Clinical Trials in Brazil: trends and experiences

• By: Ingrid Koster, Epidemiologist Master Science Public Health Service Civil Defense - Rio de Janeiro
• Date: February 16, 2010

1. Introduction

Research & Development of new drugs has being expanded around the world along several decades for some countries outside United Sates and Europe. It has been notorious that recently we have more Clinical Research activities being directed to Asia-Pacific, Central and Eastern Europe and Latin America countries.

These countries, altogether, are commonly referred as “emerging countries” or “emerging markets”, and they have been receiving more Clinical Trials each year in proportion with the origin countries. Considering only the Latin America region, it was identified approximately 1,500 new trial study sites being set up each year, as per the number of US FDA 1572s filed for the undergoing IND trials. Almost 90% of clinical trials activities are concentrated within the six major countries: Argentina, Brazil, Chile, Colombia, Mexico and Peru. Within these countries the range of drugs, devices and vaccines being tested covers the majority of therapeutic areas under research.

This is a very different scenario from the one identified some years ago, when most of sponsors just came to Latin America mainly for the rescue studies by including countries of the emerging region to achieve patient recruitment targets under their timelines to regulatory submissions. Particularly considering information from a major worldwide database for clinical studies, with headquarters in the United States, majority of the researches conducted in Brazil has their targets in Cancer - with leadership for breast cancer – then diabetes, circulatory system diseases and finally studies on HIV / AIDS. Altogether this major group represents at least 25% of the activities in Brazil. It is peculiar that in this database we only have one study for Dengue disease registered on this database for the moment. Numerically counting until 08 February 2010, the country has around 1.622 clinical trials (on humans) registered in this Clinical Trials database for those maintained by the U.S. government. The majority of these studies is sponsored by pharmaceutica industry and comes to new drugs. They are more frequent in phases 3 and 4 - when drug is ready for verification of events and ambiance into new markets - and recruiting large number of patients in several countries.

Thirty percent of these trials are still recruiting patients. However, by taking this information above mentioned in a general manner particularly for Brazil, we cannot ensure the profile for disease distribution as per epidemiological transition - non communicable diseases related to elderly populations and communicable related to poor living conditions – because we only have one pattern for the Pharmaceutical Companies focused on their actual worldwide business. According with some experts, the epidemiological transition in Brazil is still in course and has not followed the model experienced by most developed countries. We still have coexistence of old and new health problems, where despite the predominance of the non communicable diseases (chronics and degenerative) the communicable ones still lay an important role. Unfortunately the recent increasing number of Clinical Trials had not corresponded directly to the local pattern of the epidemiological disease distribution but, at least, it has been a response for an improvement of several characteristics for the Clinical Monitoring activities in Brazil.

2. Main Brazilian characteristics in the Clinical Trials trajectory

Below it is described some of the main characteristics that Brazil has been presenting along these years developing Clinical Trials:

• Increased number of Study Sites: It has been frequently necessary identify new study sites for many different trials due to Investigators availability and patient distribution also. Moreover it is common to receive a Regulatory board recommendation to have the Principal Investigator sharing or even change his/her responsibility in the case of several studies. Recently the average enrollment per site in Brazil has been the triple that of those countries located in traditional regions. This might be explained by the saturation of study sites in foreign countries plus our increasing level of quality for healthcare around the study sites in the country.
• Quality of the Study Sites (GCP and structure): The rationale for the connection between the availability of high quality healthcare and the increase of likelihood for participation in trials is based upon the greater investment in time that clinical trial implies versus the situation where just promptly choosing one available healthcare provider. The study sites have been frequently trained not only in the Protocols but ICH-GCP also. We have observed that the quality of clinical trial conducted and data from Brazil are as good as the quality of traditional regions in terms of metrics and Good Clinical Practice. We identified that study sites that are often high-enrollers, are those also resulting in more than 40% of patients enrolled in clinical trials within emerging countries. Not only is the strong ICH-GCP quality was evidenced by FDA inspections as mentioned above, but local competent authorities and sponsors now routinely expect trials conducted in Brazil and have 3 set up the necessary regulatory infrastructure (laws, regulations, departments) within the competent authorities and action plans to accomplish the high level of required quality. The good conduction for the trials over the last 20 years has inspired a level of trust mot only in the quality but on dependable functioning of the clinical trial regulation process throughout the medical communities, regulatory board and sponsors.
• Seasons of the year: This is an advantage in speeding up the patient recruitment. However it must be carefully considered for the drug development in respiratory and dermatology areas (seasonal diseases in its nature) because to have the double of the peak recruitment months per year we need to take into account the necessary time for the setup phase of the studies in Brazil.
• Ethnics and Geography: The large racial composition of the population in Brazil (Pardo, White, Asian, Black and Aboriginal) distributed among the regions of the country can contribute to the strong recommendation of having a patient database with as much as possible different ethnics groups. In spite being a large country we have compatible time zones that allows the clinical scientist from a US-based R&D headquarters, for example, may have frequent contact with the team almost in the same day. This is a distinct advantage in early Proof of Concept stage trials in which companies need to access patients and data and to talk to investigators.
• Cost and Market Access: The average cost of the clinical trials development in Brazil is around 75%–80% of the related cost of US clinical trials as per experiences. Develop the clinical trial in the country is the faster way to the market authorization approval by the regulatory professionals and government but also promotes the access of the product to the local market and presents the drug, vaccine or medical device to the national and regional medical society mainly when not well known locally. This has been one of the goals of many biopharmaceutical companies.
• Regulatory Review Processes: Along several years the regulatory submission has occurred in a sequential review processes for the ethics evaluation in Brazil: at first we had the Local Ethics Committees (Local CEPs) and National Ethics Committee (CONEP) and then Regulatory Authority (ANVISA) that, until the year 2008, only occurred after the CONEP approval. This sequential process added time as compared to a parallel process that occurs in the US and EU. However, in Brazil we could start site contract negotiations right after Local Ethics Committee approvals which often are not able to be done in parallel in US and EU due to national regulations. Additionally, while the regulatory process and contracts were moving forward during the setup phase, several monitoring activities were initiated such regulatory documents collection for “activation package”, study sites were trained and the staff identified eligible patients, for example.
• Recent Major Changes in Brazilian Regulations:The Resolution 39, that was effective on 5 July 2008, promoted a main change in the regulatory review process by establishing that the National Ethics Committee (CONEP) and MoH (ANVISA) could review the protocol in a parallel process, as it occurs in the EU. The Resolution 39 granted the ANVISA the ability to approve all study sites in one submission only, after one review cycle without pending issues to be clarified. Receiving MoH approval under the Resolution 39 it was grated a potential reduction of around six to eight weeks for the first study site to be initiated for the Protocol (1st Site Initiation Visit for national coordinator study site). This also results in a potential reduction of four to six weeks to perform the Site Initiation Visits for the additional study sites. Then, by the new Resolution 39 a potential reduction in total timelines for the first SIV from the first Local Ethics Committee submission occurred: it was reduced from 10 months to 8.5 months.

However, from its implementation until the third quarter of the last year we have faced a problem related to the limited staff for the regulatory documents review, both in ANVISA and CONEP. The government has been working on solutions for this limitation in order to avoid impact in our current review timelines and local representatives of sponsors, study sites and local Clinical Trials associations have been organizing meetings to review the regulatory process or even to provide support such for an example a best template for Informed Consent Form to speed the evaluation of the Protocols. This is an important point to be considered by the local governments in order to be aligned with the current increasing of Research Development.

3. Global trends for Research Development

It is being evaluated more carefully among not only by sponsors and Clinical Research Organizations (CRO) but by US government also. Recently, members of the World Health Organization Expert Working Group on R&D Financing have undertaken a study to ascertain the extent of financed research carried out for 2008 by using available published data for R&D. The team consolidated the data by disease category on some communicable diseases (CDs) and non communicable diseases (NCDs), a recent classification types for data on burden of disease, just for developed countries because due to limited data for low- and middle-income countries. The final version will be submitted to the 3rd World Health Assembly in May 2010, but some preliminary information showed a consistent 2:1 ratio in R&D funding allocated to NCDs (notably to cancer, cardiovascular disease, chronic respiratory disease, diabetes and mental health) and CDs respectively was the preliminary data findings from the data about five largest public investors in hhealth R&D countries (France, Germany, Japan, the UK and the US), from top ten pharmaceutical industries by income and from the largest philanthropic organizations.

Cancer research absorbs alone, in all countries, more of what flows into research for all communicable diseases. Epidemiological studies have demonstrated that since the 1980s, the burden of non communicable diseases has been increasing rapidly in low and middle-income countries. Whereas these diseases accounted for 47% of the disease burden in 1990, the proportion is projected to increase to 69% by 2020. Conversely, whereas communicable diseases accounted for 42% of the disease burden in 1990, the proportion is expected to decrease to about 17% by 2020. Non communicable diseases are now the leading cause of morbidity and mortality in every region of the world except sub-Saharan Africa, where they are prominent but overshadowed by communicable diseases and by maternal, perinatal and nutritional conditions. Although the burden of communicable diseases per person fell by 20% between 1990 and 2001, HIV/AIDS, tuberculosis, malaria and neglected diseases remain significant causes of morbidity and mortality.3 Particularly in low- and middle-income countries, HIV/AIDS, tuberculosis, malaria and diarrhea caused by communicable diseases are among the leading 10 causes of death, accounting for a combined 14.8% of deaths in 2001. owever, what we have seen globally is that new medicines R&D had followed market opportunities rather than global public health priorities even in those developed countries around the world for many years.

This information is obtained by a precise comparison of some available specific databases for Epidemiological Surveys and Studies and also those related to the Clinical Trials, and frequently performed for example in Unites States and Europe. This information is also consistent with a pharmaceutical pipeline analysis from the US for 2,900 compounds in development in 2008 and its particular distribution of 750 (25%) for cancer drugs, 312 (10%) for heart disease and stroke and 109 (3.7%) for HIV/AIDS. In a general overview it seems that the pattern of the Research & Development of new drugs has been trying to accompany the trends of the impact of major diseases on populations. In terms of product development, the diseases and conditions that affect people in the world’s major markets largely determine where the pharmaceutical industry’s investments go. But the Global Forum for Health Resarch highlights the fact that only 10% of R&D spending is directed to the health problems that account for 90% of the global disease burden - the so-called 10/90 Gap.1

4. Conclusion

Around five years ago sponsors came to Brazil mainly for rescue studies [when sponsors include an emerging region to meet enrolment targets on time]. Nowadays not only Brazil but the Latin America region is involved in planning from the very beginning. Latin America is receiving more clinical trials each year and the start up timelines from the final version of the protocol to first site initiation has being reduced in Brazil, in several Latin American countries also, but being quite similar to those countries in Western Europe. Brazil has been demonstrating an ever increasing role in the clinical development process together with the emerging countries, but despite of the qualities presented for the country and high potential to recruit a large number of patients in protocols, its high potential for the Clinical Trials has not being explored so far. Currently this issue remains in the fact that it is still the slowest country in the region in terms of regulatory evaluation by government instances. But recent information has been demonstrating that the Clinical team involved in the Protocols has been performing all the necessary efforts to speed up start-up activities while the government is working to reduce in six weeks from the Protocol evaluation process by implementing the recent changes in the Resolution 39 for the Regulatory process to evaluate the Protocols. Considering all those several advantages that were commented above, the emerging countries has presenting several necessary requirements for the multinational studies such as good study sites distributed along the countries and covering a large proportion of the population unless adequate treatment for the diseases.Finally, considering each country as per their particular improvement curve all of them are prepared for new challenges such as earlier phases or even new therapeutic areas for targeted populations’ diseases, and mostly being not completely competitive for the target number of patients but complementary for patient recruitment for the Latin America region.

5. Selected references
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About the Author

Ingrid Koster , Epidemiologist Master Science Public Health Service Civil Defense - Rio de Janeiro State and Clinical Investigation of Ministry of Health, Brazil. Independent Consultant for Pharmaceutical Companies.

Ingrid Koster has worked in Clinical Research operations as Investigator and also as sponsor in the Pharmaceutical Industries along almost 15 years in Latin America. Ms Koster combines her background and current position in Public Health with her expertise in Research and Development within Pharmaceutical Industries to bring to us not only experiences in Clinical Trials management in several Therapeutic Areas but important insights to improve knowledge and perception for the major points regarding Clinical Research development.