Pharmaceutical companies are facing increasing pressures not only to bring new medicines to market, but also to demonstrate both long-term safety and “real-world” value (i.e., clinical performance, cost-effectiveness, and improved quality-of-life). There is increasing recognition in all sectors that the conditions under which products are examined for approval are not the conditions under which they may actually be used. Hence, the increasing emphasis on – and investment in post-marketing (Phase IV) studies. Whereas some may characterize the focus on post-marketing studies as a requirement, I tend to view it as responsibility, if not a great opportunity for strategically savvy companies and for the industry overall.
There truly is a need for a new paradigm in Phase IV research that involves unprecedented levels of intra-organizational cooperation. Companies can be responsible citizens of the healthcare community while achieving a solid return on investment, but only through “silo-busting” activities. Increasingly, safety and value can be addressed --- even simultaneously --- through integrated post-approval activities, but only through cooperation between marketers and clinical scientists. Additionally, companies need to understand that Phase IV studies require a very different operational structure from that of pre-approval trials.
Robust Phase IV data can be essential for responding to regulatory mandates for additional post-approval safety information; for extending conditional product marketing approval; for formulary uptake and reimbursement; and for establishing the essential therapeutic role and benefit of a product for prescribers. Commercially, such benefits can be synonymous with brand leadership in a therapeutic area, thereby accelerating product acceptance. However, Phase IV studies must be based on a strategic foundation, irrespective of whether the target audience is a regulatory agency, the physician community, health authorities and insurers, and/or patients.
Importantly, the post-approval landscape differs in so many ways from the more straightforward pre-approval pathway. From a research design perspective, the post-approval world (i.e., real life) is not a controlled experiment. Observing a drug in real-world use yields insights that Phase III studies simply are not designed to provide. While Phase III data can provide a solid understanding of a drug’s fundamental efficacy and safety, that understanding is often limited by the very conditions required for a controlled research experiment. Today, careful evaluation of a compound through post-approval observation yields a more enriched, more comprehensive understanding of how a drug affects specific patient populations over time, in some cases helping to uncover drug risks and critical benefits that may not have been apparent in Phase III.
Increasingly, Phase IV research calls for an observational design, in stark contrast to the more traditional controlled, experimental approach warranted in the pre-approval world. The challenge many sponsoring organizations have, however, is that their processes – from study design to operational support to outsourcing to ongoing project management are all built around a randomized controlled trial (RCT) foundation. Indeed, it is common for contract research organizations (CROs) to receive a Request for Proposal (RFP) that reflects an uncomfortably expressed desire to conduct a post-approval observational study but according to a traditional Phase III operational template. CROs that are not sufficiently experienced with post-approval research will often fall into the trap of simply completing the RFP bid grid, resulting in an over-engineered study that, in many cases, can even compromise the basic observational intent. No one wins in such a scenario and, importantly, critical information is left buried.
CROs thus have a significant opportunity to play a leadership role during – if not well before – the Phase IV RFP process. We can provide experience-based and objective insights critical to the study conceptualization process. With this strategic foundation, CROs can help ensure that observational studies are appropriately and cost-efficiently engineered so as to truly paint a picture of real-world usage and outcomes. Fundamentally, we can be a critical facilitator in bringing together key parts of a sponsor’s organization in a truly collaborative fashion and, in so doing, establish strategic needs, set rational operational expectations, and enable development of precise RFPs for Phase IV services.
Coordination of goals and expectations at or before the time of the RFP is essential to realizing a well-designed Phase IV study. Companies should look to CROs as research partners (rather than simply “vendors”) in contributing to a cohesive, multi-faceted Phase IV strategy that, ideally, serves regulatory requirements while also accommodating differentiating factors that can be pivotal to demonstrating a product’s value. When CROs are brought into the study design process in the pre-RFP stage, the result can be a more insightful picture of drug value aligned with commercial as well as therapeutic objectives. Such a collaborative approach can also help a company minimize or avoid inefficiencies, cost overruns, and, importantly, the generation of data that will fail to impress regulators.
Navigating out in the wild --- the post-approval landscape --- requires a roadmap, indeed a philosophy --- that looks different from the Phase III paradigm. When CROs are viewed as true partners, we can provide the leadership and vision to help our clients achieve success through effective planning, design, and execution of Phase IV research initiatives.
PharmaNet Development Group (http://www.pharmanet.com) is a recognized leader in outsourced clinical development, and a top-ten provider of early- and late-stage drug development services to pharmaceutical, biotechnology, generic drug, and medical device companies.
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