Latin American Clinical Trial Authorizations

Overview and Update

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By Dennis Hurley, DrSc, Mirtha Lipezker, MD, Hortencia Melgar and Daniel Mazzolenis, MD, MBA

6/4/09 2:12:57 PM

he shift in clinical development from the US and Western Europe to other regions of the world is now a clear and sustained trend. This article reviews the reasons for this shift, which has many implications for the emerging markets. Specifically, this article provides an update on the regulatory timelines and requirements in one of the big three emerging markets, Latin America.

Steady Shift of Clinical Trials from Traditional Regions to Emerging Markets

As seen in Table 1, there has been steady growth in the proportion of trials being conducted in emerging markets, particularly in Central and Eastern Europe, Latin America and the Asia-Pacific region. The annualized 10-year growth rate (A10-YGR) from 1996 to 2006 in FDA-regulated investigators for traditional regions (US, Canada and Western Europe) showed single-digit growth. However the A10-YGR growth rate for the emerging markets exceeded 25%. In the most recent period for which full data are available (200407), the traditional regions had an annualized three-year growth rate (A3-YGR) that was negative, whereas the emerging markets continued to grow at double-digit rates. The implication then of Table 1 is that the prior slow growth seen in North America and Western Europe has, in the last three years, actually turned into a decrease in the number of trial sites of approximately 5% annually. This gradual shift of sites to emerging markets and the fact that these sites are often high-enrollers has resulted in more than 40% of patients now being enrolled in clinical trials in emerging markets. The stated goal of many biopharmaceutical companies is a continued shift in enrollment to emerging markets, indicating that this trend will continue. There are several reasons for this trend: GCP Quality Statistics demonstrate that the Good Clinical Practice quality of clinical trial conduct and data from emerging markets is as good as the quality of traditional regions. From January 2006 to August 2008, the reported rate of Official Actions Indicated (OAIs), the poorest classification in FDA inspections, was 5.4% in the US vs. only 0.5% outside the US. Less Site Saturation In many trials, the average enrollment per site in emerging markets is triple that of traditional

regions. This is explained by the saturation of sites in traditional regions plus the greater availability of high-quality healthcare for the majority of the population in these regions. Saturation by region is show in Table 2. The accepted rationale for the link between the availability of high quality healthcare and the lesser likelihood of participation in trials is based upon the greater investment in time that being in a clinical trial implies vs. just going to a readily available healthcare provider. A patient considers the greater investment in time to be worthwhile if he perceives that he is receiving a substantially better level of healthcare in the clinical trial setting.

Latin American Market Distinguishing Characteristics

Latin America is one of the big three emerging markets. Almost 90% of clinical trial activity is concentrated in the six major countries: Argentina, Brazil, Chile, Colombia, Mexico and Peru. The range of drugs, devices and vaccines being tested covers the entire spectrum of therapeutic areas. Quality and Trust Not only is strong ICH-GCP quality evidenced by FDA inspections as mentioned above, but the competent authorities (CAs) and sponsors now routinely expect trials to be conducted in Latin American countries and have set up the necessary regulatory infrastructure (laws, regulations, departments within CAs). The orderly conduct of trials over the last 20 years has inspired a level of trust in the quality and dependable functioning of the clinical trial regulation process and in the quality of the clinical trials themselves throughout these countries and their medical communities. Reverse Seasons It is summer in Argentina and Chile when it is winter in the US, Europe and Japan. This is a distinct advantage in speeding up the development of drugs that treat diseases that are seasonal in nature (such as certain indications in respiratory areas, dermatology, etc.) because companies can double the number of peak enrollment months per year by using these countries in addition to sites in the Northern Hemisphere. Cost The average cost of trials in Latin America is just 75%80% of the cost of US trials. Geography With the same time zones and geographic

Regulatory Focus

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Figure 1.Regulatory Flowchart for Brazil

Total Set-Up & Approval Process: 69 Months
CA (ANVISA)
Document translation into Portuguese after all required documents received from sponsor and dossier preparation before submission: 46 weeks

Investigator Local Ethics Committee Time to IRB/EC approval: 48 weeks

Time to CA approval 1220 weeks Import Product Time to import: 35 weeks

CA submission after getting the Local IRB/EC approval: 1 week

National Ethics Committee (CONEP) Time to CONEP approval : 1620 weeks

Study Start

Market Access Access to the growing Latin American market is a primary goal of many biopharmaceutical companies. Conducting trials in a given country is one the best methods to introduce, investigate or, in turn, generate data that can be used for several purposes, including faster market authorization approval, accelerated acceptance in a country formulary for reimbursement, and presentations at national and regional medical society meetings. All of these actions help the company achieve a faster, more profitable launch of a new drug, vaccine or medical device. For all these reasons, it is highly likely regulatory professionals will be called upon to help to select countries and supervise the clinical trial authorization (CTA) process in the Latin American region.

Figure 2. Regulatory Flowchart for Mexico

Reception and Translation of Required Documents
23 weeks

Comparison of US, EU and Latin American Review Processes

To put the Latin American regulatory review process for clinical trial authorization into context, a useful perspective is comparing the CTA processes in Latin America with the corresponding processes in the traditional regions of the US and EU. US In the US, each trial requires IND submission to FDA and parallel Independent Review Board (IRB) approval. The rate limiting step is mainly the IRB submissions and approvals process. However, site contracts can be the last step to be completed, especially in Academic Research Organizations (AROs). EU In the EU, there is a parallel review process, enabling simultaneous submissions to Ethics Committees (EC) and Competent Authority (CA), usually the Ministry of Health. However, site contract negotiations often are not able to be done in parallel with EC and CA reviews due to national regulations, which can add months to the start-up time required for site initiation. Latin America In Latin America the review process is sequential: first EC and then CA. This sequential process adds time as compared to a parallel process. A summary of the CTA process for the six major Latin American countries for clinical development is shown in Table 3.

Regulatory Documents From Sites EC, Hospital, Study Staff

46 weeks

Total Set-up & Approval Process: 34 months

Protocol Submission to Sector Salud (SS)

SS Approval
67 weeks

Customs release
12 days

Study Start

proximity to the US, Latin America allows a clinical scientist from a US-based R&D headquarters, for example, to have frequent contact with and easily visit a Phase 2A trial site. This is a distinct advantage in early stage exploratory trials. Language Homogeneity With only two major languages, Spanish and Portuguese, Latin America is one of the simplest regions in the world for the conduct of clinical trials. Hispanic Ethnic Group Hispanics constitute the largest minority group in the US, currently comprising 15% of the population. This number is expected to rise to 25% over the next few decades. Therefore, Latin American subjects can contribute to an NDA patient database by making it more representative of the US population.

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Table 1. FDA-Regulated Investigators 1996 vs. 2006 and 2004 vs. 2007
2006 North America Western Europe Central/Eastern Europe Latin America Asia-Pacific Rest of World (ME/Afr) TOTAL 14,555 3,923 1,793 1,095 1,054 617 23,089 SIVs has been reduced to three-to-four months, i.e., as fast as the quickest EU countrys total start-up process. The Mexico National Social Security Institute (IMSS) is Mexicos largest health system provider, covering almost half of the countrys population. Starting in 2009, IMSS is starting to review new protocols for approval in its hospitals. The consequence is that there are now potentially double the number of sites with a significant additional number of patients available for enrollment in Mexico. % of Total 63.2% 17.0% 7.8% 4.8% 4.6% 2.7% Annualized 10 year GR 1.8% 7.5% 41.4% 27.3% 25.6% 11.0% Annualized 3 year GR -5.2% -6.1% 15.9% 12.1% 10.2% 3.9%

Recent Major Changes in Latin America Regulations

Brazil Major changes in regulation have occurred in Brazil with Resolution 39, which went into effect on 5 July 2008 (see Figure 1 for new flowchart of the CTA process in Brazil). These changes made the national EC (CONEP) and CA (ANVISA) reviews for approval a truly parallel process, as in the EU, with potential savings of six to eight weeks for the first site (coordinator site) to reach site initiation visits (SIVs). Resolution 39 granted ANVISA the ability to approve all study sites in one submission and review cycle, which results in savings of four to six weeks for subsequent sites to reach SIV. The major limitation to full implementation of Resolution 39 is sufficient review staff in both ANVISA and CONEP to reduce current review timelines. Mexico On 31 July 2008, the Exemption from Import License (Customs Rule 4.3) was reestablished for imported clinical trial study drugs and lab kits, and for exported clinical samples (see Figure 2). The consequences are: reduction of two to three weeks in startup time required to import study drugs and lab kits savings on the number of hours spent on importation issues and paperwork (10%15% of total) reduction of two to three weeks in startup time required for export of biological samples, including tissue samples In Mexico, the total time from final protocol to

Conclusion
The emerging markets are playing an ever increasing role in the clinical development process. Together with Asia-Pacific and Central and Eastern Europe, Latin America is receiving more clinical trials each year. The start-up timelines

Table 2. Saturation of Clinical Trial Sites

Region US Western Europe Central/Eastern Europe Latin America Asia-Pacific Number of Trial Sites/1,000,000 inhabitants 82 11 8 2 <1

Based on FDA Form 1572 data (2007) Sources: Clinical Investigators Inspection List, US Food and Drug Administration CenterWatch, August 2008 (Investigator Participation by FDA Form 1572)

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Table 3. Start-up Times for Major Latin American Countries From Final Protocol in English to Start of Site Initiation Visits (SIV). Population 2005 (millions)
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Country

Time From Final Protocol to SIV (mos)*

5.5 to 6.5

Competent Authority Regulating Research

Recent Country-specific Information

ANMAT has recently increased its questioning of trial design, especially of placebo-controlled and related designs. CONEP and ANVISA reviews are now parallel processes per updated regulations (5 July 2008). New regulations are under discussion in the Chilean congress. FDA inspections are being conducted with positive results. Separate import license process is no longer required. Ministry of Health is receptive to queries and requests for information. Internet automation is proceeding.

Argentina

ANMAT

Brazil

190

6 to 9

ANVISA

Chile

15

4.5 to 5.5

ISP

Colombia

45

4 to 4.5

INVIMA

Mexico

110

3 to 4

SS

Peru

28

4 to 5 (5 to 6 if biologic)

INS

Total

425 million, or 80% of Latin Americas total population.

*All times include required drug import licenses, customs clearance and site contracts. If questions are raised by ECs or CA, additional time is required. ANMATThe National Administration of Drugs, Foodstuffs, and Medical Technology; ANVISAAgencia Nacional de Vigilancia Sanitaria; CONEPBrazilian National Ethics Commission; ISPInstituto de Salud Pblica; INVIMAInstituto Nacional de Vigilancia de Medicamento y Alimentos; SIVSite Initiation Visit; SSSector Salud; INSInstituto Nacional de Salud.

from final protocol to site initiation of Latin American countries vary from three to eight months, similar to those in Western Europe. Other advantages of Latin America include lower cost, proximity to the US, demographics and quality.
Authors Dennis Hurley, DrSc, is vice president, Kendle Latin America. He can be reached at hurley.dennisp@kendle.com. Mirtha Lipezker, MD, is senior director for Kendle Latin America. Hortencia Melgar is manager of regulatory affairs for Kendle Latin America. Daniel Mazzolenis, MD, MBA, is director for Kendle Latin America. The authors have a combined regulatory experience of more than 60 years in Latin America.

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