The Role of Controlled Clinical Trials in Drug Development

During the process of clinical drug development, it is critical to discriminate between patient outcomes caused by treatment with a New Chemical Entity (NCE) or a new Investigational Medicinal Product (IMP) and outcomes that occur as a result of other factors, including disease progression, patient or observer expectations, or treatment with other drugs. Controlled clinical trials are valuable tools that facilitate this discrimination.

The Control Selection Process in Clinical Trials

In clinical trials, there may be a risk of bias, which indicates a systematic tendency to record a treatment effect deviating from its actual value. The risk of bias may be introduced during any stage of a clinical trial, including its design, conduct, data analysis, and data interpretation. Thus, in controlled clinical trials, a careful selection of controls ensuring that the test and control groups are as similar as possible from the beginning of the trial and continue to be treated as similarly as possible throughout it may help minimize this risk. Furthermore, if a control compound is administered, its dose and dosing interval should be considered carefully.

Types of Control Treatments

Controlled Clinical trials may use different types of controls, depending on the characteristics of the investigated NCE or IMP and the study population. Such controls include:

• • Placebo concurrent control is an inactive treatment (not containing the test compound) that appears identical to the test drug. In placebo-controlled trials, study participants are randomly assigned to a test treatment or a placebo.
  • “No treatment” concurrent control refers to being randomly assigned without treatment in a clinical trial. Thus, in a no-treatment controlled trial, study participants are randomly assigned to a test treatment or absence of study treatment.
  • Active treatment concurrent control is used in active control (positive control) trials, in which study participants are randomly assigned to a test treatment or another active control treatment.
  • Dose-comparison (dose-response) concurrent control is employed in randomized, dose-response trials with fixed doses of an NCE. In this type of trial, study participants are assigned randomly to one of several possible fixed-dose groups. The comparison between/among groups is performed with their final doses, even though there may be a dose escalation to reach these doses.
  • External (including historical) control is used in externally controlled trials. In such trials, study participants treated with a test compound are compared to individuals external to the study, such as individuals treated during an earlier time period (a historical control group) or the same period but in a setting external to the clinical trial.
  • Multiple control groups – A subset of clinical trials may include more than one control, for example, a placebo and an active control.

Strategies for Minimizing Risk of Bias

Another important component of controlled clinical trials are randomization and blinding, which are key strategies in selecting control groups that minimize the risk of bias.

• • Randomization refers to randomly assigning study participants into a test treatment group and a control group. Randomization is key to ascertaining that the test and control groups are as similar as possible and do not systematically differ regarding baseline variables that may influence patient outcomes. In clinical trials that do not include a randomized concurrent control, it may be challenging to eliminate differences between the study groups.
  • Blinding in a controlled clinical trial helps ensure that the groups included in a clinical trial are observed and treated similarly, except for administering a test drug or a placebo. The goal of blinding is to minimize potential bias that may arise from differences in the assessment, management, and treatment of study participants or data interpretation as a result of the investigator and study participants being aware of the assigned treatment. In clinical trials that are “double-blind,” both the investigators and study participants are not aware of the assignment of participants to a particular study group, minimizing potential bias.

Factors to Consider in Controlled Clinical Trial Design

There are many factors to consider when designing and conducting a controlled clinical trial design. These can include:

• • Recruitment challenges – Implementing well-thought-out eligibility criteria and randomization may help reduce the risk of selection bias when recruiting study participants. Challenges in recruitment are one of the most relevant potential bottlenecks in clinical drug development, which may delay the drug development process and increase its cost. The design of an effective recruitment strategy tailored to the specific needs of each clinical trial may help overcome recruitment challenges. In addition, establishing study volunteer databases may help efficiently recruit study participants for controlled clinical trials.
  • The potential usefulness of biomarkers and digital endpoints – The selection of the most informative study endpoints is an essential component of the design of each clinical trial. Biomarkers have increasingly been implemented in clinical trial development, and the use of genetic, imaging, and immunological biomarkers has shown the potential to inform clinical decisions. In addition, digital endpoints, collected using sensors during routine activities of study participants, may help better track and understand their experiences.
  • Implementation of artificial intelligence (AI) – The introduction of AI in clinical drug development is still in its initial stages but has already found certain applications in pattern recognition and image interpretation. The optimal strategies that can be used to complement human intelligence with AI in the context of clinical drug development still remain to be elucidated.
  • The significance of a multidisciplinary and collaborative approach – The complexity of clinical trial design and conduct requires a multidisciplinary effort, drawing on the expertise of professionals from different fields. Collaborations among safety physicians, clinical pharmacologists and pharmacokinetic scientists, bioanalytical scientists, regulatory professionals, and biostatisticians are crucial to enhance the efficiency and safety of controlled clinical trials.
  • Adaptive study designs – Randomized controlled trials have been associated with a high cost and long duration. Introducing adaptive study designs may help increase the efficiency of clinical trials while minimizing their cost.

Controlled Clinical Trials for New Drug Applications (NDAs)

Filing an NDA with the United States Food and Drug Administration (FDA) is a critical step in clinical drug development in the United States. An NDA is typically submitted after a Phase 3 clinical trial (or, more rarely, a Phase 2 clinical trial) that has demonstrated the superior efficacy or safety of an NCE compared to currently available therapies.

Controlled clinical trials are indispensable for the compilation of an NDA. In addition to advanced Phase 2 and Phase 3 clinical trials, NDA-enabling studies also include the results of early-phase clinical trials, such as single ascending dose (SAD) and multiple ascending dose (MAD), pharmacokinetic bridging and bioavailability, food effect, and drug-drug interaction studies.

 Additionally, in NDA-enabling studies investigations of special populations or assessing the function of specific organs may be required, such as renal or hepatic impairment studies, thorough QT (TQT) studies, human abuse potential (HAP) studies, or proof-of-concept (POC) studies in special populations.

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BioPharma Services is a full-service contract research organization (CRO) with extensive expertise in early-phase clinical trials, including controlled clinical trials and NDA-enabling studies. Our multidisciplinary, award-winning team has implemented a comprehensive strategy to enhance the efficiency and safety of the clinical trials we conduct for our clients’ drug development programs.

To achieve these goals, we have established an extensive database of normal health volunteers (NHVs) and special populations, two state-of-the-art Phase 1 clinical centers, and a modern in-house bioanalytical laboratory. In addition, our highly qualified internal experts and network of external collaborators have know-how in diverse medical fields and experience with various study designs, formulations, and routes of administration.

BioPharma Services, Inc., a Think Research Corporation and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma has clinical facilities both in the USA and Canada with access to healthy volunteers and special populations.