Bayer AG

November Issue - Reflections from the real world – benefits and limitations of phase IV studies and registries

Emeritus Professor Sylvia Haas, MD

Emeritus Professor Sylvia Haas, MD

Emeritus Professor Sylvia Haas, MD

Sylvia Haas is an Emeritus Professor of Medicine and was Director of the Haemostasis and Thrombosis Research Group at the Institute for Experimental Oncology and Therapy Research, Technical University of Munich, Germany. Her scientific focus is the development of new antithrombotic therapies, laboratory monitoring of anticoagulants, biomarkers, and tumour-associated thrombosis. She is a member of several international professional societies and is on the editorial boards for several peer-reviewed journals. Click here for a full biography.

Welcome to the November 2014 edition of the Thrombosis Adviser newsletter.

Dear Thrombosis Adviser user,

Differences between randomized controlled trials and phase IV studies/registries

Randomized controlled trials (RCTs) are well established as the gold standard for assessing drug efficacy and safety. Although vital in drug development and approval, RCTs have limitations because the trial design and study outcomes may not readily translate into routine clinical practice. The need to generate clinical evidence by controlled RCTs, including the enforcement of strict inclusion/exclusion criteria, may lead to under-representation of subpopulations within a target patient group or treatment conditions that are not fully reflective of the 'real world'. For example, patients with co-morbidities or those taking multiple medications are often not included in clinical trials.

By contrast, phase IV studies and registries capture real-world epidemiological data, treatment patterns and drug use in a wider cross-section of patients. They are the first ‘real’ test of a drug in a clinical practice setting across a large number of patients, i.e. 'where the rubber meets the road'. The main objective for phase IV studies and registries is to identify or confirm the safety landscape seen in phase III studies, with additional input on rare or long-term adverse events – often only observed when several thousand patients are studied. Cost-effectiveness outcomes and quality of life observations may also be developed from these data. Observational studies and registries also have limitations, such as the potential for over-reporting of adverse events when a drug is first approved (the so-called Weber effect) and the potential for vague or missing data due to less rigorous reporting standards than RCTs.

The key differences between RCTs and real world studies are listed below:


The terms 'phase IV studies' and 'registries' should not be used interchangeably. Although the two are similar, non-interventional phase IV studies are normally limited to the observation of the behaviour of a specific drug or medical device in the real world with a set number of patients and defined study duration. Registries have a much broader scope and often do not have a predefined time frame. A patient registry uses observational study methods to collect a range of data (clinical and non-clinical) and form a comprehensive database. Registries have prespecified efficacy and safety outcomes for a population with a particular disease, condition or exposure for a specific purpose, but may also provide epidemiological or other data that were not necessarily anticipated at the outset. Data are captured in an inclusive way, disqualifying few patients and producing supplementary evidence that may be generalized to more diverse patient populations.

Real-world studies of anticoagulants

Registries are especially important when evaluating new therapies such as novel anticoagulants for stroke prevention in patients with atrial fibrillation and management of venous thromboembolism and acute coronary syndrome. Through phase IV studies and registries, a more thorough understanding of the impact of new treatments on healthcare systems can be acquired. Anticoagulation registries can also obtain real-world data about how bleeding events are managed and provide more information on benefit–risk profiles in specific patient groups. In the anticoagulation setting, there are multiple ongoing phase IV studies/patient registries and many have published data. These include:

StudyPatient typeStart dateNumber of patientsDuration of patient follow-upKey observationsReferences*

XAMOS phase IV study

Elective hip or knee replacement surgery or hip-fracture surgery

Early 2009


Enrolment to 3 months post-surgery

Confirmed favourable benefit–risk profile of rivaroxaban seen in phase III studies

Turpie et al 2012

Turpie et al 2014

XALIA phase IV study

Objectively confirmed acute DVT treated with rivaroxaban

June 2012

~4800 planned (ongoing)

1 year from the final date of patient enrolment

Results expected in 2015

Ageno et al 2014

RIETE registry

Acute DVT or PE

March 2001

>40,000 to date (ongoing)

Minimum of 3 months

Both fatal PE and fatal bleeding are more common in cancer patients with VTE than in patients without cancer

In outpatients with DVT, home treatment was associated with a better outcome than hospital treatment

Monreal et al 2006

Lozano et al 2014

XANTUS phase IV study

Non-valvular AF prescribed rivaroxaban, irrespective of stroke risk

June 2012


1 year

Findings not yet reported

Camm et al 2014

GARFIELD-AF registry

Newly diagnosed non-valvular AF and ≥1 investigator-defined stroke risk factor

December 2009

55,000 planned (ongoing)

At least 2 years

OACs frequently not used according to guidelines

Kakkar et al 2012

Kakkar et al 2013

PREFER in AF registry

Patients with a diagnosis of AF in Europe

January 2012


1 year

Frequent and possibly inappropriate use of combined oral anticoagulant and antiplatelet agents

Kirchhof et al 2014

De Caterina et al 2014

GLORIA-AF registry

Newly diagnosed with AF at risk of stroke

May 2011

Up to 56,000 (ongoing)

3 years

Findings not yet reported

Huisman et al 2014

ORBIT-AF registry

Community-based outpatients with AF

June 2010


³2 years

OAC use is high and driven by bleeding risk as well as stroke risk

Cullen et al 2013

RE-LY AF registry

Patients presenting to emergency department with AF

September 2008


1.5 years

Large variations in demographics and risk factors exist between global regions

Oldgren et al 2014

Dresden NOAC registry

Patients treated with novel OACs

October 2011

1776 treated with rivaroxaban

2 years

Rates of major bleeding with rivaroxaban may be lower and the outcome similar to that seen with VKA

Beyer-Westendorf et al 2014

Download PDF

*Not an exhaustive list.
AF, atrial fibrillation; DVT, deep vein thrombosis; OAC, oral anticoagulant; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism.

Registries can tell us how innovations may be applied for the greatest benefit to each patient on the individual level, and are, therefore, as important as RCTs. Phase IV observational studies and registries may also provide data for additional or enhanced value post-approval, to include quality of life and cost-effectiveness outcomes.

The journey from drug discovery to clinical use is a long one. RCTs are obviously essential steps, and drug development is generally thought to end with the phase III trials that lead to marketing authorization. However, phase IV studies are just as important, being the first time that a drug is assessed under real-world conditions. In addition, registries give us the clearest picture of how patients are treated in clinical practice and may generate hypotheses for future RCTs. In conclusion, real-world data and RCTs should be seen as having complementary roles in evaluating patient outcomes.

Yours sincerely,

Sylvia Haas,
Munich, Germany

Artículos seleccionados