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Originally Published March 2000

PHARMACEUTICALS

From the Inside Out: Planning a Clinical Trial Package

by Annie Lubinsky, Managing Editor

Planning a clinical trial package may be a simple or a complex process, but it must always be an efficient one as pharmaceutical companies aim to market new drugs as quickly as possible. In addition, planning the clinical trial package requires that many needs be met. Packaging designers learn as much as possible about the drug product, the protocol, and the dose regimen so that they can produce a package that protects the integrity of the drug, meets the scheduling requirements of the protocol, and helps the patient comply. Extensive planning may be required to design such a package.

"The package is designed from the inside out," says Stephen Flanagan, vice president of sales at Clinical Trial Services (CTS; Audubon, PA).

The planning process for clinical trial packages requires a team effort. Photo courtesy of Sharp.

Frank J. Tiano, vice president and general manager of PCI Clinical Services (Philadelphia), agrees. According to him, the factors to consider when designing a clinical trial package can be divided roughly into three areas: stability, the protocol, and most important, the patient. "You want to think it through carefully in order to get the client a good package under deadline," Tiano says.

SPEED AND QUALITY

The process of designing and developing the clinical trial package must be tight, because tardiness or errors are unforgivable. "There is no time flexibility when planning a clinical trial package," says Rick Sury, director of sales at Sharp (Conshohocken, PA). "Many companies are pushed by their medical research groups, so they need the packages in a very short period of time. In clinical packaging, you can't be late, and you can't have rejects."

"Of course, everyone wants everything yesterday," adds Peter Bernardo, chief operating officer of clinical packaging at Quintiles Simirex (Mt. Laurel, NJ). "We owe it to our clients to tell them our capacity, and we won't take a job we can't perform. That is because of our concern for the patients—we'd be negligent if we couldn't meet the deadline. Sometimes we will offer to break the study into three time periods and have the packages ready in time for each study period, but only if we can do this without interruptions in providing the drug to the patient."

Patient safety demands not only that packages be completed on time, but also that the efficacy of the drug be maintained throughout the study. Flanagan says, "One of the first things taken into consideration is drug stability."

Contract packagers report that they work with a number of clients ranging from start-up to experienced; usually the more experienced the company, the less help they need with choosing materials to guarantee product stability. "Many times a customer with experience doing clinical trials has already done stability tests, so they know what materials they want," says Sury.

When a pharmaceutical company is not experienced enough to know what materials should be used during the study, the experts start asking questions. Flanagan says, "We ask, 'how is the pharmaceutical company currently packaging the drug? Has the company completed stability tests?'"

Tiano adds to the list of questions: "What stability studies have been completed? Is the product light, temperature, or moisture sensitive? Is it in commercial form?"

Clinical trial packages must protect the product throughout the duration of the study. Photo courtesy of CTS.

If there are little data on stability, Mike McNear, vice president of operations at Covance Pharmaceutical Packaging Services Inc. (Allentown, PA), recommends being very conservative about the packaging. "Typically HDPE bottles offer excellent moisture protection. Even better are cold-form foil blisters, which have the highest moisture barrier. By being conservative and using very protective materials, you can hedge your bet while running stability studies."

Once stability tests have been performed and the packaging material chosen, the next consideration is the study protocol.

SYNCHRONIZING SCHEDULES

Package engineers examine the drug regimen and the visit schedule to determine the design of the package and the contents of the patient kit. McNear says, "We consider the complexity of the dosing regimen. For example, if the protocol calls for one tablet a day for 14 days, a bottle will help compliance as much as a blister. If there are three doses a day of different drugs, then we design a blister package to accommodate the regimen as well as the length of the trial." He cites programs in which weekly cards were created for the first four weeks of the trial, then monthly kits for the final three months. However, the same package may be used throughout the trial for consistency and the patient's comfort.

The visit schedule is also taken into consideration. "We usually do the adequate dosage required between clinic visits plus extra-day doses," says Bernardo.

While packaging engineers adhere strictly to protocols, there is a certain amount of flexibility allowed in the size of the packages and amount of drug in them. "If the doctor or clinic visits are scheduled for every two weeks, we can create either a two-week package or two one-week packages," says McNear.

Planning is a cooperative effort. "We review the protocol, brainstorm, present a recommendation, and design the package for the compliance of the doctor and patient, while keeping cost in mind," says Flanagan. "The package has to agree with the protocol."

LABELING

Labeling and graphics are essential to the package design, because they act as guides for the patient and must offer crystal-clear instructions. These elements are designed into the package from the beginning. "The difference between a bottle and a blister is that while both are labeled, the blister has artwork that is designed by the packager and approved by the client," says Jill Hadley, vice president of sales at CTS. Labeling can become complicated, especially when the clinical trials take place in many countries. Hadley recalls one package design that contained four languages on the blister card, "then had country-specific labeling in addition." Not only was the packager required to design a compliant package, it needed to design a global one.

Bernardo says, "Text approval always takes more time than one would think. We build more time for text approval into the schedule, because text approval by the client is unpredictable. In some companies, it is accomplished by only the regulatory and medical departments; in others, there may be a hierarchy of approvals that must be obtained."

Specialized packages for tablets and liquids meet the needs of the drug product and the clinical protocol. Photo courtesy of Almedica International Inc. (Allendale, NJ).

Labeling caused a small problem in one clinical study that McNear remembers. "The study protocol allowed the patients to self-medicate and take either one or two pills at a time, depending on how they felt," he says. "However, the package was not designed with that amount of flexibility in mind. It appeared from the package that the patient was required to take the same dose every time." In this case, the blister card was not designed to fit the flexibility of the study. Once the problem was identified, it was resolved simply by changing the graphics and labeling.

ADDRESSING THE PATIENT

As McNear's study shows, the package must promote compliance, not confusion. "The most critical thing a clinical trial package can do is offer the best possible chance for compliance," says McNear. "It is possible to create a bad package that would cause difficulties for the patient. If patients don't successfully take their medications, the clinical trial is called into question."

Bernardo agrees. "The big issue is always to assume that the patient doesn't know anything, so you have to be sure you make it easy for the patient so that people finish the study," he says.

Making it easy for the patient is part of the planning process. As is the case with stability, packagers learn what is required by asking questions. "Do the patients speak English? If not, we'll need to add icons to the package," says Tiano. "Are the patients elderly people? If so, they'll need a package with large type that's easy to handle."

Many decisions of this kind are addressed on a case-by-case basis, says Tiano. "For example, clients may say they want bottles for the study, which sounds reasonable from their point of view because bottles are quick and easy and you don't need to calculate the spaces on the web, order card stock, or find materials. But from a patient's point of view, a 500 cm³ bottle can be so big that it isn't portable or so small that the label is difficult to read." He adds that some start-up pharmaceutical companies have not yet built up a reliable pool of patients. It may be hard for those companies to find patients who practice good compliance.

"Whether we use a bottle or a blister package, we pack the drug out for patient convenience and use," says Hadley. "There may be weekly blister cards packaged in a monthly kit. To keep instructions clear, we may add a spine label, for example, which shows which package is for Week 1, Week 2, Week 3, and Week 4."

Industry is driving toward compliance packaging, according to Sury. "It's a big issue," he says. "When the patient has a bottle of tablets and is supposed to take some in the morning and some in the evening, the patient may forget to take the pills at all or may forget which doses were taken and which weren't."

A carded blister is an excellent compliance package, experts agree. "There's more rigidity, and they can be made wallet- or pocket-sized with a lot of room for explanatory text," says Sury. One of Sharp's strengths is producing carded blisters, says Sury. "We can use colors and text, and overall that type of package has a nicer appearance to the patient."

Packaging can help reduce the number of patients needed for a study, according to Bernardo. "If you do good planning on the type of treatment kit you use, you can reduce the number of patients needed for the study because the number of dropouts due to noncompliance is reduced."

The price of not designing a compliance package well is shown by one of Tiano's experiences. Early in his career while working for a large pharmaceutical company, Tiano designed a clinical trial package that he describes as "an engineering masterpiece." It was a folded blister card that contained multiple rows of large and small odd-shaped dosage forms on both halves of the card. The dosage forms were separated by discriminating colors for morning and evening doses. When the package was folded, the blisters nestled between one another so as not to crush the products. However, the package was about 8 X 11 in. in size and did not readily lend itself to patient convenience. During the study, he says, "The patient would punch out a day's worth of pills, carry them around in a tissue, and take them in random order. By doing this, the patients took the medications improperly and suffered ill effects." Fortunately, Tiano reassures us, the ill effects were short-lived, and the adversely affected patients fully recovered.

The card he designed met the needs of the study but "created a monster not convenient to carry around," he says. "The bottom line is that the patient will make or break the study."

The size of the package relates to the needs of the protocol. "If the regimen is a daily one, we try to make the package pocket-sized so the patient can carry it to work," says McNear. "We have to think not only of those who carry briefcases to work, but also people who work outside, who may have no choice but to carry the package in a pocket."

SECOND-GUESSING THEMSELVES

When designing a clinical trial package, Bernardo says, "You have to make the worst-case scenario assumption in planning and cater to that." In other words, assume the patient won't carry a bulky package all day. Assume that the patient won't return to the doctor on the scheduled visit date. "Build quality into the package by utilizing the checks and audits within the process," Bernardo explains. "That way, there are no mistakes unless the protocol is poorly designed, which is unlikely."

"We try to second-guess our potential problems," says Sury. Sharp does this by having plenty of packaging materials on hand and by carrying out detailed communication with the client.

SMALL COST, BIG RESPONSIBILITY

Communication is the key to designing the package the pharmaceutical company wants and ensuring the patient understands how to take the medications. During a clinical trial, the package serves as the means of communication between the investigators and the patients.

Some packagers, including McNear, feel that the best package is not always used. He explains, "Sometimes we let the theoretical concerns of using blister cards get in the way of using them. We'll use bottles without paying as much attention to compliance as we could. Packaging of clinical supplies is one of the last steps in the clinical trial process, but designing a compliance package needs to be done early in the process. At times, companies choose speed over compliance when faced with tight timelines."

This is a risk not worth taking, according to Bernardo. "When you look at the total cost of clinical programs, which is quite high, you'll notice that clinical packaging is a very small portion of that cost, maybe 5%," he points out. "However, the amount of responsibility attached to packaging is tremendous. It has taken time for the industry to put this in proper perspective, that the aspect involving a small percentage of cost has a huge responsibility for the success of the trial. There is no relationship between the cost and the value of clinical trial packaging."