Part 1: Study Design and Ethical Principles
Clinical trials represent the central pillar of the development of new drugs and medical devices, being essential to ensuring the safety and efficacy of treatments before they reach the market. However, conducting these studies involves a complex web of ethical and regulatory considerations that cannot be overlooked.
The history of clinical research is marked by controversial episodes that led to the progressive development of international guidelines and national regulations to protect participants and ensure the scientific integrity of studies. In Brazil, ethical and regulatory compliance, which not only protects the rights and safety of participants but also ensures scientific validity, is the responsibility of agencies such as the Brazilian Health Regulatory Agency (ANVISA), the National Research Ethics Commission (CONEP), and the National Health Council (CNS).
Outside the national context, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) works to harmonize guidelines across different regions, reducing duplication of effort and facilitating global drug development. In this series of texts, I will address common aspects about which research centers and sponsors often lack complete confidence or have doubts to ensure ethical and regulatory compliance in practice.
How does it work in practice?
Study design aligned with ethical principles
The study design must balance scientific rigor with ethical considerations. It is essential to have a strong scientific rationale, where the study addresses a valid and important scientific question. Risk minimization is also crucial, implementing measures to minimize risks to participants. The risk-benefit balance must be carefully assessed, ensuring that the potential benefits are proportional to the risks assumed. For example, a study evaluating a new treatment for a disease must demonstrate how this treatment differs from existing treatments or how it may benefit patients who do not respond to current therapies.
One of the main guidelines is to rely on preclinical evidence, including laboratory studies and animal models when applicable, that demonstrate a reasonable expectation of benefit and an acceptable safety profile. Inadequate preclinical data was responsible for tragedies such as the TGN1412 trial in 2006, where six healthy volunteers developed multiple organ failure because crucial differences in the immune response between humans and non-human primates were not identified.
The participant selection to ensure population diversity has always been a challenge. Historically, several groups have been systematically excluded from clinical trials, resulting in data with limited applicability to these populations. Inclusion and exclusion criteria must be fair, avoiding unjustified exclusions of populations. Over the years, this approach has evolved, especially in Brazil. The routine exclusion of women of childbearing age, previously a common practice, is now considered unjustified in most cases and can be replaced by adequate contraception and monitoring measures. Furthermore, it is essential to consider the social impact of the study.
In short, ethical and regulatory compliance in research requires a rigorous approach from the very beginning of the study design. The application of ethical principles, such as respect for autonomy, beneficence, non-maleficence, and justice, must guide all stages of the process, ensuring the protection of participants and the scientific validity of the results. Thus, the combination of a methodologically robust design and compliance with ethical and legal guidelines contributes to the responsible and transparent conduct of clinical research.