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International Clinical Trials

Missing Link

In the mid-1990s, physicians in the US noticed that some of their patients who had been taking an oral hypoglycemic unexpectedly began developing signs of toxicity. The only thing that had changed was that these patients had received a disease management programme six months earlier to encourage them to stay in therapy and take the dose as prescribed.

The cause of these unexpected toxicities was perplexing because these patients were taking the same approved dose as they had been taking before the education programme. The pharmaceutical company distributing the programme attributed the increased sales during this time period to increased adherence.

Emerging Side-Effects

Years later, patients suddenly developed unexpected side-effects from prescription drugs that had been on the market for five to ten years. Rofecoxib (Vioxx), which had been approved in 1999, was withdrawn from the market in 2004, while Valdecoxib (Bextra), approved in 2001, was withdrawn in 2005.

Celecoxib (Celebrex), approved in 1998, remained on the market with a black box warning. The Food and Drug Administration (FDA) encouraged the use of the lowest effective dose for the shortest duration and recommended 200mg per day (1). Cohen reported that 200mg per day of Celecoxib was not the lowest effective dose. He observed that his patients had lower incidences of toxicity and fewer dropouts because of adverse drug reactions when he prescribed half the FDA-recommended dose (2).

Simvastatin (Zocor) had been approved in 1991 but, in 2011, the FDA issued an alert that the 80mg dose be replaced by a 50 per cent lower dose to decrease toxicity. In addition, Zolpidem (Ambien) had been approved in 1992, but in 2013 the FDA recommended that the dose be halved for women, and recommended that this should also be considered for men.

These unexpected drug toxicities raised several questions:
  • Why were patients experiencing so many unexpected toxic side-effects?
  • Why was the FDA halving the approved dose for medications that had been on the market for years?
  • Was there a possibility that study participant nonadherence in the clinical trials was not adjusted for by increasing sample size, and that the final approved dose was higher than it would have been if study participants had been more adherent?
  • What happens post-launch, in real life, if patients are more adherent to the dosage regimen than the participants in the clinical trial?
Hidden Problem

A review of the last 20 years of patient adherence research in clinical trials was conducted to determine how adherence was addressed, and how patients tell their study physicians and nurses about problems with taking the study drug (3).

The results were alarming. Between 1969 and 1972, patient adherence was only assessed in 19 per cent of trials published in the British Medical Journal and Lancet. This increased to 47 per cent between 1997 and 1999, but this meant patient adherence was not addressed in 53 per cent of the trials.

Patient adherence was poorly defined in most of the studies that addressed adherence, and the methods used to monitor adherence were questionable in many cases. With many of these drugs still on the market, it is reasonable to ask how safe the dose is for these medications if patient adherence was not measured. It is unknown how patient adherence was addressed in trials from 1999 to date – something that might change as confi dential trial data becomes more transparent.

Potential Impact of Poor Adherence

The review showed that up to 30 per cent of study patients do not take the full dose of the study drug (4). To make matters worse, study patients usually do not tell the clinical investigators that they missed doses because they want to ‘please’ their doctors. Others are afraid they will be removed from the study and do not want to lose the revenue they are receiving.

A clinical trial may be well-designed, but a 20-30 per cent decrease in medication adherence may require the sample size to be doubled for the study results to be accurate (5,6). If patients in clinical trials do not take the full dose of the study drug and the investigators do not increase the sample size to maintain the power of the study, the FDA approved dose might be too high. Potential patient safety problems could arise for those patients in the general population who are more adherent than the study patients. The challenge is to increase patient adherence in clinical trials to a high level of adherence – for example, 95 per cent – so that patient safety is guaranteed for those taking the medication as prescribed.

Better Patient Engagement

Patient engagement is improving in the general population because of the major focus on patient education since the 1990s. As a result, these patients frequently receive better patient education than those in clinical trials. This needs to change: patients in trials need optimal education so that adherence can be increased to a level higher than that of the general population.

The following recommendations are made to help increase patient adherence in clinical trials:

Develop a Patient Adherence Strategy
A patient adherence strategy should be included in the study design and before starting to develop any patient education materials, compliance packaging or reminder programmes for the trial. The first step is to identify all the patient adherence barriers for the study drug and medical device. The next step is to identify appropriate learning strategies and the most effective timing and delivery of each intervention.

Consider the Patient’s Perspective
Study patients make critical decisions during trials. They often make unwise decisions because the study investigators are sometimes not sensitive to the patient’s perspective and, as a result, not meeting patient needs. Investigators should put themselves in the position of patients, asking questions such as: Is the dosage reminder annoying? What would I do if I were afraid I was developing a side-effect? What information would I want to receive to explain why I should stay on the study dose and not cut it?

Ensure Informed Consent Documents and Patient Information are Understandable
We cannot expect study patients to manage the study drug correctly if they cannot understand the informed consent (IC) documents or clinical trial instructions. Studies show that 35-94 per cent of IC documents cannot be understood by study patients (7,8). IC documents should be written at the Grade 6-8 readability level and in language that study patients can understand. The appropriate use of graphic design can help improve patient recall.

In addition, the study team must clearly explain:
  • The IC document
  • How to administer the study drug
  • When to contact the study team, rather than stopping or missing doses of the study drug
  • How to use special compliance packaging and reminder aides
  • How to complete patient diaries
  • How to use electronic tools
Study patients will drop out of adherence programmes that are not understandable, practical and easy-to-use. Poor content can cause non-adherence. It does not matter how great the technology is for a medication reminder or smart phone app. The patient will generally stop using the tool after ten uses if the content does not meet their needs.

Gain Study Patient Trust
At least 50 per cent of study patients do not tell the study team they missed doses and are overestimating their adherence. In the five-year Lung Health Study, about 30 per cent of study patients discarded the contents of their inhaled bronchodilators before a clinic follow-up visit in an effort to conceal their failure to take the medication correctly (4). Patient deception is not revealed by the usual methods of adherence monitoring (9). The challenge is for study investigators to gain their trust and convince patients that it is 'safe' for them to provide honest feedback.

Adherence Monitoring and Patient Feedback
Microelectronic adherence monitoring devices can provide a study team with useful information on the date/time the patient removed a medication from the prescription vial or blister pack. However, this data does not guarantee that the patient actually took the study medication.

Newer blister packaging embedded with a micro-electronic monitoring device would enable patients to look at the medication strip and immediately see whether they had taken the dose. This is in contrast to prescription vials, where it is very difficult for a patient to quickly check if they have taken the correct number of doses for the day.

Equally important is the personal feedback from study patients, because it will help investigators determine adherence problems the patient experienced, why they decided to miss or take extra doses, and how personal events, such as stress or a car accident, may provide an explanation for some of their symptoms. Combining accurate patient feedback with the adherence monitoring data will make the clinical trial results more accurate.

Publish Patient Adherence Results in Package Insert
Health professionals need to know how many doses of the study drug can be taken incorrectly without jeopardising the study therapeutic outcome (3). A study of 87 chronic myeloid leukemia patients demonstrated that adherence was the critical factor for achieving molecular responses, and that missing even a few doses of a drug can have a major impact on the treatment outcome (10).

Patient adherence results should be included as an outcome of the clinical trial and published in the FDA approved Package Insert. Until this information is readily available to health professionals, many will keep prescribing half doses, with no sound data to justify the decrease.

Adherence Goal

It is critical that patient adherence levels are higher in clinical trials. The goal should be to increase trial adherence to 95 per cent so that it is almost always higher than that of the general population. This will give health professionals assurance that patient safety is not in danger, because the dose and adverse event profile would be based on a higher level of study patient adherence than would be expected in the general population after the launch.


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Dorothy Smith is President and CEO of Consumer Health Information Corporation. Dr Smith is an internationally recognised clinical pharmacist with expertise in the development of patient adherence strategies, patient education programmes and patient advocacy. She is the author of 23 books and recipient of many awards, including the APhA Foundation Pinnacle Award for Leadership in Patient Education and Patient Adherence.
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