Randomised controlled trials were never designed to tell us what happens in a real-life setting

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Introduction

Despite the time, care, and investment you

have put into your randomised controlled trial

(RCT), there will be gaps in your dataset. The

strengths of RCT study design, which allow

them to overcome biases, minimise errors and

provide robust results are also the source of

their shortcomings.

Real World Evidence (RWE) is clinical data

collected outside of conventional randomised

controlled trials (RCTs). The role of RWE in the

pharmaceutical industry has seen a

transformation within just a few years,

catching the attention of pharmaceutical

companies, advisory bodies, regulators and

more. RWE is increasingly recognised and

accepted as an effective way of

supplementing your RCT data and bridging

these data gaps.

To understand what RWE can deliver, let us

first consider what is causing these data gaps

within the RCT dataset:

Only a small minority of patients meet the

enrolment criteria for RCTs

Participants are selected for RCTs based on

rigorous inclusion and exclusion criteria, which

means the trial population can differ greatly from

the general population. A study of 870 asthma

patients 1 found that

using the criteria

commonly found in

asthma RCTs (i.e.

defined range of

airflow obstruction/ no

co-morbidities/ 1 to 2

exacerbations in

previous 12 months

but 0 in the last

month/ non-smoker/

no regular inhaled

corticosteroid use) only 3.3% would be eligible for

randomisation. This figure is higher in other

disease areas but generally remains at

approximately 20%. RCT study designs, by

targeting internal validity, often sacrifice their

applicability to patients in a real-life setting. How

can we determine how the remaining 80%+ of

patients will respond if they are left out from

RCTs?

Key patient populations are not

adequately accounted for by RCTs

Particular patient populations and patient types

are underrepresented in RCTs. For example, heart

failure is a condition associated with the elderly.

However, an analysis of 251 heart failure trials 2

has shown that 25% of

trials excluded patients

due to an arbitrary

upper age limit, 75%

excluded patients with

renal or kidney disease,

36% excluded patients

who had a reduced life

expectancy and 18%

excluded patients

based on co-concomitant drug usage. A

combination of these exclusions means that there

is limited information regarding the efficacy and

safety of drugs in older patients and the patients

enrolled are not representative of those seen in

clinical practice.

RCTs face recruitment challenges which

limits what they can investigate

Within certain areas of treatment, the design and

conduct of RCTs brings additional challenges and

pressures which can bring the trial to a premature

halt at the recruitment stage. A retrospective of

such a scenario has been published for the SPARE

trial 3 which set out to compare radiotherapy and

surgical treatments in bladder cancer. One of the

key reasons for failure was due the difficulties in

finding patients to be randomised between the

two arms, due to the large difference in the two

treatment options, the impact of strong patient

preferences, as well as complexities regarding

patient eligibility. Despite concerted efforts to

improve recruitment, the RCT were closed in

2010. Although physicians and patients often have

An analysis of 251

heart failure trials

has shown that

36% excluded

patients who had

a reduced life

expectancy

A study of 870

asthma patients

found that using

the criteria

commonly found

in asthma RCTs

only 3.3% would

be eligible for

randomisation

3 © 2015 SVMPharma Ltd. All rights reserved.

to make choices between two very different

treatment pathways, conducting a RCT to

investigate this is challenging.

Adherence to treatment in RCTs differs

greatly to real-world adherence

Patient adherence to medication is a problem that has a direct impact on treatment effectiveness. Bisphosphonate therapy for osteoporosis is a prime example of an area where adherence has been of concern. Adherence to treatment is consistently high within RCTs, often reaching 80-95%, and is one of the prerequisites for enrolment. However a retrospective database analysis of 29,157 post-menopausal women taking alendronate 4, 5 showed that 42.5% of women discontinued therapy within 6 months and another 18.1% and 13.9% of women discontinued therapy at 1-year and 2-year, respectively. Therefore, only 25.5% of women received 3-years of treatment. These large differences in adherence rates between RCTs and real-life clinical practice lead to significant uncertainties in treatment effectiveness and is a problem inherently difficult to address with RCTs.

RCTs struggle to handle complex

situations and overlapping interventions

RCTs are restricted to evaluating specific discrete

interventions one at a time, whilst patients often

have co-morbidities that can lead to complex

interactions. A database of 980 patients

representative of a

typical population

visiting primary care

services had the

inclusion and

exclusion criteria of 5

hypertension RCTs

applied to them. 6 Of

the patients who

were eligible for entry

in the RCTs, 89%-

100% had multiple chronic conditions and the

mean number of chronic conditions per patient

ranged from 5.5 to 11.7. None of the RCTs

addressed the competing demands raised by

treatment of co-morbidities and the complex

realities of the situation. In RCT study design, such

issues could only be assessed in a framework

where each factor is isolated from the others

which would make the costs of the multiple

treatment arms prohibitive. RCTs, especially when

driven by the desire to secure a label or prove

safety, opt towards a highly-selected

homogeneous study population instead of a

diverse population reflective of real-life clinical

practice.

What are the consequences of having

gaps in your data?

Relying exclusively on RCTs can lead to significant

issues. The data from RCTs may not be applicable

to certain population segments, leading to

treatment ineffectiveness and patient and HCP

disappointment. The effects of variable adherence

on patient health could be missed. The actual

costs to payors and reimbursement strategies

may not be accurate, whilst promotional and

marketing campaigns may be misdirected and

inefficient.

Additionally, not having any RWE for your product

may itself be problematic. For example, there is

now the possibility that you will be directly asked

for RWE from HTA bodies (i.e. within the new

Cancer Drug Fund proposals) 7, or you may need

5 key reasons behind data gaps in RCTs

Only a small minority of patients meet the enrolment criteria for RCTs

Key patient populations are not adequately accounted for by RCTs

RCTs face recruitment challenges which limits what they can investigate

Adherence to treatment in RCTs differs greatly to real-world adherence

RCTs struggle to handle complex situations and overlapping interventions

In RCT study

designs, such issues

could only be

assessed in a

framework where

each factor is

isolated from the

others

4 © 2015 SVMPharma Ltd. All rights reserved.

to counter your competitor’s RWE generation to

protect your market share.

How can data gaps be addressed?

By first identifying and understanding the gaps,

RWE programmes can be tailored to address the

pertinent issues and provide a richer and more

well-rounded data set. RWE covers observational

studies, patient registries, large datasets e.g.

Clinical Practice Research Datalink (CPRD) and

more, but the most expedient option is via a

custom RWE data collection programme to collect

individual patient data. This has been consistently

proven to generate and enhance positive

outcomes.

These successes have been assisted by an

increasing awareness of the advantages that RWE

provides over traditional RCTs, being more

representative of a real-life population, better

demonstrative of the benefits of a drug in

everyday clinical practice and more valuable in

covering real-world patient behaviour and

adherence.

Conclusion

Conventional RCTs are necessary for

determining efficacy and safety, but real-

world clinical practice can be very different.

RWE complements RCT data and offers the

opportunity to bridge the data gaps.

Have you identified your data gaps?

References and Further Reading

1. Herland et al. How representative are clinical study patients with

asthma or COPD for a larger ‘‘real life’’ population of patients with

obstructive lung disease? Respiratory Medicine. 2004. Available at:

http://www.sciencedirect.com/science/article/pii/S09546111040020

69 Accessed Dec 2015.

2. Cherubini et al. The Persistent Exclusion of Older Patients From

Ongoing Clinical Trials Regarding Heart Failure. Arch Intern Med.

2011. Available at:

http://archinte.jamanetwork.com/article.aspx?articleid=226912

Accessed Dec 2015.

3. Paramasivan et al. Key issues in recruitment to randomised

controlled trials with very different interventions: a qualitative

investigation of recruitment to the SPARE trial (CRUK/07/011). Trials.

2011. Available at:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068963/ Accessed

Dec 2015.

4. Hiligsmann et al. The clinical and economic burden of non-

adherence with oral bisphosphonates in osteoporotic patients.

Health Policy. 2010. Available at:

http://www.esceo.org/sites/esceo/files/publications/economics/Hea

lthPolicy_Hiligsmann.pdf Accessed Dec 2015.

5. Rabenda et al. Adherence to bisphosphonates therapy and hip

fracture risk in osteoporotic women. Osteoporos Int. 2008. Available

at: http://www.ncbi.nlm.nih.gov/pubmed/17999022 Accessed Dec

2015.

6. Fortin et al. Randomized controlled trials: do they have external

validity for patients with multiple comorbidities? Ann Fam

Med. 2006. Available at

http://www.annfammed.org/content/4/2/104.long Accessed Dec

2015

7. NICE. Consultation now open on plans to reform Cancer Drugs

Fund. NICE. 2015, Available at:

https://www.nice.org.uk/news/article/consultation-open-on-plans-

to-reform-cancer-drugs-fund Accessed Dec 2015.

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CONTACT SVMPHARMA

Vaneet NayarDirector SVMPharma

enquiry@svmpharma.com

Tel: +44 (0) 1252 417030

SVMPharma Ltd

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