Key Considerations for Conducting Clinical Trials: Regulatory Compliance and Participant Safety
Clinical trials must prioritize participant safety through independent data safety monitoring boards (DSMBs) with explicit stopping rules, comprehensive informed consent processes that ensure adequate understanding, and adherence to Good Clinical Practice guidelines with proper regulatory documentation. 1
Regulatory Documentation and Approval
Essential Documents Required
Investigational Medicinal Product Dossier (IMPD) must be completed, including Part S (drug substance) and Part P (pharmaceutical formulation and development) 1
Investigator's Brochure comprising five chapters: biological properties, IMPD summaries, preclinical results (pharmacology, biodistribution, toxicology), previous human data, and clinical guidance on therapeutic indications, dosing, contraindications, and safety information 1
Study Protocol must indicate scientific justification, objectives, trial procedures, eligibility criteria, treatment administration, efficacy assessment, safety monitoring, data management, statistical aspects, quality control, ethical considerations, and funding details 1
Subject Information Leaflet and Informed Consent Forms must be in language and terms understandable to participants, clearly stating the nature, scope, and possible consequences of the study 1
Regulatory Authority Coordination
National competent authorities issue clinical trial authorization after reviewing the study protocol and Investigator's Brochure, which must comply with Good Clinical Practice guidelines (CPMP/ICH/135/95) 1
For international studies, contact major international regulatory agencies early to coordinate and unify study design, as practice patterns vary significantly between countries 1
Local authorization requires institutional ethical committee approval based on submitted protocols, case report forms, and consent documents according to national and European legislation (Helsinki Declaration, GCP principles, Bioethics law) 1
Informed Consent Process
Critical Requirements for Valid Consent
Informed consent documents are frequently too long to be read completely, making it difficult for participants to identify material facts about the trial 2
Approximately 45% of participants cannot name at least one risk, indicating inadequate understanding that invalidates consent 2
The consent process must clearly state whether participants receive some, most, or all food (in feeding trials), degree of preparation required, and restrictions associated with participation 1
Plain language statements must explain why diet concealment occurs in blinded studies and provide sample menus with portion sizes during the consent process 1
Addressing Therapeutic Misconception
The therapeutic misconception frequently prevents participants from realizing that the primary purpose of clinical research is to benefit future patients, not necessarily themselves 2
Excessive risk disclosures, insufficient information about expected benefits, and framing effects compromise rational risk/benefit assessment 2
For critically ill patients who lack capacity, family members or surrogates provide consent, but careful explanation of protocol distinctions is mandatory 1
Practical Implementation
Consider using the Brief Informed Consent Evaluation Protocol (BICEP), a short telephone-based assessment administered immediately after consent completion, which takes an average of 8.8 minutes and provides reliable evaluation of consent quality 3
Consent documents must address potential protocol adjustments due to disruptions, including when patients become symptomatic during therapy 1
Safety Monitoring and Data Oversight
Independent Data Safety and Monitoring Board (DSMB)
An independent DSMB empowered by explicit statistical stopping rules and contemporary ad hoc review of adverse events is mandatory for all clinical trials 1
The DSMB is uniquely positioned to review safety information according to blinded treatment arms, enabling appropriate safety data analysis and meaningful summary reports to trial steering committees, principal investigators, and ethics committees 4
Failure to have proper monitoring threatens trial validity if terminated prematurely and may adversely influence the risk-benefit ratio if continued inappropriately, as patients have been harmed when studies continued longer than they should 1
Adverse Event Reporting
Individual adverse event reports to ethics committees serve no useful purpose in most cases because study group identity is unknown in blinded treatment arms 4
For Phase IV pragmatic trials of post-marketed drugs, systematic complete reporting of all adverse events independent of treatment-relatedness is wasteful and mostly unnecessary 4
Defined trial endpoints do not need to be reported as safety events because they are being properly monitored and analyzed 4
Drug sponsors, investigators, institutional review boards, and ethics committees must establish memoranda explaining how clinical trial activities can be conducted effectively while allowing for possible disruptions 1
Protocol Design Considerations
Eligibility Criteria and Site Selection
Investigators unwilling to randomize all qualifying patients should not participate in the trial, as referral bias can reduce the intended study population and limit statistical power 1
Selection of academic centers versus community hospitals impacts patient types seen, and investigators with limited clinical trial experience may become concerned with small clustering of adverse events, disrupting recruitment 1
Potential referral bias must be minimized—for example, those believing in anticoagulation utility may be less likely to refer cardioembolic stroke patients into heparinoid trials 1
Control Arm Design
Protocolizing care in the control arm is justified when the protocol reflects usual care representing best current practice, informed by appropriate observational studies, surveys, and pilot trials 1
The decision to protocolize control arm care may deny participants individualized care they would have received outside the trial, requiring careful explanation during informed consent 1
For feeding trials, placebo diets should represent the study population's "usual" diet based on national nutrition survey data or apparent consumption data, noting that clinical populations may differ significantly from national averages 1
Blinding Strategies
Double-blinding is recommended, and if single-blinding is used, the reason must be transparently reported 1
Develop and report plans on who is blinded, how blinding will be maintained, and when and how to evaluate blinding success 1
For feeding trials, careful menu design, similar appearance/taste of foods, and storage in opaque containers can safeguard blinding 1
Ethical Framework and Quality Assurance
Ethical Checklists
Incorporate ethical checklists in clinical research design and implementation, using templates that address: social/scientific value, scientific validity, fair subject selection, favorable risk-benefit ratio, independent review, informed consent procedures, and respect for participants 1
Before starting studies, verify: Does the study address an important question? Is the design scientifically valid? Are subjects selected fairly? Is the risk-benefit ratio favorable? Has the protocol undergone independent review? Are adequate consent procedures in place? Are data and safety monitoring established? Have conflicts of interest been identified and minimized? 1
Ongoing Monitoring Questions
Do new data or hypotheses undermine the social or scientific value of the ongoing study? 1
Do new results from this or other studies unfavorably alter the risk-benefit ratio? 1
Monitor for drug-drug interactions between investigational agents and concomitant therapies 1
Special Populations and Contexts
COVID-19 Era Considerations
Maintain and support continuing clinical intervention trials whenever possible, including continued accrual of new participants, while ensuring patient safety and study feasibility 1
FDA and Health Canada have issued guidance for conducting clinical trials during pandemics, particularly emphasizing patient safety 1
Test all patients for relevant infections before treatment initiation, and if positive, consider delaying treatment by 10-14 days except for urgent situations 1
Rare Disease Trials
Open, early, and public declaration of potential conflicts of interest is the best strategy for promoting knowledge and safety, especially when few clinicians have experience with the disease 1
Investigator-initiated trials should strive to meet similar standards for data quality and subject safety as larger industry-sponsored trials 1
Postmarketing/post-trial surveillance should be conducted for all agents, with procedures for long-term follow-up to ensure safety and efficacy, as functional differences may not be detected in shorter approval studies 1
Leftover biospecimens with appropriate annotations (but de-identified) should be made available for other researchers when possible, included in the consenting process 1
Common Pitfalls to Avoid
Avoid anonymous consultations via third-party data gathering companies where potential conflicts cannot be identified 1
Do not allow contamination bias (trial itself changing customary care) or maturation bias (changing background scientific information) to undermine scientific validity 1
Ensure dose, timing, and route of delivery are selected to increase likelihood of success, affecting value, validity, and risk-benefit ratio 1
Consider using central institutional review boards to streamline trial startup and reduce complexity 1
Discuss trial endpoints with regulators early, including defining clinical failure and evaluating the impact of concomitant therapies 1