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Phase IV trials represent one of the fastest-growing areas of clinical research. Regulatory and payer groups are increasingly requiring larger-scale, real-world data driven by the evolving environment and increasing concerns about the safety of new medicines. From an industry perspective, Phase IV trials, in addition to their pharmacovigilance potential, constitute an important element of commercialisation that enables companies to better understand the utility of their products in the real world, address outstanding questions and broaden the outreach of their products into hitherto uninvestigated populations.

The pharmaceutical industry is under more scrutiny than ever, with many agreeing that the industry has lost the trust of consumers and regulators due to product recalls and clinical data controversies: Vioxx and Avandia ring any bells? Moving forward, the industry needs to build confidence in the clinical development process. Robust trial programs accompanied by greater transparency and disclosure of data are vital.   

A wider scope
Earlier phases of clinical development – that is to say, those leading to product registration and approval – are highly controlled and generally undertaken with a tightly defined patient population. Various inclusion and exclusion criteria mean that pivotal registration trials, no matter how robust the methodology applied, do not necessarily replicate the real-life situation, which is inevitably more variable and less homogenous. It is the Phase IV setting that offers this greater potential to study a more representative population.

Phase IV trials, also known as post-marketing surveillance or pharmacovigilance studies, are conducted after a drug has been granted a licence and is available for prescription.  The scope and scale of Phase IV trials enable products to be studied in a much larger and diverse patient population and over a longer time-period than is possible during the Phase I to III programs. Phase IV trials may be required by regulatory authorities, or the sponsoring pharmaceutical company itself may elect to undertake them for safety surveillance, further fact-finding or commercial reasons.  

Also staking an interest in the Phase IV setting are academic or research centers, which may choose to study a product, either independently or in collaboration with the sponsoring company. Studies originating from this route are commonly referred to as Investigator Initiated Trials/Studies (IIT/IIS).

Dos and don’ts
Phase IV studies may:

• Provide an extended opportunity to monitor longer-term and rarer safety issues
• Often test the product’s effects on uninvestigated populations and those unlikely to be included in the more formalised trial setting, such as pregnant women
• Investigate the product’s interactions with other medications that patients are taking in the real world
• Explore the cumulative and unique effects in different populations, enabled by the ability to detect and measure effects more accurately in a much larger group of people over a much longer period of time
• Sometimes be used to explore questions of commercial value which remain largely unaddressed in the post-registration period, such as investigation of additional patient subgroups and comparisons with competitors.
  
  However, a Phase IV trial should not:

• Detract from rigorous Phase III planning
• Be considered to be a direct marketing initiative
• Be used to initiate inappropriate dialog with healthcare practitioners or patients, eg, any communications encouraging off-label prescribing
• Be a means to investigate intentionally other unapproved and unlicensed indications for the product.

Practical considerations
How should a pharmaceutical company assess the need for a Phase IV program and subsequently define its goals and remit? Here are the planning principles we recommend:
Review the target profile of your product: Is it appropriate and realistic? Does it fulfil unmet medical needs in a commercially viable manner?

• Assess the current and proposed clinical development program. Looking beyond the required regulatory requirements:
  a) Does the Phase III program sufficiently address all the requirements of the target product profile?
  b) What are the likely remaining questions from the medical community?
• Undertake effective scenario planning: consider more than one potential Phase III data outcome. Incorporation of appropriate external insights is important, such as expert counsel, insight research and so on.
• Conduct a robust gap analysis which extends to the alternative Phase III outcome scenarios. Only armed with this information should the generation of ideas for the Phase IV program begin.
• With multidisciplinary and multi-regional input, identify specific research topics or patient groups that merit further investigation for the scenarios considered. Will these have the potential to fill these ‘gaps’?
• Prioritise the ideas generated. In our experience, this step can be more challenging than the generation of the ideas themselves. To this end, it is important to have a predefined and agreed set of criteria that will be used to assess and prioritise proposed studies.
• As with anything requiring significant investment, the proposals for the Phase IV program require challenge and validation. Internal consensus may not always be achieved, given the complexity of the stakeholders and their different needs. External counsel from independent experts is one of the best ways of reconciling different views and gaining a pragmatic perspective.

Increasing visibility
With real-world trials, the industry can instil confidence  in a product on a much broader scale. With this ability comes responsibility. Expectations of speed, accessibility and credibility in how clinical trial data are communicated are only going to increase within the medical and allied communities. The Phase IV setting is no exception.

“Phase IV trials represent a number of opportunities for any compound,” according to Gary T Choy, Global Marketing Leader, Infectious Disease at Johnson & Johnson. “With treatment paradigms shifting and standard of care being a moving target, Phase IV trials allow for testing of cost-saving individualised treatment paradigms and comparative effectiveness against competitors that may not be captured in the Phase III development program.”

We should expect to see increasing levels of investment in this area of research, accompanied by greater public visibility. The industry will have to engage in open dialog with a greater number of stakeholders, both internal and external, to shape the direction of Phase IV research.

For companies to address increasingly stringent regulator requirements effectively and maintain their competitive edge, they will have to ensure that resources are deployed effectively and in a timely manner. More confident, considered and speedy decision-making will be required of the clinical development team. 

The Author
Alice Choi, PhD, Global Head, Complete Medical Communications, a division of Complete Medical Group, can be reached at +44 (0)1625 624000 or at Alice.Choi@complete-mc.com