LATAM's Regulatory Framework For Medtech Early Feasibility Studies

The elements that define an early feasibility study (EFS) are (a) a small number of subjects; (b) a device that may be early in development, typically before the device design has been finalized; (c) a study that provides initial insights into device proof of principle and safety; and (d) a study that does not necessarily involve the first clinical use of a device. Traditionally, an EFS in the U.S. can take about one year to start, which is not competitive with international standards. Despite efforts by the FDA to implement and streamline its EFS program, medtech companies see very little progress in shortening the time from the site dossier packet received to the first patient enrolled (320 days!). (1) The difficulty in recruiting patients and the unpredictable, inefficient, and expensive regulatory process to conduct an EFS or a first-in-human (FIH) study in the U.S. forces medtech startups to conduct outside the U.S. (OUS) research, where trial regulatory hurdles are more favorable than in the U.S., and it is easier and faster to recruit subjects at a lower cost. (2)

Latin America is a compelling region to conduct medtech early feasibility studies due to its ethnically diverse population, high rate of urbanization, solid doctor-patient relations, and ethical, quality, and lower-cost clinical research. 

Latin American countries are committed to harmonizing their medical device regulations with international standards. In June 2022, the Pan American Health Organization (PAHO) organized a meeting with the national regulatory authorities (NRAs) from 19 Latin American countries to jointly develop strategies and exchange initiatives to strengthen the regulation of medical devices in the region. Among the attendees were directors, unit chiefs, reviewers, department managers, and professionals specialized in medical devices from the NRAs of Argentina, Bolivia, Brazil, Canada, Chile, Colombia, Costa Rica, Cuba, El Salvador, the United States of America, Guatemala, Honduras, Mexico, and Uruguay. (3)

Colombia’s Regulatory Framework For Medtech Early Feasibility Studies

Colombia has become a hotspot for EFS studies in Latin America primarily due to its fast regulatory approval process, excellent hospital infrastructure, and significantly lower hospital fees than the U.S.2 (2) The Colombian regulatory authority must review and approve any experimental use of novel drugs, materials, devices, or procedures conducted on human beings for scientific research. The National Institute of Food and Drug Surveillance (INVIMA) is the competent authority for clinical trials and health research. The procedure for securing authorization to undertake a medical device clinical trial involves two sequential steps:

• The research ethics committee (REC) of the healthcare institution where the trial will be conducted must issue an approval letter. This approval usually happens within 15 to 30 business days from the submission. INVIMA does not mandate the certification and registration of RECs for medical devices.

• INVIMA must review and approve the study. INVIMA’s medical device committee meets every 30 days. INVIMA’s website has the committee’s meeting schedule and document submission deadline dates. Applicants must submit their dossier about 25 days before the committee’s meeting date. The remaining meeting dates for 2022 are November 16 (submission deadline of October 21) and December 14 (submission deadline of November 25). Suppose an applicant submits a clinical trial dossier on or before the meeting submission deadline. In that case, the dossier will be reviewed, and the committee will issue its favorable answer, ask questions, or request additional documents. In some cases, there are too many submissions for the committee to review in one meeting; in that case, INVIMA postpones the review to the next scheduled meeting or schedules an extraordinary meeting to clear the backlog. This predictable meeting schedule makes INVIMA the fastest regulatory agency in Latin America for the review and approval of a medical device clinical trial.

On October 20, 2022, INVIMA announced in a public webinar presentation that from 2017 to 2022, INVIMA evaluated nearly 70 medical device clinical trials. Colombia issued its clinical research regulations in 2003. Colombia’s government realized that it needed to update its almost 20-year-old clinical research regulations to harmonize them with international standards, incentivize clinical research in therapeutic focus areas, include newer medical technologies and newer clinical trial design practices, update its bioethics standards, comply with the World Health Organization’s (WHO) Global Benchmarking Tool (GBT) for evaluation of national regulatory systems of medical devices including in-vitro diagnostics (GBT + medical devices), and comply with its membership commitment with the Organization for Economic Cooperation and Development (OECD). At the OECD, the governments of 37 democracies with market-based economies collaborate to develop policy standards to promote sustainable economic growth.

All this is part of Colombia’s 2022–2031 plan to become a knowledge economy. Developing economies focus heavily on agriculture and manufacturing, while highly developed countries have a larger share of service-related activities. This includes knowledge-based economic activities such as research, technical support, and consulting. (4,6) 

To assist the Colombian government, the Standards Alliance — a public-private partnership between the U.S. Agency for International Development (USAID) and the American National Standards Institute (ANSI) to support the capacity of developing countries in the areas of the legal and regulatory framework, standards development, conformity assessment procedures, and private sector engagement — in collaboration with the Advanced Medical Technology Association (AdvaMed) has been working to implement a project aimed at helping Colombia to maximize regulatory efficiency in the medical devices sector. The project emphasizes adopting internationally recognized best practices and implementing and reinforcing policies promoting the use of internationally harmonized voluntary consensus standards and conformity assessment mechanisms. (7)

Consumer prices in Colombia are close to 70% lower than in the U.S. (8) Medtech companies looking to conduct clinical research in Colombia should expect extraordinary cost savings in hospital fees. The Colombian peso has been one of the most devalued currencies. The peso has lost 26% of its value against the U.S. dollar in 2022, dramatically more than Chile, Peru, Brazil, and Mexico.9,10 The peso reached a historical point of over 5,000 vs. the U.S. dollar in early November of 2022.11 The lousy performance of the peso doubles currencies in crisis, such as the pound and the euro, and is devalued seven times more than the Brazilian real or Mexican peso. (12) It is a bargain for U.S. medtech to buy services from Colombian hospitals and run their trials.

Mexico’s Regulatory Framework For Medtech Early Feasibility Studies

Prior authorization from the Mexican regulatory authorities is required for any experimental use of drugs, materials, devices, or procedures conducted on human beings for scientific research. The Federal Commission for Protection Against Sanitary Risks (COFEPRIS) and the National Bioethics Commission (CONBIOÉTICA) are the two competent authorities for clinical trials and health research.

In November 2021, Mexico became the fourth country in the Americas — and the first Spanish-speaking nation — to join the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) after Canada, the U.S., and Brazil. Now that Mexico is a member, the industry expects that COFEPRIS will further strengthen the regulation of clinical research to make it even more competitive with international standards. By joining ICH, COFEPRIS is considered a highly demanding regulatory authority that follows WHO standards. The procedure for securing authorization to undertake a clinical trial involves three sequential steps: (13,14)

• COFEPRIS’ review and approval of a protocol authorization request are dependent upon obtaining a favorable decision from the health institution’s research ethics committee (REC) (comité de ética en investigación) and research committee RC (comité de investigación) where the study is being conducted, and when applicable, the biosafety committee (comité de bioseguridad). (15) The REC ensures subject safety. It provides ethics recommendations on human research protocols, including a review of the risks and benefits of the research and preparing ethics guidelines for researching humans. The REC must also approve the informed consent document. The RC evaluates the technical quality and scientific merit of the proposed research, and its opinion must contain the opinion of the REC and, where applicable, the biosafety committee.15 This favorable decision usually happens within 30 business days from filing, although it could take up to 60 days in public hospitals. CONBIOÉTICA must certify the REC, and COFEPRIS must certify the RC. The REC’s favorable decision is only later submitted to COFEPRIS with the protocol authorization request.

• The director of the healthcare institution where the trial is to be conducted must approve the study’s conduct under its relevant internal rules and timelines and issue a letter.

• COFEPRIS must review and approve the study, which, according to federal law, COFEPRIS must decide within 90 days of filing. However, in 2021, COFEPRIS promised to shorten the review processing times from 90 to 30 days.16 According to industry experts interviewed for this study, COFEPRIS' current review times are 45 to 60 days. Once the applicant obtains official authorization from COFEPRIS, the applicant has a maximum of five working days to enter this information into the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database. (15)

The Mexican peso has been a standout 2022 performer in Latin America, up 3% against the U.S. dollar.17 Consumer prices in Mexico are about 50% lower than in the U.S. (18) U.S. medtech companies looking to conduct clinical research in Mexico should expect cost savings; hospital fees in Mexico could be around 30% less than in the U.S.

Brazil’s Regulatory Framework For Medtech Early Feasibility Studies 

It’s impossible to consider conducting an EFS for a medical device in Latin America without considering Brazil due to its recruitment potential (a population of almost 220 million people in over 20 metropolitan areas) and excellent hospital infrastructure. In Brazil, the regulators of clinical trials with legislative attributions are the National Health Council, the Ministry of Health, and the National Health Surveillance Agency (ANVISA). Clinical trials are subject to first approval from the Committee for Ethics in Research (Comitê de Ética em Pesquisas [CEP]), the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa [CONEP]), and ANVISA. CONEP is the central body responsible for coordinating the network of institutional CEPs in Brazil and registering and accrediting the CEPs. Both the CEPs and CONEP are accountable for evaluating the ethical aspects of all research involving human beings and approving the research protocols. For those institutions lacking a CEP, or in the case of a researcher without an institutional affiliation, CONEP must suggest a CEP for the review and approval of the protocol. Together, the CEPs and CONEP represent the ethical review system in Brazil, known as the CEP/CONEP system. The procedure for securing authorization to undertake a clinical trial in Brazil involves four sequential steps: (19,20)

• Applications with coordination or sponsorship originating outside Brazil require an additional review and approval by CONEP. CONEP’s timeline is 15 days for document validation and 45 days for ethical assessment.

• The principal investigator (PI) must also obtain approval from their institutional ethics committee CEP. The institutional CEP must issue an initial report for review within 30 days of the PI's application. The CEP’s review of the protocol documentation for completeness should be accomplished within ten days following submission. The review period must be counted from the date the project entered “ethical assessment” (i.e., after going through the validation of documents, which takes around ten days, and when the Certificate of Presentation for Ethical Assessment [CAAE] is issued).

• The sponsor must register the clinical trial in a registry listed on the WHO’s International Clinical Trials Registry Platform (ICTRP) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE).

• A clinical trial can only commence after the applicant receives clinical trial application approval from ANVISA. By law, ANVISA has 90 calendar days to evaluate the application; however, according to João Nardo, a medical device regulatory expert in Brazil, current processing times are 120 to 180 days.

The Brazilian real was one of the best-performing currencies against the U.S. dollar earlier this year, gaining 24% from the start until early April 2022. (21) Consumer prices in Brazil are about 50% lower than in the U.S.22 U.S. medtech companies looking to conduct clinical research in Brazil should not expect extraordinary cost savings in hospital fees.

Conclusion

U.S. medtech companies are increasingly searching for a destination where they can recruit patients faster, easier, and cheaper for their early feasibility studies. Medtech companies want to avoid the uncertainty of the FDA Investigational Device Exemption (IDE) review process. Due to the difficulties that the new European Medical Device Directive (MDR) has created since May 2021, the medtech clinical trial pendulum is shifting from Eastern Europe to Latin America. Many more medtech companies are now looking at Latin America as their destination for their early feasibility research instead of Eastern Europe.

Colombia has become a hotspot for medtech early feasibility studies in the past ten years. Colombia is committed to overhauling its medical device clinical trial regulations to make the country even more competitive and attract more foreign direct investment in clinical research.

Traditionally, after Brazil, Mexico is perceived as the second slowest country in Latin America to approve a clinical trial. Mexico’s COFEPRIS, now a new member of ICH, has also promised reforms to its review process and timeline, making the country a promising destination for early feasibility medtech clinical trials. Mexico’s proximity to the U.S., its large population (over 130 million), its large number of metropolitan areas, its excellent public and private hospital infrastructure, and its expected COFEPRIS reforms make Mexico one of the top up-and-coming world destinations for clinical trials. Experts agree that Mexico can reach at least $800 million annually in clinical trial foreign investments. (23)

Brazil has been slow in reforming its medical device regulations to create a more competitive and agile framework; however, due to its recruitment potential and developed hospital infrastructure, it’s a geography that medtech companies should consider for their clinical research.

In most countries in Latin America, the approval process for Medtech trials involves obtaining institutional review board (IRB) or ethics committee (EC) approval first, followed by approval by a national regulatory agency or Ministry of Health. Based on the author's 15 years of experience conducting studies in Latin America, the time to approve a study in most Latin American countries is between 120-180 days. However, you can expect to save around 30%-50% in hospital fees compared to the U.S.

One thing to remember is that recruitment for clinical trials tends to be fast in Latin America. Patients often need medical care, and the national healthcare systems in many countries in the region make it difficult for them to access quality healthcare easily and quickly. As a result, patients are often eager to participate in clinical trials to receive treatment.

References

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2. Latin America's Landscape For Medtech Clinical Trials. Clinical Leader. [Online] July 5, 2022. [Cited: October 13, 2022.] https://www.clinicalleader.com/doc/latin-america-s-landscape-for-medtech-clinical-trials-0001.

3. Countries of the region advance in strengthening the regulatory capacity of medical devices . Pan American Health Organization. [Online] June 22, 2022. [Cited: October 25, 2022.] https://www.paho.org/en/news/22-6-2022-countries-region-advance-strengthening-regulatory-capacity-medical-devices.

4. WEBINAR: INVESTIGACIÓN CLÍNICA CON DISPOSITIVOS MÉDICOS Y REACTIVOS PARA USO EN MUESTRAS DE USO HUMANO. INVIMA Facebook Page. [Online] October 19, 2022. [Cited: October 20, 2022.] https://www.facebook.com/InvimaColombia.

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6. Knowledge Economy. Investopedia. [Online] January 22, 2021. [Cited: October 25, 2022.] https://www.investopedia.com/terms/k/knowledge-economy.asp.

7. STANDARDS ALLIANCE HOSTS COLOMBIAN MEDICAL DEVICE REGULATORY AGENCY (INVIMA) FOR WORKSHOP ON REGULATORY COHERENCE AND CONVERGENCE. ANSI. [Online] February 12, 2018. [Cited: October 20, 2022.] https://www.ansi.org/news/standards-news/all-news/2018/02/standards-alliance-hosts-colombian-medical-device-regulatory-agency-invima-for-workshop-on-regulator-12.

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13. Gobierno de Mexico. COFEPRIS. [Online] November 17, 2021. [Cited: October 14, 2022.] https://www.gob.mx/cofepris/es/articulos/mexico-primer-pais-hispanohablante-miembro-de-ich-maximo-foro-regulatorio-de-productos-farmaceuticos?idiom=es.

14. Clinical Trials Handbook. Baker McKenzie. [Online] 2018. [Cited: October 13, 2022.] https://www.bakermckenzie.com//-/media/files/insight/publications/2019/healthcare/america/dsc125067_clinical-trials-handbook--mexico.pdf.

15. ClinRegs. National Institute of Allergies and Infectious Diseases. [Online] February 16, 2022. [Cited: October 14, 2022.] https://clinregs.niaid.nih.gov/country/mexico.

16. COFEPRIS ANUNCIA CAMBIOS A PROCESOS DE PROTOCOLOS DE INVESTIGACIÓN PARA AGILIZAR TIEMPOS DE RESPUESTA Y PROMOVER LA INNOVACIÓN. Gobierno de México. [Online] August 2021. [Cited: October 17, 2022.] https://www.gob.mx/cofepris/articulos/cofepris-anuncia-cambios-a-procesos-de-protocolos-de-investigacion-para-agilizar-tiempos-de-respuesta-y-promover-la-innovacion?idiom=es.

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About The Author:

Julio G. Martinez-Clark is co-founder and CEO of bioaccess, a market access consultancy that works with medical device companies to help them do early-feasibility clinical trials and commercialize their innovations in Latin America. Julio is also the host of the LATAM Medtech Leaders podcast: A weekly conversation with Medtech leaders who have succeeded in Latin America. He serves as an advisory board member for Stetson University's Leading Disruptive Innovation program. He has a bachelor's degree in electronics engineering and a master's degree in business administration.