13.1 Introduction

This chapter focuses on phase IV trials, which are studies designed in the post-marketing scenario to certify approved medications in the real-world population [1, 2]. Phase IV refers to large studies, interventional or non-interventional, that are often used to assess serious adverse effects in a sizeable population, but that are sometimes also used to approve additional uses of a drug or to introduce physicians and patients to new treatments [1]. While only 20% of the drugs that enter phase I trials are approved for marketing, approximately 20% of new medications acquire new black box warnings after commercialization, and around 4% of drugs are withdrawn for safety reasons [3, 4]. Here we will discuss the main phase IV study designs, and the potential advantages and limitations of these methodologies.

13.2 Definitions of Phase IV Studies

A phase IV study is a clinical study where the investigational therapy includes the use of a licensed drug or device, as seen in Fig. 13.1 [1, 2]. According to the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the definitions of phase IV studies are as follows:

  • FDA : Phase IV studies are post-marketing studies that are imposed upon a pharmaceutical firm as a condition for drug approval. Phase IV trials are carried out once the drug or device has been approved by the FDA during the Post-Market Safety Monitoring (Clinical Research–fda.gov, https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm—accessed April 16th, 2017) [5].

  • EMA : Studies in phase IV are all the studies (other than routine surveillance) that are performed after drug approval and related to the approved indication. They are studies that were not considered necessary for approval but are often important for optimizing the drug’s use. They may be of any type, but should have valid scientific objectives. Commonly conducted studies include additional drug-drug interaction, dose-response, or safety studies and studies designed to support use according to the approved indication, e.g., mortality/morbidity studies and epidemiological studies (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002877.pdf—accessed April 16th, 2017) [6].

Fig. 13.1
figure 1

Overview of drug development

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Since phase II and phase III trials use planned but limited samples from the target population in a limited timeframe, some events or interactions may not present before exposure to the real world and findings may lack adequate external validity. These studies aim to demonstrate efficacy, and to this end, they seek internal validity using carefully selected individuals under ideal circumstances [2]. Internal validity, defined as the reliability of the observed outcomes and proper control of bias [1, 7], is usually obtained using selective inclusion criteria, therefore creating a strict study population. Conversely, the concept of external validity relies on the notion of generalizability; that is, to what extent the results obtained in clinical trials may be extrapolated to a broader selection of patients and settings [1, 7].

In this sense, phase IV studies are usually conducted in order to optimize the use of treatments (dosage, duration of therapy, implementation in complex drug strategies), to adapt indications including groups of individuals that were not represented in pre-approval studies, to explore potential effect modifiers (patient characteristics or comorbidities that may influence pharmacokinetics), or to observe safety issues that phase III trials were not powered to evaluate (routine, rare, or delayed side effects; interactions with other therapies; addiction and abuse) [1]. Phase IV studies can provide natural intriguing insights about unknown interactions involving populations that are heterogeneous (e.g., in regard to genetics, habits, and comorbidities) and thousands of medical products widely used in real-life.

In addition to the evaluation of the biological effects of new therapies, phase IV trials can be designed to assess cost-effectiveness or marketing proposals (acceptance and compliance by physicians and patients) [1]. Phase IV studies are particularly useful in oncology because they can provide effective treatments to patients with refractory metastatic cancers for which there are no available therapeutic options.

In the United States, Expanded Access Programs (EAPs) , also known as “Compassionate Use ”, are study models that allow patients with serious diseases or conditions; for example, cancer patients, to have access to new drugs, biologics, or medical devices [8]. EAPs are considered when patient enrollment in a clinical trial is not feasible (e.g., the patient is not eligible or there are no ongoing trials) [8] and the intention of these models is to treat patients instead of obtaining data on efficacy and safety [9, 10]. Despite the greater flexibility in inclusion criteria in EAPs, the FDA also demands the sponsor (or the clinical investigator) to demonstrate that there are no equivalent available treatments and to provide a clinical protocol, approved by institutional review boards and subject to informed consent [8].

Differently from phase III trials, which are mandatory for the approval of a new drug or therapy, only 25% of marketed drugs move forward to phase IV studies [11]. Recently, classical phase IV trials have been requested by regulatory agencies such as the FDA and EMA, but these trials are still sparsely regulated [11, 12]. Phase IV trials also do not have a definite standard approach, preferred study design, or particular statistical method.

13.3 Designs of Phase IV Studies

Although randomized clinical trials are the default study design in phase III trials, post-marketing trials can use several different approaches, each with its particular methodology and limitations. The FDA has mandated or negotiated studies ranging from controlled trials to observational studies, drug-drug interaction studies, or special population studies [1, 12, 13]. Table 13.1 exemplifies the most common designs of phase IV trials currently used.

Table 13.1 Most common phase IV (interventional and non-interventional) study designs [12, 13]
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13.4 Contributions of Phase IV Studies to Clinical Cancer Research

When it comes to the improvement of health care, it is critical to evaluate an intervention beyond the controlled research setting. Post-approval phase IV studies play a crucial role in understanding the real benefit of new interventions (drugs or devices) in large-scale populations, translating the efficacy seen in the well-controlled environment of clinical trials into real-world effectiveness [12]. Some particular groups, such as children, pregnant women, elderly patients, patients with comorbidities other than the one being studied, or severely ill patients, are often excluded from clinical trials, and in this regard, phase IV trials can help to establish the generalizability of the findings [12, 13]. Nevertheless, some phase IV studies in oncology utilize the same eligibility criteria as their phase III counterparts, as, for example, the Aflibercept Expanded Access Program in the second-line treatment of metastatic colorectal cancer [21]. In such cases, the external validity of treatment-related safety and efficacy may be compromised.

Moreover, continuous monitoring of interventions is necessary for their lifetime, given the rarity of some adverse events. It is estimated that for an adverse event with a frequency of 1 out of 10,000, it would require 65,000 patients to pick up an excess of three adverse events [11, 12], while phase III trials are only capable of detecting adverse events that occur in up to 1 out of 100 persons [22, 23]. Anecdotal reports of unanticipated cardiovascular events associated with Vioxx® (rofecoxib), an anti-inflammatory medication, and sibutramine, an appetite suppressant, illustrate the importance of post-marketing surveillance in preventing further catastrophic outcomes [24].

Despite the relevance of phase IV trials to clinical practice and despite their loose regulations, there are several barriers to randomized trials of public health interventions with regard to random allocation, control groups, the collection of data, and prospective follow-up [25]. The collection of reliable information and evaluation of data are matters of continuous discussion. There are several limitations in the current systems that identify adverse events, with these systems sometimes being dependent on physicians’ suspicions and their willingness to report, a factor that raises concern about the quality of data obtained [12]. Furthermore, the follow-up of participants in a non-interventional study may be less thorough than that in controlled trials [24]. In terms of cost-effectiveness, pharmacoeconomic studies often face the challenge of translating frequently used surrogate measures into long-term outcomes, as well as facing challenges in their adjustment to simulation models of economic performance [12].

Phase IV trials also lack clear and well-defined regulations. In 2001, the FDA made it compulsory to carry out post-marketing studies (or commitment studies) for new drug applications, but a report from 2006 exposed the fragility of this system: of 1231 commitment studies registered, 65% were still pending, 18% were ongoing, and only 14% were completed [12].

Conclusion

In conclusion, phase IV studies are necessary to better understand the effects of new interventions and their interactions in the real-world setting. Despite the importance of these studies for patient safety and perhaps for the establishment of optimized approaches, there is a lack of guidelines and regulatory criteria.