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International Clinical Trials
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When seeking ways to safely manage concomitant medication, look at the
positive impact of using a web-based, electronic concomitant medication
management system in study design, both from a perspective of global
standardisation and the interest of patient safety.
Over the past 15 years there has been a major documented change in the
world map when it comes to the conduct of clinical trials driven, by the
emergence of new economic super powers such as China and the increasing
competition faced by biopharmaceutical companies and CROs for patients
to enrol. ClinicalTrials.gov currently lists trials registered in 179
countries. To put this in perspective, the UN has 193 members. It is
fair to say that clinical trials have reached the four corners of our
diverse world. Around one-third of Phase 3 trials have sites actively
recruiting in China, Russia and the Latin America region. India, Mexico
and the Middle East also make up a significant proportion. Add to this
combination the US, Europe and Japan and you find a series of logistical
challenges.
The Challenges
During the life cycle of large trials, sites can be closed due to lack
of patient recruitment while sites from new countries are added.
Considering that trial protocols are often prepared well in advance of
selecting the country where a trial will be conducted, this can occur
months or even years after the protocol was initially designed.
Additional countries, new medications and changing protocols demand a
concomitant medication management system, which is both constantly
updated and interactive.
One has to make sure when you are enrolling a patient in a trial, in
whichever country that may be, that they are eligible for the study and
not excluded due to a concomitant medication. Global variation in names
of branded and generic drugs creates a challenge both for the clinical
research professionals designing the protocol and for the investigator
who has to make decisions on the ground. Regulatory agencies demand,
from a pharmacovigilance perspective, expedited reporting of serious
adverse drug events, and this involves having a clear understanding of
the concomitant medication history of the patient in the trial.
Drug-drug interactions in clinical practice are a common problem during
drug treatment and give rise to a large number of hospital admissions as
a result of medically important, sometimes serious or even fatal
adverse events. Drug-IP interactions during a clinical trial also pose
this risk and can also cause partial or complete elimination of
treatment efficacy. The ageing population, where polypharmacy is more
common, increases the likelihood of such interactions.
A clinical trial protocol may have detailed requirements for restriction
of co-prescribed drugs yet, at present, only a small number of trials
benefit from using electronic concomitant medication management systems.
This is a significant problem because protocol violations due to
inappropriate concomitant medication can lead to:
- Variations in treatment between centres in multi-centre trials
- Risks to patient safety and quality of care
- Delays in the delivery of R&D pipelines of the pharmaceutical
industry due to attrition of patient numbers in clinical trials
The Traditional Approach
The standard practice of the pharmaceutical industry is to provide hard
copy documentation to investigators and monitors detailing concomitant
prescribing restrictions for clinical trial patients. Investigators,
monitors and their teams then need to check a patient’s medication
against the exclusion criteria for the trial using standard formularies
of drug information resources. Ninety-five per cent of trial monitors
use traditional paper-based formularies and, for this reason, are
restricted to trial monitoring in specific clinical specialities.
Because the current practice relies purely on human intervention at
different stages of patient care in order to assess possible drug
interactions, protocol violations often occur because concomitant
prescribing has already taken place inadvertently once the patient has
been enrolled in the clinical trial. Sometimes, investigators and
healthcare professionals do not correctly match medicines prescribed to
the patient with trial exclusion groups; or it is not clear which drugs
are excluded or not, especially if the exclusion criteria are based on
groups of medicines classed by pharmacological properties or metabolic
characteristics. In addition, some therapeutic areas (for example,
neurology) have lengthy and complex trial exclusion criteria for
medicines.
In the current process, the study sponsor reviews the scientific
literature, drug interaction databases, and previous study results to
identify such drugs. It then lists them in the eligibility criteria.
Potential problems with the list include the following:
- Study personnel may be familiar with a generic or a trade name, but not the other(s)
- A prohibited drug may be an ingredient in a combination drug
- If a class of drugs such as opiates or non-steroidal
anti-inflammatories is listed instead of the individual drugs, study
personnel may not be aware that a specific drug is in the prohibited
class. This problem is more severe if a group of medications is
prohibited based on its pharmacological properties or metabolic
characteristics
- The restrictions may be complicated, for example against the combined use of more than one hypertensive drug from a class
- There may be unacceptable dosages of otherwise acceptable drugs
- Any ambiguity requires interpretation by the study coordinator or investigator
- Some therapeutic areas (such as neurology) have exceptionally lengthy and complex exclusion criteria
- Drug names may vary by country
- There may be too many drugs on the list for the study coordinator and site monitor to remember or scan reliably
- A list organised alphabetically or by class may be unintuitive for some people
- Drugs may need to be added to or removed from the list during the course of the study
- The list may be prefaced with the caveat, ‘this does not represent a complete list’
When groups of drugs are excluded by category from the protocol, the
exclusion is often illustrated by a few examples from within the
category. This list is rarely comprehensive. An example set of rules
that may be required for a protocol is shown below:
- Exclude CYP2C19 inhibitors, for example Fluvoxamine, Isoniazid, Ketoconazole
- Exclude drugs to treat Parkinson’s disease
- Restrictions on the use of conventional neuroleptic and antidepressant drugs
- Exclude drugs with the potential to cause Torsades de Pointes
- Patient must be taking a stable dose of a cholinesterase inhibitor, such as Donepezil
- Exclude warfarin, heparin and ticlopidine
- Dose restriction of paracetamol
It is unreasonable to expect study personnel to reliably handle long,
complicated or ambiguous lists of prohibited drugs. Given the risks to
subject safety and scientific validity, minimising the chance of human
error with computerised decision support makes sense.
Electronic Concomitant Medication Management
Drug databases have been developed to allow clinical decision support in
prescribing and medicines management. Decision support in prescribing
is now used routinely within GP practice systems, hospital electronic
prescribing systems and pharmacy systems.
The use of drug decision support technology to monitor concomitant
prescribing and protocol exclusions in clinical trial patients is an
important development, with the potential to reduce time spent by
physicians and clinical trial monitors. The ideal system for centralised
concomitant medication management in clinical trials would have the
following features:
- Rapid checking of prescribed medicines against protocol rules at the point of prescribing in real time
- Web-based for ease of use and scalability
- Designed for global use, and configurable for different languages, cultures and drug databases
- GCP and other clinical regulatory compliance
- Validated software and validated drugs
- Drug database and rules should be highly configurable
- 100 per cent reliable
Use of a web-based service allows protocol drug rules to be set up
electronically. This enables the checking of medications before a
patient is enrolled in a trial, thereby eliminating errors, supporting
recruitment, and, crucially, improving patient safety. Harmonisation of
medication management reduces deviation from a trial protocol and
reduces data variability. Constantly providing live feedback to the
sites and monitors ensures that awareness is maintained throughout the
trial.
Conclusion
The use of an automated and scalable solution for the management of
concomitant medication in global trials is a logical step forward in
clinical research much in the same way as the advance from paper CRFs to
electronic data capture. This will not only be for the benefit of the
patient and the investigator, but also for the organisation running the
clinical trials.
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