What are the latest developments in medical trials?

Latest Developments in Medical Trials

The COVID-19 pandemic has revolutionized clinical trial design, demonstrating that streamlined trials with essential data collection and electronic health record integration can deliver rapid, high-quality evidence while maintaining Good Clinical Practice principles. 1

Streamlined Trial Design and Implementation

The pandemic catalyzed significant innovations in clinical trial methodology:

• Large-scale adaptive platform trials like RECOVERY and WHO Solidarity demonstrated the effectiveness of streamlined protocols focused on essential data collection and mortality outcomes 1
• These trials avoided complex protocols with restrictive eligibility criteria and unnecessary data collection that plagued many smaller COVID-19 studies 1
• Electronic health records (EHRs) were successfully leveraged for both recruitment and comprehensive follow-up of trial participants 1

Recent Advances in Treatment Regimens

Multidrug-Resistant Tuberculosis (MDR-TB)

• The TB-PRACTECAL trial demonstrated that a 6-month regimen with bedaquiline, linezolid, pretomanid, and moxifloxacin (BPaLM) achieved 89% favorable outcomes versus 51% with standard care 1
• This regimen is now the WHO-recommended preferred treatment option for fluoroquinolone-susceptible MDR/RR-TB 2
• Safety outcomes were significantly improved with only 25% of patients on BPaLM experiencing grade 3/4 adverse events compared to 60% on standard care 1

Chronic Kidney Disease in Diabetes

• Recent large clinical trials have focused on SGLT2 inhibitors for kidney protection:
  • The CREDENCE trial of canagliflozin showed a 32% risk reduction for end-stage kidney disease in patients with type 2 diabetes and kidney disease 1
  • The EMPA-KIDNEY trial demonstrated a 24% lower hazard ratio for major kidney disease events with empagliflozin in patients with significant kidney disease 1
  • These trials have expanded the recommended use of SGLT2 inhibitors to patients with eGFR as low as 20 mL/min/1.73 m² 1

Challenges and Innovations in Trial Design

Regulatory and Bureaucratic Barriers

• Over the past 25 years, there has been an enormous increase in rules and bureaucracy governing clinical trials 1
• The International Council for Harmonization Good Clinical Practice (ICH-GCP) Guidelines, while intended to ensure participant safety and reliable results, are often over-interpreted in ways that obstruct affordable trial conduct 1
• These complexities have become major barriers, especially for trials of interventions with little commercial support or those relevant to low-income populations 1

Strategy Trials

• Strategy trials comparing different approaches to patient management (rather than specific drugs) face unique challenges:
  • Difficulty randomizing eligible patients due to preconceived beliefs about treatment superiority 1
  • Challenges in obtaining informed consent and requiring multidisciplinary cooperation 1
  • Higher resource requirements and longer recruitment periods 1
  • Limited funding sources, often requiring governmental/institutional support or public-private partnerships 1

Biomarker Development

• Increasing focus on incorporating biomarkers into clinical trials to improve efficiency:
  • Analysis of archived samples and datasets from completed trials provides rich opportunities for biomarker development 1
  • Industry-academia collaboration is strongly encouraged to mine RCT datasets and samples 1
  • Early-phase interventional trials in inflammatory bowel disease now routinely include exploratory biomarker development projects 1

Impact of COVID-19 on Clinical Research

• The pandemic disrupted ongoing trials but also demonstrated the potential for rapid, high-quality research:
  • Clinical research during COVID-19 was crucial for developing treatments and launching fast-track controlled trials 1
  • Adaptive trials provided rapid intermediate results, allowing for quick adjustments to treatment protocols 1
  • Major initiatives like the DisCoVeRy trial and WHO's Solidarity trial used adaptive methodologies to enable quick inclusion of thousands of patients worldwide 1

Pitfalls and Caveats

1. Evolving Standards of Care: Strategy trials are particularly vulnerable to becoming outdated as standard of care evolves during their protracted nature (slow recruitment with long follow-up) 1

2. Interpretation of Strategy Trial Results: Results require careful interpretation, especially when crossovers occur. For example, in the COURAGE trial comparing PCI plus optimal medical therapy versus medical therapy alone, 32.5% of patients assigned to medical therapy eventually received revascularization 1

3. Biomarker Collection Planning: Trial sponsors should carefully plan collection of appropriate samples (whole blood, serum, stool, peripheral blood mononuclear cells, biopsy samples) for future biomarker development 1

4. Overinterpretation of Surrogate Outcomes: Many smaller COVID-19 trials focused on surrogate outcomes rather than mortality, leading to putative benefits that didn't translate to mortality benefits in larger trials 1

The landscape of clinical trials continues to evolve rapidly, with increasing emphasis on efficiency, adaptability, and meaningful patient-centered outcomes. The lessons learned during the COVID-19 pandemic may permanently transform how we design and conduct clinical research.