Читать книгу Cobert's Manual Of Drug Safety And Pharmacovigilance (Third Edition) - William Gregory - Страница 31

Phase IV studies include different types of studies. They are done after the approval and marketing of the drug. Note that a drug may not always be marketed immediately after approval. Sometimes, the company receiving the approval may choose to sell or out-license the drug, or timing may make it wiser to wait, e.g., new seasonal allergy drugs should be marketed near the time for the allergy season to hit.

Sometimes additional studies beyond those required for approval may be desired. The company (applicant) may choose to propose and agree to additional work, i.e., a “Post-Marketing Commitment” (PMC) in the US. Many regulators also have authority to impose additional work, i.e., a “Post-Marketing Requirement” (PMR) in the US or Post-Authorization Studies in the EU. These studies may be done to clarify some safety and efficacy issues that remained after phase III, but which the health agency believed were not sufficient to prevent or delay marketing of the drug. In the US, these studies may be included in a Risk Evaluation and Mitigation Strategy (REMS) or may be independent of REMS. In the EU, EMA and member states may require further studies in their Risk Management Plans (RMPs), i.e., Post-authorization Safety Studies (PASS) and/or Post-authorization Efficacy Studies (PAES). Failure to perform such tasks in any jurisdiction where agreed or imposed may result in penalties to the company, fines, or even withdrawal or limitation of the marketing approval. Such misbehavior is usually publicized, which can impact public trust of the company and its products.

Phase IV studies may also be marketing or pharmacoeconomic studies to aid in selling the product by studying head-on comparisons with competitor drugs (see HTA note, above). They may be studies looking at sub-groups of the approved group and indication, e.g., testing a drug approved for diabetes on diabetics who are elderly or are also in heart failure. They may be done in children, not only to evaluate the usefulness and safety but also to obtain, in various markets, additional patent exclusivity. In the US, a sponsor who receives an approval for a drug or biologic to treat a “rare pediatric disease” may qualify for a “voucher”. This “voucher” can be redeemed later to receive a priority review of a subsequent marketing application for a different product. These vouchers are transferable and may be sold to other companies.

Phase IV studies may be done for specific safety reasons to investigate an AE or a signal that has unexpectedly been detected after marketing. Such studies may be classical clinical trials or they may be observational or epidemiologic studies done in large databases. The design and size are very variable, ranging from small open-label trials to massive, multi-center, double-blind comparator trials or “large simple safety studies” with simple protocols and minimal record-keeping. Sometimes patients are compensated for participation.

The so-called market-driven phase IV “seeding studies” are now forbidden in most parts of the world. These were pure marketing projects designed to encourage physicians to prescribe a particular product in place of a competitor’s product. A protocol was usually written (to justify calling the endeavor a study), but was often of poor quality. Results were not always collected by the sponsor and, if collected, were often not analyzed. Prescribers were sometimes compensated. In a more subtle way, post-marketing trials for entirely legitimate purposes may include elements aimed at getting physicians to use the new drug in place of another product (“stealth seeding trials”). By doing this, the prescriber becomes familiar with the product, and the company hopes he or she will prescribe it for other patients after the trial is completed.