What You Need to Know about Late-Stage Clinical Trials

Rita E. Numerof, Ph.D. argues the case for Real World Evidence, late-phase clinical studies and shares her top three considerations when going down this route.



The global market for pharmaceuticals continues to grow as manufacturers expand into new markets and therapeutic areas.  Increasing globalization has fueled changes in the regulatory environment, including increased data requirements at the various stages of product development, validation, approval, and production. Additionally, numerous recalls and regulatory settlements have left policymakers and consumers questioning the safety of medical products and the manufacturers that bring them to market. 

As a result, Real World Evidence (RWE) in the form of late-phase clinical studies (Phases IIIb and IV) constitutes a rapidly expanding segment of the clinical research environment and regulation of the biopharmaceutical marketplace. Regulatory agencies around the world are requiring additional data about the long-term safety and efficacy of new products when they are used by broader patient populations in real-world settings. Healthcare providers -- and those who pay for healthcare -- are demanding that new therapies provide better outcomes or greater value than existing standards of care and are increasingly looking for real-world clinical evidence to support these claims.

There are several key considerations for pharmaceutical companies looking to effectively meet these growing data requirements:

1. Determine the right type of post-market study

Depending on your immediate and long term goals, there are two major study types, each with time, cost, and regulatory implications that need to be taken into consideration. 

  • Non-Interventional (Observational) Studies:These studies are conducted to assess the safety and efficacy of approved, post-market pharmaceuticals in real-world clinical practice – where usage and all other aspects of patient care are consistent with approved indications and current practice standards. In these studies, usage is unaltered by the study itself. The doctor’s decision to prescribe the particular drug often must precede enrollment in the study by at least one month, and the assignment of treatment is not systematic, but rather retrospectively consistent with the course of care selected for the patient. There is no protocol, just an observation plan, and informed consent is typically limited to a data privacy clause. A high-volume example of an observational study would be a post-market registry – the prospective collection of ongoing and supporting data over time on outcomes of interest for analysis and reporting.
  • Interventional Studies (particularly in the form of Large Simple Trials): These studies combine the generalizability of non-interventional studies with the validity of randomized clinical trials. A large number of participants are enrolled and randomized into treatment groups, however, clinical follow-up resumes as it would in routine practice. Therefore, while patients are enrolled in a randomized manner, these patients can still be observed in the context of real-world clinical practice.

Regardless of the study methodology, data can be collected for a variety of purposes. Data can be collected to support:

  • Post-Market Surveillance: non-interventional studies are often required by regulatory authorities, to verify the safety, tolerability, and effectiveness of a marketed drug in a particular population. 
  • Pharmacovigilance programs and reporting systems: which many regions and countries require to bring a product to market. Pharmacovigilance studies in particular relate to the detection, assessment, and prevention of both long- and short- term adverse effects or side effects of a marketed pharmaceutical product. 
  • Pharmacoepidemiologic research: This research examines the risks associated with marketed products, focusing primarily on utilization and the effects of marketed drugs. 
  • Health-related quality of life claims: Post-market studies can provide information about the impact drugs have on quality of life in real-world settings. 
  • Comparative effectiveness research: Companies can gauge the economic and clinical value of a particular product in comparison with other drugs and treatment options. 

Studies can focus on specific patient populations, focused indications, or apply more generally across populations within a market. 

2. Address evolving late-phase data requirements and trial regulations

While post-market clinical data presents tremendous opportunity for manufacturers looking to make the case for their drugs, the changing regulatory environment can have serious implications for success in this area. Requirements, timelines, and the level of regulatory stringency differ from one country to another, and scarce agency resources across the globe can contribute to frustrating waiting periods and prolonged product approval timelines.

In order to maximize efficiency and minimize the impact of regulatory challenges, a common approach for navigating the diverging regional regulatory requirements governing Phase IV studies is necessary. While the degree of global regulatory variability in this space may seem daunting, approaching regional requirements in a consistent manner can make it manageable. Though regulatory oversight and enforcement vary from country to country, there are common steps that play an integral role in conducting Phase IV clinical trials. Among other things, it will always be critical to:

  • Identify the regulatory contact point that can best assist you with trial approval
  • Determine how the trial you’re looking to conduct would be defined in that particular market (i.e., is it an interventional or observational study?)
  • Identify submission elements that must be included to ensure trial approval
  • Aggregate and submit the necessary pre-market data
  • Comply with necessary ongoing reporting, auditing, and monitoring requirements.  

Understanding regional market trends – and staying abreast of market changes -- is also critical. Population growth, demographic changes, shifting lifestyles, disease trends, and market demands are all critical factors to consider within the context of your particular product. Additionally, regional health policy and reimbursement trends will have a tremendous impact on successful market entry. These should serve as guidelines for developing your market strategy and determining what data will be necessary for demonstrating the economic and clinical value of your product moving forward.

3. Establish the right partnerships

To ensure that you’re able to navigate foreign market trends and changing Phase IV study requirements on an ongoing basis, it’s important to pursue partnerships with in-region resources that are familiar with current and impending clinical, regulatory, reimbursement, and competitive landscapes. In-region resources can provide insight into cultural nuances that might not otherwise be anticipated, which may ultimately have a significant impact on timelines, costs, and successful market entry.

Finding the right research organizations and other in-region resources to engage is only half the battle – it is critical to manage these partnerships closely on an ongoing basis. Most regions are moving to regulate in-region firms as an extension of the manufacturer that partnered with them, especially with regard to the conduct of clinical trials. Given that Phase IV study requirements are largely a moving target, centralized management of partners is more critical now than ever before.  Ensuring that you have the necessary auditing capabilities in place will be crucial to the success of these relationships -- and the success of your post-market clinical research efforts. 

Why a Strategy for Late-Stage Clinical Trials Is Critical

Pharmaceutical companies can’t afford not to adopt real-world evidence as a key part of product development from both a safety and reimbursement perspective.  Developing the right approach to conducting late-stage clinical trials will be critical to deciding what types of research to conduct, executing the trials themselves, maximizing your data, and minimizing business risk.  Taking a comprehensive view on these trials will allow your company to meet growing evidence demands from payers and providers. 


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