PHASE IV—INFORM

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. 

Phase IV commitments are agreements made between the agency and sponsors to conduct postapproval studies for the purpose of gathering further safety and efficacy information. Under the FDA Modernization Act of 1997, applicants are required to submit annual reports on the status of postmarketing commitments. Additionally, under FDAMA, marketing an approved product for off-label claims would be allowed, providing one or more clinical study corrobates safety and efficacy. 

CTs authorized by the NIP (including human phase IV ones) may be inspected by the NIP GCP inspectors. Between 1994 and 1997, the former EU GCP was applied while in 1999 the International Conference of Harmonization (ICH) GCP is used. All the deficiencies found are communicated, both verbally and later on in writing, to the investigator. In the case of major deficiencies, their improvement is required. In the case of critical deficiencies, the applicant/sponsor may cdso be informed and the trial would not be accepted for registration purposes in Hungary. Moreover, within the framework of the Pharmaceutical Evaluation Report (PER) Scheme, foreign PER authorities may be informed about the noncompliance found. 

It should be noted that the company might be wise to consider, when developing new formulations, that the minimum database acceptable to regulators might be insufficient for their own purposes. The decision to launch a new formulation has to be based not only on its technical success but also according to a financial analysis of the type referred to above for new indications. Crucial information on that question can usually only be obtained by studying the new formulation using one of the other authentic phase IV approaches described in this chapter. 

However, when anything new is discovered about a drug in phase IV, then, by definition, it will not be in the product label. Furthermore, sometimes, when such a signal is observed, a retrospective trawl through the preclinical and clinical databases can often uncover consistent information whose significance had not been earlier realized. In this case, a gap exists between what is known about a drug and what information has been provided to prescribers. 

The Medical Information department may have its own medical writers dedicated to phase IV (postapproval) publications, booklets and pamphlets. Many large companies have a specific Medical Writing department usually reporting into the Research department, who will assist in writing clinical reports, publications and help prepare the clinical investigational brochure or NDA annual safety reports. These associates usually have science degrees and have been trained in technical and medical writing. 

Medical Affairs departments design valuable and often extremely creative trials that provide important later phase information about clinical research conducted with soon-to-be-marketed or already marketed drugs in regard to their relative efficacy compared to others of its class, new information concerning efficacy in related indications and additional safety and efficacy data that supplement the core data which led to original approval. Because the type of research conducted in this later phase is often in response to residual questions about safety as part of phase IV commitments agreed to upon original approval,... 

This chapter aims to provide sufficient information for the pharmaceutical physician to prepare and support effectively a clinical trial. However, clinical trials come in many forms and what is appropriate for a single-centre non-sponsored trial is totally inappropriate for a multicentre global study sponsored by a big pharmaceutical company or institution. Similarly, a Phase I non-patient volunteer study is very different to a Phase IV study. The types and classification of individual clinical trials, and the purposes to which the results are put, have been broadly described in the introduction. 

A common system of categorization for preap-proval clinical trials includes Phase 1, Phase 11, and Phase 111 clinical trials (Phase IV clinical trials are conducted postapproval to collect additional information about a marketed drug). Phase 1, 11, and 111 clinical trials can be summarized as follows ... 

Phase IV clinical trials are post-marketing approval trials to monitor the efficacy and side effects of the drug in an uncontrolled real-life situation. This is also known as a post-market surveillance trial. Information about the effectiveness of the drug compared with established treatment, side effects, patient7s quality of life, and cost-effectiveness is collated. 

Phase IV trials and surveillance begin after marketing starts. The trials continue much of the work of earlier studies that evaluated safety and efficacy. They also search for drug-drug interactions and side effects not previously detected. Because certain adverse effects afflict only tiny fractions of the treated population, some Phase IV trials necessarily involve many thousands of patients. Other studies compare and contrast the new drug to any existing ones for the same disease, search for new indications or patient populations, or look for information to assist in marketing. 

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