In January 2018 this introduction to clinical trials was prepared by the pharmaceutical consultants at PDG who routinely design and write clinical trial protocols. This paper represents a collection of quotes and resources ranging from basic primers to more advanced concepts. This is provided for drug and medical device professionals who may not serve in clinical departments, but must nonetheless be equipped to determine applicability of study designs to specific situations. Included is a description of foundational concepts, various categorical descriptions of types of studies, controls, designs, and examples of frequently occurring clinical trial structures. Included throughout are the links to source material, definitions and descriptions for ongoing reference.
While this paper was written in early 2018, we open with a 2001 definition of “clinical trial” from Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001. The definition is directed to drug development professionals, is succinct, on point, and may nicely summarize what you already know relating to clinical studies addressing safety, efficacy, comparison and characterization:
“Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or efficacy…”. Following is a link to the Directive.
If you are interested in clinical trials and seeking a grant, refer to NIH’s Definition of a Clinical Trial last updated August 8, 2017. It is also helpful to appreciate a patient directed definition of clinical trial. Following is an excerpt from FDA:
What are clinical trials?
Clinical trials are research studies in which people volunteer to help find answers to specific health questions. When carefully conducted, they are the safest and fastest way to find new treatments and ways to improve health. Clinical trials are conducted according to a plan, called a protocol, which describes:
- the types of patients who may enter the study
- the schedules of tests and procedures
- the drugs involved
- the dosages, or amount of the drug
- the length of the study
- what the researchers hope to learn from the study [outcomes and endpoints]
Why are clinical trials done?
Clinical trials are conducted for many reasons:
- to determine whether a new drug or device is safe and effective for people to use.
- to study different ways to use standard treatments or current, approved treatments so that they will be more effective, easier to use, or decrease certain side effects.
- to learn how to safely use a treatment in a population for which the treatment was not previously tested, such as children.
Clinical trials are usually conducted in a series of steps referred to as Phases. Each Phase has its own purpose and helps researchers answer different questions. Following is a description of the Phases as defined by FDA (21 CFR 312.21). As noted in the regulation, the Phases are generally conducted sequentially, but may overlap:
Phase I includes the initial introduction of an investigational new drug into humans. Phase I studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase I, sufficient information about the drug’s pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase II studies. The total number of subjects and patients included in Phase I studies varies with the drug, but is generally in the range of 20 to 80…Phase I studies also include studies of drug metabolism, structure-activity relationships, and mechanism of action in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes.
Phase II includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase II studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects.
Phase III studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather the additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for physician labeling. Phase III studies usually include from several hundred to several thousand subjects.
Why are studies described as Phases 0 or IV?
First, it should be noted that FDA regulation addresses clinical investigation of a previously untested drug. Initial clinical investigations cover a wide range of testing, experimentation and observation. So, while 21 CFR 312.21 only defines Phases I-III, clinicaltrials.gov, describes five Phases, including Phase 0, and defines these investigations as “early Phase I.” According to the American Cancer Society, “Even though Phase 0 studies are done in humans, this type of study isn’t like the other Phases of clinical trials. The purpose of this Phase is to help speed up and streamline the drug approval process. Phase 0 studies are exploratory studies that often use only a few small doses of a new drug in a few patients. They might test whether the drug reaches the tumor, how the drug acts in the human body, and how cancer cells in the human body respond to the drug. The patients in these studies might need extra tests such as biopsies, scans, and blood samples as part of the study process. The biggest difference between Phase 0 and the later Phases of clinical trials is that there’s almost no chance the volunteer will benefit by taking part in a Phase 0 trial – the benefit will be for other people in the future. Because drug doses are low, there’s also less risk to the patient in Phase 0 studies compared to Phase I studies.”
Generally speaking, Phase IV may describe any study conducted after FDA approval. For example, CenterWatch explains that “After a drug has been approved by the FDA, Phase IV studies are conducted to compare the drug to a competitor, explore additional patient populations, or to further study any adverse events.”
Suvarna notes that “Not all Phase IV studies are post-marketing surveillance (PMS) studies but every PMS study is a Phase IV study…JUST as Phase I is sometimes referred to as the acid test of drug development (where the rubber meets the road), since it is the first time that the drug is being tested in humans, Phase IV may be considered as the real test since for the first time that the drug is tested in the real world. …Drug products are launched after regulatory authorities have scrutinized a vast amount of data from animal and clinical studies and found it to show that the drug is sufficiently effective and adequately safe in specified indications.”
Why are studies described as Phase IB, IIB, or IIIB?
Phase I A&B
It is not unusual to hear Phase IA and IB described as single ascending dose trials versus multiple ascending dose trials, or as first-in-human versus first proof-of-concept trials. For example, Mahan notes that “Dose-toxicity and dose-efficacy curves are determined during this Phase and include single ascending dose trials (Phase IA), multiple ascending dose trials (Phase IB), and food effect studies.” At the same time FDA guidance specifies that “Phase IA/first-in-human trials in general, we recommend single- and/or multiple-ascending-dose trials in healthy adult subjects to assess safety and pharmacokinetics for the first-in-human trials. Sponsors also can conduct single-dose and short-duration multiple-dose pharmacokinetic (PK) trials in HCV-infected patients…Phase IB (proof-of-concept) trials the first proof-of-concept antiviral activity trial in HCV-infected patients should be a repeat dose, randomized, dose-ranging, monotherapy trial with collection of intensive PK, safety, and HCV RNA data.”
Mahan also provides an excellent definition and description of Phase I (as well as Phases II and III): “A Phase I clinical trial evaluates the best way to administer a drug, its frequency and dose, the maximum tolerated dose (MTD), and side effects. Tolerability, pharmacokinetics, and pharmacodynamics are evaluated. These studies determine, most importantly, if the treatment is safe. Trials usually include 20 to 100 patients and are monitored by the clinical researcher. Doses are increased if there are no severe side effects and patients are tested to determine if he or she is responding to the therapy. These escalation dose studies are used to determine the best and safest dose that can be administered and is a fraction of the dose that caused harm during animal testing. Unnecessary exposure of subjects to sub therapeutic doses while maintaining safety and rapid accrual is the primary goal of Phase I trials. Subjects, in most cases, are healthy volunteers although patients with a certain disease may be required.”
A special note regarding Phase I studies
While Phase III studies are regarded as those designed for NDA registration purposes, it is important to note that the Phase I pivotal PK/PD studies may be used to prove therapeutic equivalence for ANDA approval. Gieser explains that pivotal bioequivalence studies are those required to bridge the proposed formulation (test) to that used by the reference listed drug (RLD) in Phase III clinical trials. For reference, Jaap, et. al describe various other uses of PK/PD studies.
Phase II A&B
“While a Phase I clinical study focuses on determining the MTD [maximum tolerated dose], Phase II studies evaluate potential efficacy and characterizes treatment benefit for the disease in a convincing manner…These studies are performed on larger groups (100 to 300 subjects) and are designed to assess how well the drug works and to continue safety assessments. Therapeutic doses which were determined during Phase I are administered and patients are monitored by the clinical researcher. Trials are often conducted in a multi-institution setting. Phase II may be divided into Phase IIA which are pilot clinical trials to evaluate efficacy and safety in selected populations with the disease or condition to be treated, diagnosed or prevented (objectives may be on dose-response, type of patient, frequency of dosing, or other identifiers of safety and efficacy) and Phase IIB which are the most rigorous trials designed to demonstrate efficacy.” (Mahan 2014)
Phase III A&B
“Phase III trials are the full-scale evaluation of treatment and are designed to compare efficacy of the new treatment with the standard treatment. These are the most rigorous and extensive type of scientific clinical investigation of a new treatment. This is the “pre-marketing Phase” of clinical trials…Large groups (100 to 3000 subjects) are recruited and trial designs have included randomized controlled trials (parallel design), uncontrolled trials (single treatment), historical controls, no-randomized concurrent trials, factorial designs, and group sequential designs…Phase III clinical trials may be divided into Phase IIIA which are trials done after efficacy of the therapy is demonstrated but before regulatory submission of a New Drug Application (NDA) or other dossier and Phase IIIB which are conducted after submission of an NDA or other dossier but before approval and launch.” (Mahan 2014)
Overview and Examples
Obviously, there are a variety of different clinical study types and structures. The paragraphs that follow include five different categorical descriptions of types of studies, controls, designs, definitions and examples, including links to the source material.
Before studying the material, it is helpful to review a few additional basics: in an easy to review slide deck, Kalogeropoulos explains that interventional (or experimental) designs are those in which an exposure is assigned, while observational studies are those where the investigator simply observes what happens. Retrospective studies are those in which the outcome has already occurred and thus may only be observational, while prospective studies anticipate a future outcome and may be either interventional or observational. Interventional studies may be either parallel or crossover, and observational studies may be either cross-sectional, case-control or cohort in design.
FDA’s page entitled “What Are the Different Types of Clinical Research?” identifies and defines at least seven types of studies:
- Treatment Research
- Prevention Research
- Diagnostic Research
- Screening Research
- Quality of Life Research
- Genetic studies
- Epidemiological studies
FDA regulations [21 CFR 314.126] cite five different kinds of controls that can be useful circumstance
- Placebo concurrent control
- Dose-comparison concurrent control
- No-treatment concurrent control
- Active-treatment concurrent control, and
- Historical control
The NIH Director’s Panel on Clinical Research has issued the following three-part definition of clinical (Source Rubio et al 2010)
- Patient-oriented research
- Epidemiologic and behavioral studies
- Outcomes and health services research
According to Evans , “Many structural designs can be considered when planning a clinical trial. Common clinical trial designs include single-arm trials, placebo-controlled trials, crossover trials, factorial trials, non inferiority trials, and designs for validating a diagnostic device. The choice of the structural design depends on the specific research questions of interest, characteristics of the disease and therapy, the endpoints, the availability of a control group, and on the availability of funding. I discuss common clinical design structures, highlight their strengths, limitations, and assumptions, and provide guidance regarding when these designs may be considered in practice.”
The Georgia State University Library page describes and defines the following:
- Meta-AnalysisA way of combining data from many different research studies. A meta-analysis is a statistical process that combines the findings from individual studies. Conn V. Nurs Res. 2010 May-Jun;59(3):224-31.
- Systematic ReviewA summary of the clinical literature. A systematic review is a critical assessment and evaluation of all research studies that address a particular clinical issue. Wanchai A, Armer JM, Stewart BR. Clin J Oncol Nurs. 2010 Aug;14(4):E45-55.
- Randomized Controlled TrialA controlled clinical trial that randomly (by chance) assigns participants to two or more groups. Barrett B, et al. Ann Fam Med. 2012 Jul-Aug;10(4):337-46.
- Cohort Study (Prospective Observational Study)A clinical research study in which people who presently have a certain condition or receive a particular treatment are followed over time and compared with another group of people who are not affected by the condition. Croucher R, et al. Addiction. 2012 Dec;107 Suppl 2:45-52.
- Case-control StudyCase-control studies begin with the outcomes and do not follow people over time. Researchers choose people with a particular result (the cases) and interview the groups or check their records to ascertain what different experiences they had. Persaud N, et al. CMAJ. 2012 Nov 20;184(17):E921-3.
- Cross-sectional studyThe observation of a defined population at a single point in time or time interval. Exposure and outcome are determined simultaneously. Steiner MJ, et al. Pediatrics. 2011 Sep;128(3):463-70.
Suvarna describes various types of Phase IV studies including:
- Non-Interventional Studies
- Large Simple Trials
- Post-Marketing Surveillance Studies
- Case-Control Studies
- Drug Utilisation Studies
ClinicalTrials.gov provides a “Glossary of Common Site Terms”. However, the terms available in the glossary are those relevant to the content on ClinicalTrials.gov, only. Therefore, links are provided for help with the medical terms, e.g. MedlinePlus® Medical Encyclopedia, as well as more advanced information for study record managers: Protocol Registration Data Element Definitions, Expanded Access Data Element Definitions, and Results Data Element Definitions.
According to Burns, “evidence-based medicine (EBM), is about finding evidence and using that evidence to make clinical decisions. A cornerstone of EBM is the hierarchical system of classifying evidence. This hierarchy is known as the levels of evidence [LOE]. Levels of evidence (sometimes called hierarchy of evidence) are assigned to studies based on the methodological quality of their design, validity, and applicability to patient care”. In his article, Burns describes four variations of LOE in tabular format:
- Canadian Task Force on the Periodic Health Examination’s Levels of Evidence – “levels of evidence were originally described in a report by the Canadian Task Force on the Periodic Health Examination in 1979”
- Levels of Evidence from Sackett – “levels of evidence were further described and expanded by Sackett in an article on levels of evidence for antithrombotic agents in 1989”
- Levels of Evidence for Prognostic Studies – “levels of evidence developed by the American Society of Plastic Surgeons (ASPS) for prognosis”
- Levels of Evidence for Therapeutic Studies, which follows:
Levels of Evidence for Therapeutic Studies
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Other useful tables describing LOE are found at describing levels of evidence at Winona State University, Darrel W. Krueger Library Evidence Based Practice Toolkit.
When designing a study or selecting a pharmaceutical consultant or CRO, the numerous factors to consider must not overlook the integration of regulatory strategy. In addition to designing clinical protocols, the authors routinely source and oversee CROs on behalf of their clients. In doing so, they seek and validate solid track records, sound processes, up-to-date technology, compliant quality systems, and willingness and ability to adhere to clear performance parameters.
Feel free to contact us for help with your next project.
About the Authors
Charles Jaap is Vice-President of Operations and Business Development for PDG®, a global pharmaceutical and medical device consultant with extensive experience in the strategic development of drug products and medical devices.
Dr. Catherine Patterson is Director of Scientific Research for PDG® and offers expertise utilizing her background in Molecular Biology with academic experience in grant writing and publishing. She actively participates in safety surveillance activities, clinical trials and regulatory submissions on behalf of PDG clients.
Mikel Alberdi, MPH, RAC is Director of Regulatory Affairs/New Product Development for PDG®. He has over 13 years of regulatory affairs experience, with expertise in facilitating FDA meetings and compiling NDA, 505(b)(2), and ANDA submissions.
The opinions and statements in this paper are solely those of Charles Jaap, Catherine Patterson, and Mikel Alberdi, and do not necessarily reflect those of PDG®.