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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.
A term that has appeared in the last few years is late phase studies, referring to the grab bag of requirements that agencies and companies are doing both for registration, evaluating risk, and marketing reasons. They include registries (product, disease, safety), post-marketing observational studies, classic phase IV trials as discussed earlier, clinical effectiveness trials (i.e., real world evidence), OTC trials, community-based trials, health economic and outcomes studies (retrospective, prospective, observational), cost-effectiveness, burden of disease, patient reported outcome (PRO, Quality of Life [QoL], chart review, survey (physicians, patients), health economic piggyback trials, risk management, expanded access, drug safety, and others.
Commercially-driven “Customer Engagement Programs”, e.g., patient support programs, etc., where there is the possibility of two-way communication, are an additional source of AEs after a product is marketed. Patient safety is usually not the focus of such programs, but any safety data that are generated must be evaluated.
Other study designs that merit mention include pragmatic clinical trials and low interventional studies. Pragmatic trials are randomized trials designed to assess how effective a treatment actually is in routine, everyday practice. These studies have limited protocol-driven requirements so that there is minimal impact on the patient’s standard treatment for the condition of interest. Following randomization, follow-up patient care is managed by the healthcare provider(s) according to their normal standard of care. Pragmatic studies address practical questions about risks, benefits, and costs of an intervention as it is used in daily practice under usual circumstances. This type of study can also be used to assess compliance, i.e., whether patients actually follow the instructions as to daily dose, timing of drug intake, avoiding known interactions with foods or other medicines, etc.
In some pragmatic studies, non-standard of care diagnostic or monitoring procedures are included, but these must not pose more than minimal additional risk or burden to the safety of patients compared to normal clinical practice. Secondary data sources (e.g., electronic health records, claims data, safety monitoring databases, etc.) may be used to obtain follow-up information.
Low interventional studies do not involve any protocol-required assignment to an intervention that is expected to impact a clinical outcome. However, they do require non-standard of care diagnostic or monitoring procedures which do not pose more than minimal additional risk or burden to the safety of patients compared to normal clinical practice. Low interventional studies are designed and conducted in real-world healthcare settings to evaluate, for example, epidemiology or natural history of a disease or the safety or effectiveness of an intervention under routine care conditions.
Investigator-Initiated Research (IIR) includes Investigator-Initiated Trials (IITs) and Investigator-Initiated Studies (IISs), also called Investigator-Sponsored Trials (ISTs). These usually arise from new ideas thought up by researchers in the academic world or occasionally suggested by the pharmaceutical company. New uses or ways of administering drugs are frequently proposed by academic researchers to pharmaceutical companies. Many companies actually have physicians, PhDs, or pharmacologists on staff (often called “medical liaisons”), who travel to academic medical centers and seek out such clever new uses. Such trials are usually done at single centers. Sometimes, the investigator will come up with the idea and approach the company (sponsor or patent holder) for assistance with either a grant or product supply (especially if the product is costly).
This type of study can be instrumental in the scientific development of a drug. The advantages of IIR are that new ideas are found and explored, costs are usually relatively low, and the studies can be done fairly quickly. The disadvantage is that many details that should be determined before the trials are not addressed (e.g., effective dose and safety in this population). IIR that fails usually ends that idea. Thus, if too low a dose is chosen, one might never know that a higher dose would produce positive results. Funding is usually from the pharmaceutical company in the form of a grant-in-aid, drug supply, protocol, or case report form support.
It is very rare that a contract or agreement is not signed by both parties. The legal sponsor of the study is not the pharmaceutical company but rather the investigator. It is he or she who opens the IND with the FDA or the equivalent in other countries (often with the help of the pharmaceutical company by giving the investigator