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International Clinical Trials

The Clinical Trial Landscape

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. 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 patientís 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, Ďthis does not represent a complete listí

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 Parkinsonís 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.


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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Dr Mark Dale is a Medical Consultant, a graduate of Manchester University and currently CEO of MAC Clinical Research, providing clinical research facilities, consultancy and eClinical technologies to the pharmaceutical industry. Mark has worked on over 100 studies as Chief and Principal Investigator, and has published over 30 articles in peer-reviewed journals. In 2011, he was awarded the NW Institute of Director Award for Innovation.
Dr Mark Dale
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