANVISA by a Brazilian company. Thus, the regulatory pathway for obtaining a marketing authorisation begins with the incorporation of the legal entity in the country.
After establishing the legal entity, the company must obtain the necessary permits and licences before ANVISA and the local sanitary authorities, for each activity it intends to perform, such as sales, distribution, importation, exportation, among others.
After obtaining clearance to practice its activities, the company may submit a request for the marketing authorisation of a product.
For each of these regulatory steps, the company must file a petition before ANVISA, or before the local authority, and pay the corresponding fee. The values may vary according to each type of fee, the complexity of the sanitary surveillance services involved in the activity and the company size. For example, the petition for certification of GMP of a medicines production line in Brazil and Mercosur may cost nearly 30,000 reais if the company size is deemed as big and nearly 3,000 reais if it is deemed as small.10
There are different types of marketing authorisations, according to the product the company intends to market. Medicines are subject to registration, which encompasses a previous technical analysis before ANVISA's decision on the approval. Medical devices may be subject to registration or notification, depending on the risk classification of the product. Notification is intended for lower-risk medical devices, as it is a simpler administrative procedure that waives prior technical analysis for the product's regularisation.
There are also fast-track procedures for special products, such as medicines intended for neglected diseases, public health emergencies or the paediatric population, as well as vaccines and hyperimmune serums to be incorporated into the Ministry of Health's National Immunisation Programme and medicines considered as strategic to SUS.
Generic drugs may be subject to fast-track registration procedures, provided that the product is one of the first three generic drug applications for an active pharmaceutical ingredient or association and pharmaceutical form. To obtain fast-track approval, the three generic drug applications must be from different economic groups.11vi Regulatory incentives
The patent analysis by the Brazilian Patent and Trademark Office (BPTO) and the marketing authorisation procedure before ANVISA are independent administrative procedures that do not communicate with each other.
Until August 2021, BPTO's procedure for patent analysis had to be preceded by ANVISA's prior consent in case of patents for pharmaceutical products and processes, due to Section 229-C of the Brazilian Industrial Property Law (Law No. 9,279/1996). That mechanism was deemed responsible for delays in the analysis of many patent requests related to pharmaceutical products.
On 26 August 2021, Section 229-C was revoked by Law No. 14,195/2021. Since then, ANVISA no longer has a role in the analysis of pharmaceutical patents, which should speed up the patent analysis procedure.
In 2014, the Ministry of Health issued a specific Ordinance regarding the National Policy for the Integrated Care of People with Rare Diseases.12 This Policy aims to act towards the promotion, prevention, early detection, timely treatment, reduction of disability and palliative care for people with rare diseases.
In line with this policy, ANVISA issued special rules for the approval of clinical trials to be conducted in Brazil for the evaluation of medicines for rare diseases, the GMP certification for medicines for rare diseases and the marketing authorisation for new medicines for rare diseases. In case of ultra-rare diseases, CNS established a five-year term, from the date of registration, for the subject's free access to the best proven prophylactic, diagnostic and therapeutic methods.
During the covid-19 pandemic, ANVISA issued many exceptional and temporary rules to facilitate the importation, commercialisation and distribution of products considered as essential in the fight against the virus. The products encompassed by these rules were mainly medicines used for the intubation of patients, medical devices used in intensive care units, personal protective equipment, and medical gases.vii Post-approval controls
Any marketing authorisation holder must have a post-approval control of its products placed on the market.
In case of medicines, the company must establish and maintain a well-documented pharmacovigilance system in Brazil, which must encompass a standard operating procedure for the pharmacovigilance-related processes, periodic reports about the safety of the products and a risk-management plan.13 The pharmacovigilance system must be controlled by a professional with a duly trained staff of a number that is compatible with the pharmacovigilance activities.
Likewise, medical device companies must establish and maintain a techno-vigilance system. The techno-vigilance system is a 'surveillance system of adverse events and technical complaints of medical devices in the post-commercialisation phase'.14 The system must encompass risk-management operations and must be controlled by a professional with a higher education degree and registered in the professional council.
It is possible to make post-approval amendments to marketing authorisations of medicines and medical devices. The petition of amendment must follow ANVISA's subject code criteria and must be accompanied by payment of the corresponding fee.
ANVISA establishes the procedure of transfer of ownership in case of corporate or commercial operations between companies.15 According to this procedure, the current holder of the marketing authorisation must file the petition to revoke the products' approval on the same day the successor files the petition to obtain the approval. ANVISA publishes the transfer by revoking the previous approval and granting the new one on the same day.
The marketing authorisation holder may request the cancellation of the product's approval on its own request. The marketing authorisation approval may also be revoked or suspended by ANVISA as a sanction related to a sanitary infraction.viii Manufacturing controls
To manufacture products subject to sanitary surveillance in Brazil, a company must possess a permit from ANVISA (an AFE) specifically for that activity. In case the company intends to sell a product manufactured in a different country, then, depending on the product, it may need to obtain a Good Manufacturing Practices certificate (GMPc). Once published on the Official Gazette, the GMPc is valid for two years.
To grant a GMPc, ANVISA will inspect the manufacturing site. In case of factories outside of Brazil, ANVISA may also request information to other regulatory agencies and third-party audit bodies recognised by ANVISA.16
In case of medicines and medical devices, the GMPc is granted for each establishment, per production line. Medical devices of lower risk classes (risk classes I and II) are not subject to GMP certification.
In case of transfer of ownership, the successor company must update the company's data before ANVISA. The transfer of ownership of manufacturing facilities does not imply a new certification of GMP, provided that the technical and sanitary conditions of the manufacturing site remain the same.ix Advertising and promotion
The advertising and promotion of medicinal products is regulated by Federal Laws No. 6,360/1976 and No. 9,294/1996, as well as by the Brazilian Federal Constitution (Section 220, Paragraph 4).
The advertising and promotion of products subject to sanitary surveillance cannot induce false interpretation, error, or confusion as to the origin, provenance, nature, composition or quality, and that attribute to the product different characteristics and purposes from those it actually has.17
Prescription medicines and medical devices may only be advertised through publications strictly directed towards healthcare professionals, namely physicians, dental surgeons and pharmacists.
The advertising of over-the-counter medicines to the public is allowed. The companies must, however, follow the rules regarding advertisement and promotion of medicines, such as Resolution ANVISA No. 96/2008. There are expressions that must appear in the advertisement of specific over-the-counter medicines, depending on the active substance and its contraindications.
This rule also prohibits the stimulation of the indiscriminate sale of medicines, the suggestion of diagnosis to the public, the use of images of people taking the medicine, the suggestion that the product may have pleasant organoleptic features, such as good taste or good smell, through images or expressions, the noncompliant promotion of generics, among other actions.
There is no similar rule for the publicity of medical devices. Nonetheless, there are industry codes regarding the medical devices market that establish as good practices that medical devices should be advertised only to healthcare professionals, in accordance with the product's marketing authorisation.
The violation of advertising and publicity rules constitute a sanitary infraction and may subject the company to the penalties addressed in Federal Law No. 6,437/1977, such as warning, fine, suspension or prohibition of advertisement, suspension of sales and imposition of a rectifying message.x Distributors and wholesalers
Distributors and wholesalers of medicines and medical devices must obtain the necessary and specific permits before ANVISA and the local sanitary authorities.
To distribute medicines and medical devices, companies must comply with the good distribution and warehousing practices and obtain the corresponding certification. The certification is issued per establishment.
Distributors may act as marketing authorisation holders of imported products subject to sanitary surveillance in Brazil. In this case, the distributor shall be licensed as importer and shall sign an agreement with the foreign manufacturer to properly assign regulatory responsibilities according to the Brazilian law and regulation.xi Classification of products
The regulation distinguishes between prescription medicines, that may only be marketed under the presentation of a prescription, and over-the-counter (OTC) medicines, that may be marketed without a medical prescription.
To be an OTC medicine, a product must be on the market with the same indications, administration route and therapeutic range for at least 10 years, including five years of commercialisation in the Brazilian market. Medicines may also become OTC medicines if marketed for five years abroad in the same conditions as specified in the Brazilian regulation for over-the-counter medicines.18
In addition, to become an OTC medicine, the company must prove that the product is safe when used without the guidance of a prescriber, including adverse reactions with known causes and that are reversible after the suspension of use of the medication, low potential for toxicity and low potential for clinically relevant food and drug interactions. The medicine must fulfil other requirements, such as being manageable by the patient and indicated for a short period of time, among others.
The classification as an OTC allows advertising strategies that target the lay public, instead of strategies exclusively directed to healthcare professionals, as is the case with prescription medicines.
OTC medicines may be displayed at the pharmacy or drugstore within the public's reach. Prescription drugs, by their turn, must be placed in areas restricted to the circulation of employees.
Prescription medicines may also be subject to special control depending on the active ingredient. Controlled substances are addressed by a specific topic in this article.
ANVISA regulates medical devices in Resolution ANVISA No. 185/2001. Medical devices are classified according to four different risk classes. Classes I to IV range from the lowest to the highest risk level associated to medical devices. Products of lower risk classes (classes I and II) are subject to a simpler form of marketing authorisation called notification. Products of higher risk classes (classes III and IV) are subject to the registration procedure.
Products are also classified within the four risk classes according to four different categories and 18 rules:
- non-invasive products (rules 1, 2, 3 and 4);
- invasive products (rules 5, 6, 7 and 8);
- additional rules applicable to active medical devices (rules 9, 10, 11 and 12); and
- special rules (rules 13, 14, 15, 16, 17 and 18).19
Federal Law No. 9,782/1999 assigned to ANVISA the health control of ports, airports, and borders. Resolution ANVISA No. 81/2008 is the main regulation of imports subject to sanitary surveillance.
To import health-related products, the importer must obtain a specific permit (AFE) for that activity before ANVISA and follow the procedures set forth in the technical regulation (Resolution ANVISA No. 81/2008).
One of the most common procedures corresponds to the obtaining of ANVISA's previous and express approval through an import licence at the Integrated Foreign Trade System (SISCOMEX). SISCOMEX is an online platform coordinated by the Brazilian Federal Revenue and the Secretariat of Foreign Trade that integrates enforcement actions related to imports and exports of different governmental bodies.20 This procedure includes controlled substances, biological products, hemoderivatives, medical devices, food products, medicines, cosmetics, personal hygiene products and sanitising products, among others.
Other import modalities encompass:
- express delivery, which is used for international orders transported by air, by courier company, which requires speed in the transfer and immediate receipt by the recipient;21
- international postal delivery, which is performed by the state company the Brazilian Postal and Telegraph Company;22
- international air parcel, which is a form of transport of goods and products by airlines, on demand, subject to sanitary control;23 and
- the non-electronic simplified import declaration, which is a document under the responsibility of the Federal Revenue.24
Companies may outsource the procedure through an importing company. Notwithstanding, outsourcing of the procedure does not exempt the marketing authorisation holder from its regulatory obligations, including those associated to the import.
The imports and exports of some products are subject to special restrictions. For example, some controlled substances are subject to an import authorisation and an export authorisation before the products' arrival or departure and the substances may only enter or leave Brazil through two ports and two airports, located in the states of São Paulo and Rio de Janeiro.25
Products destined for scientific research are also subject to special import and export rules. For example, products intended for scientific research that does not involve human beings as subjects may obtain an automatic approval of the import licence, provided that the scientific institution is accredited at the National Council for Scientific and Technological Development.26xiii Controlled substances
Federal Law No. 11,343/2006 establishes the National System of Public Policies on Drugs. According to this law, drugs are narcotics, psychotropic substances, precursors, and others under special control of Ordinance No. 344/199827 of the Ministry of Health.
Ordinance No. 344/1998 defines the lists of controlled substances and the specific requirements for the performance of commercial activities involving those substances, including the obtaining of a special authorisation (AE). Activities such as manufacturing, distributing, transporting, packaging, importing and exporting controlled substances require an AE issued by the sanitary local authority, for each establishment.
Controlled substances are divided in lists according to the type of substance and the effects it may cause on human beings. For example, list A1 refers to narcotics, A2 refers to narcotics that are only allowed in special concentrations, lists A3 and B1 refer to psychotropic substances and list B2 to psychotropics substances that may cause anorexia. The lists go from A to F, subdivided in other categories.
The advertisement of controlled substances must be strictly directed towards healthcare professionals allowed to prescribe those substances, through journals with an exclusively technical content.28
Pharmacies and drugstores are subject to restrictions regarding the sale of controlled substances. The commercialisation of some substances is subject to a special control prescription that must be issued in two copies: one that must be kept by the patient and another that must be retained by the pharmacy or drugstore.29 Pharmacies and drugstores must establish a segregated system for storing controlled substances, such as a locker or a specific room.30xiv Enforcement
Enforcement actions encompass all products subject to sanitary surveillance, such as medicines, medical devices, food products, cosmetics, sanitising products, hygiene products, controlled substances, among others, as well as the activities involving such products, including advertising strategies.
These actions may be taken by the federal, state or municipal authorities, depending on the matter and the jurisdiction. Imports and exports are subject to federal surveillance.31
Establishments are subject to inspections from the local sanitary authorities of their jurisdiction (state or municipality). These inspections may happen on the company's request, as a requirement for obtaining a specific approval (a licence, for example), or as a regular exercise of enforcement actions by the authorities.
Ports, airports and borders also have federal agents responsible for the sanitary surveillance of imports and exports.
Members of industry associations regarding medicines and medical devices are subject to the association's code of conduct. In principle, the violation of such rules will subject the offender to the association's disciplinary proceeding, which is usually evaluated by an independent ethics committee.