Randomized controlled trials (RCTs) are considered the gold standard in the hierarchy of research designs for evaluating the efficacy and safety of a treatment. While they are required for drug registrations, RCT results often have limited applicability to patients in everyday clinical care. Medical functions in the pharma industry are often tasked with non-registration trials (phase IIIb, phase IV, observational studies) to build further knowledge on treatment post registration trials. These studies often aim to provide expanded evidence because of their use of large or more diverse populations or longer follow-up periods.

There are three noticeable trends in non-registration trials. The first trend is going pragmatic. GlaxoSmithKline’s (GSK) Salford Lung study is the most high profile pragmatic trial that was conducted in the pre-licensing phase. The trial examined the safety and effectiveness of a new treatment BreoEllipta for chronic obstructive pulmonary disease (COPD) and asthma.1

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Why did GSK invest so much on a pragmatic trial? The profile of BreoEllipta may give the reason. BreoEllipta is an incremental improvement on existing therapies. The perceived main benefit is improved adherence. The payers are probably unwilling to pay for just “once daily” or improved adherence. GSK needed to demonstrate the superior effectiveness of BreoEllipta in the real world setting, and it is impossible to demonstrate the effectiveness in a double blinded, randomized trial. The other driver might be HTA (health technology assessment) bodies’ desire to see an effectiveness study and the value that it could bring. The Salford study involved over 2,800 consenting patients, supported by 80 GP practices and 130 pharmacies in Salford and the surrounding Greater Manchester area. The study embraced heterogeneity of patient population and was conducted in a usual care setting. It also used electronic health record (EHR) systems to gather safety and effectiveness data.

A less talked about pragmatic trial is AstraZeneca’s DECIDE study, a pragmatic trial to evaluate the comparative effectiveness between Dapagliflozin and the standard of care in type 2 diabetes. AstraZeneca collaborates with Clinical Practice Research Datalink (CPRD) on this study. The effectiveness data on patients would be collected via the CPRD network.2

It is expected that the pragmatic trial trend will continue to grow due to several drivers. The first is the increasing pressure to compare new therapies to standard of care treatments from payers. The second is less differentiating features of new drugs. In addition, many pharma companies are experimenting with “beyond the pill” solutions. The impact of those solutions on the effectiveness can only be demonstrated in pragmatic settings.  

The other new trends are seen in the area of observational research. Observational research in pharma is traditionally conducted as either a prospective, non-interventional study or a retrospective study, utilizing patient-level data that are already collected. However, as new advances in technology are changing the way patients are receiving care or managing health, traditional observational research approaches don’t seem able to address the increasing complexity of research questions or to utilize new generated data at an amazing speed by modern technologies. In addition, more data points are now required to understand heterogeneous diseases.

New trends are emerging and really changing people’s perception of how observational studies can be conducted. One prominent trend is an approach to bridge prospective and retrospective design enabled by EHR systems. In this approach, while doing the primary data collection (prospective), EHR at study sites is utilized to gather patients’ historic clinical information and collect clinical data from their usual care. In addition, patients can be followed up beyond the prospective study period via EHR, providing a much longer follow-up to study disease progression and long-term treatment effect.

The second trend in observational research is multiple channel data collection. This approach is not only helpful in evidence generation for board stakeholders, but also required to understand heterogeneity in diseases or treatment response. More and more observational studies are seen incorporating PRO (patient reported outcome) data via mobile health (mHealth) apps, biosensor data via wearables, and even environmental data, e.g. weather, air pollutant, to understand the environmental impact. In addition, the inclusion of biomarker analyses from biosamples is also becoming more popular in observational research, to characterize chronic disease population and their response to treatment by disease mechanism.

A good example for these two trends is AstraZeneca’s NOVELTY study, a multinational, prospective, observational study of patients with a diagnosis or suspected diagnosis† of asthma and/or COPD. In this study, electronic health records from Nordic countries, the UK and the USA will be utilized to collect retrospective data of trial patients. Biomarker analyses will be conducted to further understand the phenotypes and endo-types of COPD and asthma patients. mHealth devices are also used for selected patients.

We are in a new era of research. Not limited by regulatory requirements, non-registration trials are embracing new, exciting trends to advance science and evidence generation.


*Hui Cao is the Executive Director, CoE for Real World Evidence at Novartis Pharmaceuticals



  1. Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice.Vestbo J, Leather D, DiarBakerly N, New J, Gibson JM, McCorkindale S, Collier S, Crawford J, Frith L, Harvey C, Svedsater H, Woodcock A; Salford Lung Study Investigators. N Engl J Med. 2016 Sep 29;375(13):1253-60
  2. The DECIDE trial https://clinicaltrials.gov/ct2/show/NCT02119819
  3. The Novelty study http://aznoveltyproject.com/
  4. Get Real https://www.imi-getreal.eu/LinkClick.aspx?fileticket=k9bCTnl2tTI%3D&portalid=1