Clinical Trial Approval Process In Brazil - Clearing The Roadblocks To International Studies

By John Andrews and Eduardo Pizolato

The regulation of clinical research in Brazil started at the national level in 1996 with the publication of Resolution 196 from the National Health Council (CNS, which is a Portuguese acronym). The CNS provides statutory regulation of all research involving human beings, including ethical evaluation, which is performed by LocalEthics Committees (CEPs) and, in certain cases, by the National Ethics Committee (CONEP). Further regulatory assessment is the responsibility of the National Health Surveillance Agency (ANVISA) and is required for trials with drugs and medical devices aimed at future marketing applications.

Brazil’s health statutes have grown over the years since inception and now include approximately 20 regulations at the national level, from the Brazilian Ministry of Health and the National Ethics Committee, as well as the international requirements included in the International Conference on Harmonization (ICH), principles of Good Clinical Practice (GCP), and the Helsinki Declaration.

The complexity of the Brazilian human health regulatory environment originated from the country’s concern for the safety of its people as potential participants in international studies. The socioeconomic disparity in certain regions of Brazil relative to the countries of origin of the pharmaceutical sponsors of clinical trials was seen as a potential enticement for study participation that may disguise the risk.

As a result, the regulation of clinical research in Brazil ensures a high ethical standard comparable to internationally accepted benchmarks, yet has resulted in a lengthy process, slow to reach its conclusion due to the requirement for several independent and somewhat redundant reviews and approvals.

The Process
“From 2005 until today, there was a 4% decline in the number of recruiting patients for new studies in Brazil,” says Fabio Thiers, founder of ViS Research Institute, whose information is derived from work performed in conjunction with the Massachusetts Institute of Technology and the National Bureau of Economic Research, which evaluates the growth and decline of this economic segment.

Furthermore, considering just clinical trials of new pharmaceutical products conducted in BRIC (the acronym for the four largest emerging markets: Brazil, Russia, India, China), the number of trials performed has decreased in all nations, but the decrease in Brazil was greater than in any of the other three countries. A total of about 50 trials of new chemical entities was performed in Brazil compared to about 75, 100, and 150 studies performed in India, Russia, and China, respectively.

The origin and disparity in the number of clinical trials performed in Brazil are largely due to the period required for the approval of clinical studies by the National Research Ethics Committee, the CONEP. A survey by the University of São Paulo showed that the national average just for ethics approval of a study by the Local Ethics Committee followed by approval by CONEP may be as long as 100 to 150 days. According to the Association of Pharmaceutical Research, the national average for the overall approval of a new clinical trial from the time the documents are first submitted by the sponsor to ANVISA and by the investigator to the Ethics Committees, until the full review and approval by all agencies involved is complete and the drug has been imported into Brazil and accepted by Customs, may be as long as 10 to 14 months. In contrast, the United States, Canada, Russia, and most other countries around the world range from 3 to 6 months, with China being the only other country with an approval time of at least a year.

It is widely recognized that a major bottleneck in clinical trials in Brazil is the long time line for study approval in relation to other countries, resulting in the loss of the country’s competiveness in the case of international multicenter trials.

The Cause
The president of CONEP, Gyselle Tannous, has stated publicly that the delay in clinical trial approval derives from the arduous national policies that are in place to ensure conformity to the international requirements governing the use of humans in experimental trials. For example, the standard template required for national approval of any study requiring the patient to give informed consent consists of 30 pages. “Hardly any patient will read it all. We have to make changes,” said Tannous. Another bottleneck in the arduous process is the need to provide each study subject free access to treatment for the disease under study until the new drug is commercially available. “Clinical research is a field of conflicts of interest. We are rigorous in the defense of the rights of research subjects,” she stated.

The Ministry of Health recognizes this issue and is implementing changes quickly in order to shorten the study-approval time line to international standards. In the last six years, according to estimates by ABRACRO — Brazilian Association of Clinical Research Organizations — Brazil missed realizing investments of more than $200 billion (USD), although Brazil has more than 300,000 active physicians/investigators and more than 600 local ethics committees installed. If this matter can be successfully addressed, capturing this missed revenue, the impact on the national economy, the viability of Brazil as a participant in international drug development, and the resulting improved healthcare that can be offered to its citizens will be substantial.

These issues have been discussed in meetings between investigators, ethicists, the pharmaceutical industry, and the Brazil Ministry of Health. The investigators agree with the importance of the Local Ethics Committee authority over participating institutions and the coordinated review and approval process through CONEP, which manages and administers the work. The proposal for revision of the process is to create and release five regional CONEPs and require just one ethics review in which the approval process is monitored and time lines are standardized as much as possible.

Facilitating the Clinical Trial Approval Process in Brazil
By 2015, the Brazilian Ministry of Health plans to invest $1.5B (USD) in research of new drugs, treatments, vaccines, and devices. The value is almost four times greater than the investment portfolio accumulated in the last four years, about $400M (USD).

The regulatory agencies in Brazil are addressing changes in the review and approval process in order to speed up the actual time lines for study start-up. Implementation of the improvements began in 2005 with the publication of Resolution 346. This new regulation facilitates the process of the multicenter research protocol review by the National Ethics Committee, requiring the dossier to be submitted only once by a single Local Ethics Committee, unlike the previous process in which each Ethics Committee from each participating research center was required to submit the same dossier for individual review and approval.

In 2008, the ANVISA published new regulations for clinical trials in Brazil, Resolution 39. The major importance of this resolution was the establishment of parallel procedures for both regulatory and ethical review, as well, under certain circumstances, importation of investigational products even before the ethics approvals of the study.

Until recently, the ethics approval process was performed using hard paper copies and the national postal system, without taking advantage of the efficiencies of modern communications technologies. According to Reinaldo Guimarães, Secretary of Science and Technology of the Ministry of Health, “In part, industry and investigators are right; the first step will be to put in place a system that will allow the online tracking of protocol assessment.” Consequently, in November 2011 the minister of health launched the Platform Brazil and Brazilian Registry of Clinical Trials (REBEC), programs that will unify data from research involving human subjects. With this platform, researchers can follow the project review via the internet. With REBEC, the first database for registration of clinical trials, the researcher will not have to resort to foreign databases to record the trial and track its progress. The REBEC is endorsed by the WHO. With the unification of data, the expectation is that time for authorization of research in Brazil will be decreased by many months, solving one of the main frustrations of the scientific community, research institutes, and laboratories. The National Ethics Committee posted a letter on its website stating, “We advise that after the usual vacation of CONEP, from Dec. 15, 2011 to Jan. 15, 2012, all studies must only be submitted to ethics review by electronic system named Plataforma Brasil.” We hope that Platform Brazil will help speed up the ethics time lines in Brazil. The expected total new ethics time line —EC and CONEP — is now eight weeks.

Platform Brazil is a national and unified electronic database of clinical trial records that allows for the submission of study-related documents in digital form. It allows studies to be followed through their different stages — from submission to final approval by the EC and CONEP, and, when necessary, also allows monitoring of the study progress through approval phases, including the submission of interim and final reports.

About The Authors
John Andrews, Ph.D., serves as the director of regulatory affairs for the Americas for Chiltern International. Dr. Andrews has spent the majority of his career developing antivirals. He has published in the field and has been an invited speaker at FDA advisory panels and has served on expert panels for the evaluation of new surrogate markers for viral diseases.

Eduardo Pizolato serves as the regulatory affairs officer for Brazil for Chiltern Pesquisa Clínica. He is experienced in all phases of clinical studies, including start-up and the regulatory and clinical importation process in Brazil, working with sites and vendors. His main therapeutic areas are oncology, infectious diseases, rheumatoid arthritis, hematology, and HIV studies.