Latin America vs. Other Emerging and Non-Emerging Markets in Clinical Research: Regulations, Investigators and Ethics Committees

Latin American (LA) countries operate increasingly in accordance with international standards and guidelines. This has been a major driver for increasing interest and placement of clinical studies in the region. Even though LA countries are considered to have many similarities, it is important to keep in mind that, in reality, they are 20 different countries, with different cultures, regulatory requirements, pathologies, incidence rates, standards of care, etc. For this reason, it is fundamental to have local knowledge to accommodate diversity while leveraging shared characteristics. This paper will provide a quick overview of LA’s current clinical research environment, summarize its challenges and opportunities, vis-à-vis successful stories of other countries out of LA, in the competitive scenario of global clinical trial placement.

Brief Overview on Latin America

Latin America expands across two hemispheres and consists of 569 million people [1]. Nearly half of them concentrated in Brazil (192 million) and Mexico (103 million). Interestingly, virtually all the population speak only two official languages [2]:

• Spanish - 339.1 million
• Portuguese - 191.8 million

This is an excellent advantage over comparable populations i.e. Europe, regarding document translations, training of personnel, etc. Spanish-speaking countries, however, have subtle linguistic differences that can result in miscommunication if not properly addressed [3].

77% of the population is concentrated in urban areas. Four major metropolitan areas congregate 62 million people: Mexico City (19.0), Sao Paulo (18.8), Buenos Aires (12.8) and Rio de Janeiro (11.7) [1]. LA investigators have access to thousands of patients in a single area, and many are treatment naïve and trial naïve. That explains the high success rates in subject enrollment and retention, and reduced cost of studies in LA sites [3].

Heart disease, arthritis, cancer and infections are as prevalent as in the US. Seasonal disease state occurs six months out of phase with North America allowing for year-round recruitment [3].

Mexico, Brazil, and Argentina were traditionally the three bestestablished countries for clinical trials in Latin America. Other countries like Chile, Colombia, and Peru are rapidly evolving, thus also becoming very attractive [3].

Clinicaltrials.gov is probably the best source for analysis of the evolution on study placement. Open industry-funded trials listed on March 22, 2011 Brazil with 368 studies, followed by Mexico (260), Argentina (231), and Chile, Peru and Colombia with very similar numbers among them of just over one hundred. It is noteworthy that all countries in the region have industry-funded studies.

Figure 1-

A recent article published by Clinical Trial Magnifier in February of 2009, showed an average increase of 25% of the regional proportion of industry-sponsored phase II and III clinical trials between two periods (2005 -2007 and 2006 – 2008), and places LA as the fastest-growing region of industry studies [4]. Moreover, absolute number of sites is quite substantial, when compared to other regions (Fig 1) [5].

In spite of that, an analysis of the density of clinical trials, measured by the number of recruiting sites per million inhabitants, Thiers et al. [6] showed that traditional countries, like Germany, the UK, France, had indexes around 50, and the USA 120, while countries in LA had much lower densities: Argentina – 19, Brazil – 4, Mexico – 6.2. This is a strong indicator of the potential for more studies to be placed in Latin America.

Of critical importance when analyzing the participation of LA in Clinical Research is the evaluation of the quality of the data that is coming from their sites. In 2009, the Clinical Trial Magnifier [7] published an analysis of the number of US FDA data on site audit inspections, one of the abstracts mentioned: “US FDA site inspection findings during the post ICH period, 1997-2008, fail to justify clinical research globalization concerns as recently put forth in the US and EU”. In that same publication, Eastern Europe (with 150 completed US FDA site inspections), LA (81), and Asia (36), all fared better than Europe in the percentage of sites demanding official action, respectively: 1.3%, 2.5% and 0%, versus 3.5% in Europe.

It is therefore ironic that the European Medicines Agency (EMA) recently posted a strategy paper expressing growing concern about how well clinical trials are conducted from an ethical and scientific standpoint in regions outside Europe and North America, namely Africa, Asia, Latin America, and Russia. Available data strongly imply that equal or even stronger concerns should be directed towards Western European investigator sites [6].

Current Regulatory Environment in Latin America

Argentina

Considered one of the most advanced regulatory legislations in Latin America. Its regulatory Agency, ANMAT, has recently undergone thorough changes that resulted in an increase of its regulatory approval timeline from a very competitive 3-month period to a concerning 6- to-8-month period. A strong mobilization of academia and industry followed, and regulators are currently taking new steps to reduce approval times. IRBs/ ECs approval timeline is 1 month, and the supplies importation can take 15-20 days. This means that the total approval timeline is currently around 7 months, with a declining trend. ANMAT also has a very active inspection program of sponsors and research sites.

Brazil

A new resolution aimed at improving the approval cycle time with a declared objective of reducing cycle time to 45 days in 2009 was issued by Brazil’s regulatory agency ANVISA in 2008 (RDC 39/08). This resolution included a parallel review and approval process by ANVISA and the National Committee for Ethics in Research (CONEP), replacing the current sequential process. The use of GCP Documento de las Americas and the inclusion of import license in first approval has, among other things, trimmed some weeks in the long approval time of the country. Unfortunately there is a long way to go for Brazil to reduce its painful 8- to 10-month period to start a study up.

Mexico

The expected timelines may vary greatly depending on where (public or private institutions) the trial will be conducted. Currently the established timelines for Ethics Committees (EC) approval are between 30 to 60 days, and Ministry of Health (MoH) 60 to 90 days, for a total of 4-5 months. Unfortunately, reality may be very different for some trials.

Chile, Peru and Colombia

In Chile, there is a favorable government environment and a fast importation process. Approval timelines are at a very competitive point between 3 - 4 months. Colombia has a well-established legal framework and is currently one of the fastest-growing countries for clinical trials and the approval timelines also at 3-4 months. Since 2008, a new bylaw has established that research sites must be certified by Colombia’s regulatory agency INVIMA to conduct clinical studies, which caused some additional work, but also increased the quality standards of the accredited sites. Peru has fast approval times and a number of new private sites are being created.

The stability and good image of Chile, and a return to political stability in Colombia and Peru associated with good and productive sites and fast approval times, make those countries very fast-growing regions for clinical trials with new drugs.

Central America and the Caribbean

These countries, except for Costa Rica and Puerto Rico, that have been involved in clinical research for several years, are starting to have a more relevant participation in Clinical Research. The approval timelines vary little across the area, around 3 - 4 months. It is noteworthy that Costa Rica is currently revising its clinical trials legislation and the approval of all new trials is on hold, but a new law is ready to be discussed in the National Congress and is expected to be in effect by the second semester of 2011. Other countries, like Guatemala, Panama and Dominican Republic, are starting to catch up with private research sites created by investigators trained in the USA.

Challenges and Opportunities

Even though there are adequate regulations established, in most countries real life approval times are longer than expected. It is important to consider that we do not know how long it really takes, especially because there is a wide variation related to study design and sponsor knowledge of the regulatory environment in each country. Also, officials from regulatory agencies may have different interpretations of the legislation. Due to that,one can expect regulatory approval times in several LA countries to be 3 - 4 months longer than expected. Surveys showed that 41% of trials in LA have more than a 1-month delay in enrollment [8].

Figure 2-

Notwithstanding the above, this region still has an incredible capacity and potential for clinical trials, but the local environment needs to be understood. Many sites located in large and medium cities have an extraordinary access to patients and even when approvals may be delayed as compared to other countries, fast recruitment in LA countries compensate for the idle time. Moreover, retention rates and patient adherence are also very high, thanks to a strong relationship created with study site personnel.

Successful Stories from Other Countries

There is definitely an advantage from learning from successful countries that are benefiting from the investment in R&D and the great value that it brings to their communities (i.e. access to latest knowledge and technology). Also, this can certainly be of inspiration to regulators, investigators, EC and patients.

Korea

This country is an excellent example of how government, hospitals/ investigators, industry and population came together to develop an environment of excellence in R&D infrastructures and capabilities.

The evolution of this country has been very interesting. In 1995, the Korean FDA (KFDA) implemented GCP guidelines for ethically sound clinical studies, such that Korea became the 2nd country in implementing GCPs in Asia. However, before 2000, new drug clinical trials were permitted only for domestically developed compounds. At that time, the number of clinical trials was less than 50, some were new drug trials for domestic R&D, and the others were registration trials of drugs that already had a global marketing permit. It is important to point out that no international trials were conducted at that time.

In the early 2000s, the KFDA adopted the bridging concept in reviewing foreign-developed new drugs for marketing approval in Korea, and KGCP was revised to be equivalent to ICH-GCP. This enabled Korea to participate in multinational trials and, in November of 2002 a National Technical Roadmap for Clinical Research Technology was developed. The plan included very specific milestones to drive the country to a leading position in R&D. As a result, there was dramatic reduction of the requirements and review timelines for INDs; the approval process became parallel for both Ethics and Regulatory approval; and the entire approval process was reduced to only 30 working days. Government co-funded Clinical Trials Research Centers (CTCs) were established.These sites would receive 4 million US dollar/5yrs from government, a minimum 4 million US dollar/5years as matching investment from each hospital, plus investments from industry and local government. Today, there is a network of 14 CTC across the country. Besides these CTCs, it was also established that only hospitals accredited by the regulatory authority could conduct Clinical Trials and by 2008, 126 hospitals had been accredited for the conduction of Clinical Trials by KFDA. The IRBs are also required to be composed and operated according to KGCP. These are independent IRBs with their own SOPs and with expedited review processes. As part of the strategy, these IRBs are required to conduct regular training session as per KGCP and ICH-GCP for investigators, pharmacists, CRCs and other medical staff. The KAIRB (Korean Association of IRBs) was established to organize IRB education, enhance review capacities, and foster IRB networking.

In summary, by 2008 the KoNECT (Korea National Enterprise for Clinical Trials) had a network of 14 total CTCs, 19 education centers for Clinical Investigators, Clinical Pharmacologists, CRAs, CRCs, Biostatisticians, DB managers, Clinical Trial Pharmacists, etc and 16 research units (new technology centers) for critical path technology: IT, biomarker, PK/PD modeling, simulation, etc.

As a result the clinical development activities in Korea increased exponentially. Clinicaltrials.gov lists 538 open industry-funded trials in Korea. A recent analysis showed that it is the third emerging country in trials for the industry [9].

Canada

“Advantage Canada” and “Mobilizing Science and Technology to Canada’s Advantage” are the government frameworks that support the country’s Innovation Policy in benefit of their strong knowledge-based economy. As part of the process an agreement was reached with all pharma companies operating in Canada that at least 10% of their sales should be re-invested in R&D activities in the country. As a result of this, the country gets great re-investment in R&D and the companies reinvesting in R&D get substantial tax benefits, definitely a win-win situation to all interested parties.

The mechanism by which the government expect pharma to partner with them is the basis for two organizations : STIC and CIHR. STIC (Science, Technology and Innovation Council) is the government advisory board that makes assessment and recommendations to the federal government on where it needs to spend its money when it comes to matters of Science, Technology and Innovation. Their latest report, State of the Nation 2008, provides comparative information between Canada and competing countries related to R&D investments etc, www.stic-csti.ca/eic/ site/stic-csti.nsf/eng/h_00011.html ). CIHR (Canadian Institute of Health Research) is the federal agency that funds health research. They have a couple of key initiatives aimed at partnering with pharma to jointly fund clinical research in Canada, so as to bridge the gap between academic and commercialization research, giving everyone an opportunity to interact and build on each other's capabilities.

The national priority is to encourage greater private sector Science and Technology investment. The government wants to create an investment climate that encourages the private sector to compete against other regions on the basis of innovative products, services, and technologies. Organizations at the forefront of scientific development and technological achievement create high-quality, knowledge-intensive jobs with high wages. That makes the economy more competitive and productive, providing the means to achieve an even higher standard of living and better quality of life. The private sector in Canada needs to turn knowledge into products and services that improve wellness and wellbeing of its citizens.

Lessons Learned

Long trial start-up times, excess bureaucracy, unclear regulation, in an environment of competitive enrollment, result in less trials being allocated in Latin America. It is critical to join efforts among sponsors, health authorities, ethical committees, institutions, investigators, scientific societies, academia, etc [10].

Sponsors need to work closely with local regulators to better understand requirements. By understanding the environment, sponsors need to give opportunity to the high recruitment rates to offset the delays on study start-up. Regulators need to define clear processes, procedures and timelines, and commit to adhere to them. A closer look to the Asian “competitors” shows that they are moving quickly and efficiently. Korea is just an example, there are others like Hong Kong and Singapore.

In summary, LA countries should learn from successful countries that are benefiting from the investment in R&D and the great value it brings to communities such as access to latest knowledge and technology.

References

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2. United Nations World Urbanization Prospects 2005. Available at: http://www.un.org/esa/population/publications/ WUP2005/2005wup.htm, accessed on Mar 28th, 2011
   
3. Virk, KP. – Latin America’s Trial Climate. Applied Clinical Trials, June 1st, 2009, available at: http://appliedclinicaltrialsonline. findpharma.com/appliedclinicaltrials/CRO%2fSponsor/ Latin-Americas-Trials-Climate/ArticleStandard/article/ detail/602046?ref=25, accessed on Mar 28th, 2011.
   
4. Clinical Trial Magifier, Feb 2009.
   
5. Clinical Trial Magnifier, Sep 2008.
   
6. Thiers, FA., Sinskey, AJ., Bernd, ER. – Trends in the Globalization of Clinica Trials. Nature Reviews Drug Discovery 7: 13-14, 2008.
7. Clinical Trial Magnifier, Apr 2009.
   
8. E. Isola – DIA S. Paulo – Sept 2006
   
9. Alvarenga, LS., Martins, EN. – Biophramaceutical industrysponsored global clinical trials in emerging countries. Rev. Assoc. med. Bras. 56; 28-33, 2010.
   
10. CenterWatch September 2006