WEAK 1. Introduction to Clinical Trails and Medical Studies (Source: https://online.stat.psu.edu/stat509/)

Zulfiqar Ali, Ph.D

Assistant Professor of Statistics, CSS, University of the Punjab, Lahore,

October 10, 2023

What is Clinical Research?

  • Clinical research involves investigating proposed medical treatments, assessing the relative benefits of competing therapies, and establishing optimal treatment combinations.

Role of Statistics in Clinical Research

  • Clinical research plays a vital role in advancing medical knowledge and improving patient care.
  • It involves addressing critical questions such as:
  • Should a man with prostate cancer undergo radical prostatectomy, radiation therapy, or opt for a watchful waiting approach?
  • Is the incidence of serious adverse effects among patients receiving a new pain-relieving therapy greater than that in patients receiving the standard therapy?

Remarks

  • Before the widespread use of experimental trials, clinicians relied on individual patient experiences to answer such questions.
  • They used clinical judgment and reasoning, often based on reports of interesting cases.
  • However, they did not formally address the concepts of variability among individuals and its sources.

The Emergence of Statistics

  • In the twentieth century, the field of statistics emerged as the “theoretical science or formal study of the inferential process, especially the planning and analysis of experiments, surveys, and observational studies” (Piantadosi, 2005).

  • Clinical research began to utilize statistical methods to provide formal accounting for sources of variability in patients’ responses to treatment. The use of statistics in clinical research serves several crucial purposes:

Formal Inference

  • Formal Inference: Statistics enables clinical researchers to draw reasonable and accurate inferences from collected information. It allows them to make sound decisions even in the presence of uncertainty.

2. Error and Bias Reduction

  • Error and Bias Reduction: Mastery of statistical concepts can prevent numerous errors and biases in medical research, ensuring that research findings are robust and reliable.

Characteristics of Statistical Reasoning

  • Statistical reasoning in clinical research is characterized by the following key principles:
  • 1. Objective Framework: Establishing an objective framework for conducting an investigation.
  • 2. Balancing Data and Theory: Placing data and theory on an equal scientific footing.
  • 3. Designing Data Production: Designing data production through experimentation.
  • 4. Quantifying Chance: Quantifying the influence of chance on research outcomes.
  • 5. Estimating Effects: Estimating systematic and random effects in the data.
  • 6. Theory-Data Integration: Combining theory and data using formal methods.

The Interplay Between Clinical and Statistical Reasoning

  • Carter, Scheaffer, and Marks (1986) highlighted that statistics is unique among academic disciplines because statistical thought is needed at every stage of virtually all research investigations.
  • This includes planning the study, selecting the sample, managing the data, and interpreting the results.

Conclusion

  • Both clinical and statistical reasoning are crucial to the progress of medicine.

  • Clinical researchers must generalize from individual cases to larger populations and combine empirical evidence with theory. In both medical and statistical sciences:

    1. Empirical knowledge is generated from observations and data.
    1. Medical theory is based on established biology and hypotheses.
    1. Statistical theory is derived from mathematical and probabilistic models.

Theme of lecture

To establish a hypothesis in clinical research, it requires a theoretical basis in biology and statistical support based on observed data and theoretical statistical models.

Lecture Part 2

What constitutes a ‘clinical trial’?

  • A ‘clinical trial’ is a specific type of medical research study designed to test the safety, efficacy, and/or effectiveness of medical treatments, interventions, therapies, or procedures on human subjects.
  • Here are some key characteristics and components that constitute a clinical trial:

Experimental Nature:

  • A clinical trial is an experiment by its nature. It involves a systematic investigation in which researchers intentionally apply a medical treatment or intervention to a group of human subjects to observe its effects.

Human Subjects:

  • Clinical trials involve human participants or subjects who volunteer to be part of the study.
  • These subjects may have a specific medical condition, be at risk for a particular disease, or be healthy individuals participating in preventive or exploratory research.

Controlled Conditions:

  • Clinical investigators carefully control various conditions throughout the trial, including the selection of subjects, the application of the treatment or intervention, the evaluation of outcomes, and the methods of data analysis.
  • This control is essential to minimize bias and ensure the validity of the study’s results.

Design and Structure:

  • Clinical trials are designed with specific structures and protocols that isolate the factors of interest. Researchers aim to control variability attributable to factors other than the treatment under investigation.

Variability in Human Research:

  • It’s important to acknowledge that there is inherently larger variability in research involving humans compared to controlled laboratory situations. Human populations are diverse, and individual responses to treatments can vary widely.

Preference for the Term ‘Clinical Trial’:

  • The term “clinical trial” is preferred over “clinical experiment” because it conveys a sense of respect for the value of human life.
  • The use of the term “trial” emphasizes that participants are entering into a carefully designed and monitored study for the purpose of advancing medical knowledge, improving healthcare, or evaluating the safety and efficacy of new treatments.

In what contexts are clinical trials used?

  • Clinical trials are a critical component of medical and public health research, and they are used in various contexts to address a wide range of questions and objectives.
  • Here are some key contexts in which clinical trials are used:

Drug Development and Approval:

  • Clinical trials are extensively employed to evaluate the safety and efficacy of new pharmaceutical drugs. Regulatory agencies, such as the U.S.
  • Food and Drug Administration (FDA), often require clinical trial data to grant approval for marketing and widespread use of these drugs.
  • This is a crucial step in bringing new medications to the market.

Vaccine Development:

  • Clinical trials play a pivotal role in the development and testing of vaccines for various infectious diseases.
  • The efficacy and safety of vaccines are rigorously assessed in clinical trials before they are made available to the public.

Medical Device Evaluation:

  • Clinical trials are used to assess the safety and effectiveness of new medical devices, especially high-risk devices.
  • Manufacturers must provide clinical data to demonstrate the device’s performance and safety before it can be marketed.

Surgical Interventions:

  • While surgical procedures pose unique challenges in clinical research, they are still subject to clinical trials, especially when evaluating new surgical techniques, devices, or approaches.
  • These trials aim to establish the safety and efficacy of surgical interventions.

Therapeutic Interventions:

  • Clinical trials are conducted to test the efficacy and safety of various medical therapies, including medications, surgical procedures, and non-pharmacological treatments.
  • These trials help determine which treatments are most effective for specific medical conditions.

Preventative Measures:

  • Clinical trials are used to evaluate the effectiveness of preventative measures, such as vaccines, lifestyle interventions, and dietary supplements, in reducing the risk of disease or health complications.

Diagnostic Procedures:

  • Trials are conducted to assess the accuracy and reliability of new diagnostic tests and procedures. These trials help determine the utility of diagnostic tools in clinical practice.

Confirmatory Studies:

  • Clinical trials are often used to confirm the findings of earlier research.
  • When initial results are promising or surprising, subsequent trials may be conducted to replicate the findings and establish their robustness.

Population-Specific Research:

  • Clinical trials may focus on specific populations, such as pediatric or geriatric patients, to tailor treatments and interventions to their unique needs and characteristics.

Comparative Effectiveness Research:

  • Some clinical trials are designed to compare the effectiveness of different treatments or interventions. - These studies help inform healthcare providers and patients about the best treatment options.

Rare Diseases and Orphan Drugs:

  • Clinical trials are crucial for researching rare diseases and assessing the efficacy of orphan drugs (medications developed for rare conditions) due to the limited patient population.

Global Health:

  • Clinical trials are conducted in various parts of the world to address global health issues, such as infectious disease outbreaks or the evaluation of interventions for diseases that disproportionately affect certain regions.

Challenges in Clinical Trials: Time, Labor, and Expenses

1) Collaborative Effort

  • Clinical trials require a cooperative effort from various professionals.
  • This includes physicians, patients, nurses, data managers, methodologists, and statisticians.
  • Each role is crucial in ensuring the success of the trial.

2) Patient Recruitment

  • Patient recruitment is often a significant challenge.
  • Finding suitable candidates who meet the trial’s criteria can be difficult.
  • Slow recruitment can prolong the trial’s duration and increase costs.

3) Costly Endeavors

  • Clinical trials can be extremely expensive.
  • Some multi-center trials, which involve multiple institutions, can cost hundreds of millions of dollars.
  • Funding such trials is a significant challenge in itself.

4) Lengthy Timelines

  • Clinical trials are time-consuming.
  • They may take five years or more to complete, from the planning phase to data analysis.
  • This extended timeline can delay the availability of new treatments to patients in need.

5) Prevention Trials

  • Prevention trials aim to determine if treatments can prevent the onset of disease.
  • While crucial, they are often the most cumbersome, lengthy, and expensive trials to conduct.
  • The need for long-term follow-up and a large number of participants adds to the complexity.

6) Window of Opportunity

  • window of opportunity refers to a specific timeframe during which a study is most feasible and can have the greatest impact on clinical practice.

7) Comparative Trials

  • In the context of comparative trials, this window often occurs early in the development of a new therapy.
  • This is when the treatment is still a subject of interest and debate among healthcare professionals.

8) Risk of Widely Accepted or Discounted Therapies

  • If a treatment becomes widely accepted or discounted based on anecdotal experience, it can close the window of opportunity for a formal efficacy test.
  • Clinicians may start using the treatment routinely without rigorous scientific evidence.

9) Challenges in Such Cases

  • Even when some clinicians remain unconvinced of the treatment’s efficacy or relative safety, conducting a comparative trial becomes problematic.
  • Patient recruitment can be challenging, as some patients may prefer the treatment they perceive as widely accepted.

10) Missed Opportunities

  • Missing the window of opportunity can have significant consequences.
  • We may lose the chance to collect robust data and draw evidence-based conclusions about the treatment’s effectiveness.

11) Balancing Act

  • Finding the right balance is essential.
  • It’s crucial to strike a balance between early investigation when a therapy is still actively debated and the need for rigorous clinical testing.

Remarks

  • Some important medical advances have been made without the formal methods of controlled clinical trials, i.e., without randomization, statistical design, and analysis. Examples include the use of vitamins, insulin, some antibiotics, and some vaccines.