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Originally Published May 1999

PHARMACEUTICAL

Should Clinical Trial Packages Be Child Resistant?

Creating a child-resistant package that also promotes compliance presents a challenge to clinical trial packagers.

by Annie Gorton, Associate Editor

Packagers focus a great deal on compliance when developing packaging for clinical trials. Clearly, the success of a clinical trial depends upon patient compliance, and this is one area that can largely be helped or hindered by packaging. Patient kits are designed not only to promote compliance, but also to maintain the blind and keep the product stable throughout the life of the study. These packages carry heavy responsibility, and soon, yet another demand may be placed upon them—clinical trial packages may need to become child resistant as well.

Many clinical trial packagers don't think about child-resistant packaging unless the pharmaceutical company that manufactures the new drug requests it. Several packagers say that child-resistant packaging is unusual for clinical trial products; in fact, the issue of whether or not child-resistant packaging should always be required for clinical trial products used in the patient's home is under discussion in the industry.

Monte Maroevich, manager of Dow Clinical Labeling at Dow Pharmaceutical Sciences (Petaluma, CA), says, "There's a movement to look into child-resistant packaging, to determine whether or not to use it and why."

POISON PREVENTION PACKAGING ACT

According to a letter written to the Pharmaceutical Research and Manufacturers of America from the U.S. Consumer Product Safety Commission (CPSC; Bethesda, MD), a packager must use child-resistant packaging for oral drugs used in outpatient clinical trials. Like prescription medications, investigational new drugs need to be packaged in compliance with the CPSC's Poison Prevention Packaging Act (PPPA).

However, child-resistant packaging is not always used for clinical trial products. As a new pharmaceutical progresses through the different phases of a clinical trial, the packaging changes to accommodate the study protocols. Chuck Gettis, manager, business development at ProClinical Inc. (Phoenixville, PA), explains: "When packaging a product for a clinical trial, the packaging is going to be different from that of a marketed product. In Phase I, you have a limited patient population, so you may send 100 tablets or capsules in a bottle to the hospital to be administered to patients. As you move from Phase I to Phase III, the specifications become more exacting. In a lot of cases, clinical trial drugs are packaged in blisters, not bottles. Now some of our customers are asking for child-resistant packaging, which is unusual in clinical trials. Those customers are interested in child-resistant packaging particularly in a Phase III study, when patients receive their medications and take the supplies home with them."

Packagers don't always agree that child-resistant packaging is necessary. Several have said that because investigational drugs are clinical, not consumer, products, they do not need to follow the same rules. These packagers feel that child-resistant features are optional.

Sandra Luciano, healthcare market development specialist at AlliedSignal (Morristown, NJ), feels that using child-resistant packaging makes sense. "In Phase III, the product may go home, and that's the reason to use child-resistant packaging," she says. "Clinical trial companies will need to come up with a viable system to comply with child-resistant packaging without increasing costs. This will be a big task."

The problem is a matter of interpretation, says Suzanne Barone, project manager for poison prevention at CPSC. "Our position is that oral drugs dispensed by a medical professional and that go home with the patient are required to have child-resistant packaging. This is a position that is not well known. Once we became aware that there was some confusion, we have made it our purpose to educate people in industry."

Perhaps one reason for the confusion is that for a long time, clinical trial packagers have focused strongly on compliance. "The function of clinical trial packaging is for the package to support the clinical objectives outlined in the protocol," says Donna Christopher, director of operations at Applied Clinical Concepts Inc. (Durham, NC). For many studies, the blister package is preferred because it helps patients take their medications properly, which in turn supports the clinical trial's aims.

BLISTERS ARE PREFERRED

Clinical trial packaging has evolved over the years to keep up with the demands of increasingly complicated clinical studies. Frank J. Tiano, vice president and general manager of PCI Clinical Services (Philadelphia), says, "The clinical trial package has changed through history. Originally, glass bottles, either clear or amber vials, were used in clinical trials. But as the trials became more sophisticated, blisters were used. It used to be that the drug was the most important part of a clinical trial. Now packaging is a close second." A well-designed package is critical to a successful clinical trial because it plays a large role in promoting compliance.

Because it has such exacting demands placed upon it, clinical trial packaging is a specialized area. Ray Renza, senior vice president of corporate development, Sharp (Conshohocken, PA, and West Caldwell, NJ), says, "The tracking is different, there can be no mistakes, and you must follow CGMPs."

Jill Hadley, director of marketing at Almedica Services Corp. (Allendale, NJ), says, "The purpose of clinical trial packaging is getting the right supplies to the right patient at the right time. It's important that the design of the packaging promote compliance. For example, in a blister card study, you use graphics and color to help the patient distinguish what to take at the right time."

Clinical Trial Services (Audubon, PA) addresses the issue of compliance in much the same way. Elyse Braxton, manager of new business development, says, "To aid compliance, we use color coding, such as yellow for day and blue for evening. We work with the drug company to make the language as patient friendly as possible."

Renza adds, "To ensure compliance, we use a color code or print the day of the week which the dose is intended for."

A related issue is ease of use. Compliance can better be achieved when the dose is already assembled for the patient and when the package is easy to carry. Clinical trial packagers work to design the best package for the trial, whether it's a bottle for a single-drug study or an elaborate blister for testing multiple drugs. "Size can be a problem," Braxton says. "AIDS patients, for example, may need to take several medicines a day, which could require a large package. We try to create a package small enough so patients will take their medicines, though we have no control over compliance or the patient."

Anderson Packaging Inc. (Rockford, IL) uses colors and text to aid compliance.

Currently, many Phase III clinical trial kits are in the form of blister packages, which are often placed into cards or wallets containing labels and instructions for the patient. This type of package is easy to use and helps the patient take medications on time. Bob Misher, vice president of clinical packaging at Blis-Tech, a division of Oread (Fairfield, NJ), explains: "In commercial packaging, the blister is used for a specific reason, such as ease of use or unit of use. In a clinical trial, the blister is used to improve compliance of complicated dosing regimens. A person may have to take numerous doses several times a day. As an example, a patient may be required to take eight capsules per day, consisting of three different drug products or strengths. If the study drug is packaged in bottles, the patient dosing becomes complicated. Compliance using bottles is very unlikely. With a blister package, the dosing regimen is easier for the patient to visualize, and therefore, compliance is improved."

THE CHALLENGES OF CHILD-RESISTANT PACKAGING

Clinical trial packagers say that switching to child-resistant packaging, especially when blisters are used, would be an expensive, time-consuming, and difficult process. Hadley says, "It's easy to put a child-resistant cap on a bottle, even for a clinical trial. It is more difficult and expensive to create a child-resistant blister than a regular blister because you use different materials."

Cost isn't the only consideration. The blister packages used in a clinical trial are often "trapped" inside a printed card or wallet, making the usual child-resistant features impossible to use. "One of the most widely used child-resistant techniques is a peel-push format using a paper- or a poly-lined foil," says Misher. "The problem is once you trap the blister in a card, you no longer have access to the foil in order to peel the laminate from the foil."

Mike McNear, vice president of operations at Covance Pharmaceutical Packaging Services Inc. (Allentown, PA), feels that requiring child-resistant blister packages might hinder the clinical trial process. "If we have to comply with the regulations as written for commercial products, it would be very difficult to use blister cards for clinical trials," he says. "Some complicated trials require blister cards to help ensure patient compliance."

Barone says she is well aware of the importance of using a convenient packaging form for a clinical trial. "We don't want to do anything to affect a study, but there are ways to have both compliance and safety," she says.

COMPLIANCE REMAINS A PRIMARY CONCERN

Some packagers have said that child-resistant packaging could make a clinical trial more difficult for both packagers and patients. "A clinical study by its very nature is complicated, so we attempt to make the packaging simple," says Misher. "By adding child-resistant elements, it makes an already complicated study package more difficult to use by the patient."

Although the PPPA requires child resistance, it prohibits CPSC from mandating package designs. However, Barone notes that there are packages that both promote compliance and help keep children safe. For example, the Healthcare Compliance Packaging Council awarded its Compliance Package of the Year for 1997 to Procter & Gamble's Helidac Therapy Kit, a compliance-oriented child-resistant package. The blister card contains three separate drugs that must be taken four times a day. Perhaps this is one design that may be adapted to meet the needs of a clinical trial.

McNear adds that testing child-resistant packages for clinical trials would be a complicated process. "This would be expensive and time consuming," he says. "You may have six or seven different designs of blister cards to meet the design of a study. Each separate package would have to be tested. That's not realistic."

Testing may not be required, however. Barone explains: "There's no requirement in the PPPA to test packages. The pharmaceutical company simply needs to feel comfortable that the package they use in a clinical trial is child resistant. They can determine that through testing, or they can buy a package from a manufacturer and rely on the manufacturer's data. There are no testing requirements or certification. It's up to the company how they want to go about achieving and assuring child resistance."

The most important question is not how to redesign clinical trial packaging so that it is child resistant, but why child resistance is necessary.

IS CHILD-RESISTANT PACKAGING NEEDED?

"Do we need child-resistant clinical blister packaging?" Misher asks. "In the commercial market, you do have incidents of accidental poisonings. But do we have the data showing accidental poisonings are a problem with clinical trial drugs? In addition, the volume of clinical trial drugs is extremely small compared with the whole pharmaceutical market. We don't know if accidental poisonings are a problem or not."

Barone agrees that there is little data available on poisonings from clinical trial products. "We have concerns about all drugs," she says. "These are drugs we don't know about. We have anecdotal evidence of poisonings, but we're not sure whether poisonings from clinical trial drugs would go to a poison control center rather than to the clinical trial people. No study has been done to look into this issue."

McNear points out that clinical trial products aren't like consumer products. "Clinical trial materials are a very controlled commodity, which should help minimize the risk," he says. "If we wish to develop child-resistant blisters for use in clinical trials, we need to measure the risk of accidental poisonings against the need to effectively bring new, innovative products to the consumer. As an industry, we can strive to develop child-resistant features that are unique to blister packages used in clinical trials."

Instead of child-resistant packaging, many clinical trial studies are using informed consent to meet the regulatory requirements. The form states that the packages must be kept out of the reach of children. In addition, clinical trial kits often contain a warning label. However, these precautions may not be enough, according to those who want child-resistant packaging for all drugs that enter a patient's household.

Clinical trial packages are subject to exacting specifications that may become even more stringent if child resistance is required. While contract packagers recognize the importance of keeping children safe, they also need to keep the package compliance oriented and easy to use. Reconciling the two may not be easy, and there's more to be said on this issue. Right now, according to Barone, CPSC is working to educate the industry. "We are willing to get together and look at the issue from all sides—from the points of view of packagers, pharmaceutical companies, and clinical trial professionals—to see if we can work out a way that protects children and does not interfere with clinical studies."

Opening photo courtesy of Sharp (Conshohocken, PA, and West Caldwell, NJ)