Aparna Shekar1,2, Gerald L. Klein, MD3, and Peter C. Johnson, MD3
1Ph.D. Candidate, Vanderbilt University, Nashville TN, 2Intern, MedSurgPI, LLC., Raleigh NC, 3Principal, MedSurgPI, LLC., Raleigh NC
Clinical trials are scientific experiments designed to test new medications, devices or other therapeutic interventions, or to further gain insight on those treatments for use in human medicine. They aim to produce insight into the safety and efficacy of medical interventions and strive to produce improvements in medical care. Clinical trials have evolved substantially since James Lind’s Scurvy trial in the 1700s1, to become more structured and supervised, and to generate more rigorous, reproducible results. But along with being thorough came a new set of challenges - clinical trials today face a gamut of scientific, ethical, regulatory and financial roadblocks. Biopharmaceutical development is a global business today. Companies are routinely conducting clinical trials in foreign nations with the intent that the data will also to be used to support US claims2,3. In 2008, 80% of all marketing applications submitted to the FDA contained data from foreign clinical trials (https://oig.hhs.gov/oei/reports/oei-01-08-00510.pdf). There are several reasons for this trend, including but not limited to lower costs of conducting trials abroad. In 2013, the Tufts Center for the Study of Drug Development estimated that the total costs for developing, seeking approval and marketing a new chemical entity costs $2.6 billion on average, creating an impetus for decreasing the costs of clinical trials. Countries that have grown to be popular choices for conducting clinical trials include those in Latin America, Asia, Europe and Africa where lower operating costs occur. Some of these lower costs include human resources, clinical procedure costs, site monitoring costs, regulatory, and compensation in case of injuries/deaths that may occur4. Other significant benefits of foreign clinical trials include the ability to enable globalized medical product discovery and development, expand diversity of the test subject pool, shorten drug development timelines and less litigious and, importantly, to test patients that are naive to treatments not found in third world countries. Due to these advantages, the number of foreign clinical trials conducted to meet US FDA regulations has more than doubled over the past decade.
However, there are major risks involved in conducting clinical trials outside the United States. Companies need to consider and prepare in advance to understand country-specific insurance requirements, legal restrictions and regulations regarding conducting clinical trials with human subjects. They also need to determine if the trial design conforms to FDA standards so that trial data can be accepted by the FDA for review. In the absence of prior careful consideration, sponsors may inadvertently violate local insurance laws, expose themselves to excessive liability, or even unknowingly purchase insurance coverage that is well beyond the requirements of a particular country. It is particularly important for sponsors to thoroughly understand and follow FDA guidelines for conducting clinical trials in a foreign country. Under Section 1123 of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012, data from foreign clinical trials should be accepted by the FDA, provided such studies comply with U.S. federal standards on Good Clinical Practices (GCPs). As of 2016, the FDA has issued guidelines stating that it may accept clinical trials conducted outside the US under the classification of an Investigational New Drug (IND) and comports with all FDA regulations as if the trial were being conducted within the United States. Additionally, it may consider a trial not conducted under the classification of IND, so long as the study conforms to whichever of the following rules provides greater protection of the test subjects: (i) the ethical principles contained in the 1983 version of the Declaration of Helinski or (ii) human rights regulations in the foreign country in which the trial is conducted. The new Questions and Answers (Q&A) Guidance from the FDA issued on February 21, 2018 provides further clarification on how to conduct these trials. The International Conference on Harmonization (ICH) and World Health Organization Good Clinical Practice (GCP) standards provide a unified measurement for the USA, European Union, Japan, Australia, Canada, the Nordic countries and several others. A complete list of countries that have adopted this guideline is available online at www.ich.org. Additionally, research groups have also developed methods that can predict country-specific financial requirements, outcomes of trials and risks involved in foreign locations that are developing countries, that may help sponsors in identifying an appropriate country in which to conduct their trial5,6. This new Q&A guidance document emphasizes the importance of a description of how investigators were trained to comply with GCP and how the study was monitored so that the investigations were done in accordance with the protocol (Section 812.28(b)(12)).
Ultimately, it is important to maintain scientific integrity and patient safety, which leads to better trial outcomes. Several resources are available that can help companies understand the strict guidelines that they are required to follow to manage potential risks. Companies can seek aid from experts on ICF and GCP guidelines, foreign insurance policies, medical insurance policies, informed consent requirements and FDA liaisons. Our experts from MedSurgPI, LLC. can aid pharmaceutical and medical device companies in making informed decisions and adopting appropriate steps before they embark on conducting clinical trials in foreign countries. MedSurgPI, LLC. by providing experienced product development expert services to its clients is well positioned to bridge the business and medical understanding that such risk management requires.
References:
1 Lind and scurvy - 1747 to 1795.
2 Capeding, M. R. et al. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. The Lancet 384, 1358-1365, doi:10.1016/s0140-6736(14)61060-6 (2014).
3 Ezeome, E. R. & Simon, C. Ethical problems in conducting research in acute epidemics: the Pfizer meningitis study in Nigeria as an illustration. Dev World Bioeth 10, 1-10, doi:10.1111/j.1471-8847.2008.00239.x (2010).
4 Dezfuli, M. Outsourcing Clinical Trials Outside of the US. Pharmaceutical Regulatory Affairs: Open Access 06, doi:10.4172/2167-7689.1000194 (2017).
5 Lorenzo, C., Garrafa, V., Solbakk, J. H. & Vidal, S. Hidden risks associated with clinical trials in developing countries. J Med Ethics 36, 111-115, doi:10.1136/jme.2009.031708 (2010).
6 Hidden risks associated with clinical trials in developing countries.