<div class="Insight_area"><!--전문가인사이트 헤더--> <div class="article_head"><!--제목--> <div class="titarea"><!--메인타이틀--> <p class="mtit mt30" style="font-size: 28px;">Registration of New Drugs, Generics and<br />Similar in Brazil</p> <!--서브타이틀--></div> <!--//제목--> <!--전문가 소개영역--> <div class="photozone "><!--전문가사진--> <span class="pz_photo"><img style="width: 110px;" src="/fileDownload2?fileGubun=phm&fileId=00000000000000313329" alt="전문가" /></span> <!--//전문가사진--> <!--전문가정보--><dl class="pz_cont line3"><dt><strong>글</strong> <!--이름--> <span class="nm"> Vera Lucia M. Noguchi </span></dt><!--소속명/직위--><dd class="ex">GPKOL위원</dd></dl><!--//전문가정보--></div> <!--//전문가 소개영역--></div> <!--//전문가인사이트 헤더--> <div class="docarea"> <div class="doctorinfo"><strong>세부 전문분야 및 컨설팅 내용 </strong> <ul class="wp100"> <li>GMP: Quality System management and Good Drug Manufacturing Practices</li> <li>RA: Preparation and submission of generic and biological drug registration dossiers with ANVISA</li> </ul> </div> <div class="doctorinfo mt20"><strong>학력사항</strong> <ul class="wp100"> <li>2012 ICTQ / Quality Management / Post-graduate</li> <li>1988 UFRJ / Industrial Pharma</li> </ul> </div> <div class="doctorinfo mt20"><strong>경력사항</strong> <ul class="wp100"> <li>2007-2016 Instituto Vital Brazil SA QA/RA Manager</li> <li>1998-2007 CENTRALERG Ltda QA/RA Manager</li> </ul> </div> </div> <!--전문가인사이트 내용--> <div class="article_body"><!--내용style1--> <div class="cont mt30"> <p class="cotit mt20">Abstract</p> <p>The activity of drug registration, in Brazil, is responsibility of the National Health Surveillance Agency (ANVISA), created by Law no. 9.782, of January 26, 1999. The regulatory framework, Law no. 6.360/1973 provides that products subject to sanitary surveillance, medicines, among others, must be registered before they are marketed. The current legislation provides the criteria for the granting and renewal of registration of medicines with synthetic and semi-synthetic active ingredients, classified as new, generic and similar is the Resolution RDC no. 60 of october 10, 2014, which describes the step by step in assembling the dossier registration, consisting of administrative and technical documentation for submission at ANVISA. The registration will be valid for 5 (five) years and may be renewed for equal and successive periods, maintaining the initial registration number. Any change in the formula must be submitted to the Agency for analysis.</p> </div> <div class="cont mt30"> <p class="cotit mt20">Introduction</p> <h2>1. Creation of ANVISA</h2> <div class="imgarea fr"><img class="mb0 " style="border: none; margin-top: 5px;" src="/fileDownload2?fileGubun=phm&fileId=00000000000000302322" alt="이미지1" /></div> <p>The activity of drug registration, in Brazil, is responsibility of the National Health Surveillance Agency (ANVISA). The Agency was created by the Law no. 9.782, of January 26, 1999 and has the institutional aim to promote the population's health protection, through the sanitary control of the production and consumption of goods and services subject to sanitary surveillance, including the environments, processes, inputs and technologies related to them, as well as control of ports, airports, borders and customs areas.</p> <br /> <h2>2. Current scenario in the global context</h2> <p>Over the past five years, ANVISA directed its international operations towards two strategic lines: the approach with strategic partners and strengthening of the institutional image in the international scenario. Concerning the approach with strategic partners, the Agency sought to strengthen the relationship with other National Regulatory Authorities in the Americas, by intensifying the exchange of strategic information and the optimization of resources and expertise in the region. Among the main actions carried out, it highlights the exchange of inspection reports to support the Certification of Good Manufacturing Practices and the exchange of information on the withdrawal of products from the market. <br /><br /> In addition to these actions, several working tools were signed and activities were developed in relation to action plans with the Food and Drug Administration (FDA/USA), the Health Canada (HC/Canada), the National Authority of Medicines and Health Products (INFARMED/Portugal), the National Administration of Drugs, Food and Medical Technology (ANMAT/Argentina), the National Institute of Surveillence in Medicines and Foods (INVIMA/Colombia) and the Center for State Control of Medicines, Equipments and Medical Devices (CECMED/Cuba); on top of that, confidentiality agreements were signed between ANVISA and their counterparts in key countries such as Chile, Cuba, Colombia, China, France and Sweden. <br /><br /> In the area of international cooperation new projects have been developed, aligned to the priorities of Brazilian foreign policy and today's technological demands, through strategic partnerships between ANVISA and China, Chile, Colombia, Ecuador, France, Sweden and Portugal. In this scenario, the Agency has been active in international forums related to health surveillance, such as the Summit of Leaders of the Drug Regulatory Agencies; the Meeting of Representatives of National Centers of the WHO Drug Monitoring Program; Meeting the International Regulatory Cooperation of Herbal Medicines (IRCH) – WHO technical forum on herbal medicines; the International Medical Device Regulators Forum (IMDRF) – new forum for regulators health products; the ISAGS/UNASUR; MERCOSUR; the World Trade Organization (WTO) and the Pan American Network on Pharmaceutical Harmonization (the IV Conference was organized and hosted by ANVISA in 2011). In this context, the fulfillment of all international commitments undertaken by the Agency has been confirmed. <br /><br /> In reference to international missions occurred in 2011, the international area of ANVISA took part in 1.205 missions, including inspections, training, cooperation and negotiations, acting both in the preparation of the collaborators for these missions and in the communication with national and international organizations. <br /><br /> Currently ANVISA has been recognized by international organizations with known expertise as a reference in the world scenario on the regulation of products under sanitary surveillance. It is important to note that in 2011 ANVISA obtained the official certification of PAHO/WHO as Regional Reference Regulatory Authority Level IV – the highest evaluation – regarding regulation, monitoring and inspection, and participated in the discussion about the reform process of World Health Organization (WHO). <br /><br /> Other regulatory Agencies, which are among the world's best, also recognize ANVISA’s expertise, expressed by more than 30 bilateral agreements with the Agency for information sharing on registration and inspection processes. In turn, the European Medicines Agency (EMA) granted in 2015, the regulatory equivalence status with ANVISA for the production of the Active Pharmaceutical Ingredients (API), the raw material of medicines, after careful analysis of the processes performed by ANVISA. <br /><br /> All these facts ensure that the procedures adopted by ANVISA for registration of medicines, supervisory and other regulatory activities achieve the highest standards in the world, ensuring the safety and quality of products and the health of the population.</p> </div> <div class="cont mt30"> <p class="cotit mt20">Registration of Synthetic and Semisynthetic Medicines</p> <h2>3. Legal Base</h2> <p>According to the Law no. 6.360/1976, Art. 12, “none of the products of this law, including those imported, can be industrialized, displayed for sale or delivered to the consumer before being registered by the Ministry of Health”. And according to the first paragraph, “the registration referred to in this Article shall be valid for 5 (five) years and may be renewed for equal and successive periods, maintaining the initial registration number”. It is also important to mention the Art. 13, in which it states that “any change of formula, changing elements composition or its quantitative, addition, subtraction or innovation introduced in the preparation of the product, require the prior written consent of the Ministry of Health and will be immediately communicated to the registration area of ANVISA”. <br /><br /> Regarding the regulatory base, it is also important to mention the Decree no. 8.077/2013, which regulates the conditions for the functioning of companies subject to health licensing, registration, control and monitoring, as part of health surveillance of the products mentioned in Law no. 6.360/1976, and other measures.</p> </div> <div class="cont mt30"> <p class="mt20 cotit">4. History</p> <div class="imgarea fl ml10"><img class="mb0 " style="border: none; margin-top: 5px;" src="/fileDownload2?fileGubun=phm&fileId=00000000000000308633" alt="이미지1" /></div> <p>Although the discussion on Generic Drugs in the country started in the 70’s, only in the 90’s the Decree no. 3.181/1999 was published, which regulated Law no. 9.787/1999 on the registration of these medicines in the country. Since the publication of this regulatory framework, the conditions for the implementation of Generic Drugs were created in line with the internal rules adopted by the World Health Organization, European countries, USA and Canada, and introduced concepts not previously used for registration of medicines in Brazil, such as pharmaceutical equivalence and bioequivalence, setting a new standard for drug registration in the country, thus ensuring quality, safety and efficacy, and the interchangeability with reference medicines. With the improvement of the general legislation in place, from 2001, a total of 700 registers of these drugs were granted in Brazil.</p> <p>Among the advantages that the Generic Drug entry in the Brazilian scenario provided, we highlight the following:</p> <ul class="mt20 mb20"> <li>a) The provision of better quality drugs, safe and effective, proven by pharmaceutical equivalence and bioequivalence tests</li> <li>b) The provision of lower-priced drugs, as manufacturers did not need to invest in research for development</li> <li>c) Decrease in prices of reference drugs to compete with these generic drugs</li> <li>d) Increased access to medication</li> <li>e) Strengthening of national industry</li> <li>f) The medical community behavioral change</li> <li>g) Promoting technological development of industries and hence the country</li> </ul> <p>From January 2015 on, Resolution RDC no. 60/2014 was brought in line with the previous ANVISA legislation, establishing the minimum requirements for the granting and renewal of drug registration with synthetic and semi-synthetic active ingredients, ranked as new, generic and similar. This resolution updates and harmonizes the technical criteria of quality, safety and efficacy for the registration of medicines classified as new, generic and similar. Such harmonization and updating was carried out from issues that had arisen over the years, during the analysis of the submitted cases that were not included in the current standards. This replaced the resolutions RDC no. 136/2003, RDC no. 16/2007 and RDC no. 17/2007, which became obsolete due to technological development observed in the country. <br /><br /> According to the third Superintendence of Drugs and Biologicals SUMED/ANVISA Report, in the third quarter of 2015, were submitted to ANVISA, to the screening unit, 336 renewal requests concerning the registration of synthetic drugs. From this total of petitions received, 44% were assessed at the unit – of which 36% were referred for further technical and sanitary evaluation; 5% were related to previous processes that were already waiting the completion of the analysis of administrative appeal; 1% were closed due to the publication of the old drug deregistration, together with the new registry publication as a clone drug (RDC no. 31/2014); 17% had their approval published; 40% were awaiting publication, and 1% were rejected, the main reason being the absence of documentary evidence of sales of the drug in the last five years after registration. In the same period, more petitions were accounted for new registration, of which 88 were accepted and 78 were rejected. Among the deferred petitions were thirteen of new Drugs, six for new Generics in Brazil and two for unprecedented molecules (Innovative): Benzoate alogliptin + metformin hydrochloride (Nesina Met) and Ibrutinibe (Imbruvica)(2). <br /><br /> Already in 2016, according to the content published on the ANVISA website, to date, there have been 22 new Generics: 15 for a given active substance or association, 6 for a given dosage form and 1 for concentration(1). <br /><br /> Regarding Similar drugs, it is emphasized that in the period before 1999, Brazilian law allowed the manufacturers to choose the reference product to be used for registration of Similars. Moreover, there was no requirement of proof of therapeutic equivalence between Similar and the reference used. Since the publication of technical regulations for Generics and, taking into account the experience gained with the registration of Generic drugs, it has become unacceptable the existence of different criteria for the registration of Similar drugs in the country. Thus, it came into force the legislation that brought the obligation of compliance with the requirements of pharmaceutical equivalence and relative availability for the registration of Similar drugs(3).</p> </div> <div class="cont mt30"> <p class="mt20 cotit">5. Interchangeability</p> <p class="mt50">The safe replacement of Reference drugs by its Generic is ensured by bioequivalence studies submitted to ANVISA. In 2014, based on the RDC no. 58/2014, which defined the measures to be adopted by the Agency and by the registration holders for the interchangeability of similar drugs with the reference drug, a list of similar drugs was made available on the Agency’s website for the purpose of consultation by health professionals or by any interested party, indicating the interchangeability with reference drugs. This list is updated monthly considering new registrations of Similars, granted or renewed following the analysis of the above mentioned comparative studies.</p> </div> <div class="cont mt30"> <p class="mt20 cotit">6. Assembly of the Registration Dossier</p> <div class="imgarea fr mt40 ml10"><img class="mb0 " style="border: none; margin-top: 0;" src="/fileDownload2?fileGubun=phm&fileId=00000000000000308304" alt="이미지1" /></div> <p class="mt50">For a drug to be registered and marketed in Brazil, according to Art. 16 of Law no. 6.360/1976, it is necessary that ANVISA assess the administrative and technical-scientific documentation related to quality, safety and efficacy of the product: <br /><br /> “Art. 16 The registration of drugs, medicines, raw material and medical products, given their sanitary characteristics, drug or prophylactic, curative, palliative, or for diagnostic purposes, is subject, in addition to meeting specific requirements, the following specific requirements: <br /><br /> II - the product, through scientific evidence and analysis, be recognized as safe and effective for the use for which it is proposed and has the identity, activity, quality, purity and safety necessary; III - in the case of new products, which are offered extensive information on its composition and its use for assessment of their nature and determining the necessary degree of safety and efficacy”. <br /><br /> Thus, the application for drug registration demands that the applicant submit a dossier to ANVISA containing the administrative documentation, quality verification, safety and efficacy of the medicine, in addition to certification compliance with the principles of Good Manufacturing Practices of the line in which the drug will be manufactured and their sanitary permits for the operation of the company, in accordance with the provisions of law. <br /><br /> For proof of safety and efficacy shall be included in the registration dossier, among other documents, the pre-clinical study reports (a.k.a. non-clinical) and clinical study reports Phase I, II and III (performed in humans). In addition to the clinical requirements, the quality assurance of the product under study, the shelf life and storage conditions, along with the essential quality specifications, must necessarily be presented in the dossier. Thus, to ensure the quality, safety and efficacy of the product, its production and release for use should be based on compliance with sanitary regulations. <br /><br /> According to Resolution RDC no. 60/2014, the dossier for New Drug registration consists of 32 documents and for Generic and Similar consists of 30 documents. To instruct the petitions registration, it is necessary to observe the required documentation in the instruction checklist and the Subject Code (chosen on the ANVISA website). The Agency will not issue technical requirement for the petition with the absence of documents, incomplete forms or statements and missing information, resulting in the prompt dismissal of the petition.</p> <p>The registration stream comprises 5 steps as shown in Figure 1 below:</p> <ul class="mt20"> <li><strong>Step 1</strong>: Sanitary Regularization of company</li> <li><strong>Step 2</strong>: Identification of petitions at ANVISA</li> <li><strong>Step 3</strong>: Petitioning at ANVISA</li> <li><strong>Step 4</strong>: Analysis of the petition by ANVISA</li> <li><strong>Step 5</strong>: Petitioning Result</li> </ul> <div class="imgarea mt20 mb10"><img class="mb0 " style="border: none; margin-top: 10px;" src="/fileDownload2?fileGubun=phm&fileId=00000000000000313328" alt="이미지1" /></div> <p class="table_tip al_c">Figure 1 – Registration Flow of New Drugs, Generic and Similar at ANVISA</p> </div> <div class="cont mt30"> <p class="mt20 cotit">7. Main Grounds for Refusal</p> <ul> <li>a) Problems in the production report of active pharmaceutical ingredient (DMF)</li> <li>b) Lack of documentation</li> <li>c) Items related to quality control (QC) and stability study</li> <li>d) Irregularities in labeling</li> <li>e) Problems in production report (finished product)</li> <li>f) Biowaiver report</li> <li>g) Lack of Good Manufacturing Practices Certification (CBPF)</li> </ul> </div> <div class="cont mt30"> <p class="mt20 cotit">Conclusion</p> <p>Currently ANVISA has been working towards regulatory convergence, alignment of technical understanding and exchange of experience with the world's leading regulatory agencies, taking into account best practices, internationally accepted principles and standards in the regulatory process, in order to harmonize procedures and eliminate duplicate requirements for medicines registration, in order to expedite the availability of products to the population in the shortest time possible. In this sense, it has signed several mutual cooperation agreements with other countries, which will enable the exchange of information on regulatory activities in the fields of pharmaceuticals and medical devices. But for a global regulatory consensus, there are still many points to be discussed and standardized(4).</p> </div> <div class="cont mt30"> <p class="cotit mt20">Reference</p> <div class="ac_00 linkarea " style="letter-spacing: 0; width: 690px;"><ol style="letter-spacing: 0;"> <li class="mt0">1. ANVISA, Registros de Genéricos inéditos em 2016. Available at <a href="http://portal.anvisa.gov.br/documents/33836/352400/Lista+de+Medicamentos+Genericos+Ineditos+registrados+em+2016/f628710d-4037-4564-99b6-cf79ec12998e">http://portal.anvisa.gov.br/documents/33836/352400/Lista+de+Medicamentos+Genericos+Ineditos+registrados+em+2016/f628710d-4037-4564-99b6-cf79ec12998e</a>. Acessed in: 10/29/2016.</li> <li>2. ANVISA, Third Relatório da Superintendência de Medicamentos e Produtos Biológicos SUMED/ANVISA, Nov/2015. Available at <a href="http://portal.anvisa.gov.br/documents/33836/0/3%C2%BA+Relatorio+Gerencial+de+2015/cebe61db-2cb5-44af-8977-a78e71bd8aff">http://portal.anvisa.gov.br/documents/33836/0/3%C2%BA+Relatorio+Gerencial+de+2015/cebe61db-2cb5-44af-8977-a78e71bd8aff</a>. Acessed in: 10/28/2016.</li> <li>3. Araújo LU, Albuquerque KT, Kato KC, Silveira GS, Maciel NR, Spósito PA, et al. Medicamentos genéricos no Brasil: panorama histórico e legislação. Rev PANAM Salud Publica 28(6), 2010; 28(6):480-492.</li> <li>4. Regulatory collaboration-IGDRP generic drug product regulatory gap analysis. WHO Drug Information, Vol. 30, N° 3, 2016, 361-369.</li> </ol></div> </div> </div> </div>
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