Blisters for Clinical Trials
Helping improve the accuracy of clinical trial data, blister packaging is fast becoming the package of choice to promote compliance as well as to monitor it.
, Managing Editor
The importance of accurate clinical trial data cannot be overstated. The outcomes of such trials determine whether a new drug is approved for medical use, as well as the correct dosage requirements for that drug. Inaccurate results could lead to the release of a drug that is unsafe for patients to take--or the withholding of a drug that might potentially save lives. For these reasons, patient compliance during clinical trials is essential.
Blister packaging not only helps patients comply with drug regimens during a trial, but it can also help trial investigators measure a patientï¿½s compliance, allowing them to better assess outcomes. Investigators can then make determinations such as whether ad-verse reactions or inadequate therapeutic responses are a result of the drug or a result of the patient not taking the medication correctly. This information may also help prevent patients from dropping out of the trial unnecessarily.
Blisters versus Bottles
Blister cards are gaining popularity over bottles as the accepted form of clinical trial packaging. Not only does the blister card give the patient a visual aid to taking medication correctly, but it also helps the trial investigator determine the patient's level of compliance. Bottles, on the other hand, rely on patient discipline. "One of the things a lot of clinical trials do is put extra pills in a bottle to check compliance," says Allan Wilson, MD, PhD, president of Information Mediary Corp. (Ottawa, ON, Canada). "But this confuses the patient. Another strategy is the medication diary, in which the patient is supposed to write every time he or she takes a pill." However, as Wilson has found through his experience as a clinical trial doctor, patients often rely on memory to fill in the medication diaries at the last minute, just before meeting with the investigator. The diaries are often adjusted to compensate for missed pills.
Nathalie Brisson, sales director for Ropack Inc. (Montreal), raises another issue regarding the use of bottles. "If the patient loses the bottle, he or she loses everything. With the blister card, there may be a five- or seven-day treatment on one card. If the card is lost, there are still other cards available."
Have Blisters, Will Travel
As stated above, blister cards can be easier for patients to carry with them than bottles. "The idea is to keep the card as small and compact as possible," says Joe Saccomanno, director of study planning and development for BlisTech Corp. (Fairfield, NJ). "We use multifold panels on occasion to keep the card small."
Martin Noblet, director of marketing for Almedica International Inc. (Allendale, NJ), advises his clients to avoid oversized packs. "If you have a pack that's 81/2 X 11, it won't fit in your pocket. So, the risk is that the patient will take out the tablets he or she needs for the day and then take them out of sequence. If the first two are placebos and the last one is active, there's the danger of the order being reversed."
MeadWestvaco Corp. (Stamford, CT) has come up with a child-resistant solution that makes it more convenient for patients to take their medication. Surepak is made of a tear-resistant paperboard combined with a high-strength plastic frame. It comes in two standard sizes for the clinical trials market. A locking mechanism on one side of the frame snaps closed over the cover and holds it in place. When the lock is opened, the cover lifts up and an inner blister card attached to the underside of the cover lifts with it. "We built the child resistance feature into the outer part of the package to eliminate the need for child resistance to be part of the blister inside. This makes it easier for patients to access their medication and allows the use of standardized blisters in clinical trials," explains Jeff Robb, vice president of marketing. "The locking/opening mechanism also en-gages the patient in the process, providing a novel method of interacting with the package."
Designing a Blister
The development of the Surepak was a collaborative effort between MeadWestvaco and Fisher Clinical Services (Allentown, PA). According to Jeff Hallquist, sales director for Fisher, it is imperative for the clinical supply professional to consider the goal of the trial when determining the blister card design. "If accountability is critical to attaining the goal, how do you design that blister card in a fashion that makes it easy for the patient to be compliant? If you have a dosing schedule that's three times a day--morning, noon, and night--and you design a card that has three columns and seven rows, it becomes [clearer] to the patient and easier for him or her to select the right dose at the right time. You need a supportive design where the drug is organized based on the intended schedule of delivery."
Incorporating graphics into the blister design can help improve patient compliance. "The industry has a lot of war stories about people not complying with trials," says Charles Mastroni, research associate clinical packaging specialist, Boehringer Ingelheim (Ridgefield, CT). "Blister cards can help through the use of graphics, and [the investigator] can identify visually each dose the patients are supposed to give themselves and at what time of the day." For example, icons such as the sun and the moon can be used to indicate morning and evening doses.
Frank Tiano, former vice president of Cardinal Health (Philadelphia) and president of Clinical Supplies Consulting Services (East Norriton, PA), agrees that it's important to use icons in clinical trials. "You're often dealing with [patients for whom] English is not the primary language." Noblet points out that icons and symbols are also helpful for multilingual blister cards. The company recently finished work on a design in Europe that used flag icons in place of country abbreviations to indicate the different languages used.
BlisTech also offers booklet labels for multilingual studies. "Instead of incorporating all that text onto the blister card, we'll look at using the booklet-style label that we can apply to the outside flap of the blister card. That can have up to 17 different languages," says Saccomanno.
Efforts are also being made to incorporate the patient diary into the blister card. "Sometimes we'll embed a diary card in the blister card," Saccomanno adds. "We selectively do not varnish areas of the diary card that require handwritten information because it's difficult to write on a varnished surface. That card serves a dual purpose. We can have a portion of the lid perforated so if during post-return drug processing we have to return the diary card to the client, we can do that without removing the identification label on the blister card. The label is perforated so half of it with the patient number and study number remains on the card and the other half comes off when the diary card is detached from the blister."
Another means of enhancing compliance that is sometimes overlooked, says Noblet, is to "focus on making the important information more visible than the unimportant," such as the patient's code number or the pack code number. Using a larger font is another way to draw attention to the most important information.
While all of the above features make it easier for patients to take their medication as directed, they do little to assure the clinical trial investigator that this has in fact taken place. "Patients know they are on an experimental drug, and some will get worried and decide not to take it," says Mastroni. "But they have agreed to be part of the trial. They have 'white coat' fear."
Wilson of Information Mediary has been involved in clinical trials for 20 years. "I work with psychiatric pa-tients, by and large, and we know that our patients are notoriously noncompliant. A lot of judgments we make about changing medication are based on patients' self-reports. So, for patients with schizophrenia, if we give them medication and they come back the next month and say theyï¿½re still hearing voices, the assumption is that theyï¿½re taking the medication once or twice a day as prescribed. But this probably isn't the case at all. So, then we switch medications, and you get onto a merry-go-round of having your clinical judgment driven by a patient's compliance."
Current methods of measuring compliance include using pill counts or patient medication diaries. But these can be inaccurate and do not address the issue of patients taking their medication when scheduled. Even if patients fill out their medication diaries accurately, notes Wilson, it takes a lot of time for the researcher to record the data. Blister packaging provides visual evidence that the medication has been taken, but it does not indicate when the medication was taken or if it was taken in the correct sequence.
Information Mediary has attempted to address this problem with the Med-ic Smart Package, an electronic device that is integrated into blister packaging to record each time a pill or capsule is expelled from the package. The device adapts to any existing blister package configuration, and it does not add any bulk to the package. It can also be tailored to specific clinical requirements, such as monitoring the temperature, vibration, humidity, radiation, and light to which the package might be exposed. "This might be important to a clinical trial if you wanted to know whether the patient left the medication on the dashboard of a car in the sun for two days," says Wilson. Visual and auditory reminders can also be added to the device.
At the end of the clinical trial period, the patient returns the blister package to the clinician, who then uses a radio-frequency scanner to download the information from the package to the database.
When used in clinical trials, the Med-ic allows the investigator to obtain accurate data on a patientï¿½s dosing schedules. This can help prevent bias in the clinical trial results, as well as erroneous decisions to abandon or continue the trial. For example, "you often get situations in which patients say they want to drop out of the study because they're getting a headache every morning," says Wilson. "If they're taking a pill twice a day, it may be that they're getting up at noon instead of 8:00 a.m., as you expect most people to do, and taking their first pill at that time. Maybe when they take their first pill, their plasma levels are too high because they're sandwiching their pills close together. If you knew this, you might be able to keep such patients in the clinical trial, whereas otherwise you would have to delete them from the study."
Saccomanno adds that most clinical trials incorporate a placebo run-in phase to the study medication plan. "I see the Med-ic device being invaluable during this screening phase as a proactive tool in providing more comprehensive compliance information to site personnel. In this way, once the screening phase data are evaluated at the site during the patient's visit, a more focused compliance retraining can be offered to the patient, if needed, prior to initiating the patient's randomized, very costly, medication phase."
While technologies such as these are not in widespread use for clinical trials at present, many in industry agree that they will gain greater acceptance in the future. At press time, the Med-ic was scheduled for production in mid-March 2003. Shorewood Packaging, a business of International Paper (New York City), will distribute it.
While packaging plays a major role in clinical trial compliance, instructing the patients prior to the trial is just as important. "Patient education at the beginning of the trial is crucial to their understanding to take the right dosage at the right time," says Fisher's Hallquist. This should be backed up with a package design that is simple and easy to open.
"When people get so hung up on packaging and labeling, I'm concerned that they lose sight of the fact that there's a human being out there taking this medication," says Clinical Supplies' Tiano. "It they can't open the pack-aging and decipher the readings, the whole study comes to a screeching halt. The best designed study goes nowhere if patients can't get the medication out of the package and take it for the proper duration and frequency."