TY - JOUR
AU - Macek,, Thomas
AB - Q : I was taught that there are four phases of clinical trials. I have noticed in recent years that additional phases are appearing in the literature. What are these different phases, and what do they mean? A : Traditionally, a drug in development moves through four phases of clinical trials (I–IV).1 In recent years, new categories of trials have appeared in the literature with increasing frequency. These phases include subcategory designations (a and b) after their Roman numeral (e.g., IIa, IIb) or are combination phases (e.g., Phase I/II). While there are no formally adopted, rigid definitions of these atypical phases of clinical trials by regulatory agencies or the pharmaceutical industry, a general understanding of these phases exists. These trial designations appear to be contemporary; however, they are not new to the industry. Combination phases emerged in the late 1970s in cancer development programs, and the use of these phase designations was subsequently transferred to the pharmaceutical industry.1 A search of the medical literature using Medline and International Pharmaceutical Abstracts databases revealed the use of phase subcategories a and b as early as 1979. Phases with subcategory designations Phase I trials establish a dosing range and evaluate pharmacokinetic and pharmacodynamic parameters, acute adverse effects with increasing doses, and early evidence of efficacy. They typically involve a small number (20–80) of healthy volunteers, although for some drugs patients with the disease may be studied (e.g., patients with cancer).2,–5 Studies may also include special patient populations, such as those with hepatic or renal impairment. These studies are often conducted in an inpatient environment to allow for close monitoring of the patient.5 Phase Ia studies are the first to be conducted in humans. Generally, these are single-dose-escalation studies that may be randomized but not controlled. The aim is to determine the maximum tolerable dose and identify acute adverse events and dose-limiting toxicities. Phase Ib trials are conducted in healthy adults or patients who have the disease or condition for which the drug is being studied. The maximum tolerable dose determines the dosage range for the multiple doses given in Phase Ib studies. These trials continue to explore the drug’s tolerability and pharmacologic properties. Phase Ib trials can also provide preliminary efficacy assessments. Phase II trials evaluate the preliminary evidence of efficacy and common short-term adverse effects of a drug. They include more subjects, about 100–300, who have the targeted disease. Phase II trials are typically controlled and longer in duration than Phase I trials but shorter than Phase III trials.2,–5 They can help to develop and refine the research methods for Phase III trials. The primary objective of Phase IIa trials is to perform concept testing, the assessment of safety and tolerability. Phase IIa trials also continue to explore dosage ranges and pharmacologic properties. After the completion of Phase IIa trials, a manufacturer can request to meet with the Food and Drug Administration (FDA) to analyze the available data from trials up to that point, focusing on exposure–response data.3 The purpose of this meeting is to improve the efficiency of drug development by identifying optimal doses and study design for subsequent studies.6 Phase IIb trials are typically randomized, controlled trials comparing the investigational drug with a standard treatment. These trials aim to demonstrate efficacy, safety, and tolerability in the targeted population for a longer period of time than in previous trials. Phase IIb trials may include multiple doses to continue to assess the dose–response relationship and identify the most effective dose or doses to use in Phase III trials. Phase III trials evaluate the efficacy and safety of the drug, typically in a large number of subjects (1000–3000). Less common adverse effects are likely to be revealed because these studies last longer than previous studies and more patients are being studied. These studies are usually randomized and controlled, with either a placebo or active treatment control group. Data obtained from Phase III trials usually provide the basis for the product labeling. These are the most difficult, time-consuming, and expensive trials to conduct.5 Phase IIIa trials are the large, pivotal studies designed to be included with the submission of a new drug application (NDA) to FDA.2 They serve as evidence of longer-term safety and efficacy in the targeted population. Phase IIIb trials are larger studies completed in patients with the same targeted conditions and using the same dosage listed in the NDA but are performed after submission of the NDA to FDA.2,7 These studies are not intended to be pivotal, as efficacy and safety have already been proven in earlier clinical trials. Phase IIIb trials are meant to be efficacy trials that more closely mirror clinical practice in the patient population likely to be treated. They often include large, heterogeneous patient populations and have less rigid inclusion and exclusion criteria. These studies also reveal additional safety information that can supplement the product profile. Because they are conducted before drug approval, these trials are performed under investigational new drug (IND) regulations.7 Phase IV trials, also known as postmarketing trials, are conducted to further characterize a drug’s effectiveness (efficacy under real-life conditions) and safety for the approved indication.2,–5 These trials help to define optimal use and to discover more about the long-term risks associated with the drug. Phase IV trials may be mandated by FDA to gather additional safety and efficacy data. Because these trials are conducted after the drug has been marketed, they are not subject to IND regulations. Adverse events discovered in Phase IV trials may result in product withdrawal from the market or the addition of black-box warnings.5 Of the 548 new chemical entities approved between 1975 and 1999, 56 (10.2%) received black-box warnings or were withdrawn from the market.8 Combination phases The FDA Modernization Act of 1997 created fast-track approval, a new approval category for drugs intended to treat serious or life-threatening conditions for which there is an unmet medical need.9 While not specific in its definitions, this act does recognize the need for combination-phase trials. Generally, combining two phases of trials accelerates the clinical development process. These combination-phase trials are useful for drugs indicated for the treatment of diseases that have few treatment options, less common diseases where trial recruitment and participation are often limited due to the small number of affected patients, and life-threatening diseases where shortening the drug development time is important.1 As expected, a single trial combining two phases would meet the objectives of each individual phase. Phase I/II trials typically include pharmacokinetic and dose-finding assessments, with preliminary safety, tolerability, and efficacy evaluations. Phase II/III trials are usually randomized, controlled studies that evaluate the safety and efficacy of multiple doses, often in comparison with a standard treatment. Combination phases can be subcategorized with a or b designations as described above (e.g., Ib/II, IIb/IIIa). Limitations of phase definitions FDA has defined only four phases of clinical trials (I–IV).4 While there is common agreement about the definitions of phase subcategories and combination phases, these definitions are somewhat subjective. The definitions provided here are only meant to serve as guidance for interpreting the different phases that regularly appear in the medical literature. Keep in mind that the classification of a clinical trial’s phase is at the discretion of sponsors, who are entitled to assign the designation they feel best fits the trial design. Since there is a lack of regulatory guidance, these definitions may vary among sponsors and, consequently, among trials. References 1 Sandage BW. Balancing phase II and III efficacy trials. Drug Inf J . 1998 ; 32 : 977 –80. Crossref Search ADS 2 Terres CR. Pharmacoeconomic analysis in new drug development: a pragmatic approach to efficiency studies. Clin Res Regul Aff . 1998 ; 15 : 209 –23. Crossref Search ADS 3 Rados C. Inside clinical trials: testing medical products in people. FDA Consum . 2003 ; 37 (5): 30 –5. 4 Food and Drug Administration. Code of federal regulations, title 21, volume 5 (sections 312.21, 312.85). www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm (accessed 2006 Feb 27). 5 Wikipedia. Types of clinical trials. http://en.wikipedia.org/wiki/Clinical_trials (accessed 2005 Nov 21). 6 Center for Drug Evaluation and Research. Concept paper: end-of-phase-2A meetings with sponsors regarding exposure-response of IND and NDA products. www.fda.gov/ohrms/dockets/ac/03/briefing/3998B1_01_Topic%201-Part%20A.pdf (accessed 2005 Nov 14). 7 Faich GA. Phase IIIb and treatment IND safety reporting. Drug Inf J . 1993 ; 27 : 1173 –7. Crossref Search ADS 8 Lasser KE, Allen PD, Woolhandler SJ et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA . 2002 ; 287 : 2215 –20. Crossref Search ADS PubMed 9 Food and Drug Administration. Food and Drug Administration Modernization Act of 1997. www.fda.gov/cder/guidance/105-115.htm (accessed 2005 Nov 21). Author notes The Q & A column features ASHP staff responses to inquiries from pharmacists in health systems. Through this column, more practitioners can benefit from the answers prepared by the staff. The column may also include answers solicited from others, including government agencies such as OSHA, FDA, and DEA. Pharmacists with questions for ASHP should write directly to the appropriate staff member, not AJHP. Frequently called extensions are listed in every issue of AJHP on the page after the Table of Contents. Copyright © 2006, American Society of Health-System Pharmacists, Inc. All rights reserved.
TI - Defining the phases of clinical trials
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp050537
DA - 2006-04-15
UR - https://www.deepdyve.com/lp/oxford-university-press/defining-the-phases-of-clinical-trials-ToE3ddtCDa
SP - 710
VL - 63
IS - 8
DP - DeepDyve
ER -