Clinical trials in the FDA drug approval process


The FDA has laid down several rules and regulations to protect individuals who volunteer to take part in clinical trials. FDA also emphasizes and upholds the need to safeguard participants from foreseeable risks and plays an influential role in encouraging pharmaceutical and biotechnology companies to ensure that they provide detailed and step wise drug development plans before execution.1,2

Critical steps to a clinical trial

FDA regulations include adherence to Good Clinical Practice (GCP) and human subject protection (HSP). FDA views the following pointers as crucial before the start of any clinical trial:

  • Informed consent: This extremely critical step gives potential subjects an opportunity to understand what they can expect from the trial by communicating with individuals in charge of the research study. The process of obtaining consent not only helps an interested candidate understand the study risks and benefits but also establishes a healthy rapport with the research team. FDA mandates the need to document written or thumb-printed consent forms of each participant before start of trial.1,2
  • 21 CFR 312: This FDA regulation describes the Sponsors responsibility of selecting qualified investigators, monitoring the progress of the trial, compliance to investigational plan, and periodic review of safety and efficacy data received during the trial.3
  • 21 CFR 314.216: This regulation provides a broad description of what a robust study should comprise of, i.e., measures to minimize bias, method of assigning subjects to treatment or control groups, method of selection of appropriate patient subject population, and reliable and validated methods of assessment of subject response.3
  • ICH guidelines: To protect subjects and to maintain data quality, FDA advices Sponsors to follow ICH guidelines for Good Clinical Practice (ICH E6), ICH guidelines for pharmaceutical quality system (ICH Q10) and FDA guidance documents for the industry.3
    • Quality Risk Management plan (ICH Q9): The study protocol is considered the blueprint for quality and should document a plan for monitoring of potential risks that may arise during the trial.3
    • Diversity in enrolled population: To make clinical trials inclusive, FDA recommends considering various trial designs or methodologies to broadening the eligibility. For instance, reducing the frequency of planned visits to trial sites in areas with limited transportation and the use of technologies such a mobile/telephone for seamless access.4
    • Recognition of the role of patients, patient advocates and caregivers in the success of clinical trials: A key factor to successful patient enrollment and trial completion has been inclusiveness which is influenced by factors such as geographical location of the trial, race, gender, age, and ethnicity of the target population. It is also important to factor in the influence of the social fabric on potential participants. Participants and caregivers can provide insights into what they look for before enrolling into a trial. This helps a Sponsor to design trials that have higher enrollment rates.4
  • Expanded access: For patients that do not meet the eligibility criteria but suffer from a serious or life-threatening condition with no successful treatment regimens, FDA allows expanded access of investigational drugs to such patients. In such cases, data from expanded access may be an effective resource for future drug discovery and development plans.4

FDA assistance during clinical trials

Drug manufacturers and developers can seek FDA expertise during any of the clinical trial phases of a drug such as during pre-IND application, study design inputs for Phase III studies, or while assessing an IND application.5

Monitoring of databank

FDA monitors information on the website to check for compliance and enforcement issues by the party responsible for conducting the trial. In addition, FDA makes it necessary for Sponsor companies to inform the enrolled subjects in their consent forms about the availability of details of the clinical trial on the website. However, it should also be made clear that the website would not divulge any personally identifiable information of any trial subjects. The aim of this website is to promote transparency between the public and Sponsor party.6

The Critical Path Initiative by FDA

With a growing number of clinical trials moving out of USA, it became necessary to improve quality and efficiency of clinical trials with respect to handling enormous amounts of data and patient representation from USA. FDA launched the Critical Path Initiative (CPI) in the year 2004 to bridge the gap between declining medical treatment options and new discoveries in the field of technology and pharmaceutical research. This led to modernization of clinical models, manufacturing processes, and use of information technology to move from a paper-based model to electronic storage of data. In public-private partnership with the Duke University, North Carolina, the FDA launched another initiative in 2007 called the Clinical Trial Transformation Initiative (CTTI) to promote efficient and effective monitoring of clinical trials, improve SAE reporting, increase collaborations with educational and research institutes, and provide training courses to clinical investigators.7

FDA’s flexible approach to drug approval

While FDA is in charge of drug regulation and approval to uphold patient rights and safety, the evidence from clinical trials based on which FDA approves a drug may vary widely. A cross-sectional analysis carried out by Downing NS et al on clinical trials of new drugs between 2005 and 2012 demonstrated FDA’s flexibility in making approval decisions across indications. While majority of the trials were randomized and double-blinded, many studies varied in their choice of study duration, sample size, comparators, and endpoints, especially in cases of orphan drugs, and potential therapies for debilitating or life-threatening diseases.8

The way forward

In the recent years, FDA has been focusing on retraining staff to support the use of emerging technologies that help hasten regulatory approval of trials. For instance, FDA has been recruiting scientific experts in the field of genome sequencing in order to help construct a gene library for common and uncommon pathogens that can speed up approval for trials that address a critical or dangerous disease condition. FDA also encourages the development of personalized medicines/precision medicines although they are associated with increased cost for the drug developer and patients. In cases of personalized medicine programs, FDA calls for critical analysis of safety and efficacy data by researchers and drug developers during early phases of the clinical trial, i.e., by improving genetic science knowledge and carrying out meta-analyses.9 Such steps ensure that a quality system is built into clinical trials thereby ensuring unnecessary rework and audit-ready trials.10


    1. USFDA. FDA 101: Clinical Trials and Institutional Review Boards. Accessed on May 27, 2020.
    2. Mulinde J. Clinical Quality By Design: FDA Point of View. DIA 51st Annual Meeting . 2015. Accessed on May 27, 2020.
    3. US Department of Health and Human Services. Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry. June 2019. Accessed on May 27, 2020.
    4. USFDA. Step 3: Clinical Research. Accessed on May 27, 2020.
  1. USFDA. The critical path initiative. Report on Key achievements in 2009. Accessed on May 27, 2020.
  2. Downing NS, Aminawung JA, Shan ND et al. Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents. JAMA. 2014;311(4):368-377. DOI: doi:10.1001/jama.2013.282034
  3. Junod SW. FDA and Clinical Drug Trials: A Short History. USFDA. Accessed on May 27, 2020.

USFDA. Science moving forward. A progress report to the FDA Science Board. Accessed on May 27, 2020.

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