Phase IV studies

For drugs approved under accelerated approval regulations on the basis of a surrogate endpoint or an endpoint other than survival or irreversible morbidity, FDA may require a Phase IV study to confirm the drug s efficacy. Failure to show efficacy may result in withdrawal of approval. 

The FDA Modernization Act of 1997 contains a requirement for public disclosure and congressional reporting by October 2001 of Phase IV studies. FDA intends to meet the public disclosure requirement by posting Phase IV study commitments, the projected end of the study, and the current status of the study on their web site [102]. Sponsors whose new drug was approved with a Phase IV study requirement must submit an initial status report to FDA within one year of approval. According to data compiled by Public Citizen s Health Research Group [103], not one of the Phase IV study commitments for 107 new molecular entities approved between January 1995 and December 1999 had been completed as of December 1999. 

LD Sasich, P Lurie, SM Wolfe. The drug industry s performance in finishing postmarketing research (Phase IV) studies, a Public Citizen s Health Research Group report, [Internet]. URL http // www.citizen.org/hrg/PUBLICATIONS/1520.htm, accessed 4-14-2000. 

When some pharmaceutical products are approved, the FDA will ask the manufacturer to commit to postmarketing phase IV studies. These studies are mandatory for accelerated approval of products to treat serious and life-threatening illnesses ("fast-track" products) and deferred pediatric studies where safe use in children needs to be clarified. Other studies may be requested by the FDA before or after granting marketing approval if the FDA concludes that additional information is important to the prescribing and use of the product. 

Zolpidem MR Sanofi-Aventis Launched-Phase IV studies... 

Phase IV. Studies or trials conducted after a medicine is marketed to provide additional details about the medicine s efficacy or safety profile. Different formulations, dosages, durations of treatment, medicine interactions, and other medicine comparisons may be evaluated. New age groups, races, and other types of patients can be studied. Detection and definition of previously unknown or inadequately quantified adverse reactions and related risk factors are an important aspect of many Phase IV studies. If a marketed medicine is to be evaluated for another (i.e., new) indication, then those clinical trials are considered Phase II clinical trials. The term postmarketing surveillance is frequently used to describe those clinical studies in Phase IV (i.e., the period following marketing) that are primarily observational or nonexperimental in nature, to distinguish them from well-controlled Phase IV clinical trials or marketing studies. 

Sasich, L., Lurie, P, and Wolfe, S.M., The drug industry s performance in finishing postmarketing research (phase IV) studies, letter and report from Public Citizen, Health Research Group Publication 1520, Washington, DC, April 13,2000. 

Establishes new requirements for Phase IV studies that the manufacturer has agreed to conduct as a condition for NDA approval. 

Phase III studies are a continuation of phase II, but many more patients are involved. The purpose of phase III studies is to verify efficacy established earlier in phase II studies and to detect adverse effects that may not have surfaced in earlier studies. Phase IV studies are conducted when the drug has been... 

Before a vaccine is given to the general population, all potential adverse events cannot be anticipated. Thus, many vaccines undergo phase IV studies—formal studies on a vaccine once it is on the market. Also the government relies on the Vaccine Adverse Event Reporting System to identify problems after marketing begins. Adapted from an FDA document)... 

Kazi A, Hoick SE, Diethelm P. Phase IV study of the injection Norigest in Pakistan. Contraception 1985 32(4) 395-403. 

Lavezzari M, Milanesi G, Oggioni E, Pamparana F. Results of a phase IV study carried out with acipimox in type II diabetic patients with concomitant hyperlipoproteinaemia. J Int Med Res 1989 17(4) 373-80. 

Post-marketing studies, also called phase IV studies, often have several objectives ... 

AC Rossi. Discovery of adverse drug reactions. A comparison of selected phase IV studies with spontaneous reporting methods. JAMA 249 26-28, 1983. 

The story does not end here. Later Phase IV studies showed the SSRls to be effective in treating social phobia, and postmenopausal symptoms, and this expanded their use far beyond the use of the tricyclic antidepressants the SSRls were designed to replace. The tricyclics were—and are—good, safe, and efficacious drugs, but they had—and have—the dry mouth side effect. This is not very dangerous, but it is a very unpleasant side effect. 

Phase IV Studies performed after marketing approval, related to the approved indication, and used to obtain abetter understanding of the benefit-to-risk relationship and to identify less common adverse events (therapeutic use). 

Preclinical and clinical trial data and data from phase IV studies have shown that levofloxacin, moxifloxacin, and gatifloxacin cause prolongation of the QT interval, but that the potential for torsade de pointes is rare and is influenced by several independent variables (for example concurrent administration of class la and III antidysrhyth-mic agents) (25). There is a moderate increase in the QT interval associated with sparfloxacin, averaging 3%, and the few serious adverse cardiovascular events that have been reported during postmarketing surveillance all occurred in patients with underlying heart disease (26). 

Sawada M, Nakamura S, Yamada A, Kobayashi T, Okada S. Phase IV study and post-marketing surveillance of ofloxacin in Japan. Chemotherapy 1991 37(2) 134-42. 

Although early studies suggested that gatifloxacin has little effect on the QT interval of the electrocardiogram (7,12), clinical trial data and data from phase IV studies... 

Preclinical and clinical trial data and data from phase IV studies have suggested that levofloxacin causes prolongation of the QT interval (10). There were cardiovascular problems in 1 in 15 million prescriptions compared with 1-3% of patients taking sparfloxacin, who had QTc prolongation to over 500 ms. Poljmorphous ventricular tachycardia with a normal QT interval has been associated with oral levofloxacin in the absence of other causes (6,9,11,12). 

Phase IV studies (in some companies subdivided into phases IV and V) are mostly conducted after initial product approval (although, occasionally, some may begin prior to product launch, with the risk that the product is not approved on schedule, but with the potential to gain a competitive advantage). 

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