Medical Device Link.

CLINICAL TRIALS

In the On-Demand service from Clinical Supplies Management, clinical supplies are packaged and labeled as they are ordered by the clinical site, minimizing overage budgeting and wasted inventory.

Clinical trials impose challenges on medical teams running the trials and on packaging departments. Packaging choices can address nonadherence, which results in inaccurate drug profiles that put patients at risk and which may drastically skew revenue projections for the drug.

As overseas trials grow as a means of access to naïve study populations and new markets, clinical supply and service providers are responding with expanded global depot networks. Market-responsive supply solutions address drug and packaging supply cost and waste.

“Pharmaceutical companies spend millions of dollars on clinical trials. If people don’t take the drug correctly, the trial value is greatly diminished. The efficacy of the drug and the drug’s side effects will be understated,” says Thomas Jeatran, Tom Jeatran Consulting (Minneapolis).

Nonadherence is not the only issue that complicates trial results and analysis. Trials are not always predictive of marketplace response to the drug in the general population for other reasons.

“People in trials are a very select patient group that is monitored much more closely (than the general population). Usually, individuals have only one thing wrong with them and are being treated for that condition. If they have other illnesses, they are usually excluded from the trial because there will be too many variables, making it difficult to analyze the data. In the real world, people have underlying illnesses and might be talking other drugs,” says Jeatran. Jeatran was employed at Eli Lilly for 35 years in regulatory affairs and as a clinical trials materials consultant.

Jeatran notes that there is a large opportunity for error when patients are reconstituting drugs. Drug use monitoring is complicated when clinicians have to collect and measure partially filled vials.

“I would estimate that at least half of these doses are off by at least 10%. I advocate the use of prefilled unit-dose syringes for parenteral drugs. The correct dosage is being delivered, and it is much easier for the patient to administer,” he says.

SKEWED REVENUES

When persistency falls off in a clinical trial, “at some point, a measurable number [of patients] are taking a significantly lower number of doses,” says Ward Smith, clinical trials specialist, MeadWestvaco (New York City). “Some study participants maintain the appearance of being compliant with dosing by reporting that they are taking the drug properly. However, exposure to too little drug will leave researchers with the opinion that these patients are not responding to the medication,” Smith says. The company may then get approval and go to market with the drug at a higher dose than is therapeutically necessary.

“FDA is looking for how far the results vary or separate from the placebo in approving the drug. It is well documented that since 1980, one in 4.5 approved drugs has suffered a postmarket dose reduction of 50% or greater. Thus, in almost 20% of cases, Phase 4 postmarketing studies demonstrate that the general population is exposed to doses that are much higher than needed.

“Packaging impacts the drug development process. You need packaging that will guide patients toward compliance,” Smith adds.

Electronic compliance monitoring via smart packaging provides the ability to capture more-accurate information on trial-subject behavior. Captured data can be transferred to software for analysis. Smart blister packages log the time each dose is expressed from the package to establish that drugs are taken at the prescribed frequency and intervals. However, “You can show that the package was opened, but the question always remains, ‘Did the patient take the drug?’” says Jeatran.

A study titled, “Medication Compliance as a Feature of Drug Development,” by the Division of Clincial Pharmacology, Department of Medicine, Stanford University, suggests that the removal of the dose from the package is to some extent predictive that the drug has been taken by the patient. “Although the removal of a dose does not ensure that the patient will ingest it, our experience suggests that it is highly improbable that doses are consistently removed without being taken by the patient over a monitoring period of approximately 90 days,” the study indicates.

By looking at actual history through electronic monitoring to measure an individual’s drug use, well-designed clinical trials “give you more information, which can streamline and enhance the drug-development process,” the study says.

“It has been demonstrated that by knowing the precise timing of drug dosing events, [clinicians derive] greater accuracy and precision in estimating pharmacokinetic patterns,” the authors conclude.

Simply knowing the number of times a bottle was opened per day can offer significant value compared with standard patient assessment methods, according to a study by the University of Texas Southwestern Medical Center. The study evaluated the use of MEMS (Medication Event Monitoring System) bottle caps by schizophrenia patients taking antipsychotic medication. Aardez Ltd. (Zug, Switzerland) supplies the MEMS device.

The study compared MEMS cap adherence with clinician-rated assessment in 21 outpatients over three consecutive months. MEMS-cap monitoring found high levels of clinically meaningful nonadherence, while assessment using the Clinician Rating Scale “dramatically underestimated” nonadherence.

“Patients were frequently nonadherent, despite consistently obtaining prescription refills and regularly attending monthly research study visits. These findings question the ability of clinicians to detect clinically meaningful antipsychotic nonadherence, even in patients with nearly complete nonadherence,” the study states.

TRACKING WITH CHIPS

Smith says that while academia has embraced the value of electronic monitoring, adoption by drug companies is just emerging. “Technical packaging requires two champions in marketplace clinical trials. The medical team that is designing the trial understands the value of biostatistics and proper dosing for analyzing drug efficacy. The packaging department has ownership logistically and is focused on cost-per-package. This is the paradox that has slowed acceptance of technical packaging by big pharma. Progressive thinking is required on the packaging side to look beyond departmental goals and objectives,” Smith says.

The contemporary FDA has recognized the value of accurate dose counts for firms modeling Phase 3 results using available software applications. Included are demonstration of doses assigned, taken, and not taken in Phase 2 for the Phase 3 modeling, Smith says.

Since the debut of the MEMS cap in 1987, alternative chip-based systems have come to market. They include the Med-ic ECM (electronic compliance monitoring device) from Information Mediary Corp. (Ottawa, ON, Canada) and Meadwestvaco’s Cerepak system for measuring how many pills are taken and at what intervals. “An advantage of Cerepak is that we can monitor the blister location, which is an important attribute when you have titrated doses that have to be taken in sequence,” says Smith.

While electronic packaging usage is in its infancy, standard compliance packaging is used today in 40% of clinical trials, and its use is growing. For controlled substances with understood toxicity levels, FDA requires the use of a recognized child-resistant (CR) feature. “The CPSC guidelines for clinical trials do not call for the use of an F=1 package, but rather packaging with a recognized CR feature as listed in ASTM D-3475,” says Smith.

“Our DosePak and Perfpak have achieved F=1 ratings on many occasions,” explains Smith. Given this rating, “companies using a blister card solution can avoid the time and cost of conducting CR testing should the blister configuration or pill size change, which happens frequently during study design.”

GLOBAL STUDIES

Bilcare Global Clinical Services supports global clinical trials with supply packaging and distribution centers in the Americas, Asia, and Europe.

Overseas trials have increased dramatically as drug firms seek naïve patient populations that have never received the drug or might have never been on any medication for the disease state. A recent A.T. Kearney study found that almost half of the clinical trials conducted by the 12 largest pharma companies in 2005 included an offshore location.

And pharmaceutical companies are facing more requirements from overseas markets.

“Countries are saying they expect pharma and biotech firms to meet their regulations, which may be different from FDA regulations,” says Steve Jacobs, president, Bilcare Inc. (Phoenixville, PA).

Jacobs notes that infrastructure challenges have affected trials in Asia. “There are tremendously dense populations in some of the cities, but reaching the rural areas where patient populations for specific disease states exist may be difficult. Some companies have found that the accessible population for a trial in Asia was actually only the size of the population of San Francisco.”

At Fisher Clinical Services Inc. (Allentown, PA), “we are seeing larger global studies with companies moving into Latin American and Asian markets where naïve populations are becoming more accessible with improved logistics and information systems,” says Jeff Hallquist, director of sales, Fisher Clinical Services. “We are also seeing sponsors’ postmarketing studies with 10,000-plus patient populations involving many countries with shortened enrollment periods.”

Jacobs says that Bilcare Global Clinical Services is well positioned to provide global contract research organization (CRO) services, with clinical supply packaging and distribution centers in Asia, the Americas, and Europe. “With our worldwide project management capabilities, we can substantially reduce time lines [from the] first patient in [to the] last patient dosed,” says Jacobs.

Bilcare’s U.S. division can leverage the resources of parent Bilcare Ltd. (Pune, India) to support overseas trials. “Companies shipping finished product through ports of entry face customs and infrastructure issues. You can ship bulk drugs to our facility in India for packaging, labeling, storage, distribution, and trial analysis,” Jacobs says.

Companies searching for advantageous pricing in packaging materials overseas are on the lookout for materials that meet their quality standards. Bilcare is a potential source, having started as a film and foil producer in India. It also has a Singapore facility, Jacobs says.

Fisher has more than 20 depots supporting the clinical distribution of patient kits to clinical sites. “We have also added secondary packaging operations in Singapore to support the labeling of products for the Asia-Pacific Rim and expanded our depot network into Latin and South America, Asia, and Eastern Europe,” says Hallquist.

Almac Clinical Services (London) this year forged an agreement with a pharmaceutical distributor for covering the Southeast Asia region from a hub facility in Singapore. “Further agreements are now operational in China and India, two key emerging markets within the clinical trials industry,” says a spokesperson for Almac.

Providers of clinical trial materials management services comply with CGMP controls for packaging and labeling clinical supplies, while looking for ways to efficiently supply trials that have grown in scope. Efficiencies can be created by standardizing supplies, allowing automation and flexibility in kit distribution. Bar codes and the use of multilingual booklet labels support kit-assignment control with the use of integrated voice response systems [IVRS], says Hallquist.

“We can design and package kits and pool these materials in order to have a more-flexible inventory ready to go for orders from any clinical site in the trial. All of the kits are produced the same way at the same time, reducing costs by taking advantage of economies of scale. Fisher Clinical Services has more than 120 packaging suites globally, providing the capacity and ability to leverage scale,” says Hallquist.

Packaging configuration is standardized where possible. For example, the same-sized blister card may be used in supporting weekly and/or monthly supplies used in different study indications. To support the variable label requirements of different countries, multilingual booklet labels can be designed. “We also take advantage of Clintrak Clinical Label’s many years of experience, ample capacity, and speed of delivery to design and print the booklets with the compliant text for each country,” Hallquist says.

Rockwell Automation (Milwaukee) features support for Unicode in the latest version of its clinical trial management software. Unicode allows computers to represent complex fonts such as those used in the Asia-Pacific region.

“Regulations generally demand [assurance] that patients can read the instructions in their native languages. Label designers can use the Unicode fonts to directly design and print regulatory labels in any language, in a powerful label approval process that reduces clinical trial supply times,” says Martin Dittmer, segment business leader, life sciences, Rockwell Automation. The firm’s RS PMX CTM 4.0 organizes material and information flow for clinical trials. Components include a Web-based integrated label editor that tracks the status of patient-customized labels through the approval process and different trial phases. The RS PMX CTM label module speeds the process of new label creation, approval, and use and reduces errors inherent with widely used fax-based methods.

“We manage clinical trial materials from active ingredient production through distribution to the patient. With the reconciliation component of RS PMX CTM 4.0, users can meet regulations that require demonstration of the complete life cycle of the investigational medicinal product,” says Dittmer.

PACKAGING TO DEMAND

Clinical Supplies Management (CSM; Fargo, ND) addresses clinical trial study costs and lead times with its On-Demand packaging and labeling service. In this approach, clinical supplies are packaged and labeled as they are ordered by the clinical site, instead of being prepared and held in inventory at the start of a study.

On-Demand eliminates the need to forecast supply requirements and to budget large overages to guard against supply shortfalls.

“In the On-Demand model, bulk inventory is packaged and labeled in response to requests from the clinical trial site. Clinical supplies are prepared and allocated according to need. This provides flexibility to customize supplies for multiple studies and protocols,” says Gerald Finken, president, CSM.

“There is no finished product inventory, so companies eliminate inventory risk. If clinical sites don’t enroll, the drug is delayed, or the study changes, they are not facing expensive repackaging or left with wasted drug product,” Finken adds.

New packaging can be implemented in days, with minimal waste, if study protocols should change, and overage spending is eliminated. Finken says that drug firms typically budget for 100% overage, for example, packing out 1000 units for a 500-person trial. Besides adding costs, overage budgeting ties up stock. Where a drug’s supply is limited, companies may lack product to complete their trials.

Using phased campaigns, companies have sought to minimize overage spending and waste resulting from expired product. “In campaigns, you still have the workload inherent in launching and managing multiple campaigns. With On-Demand, you eliminate the overage requirement and avoid shelf-stability risks,” he says.

Finken notes that the clinical-supply process often slows the drug-development process. As trials increase in size, it can take six to eight weeks to convert bulk drug into clinical packaging ready to ship. CSM’s lead time for starting a study is two to three weeks, as kits are packaged according to daily requirements.

In routine practice, “about 75% of the time, the overage is thrown out the door,” he says.

Customers are not paying up front for a full run of inventory in On-Demand. CSM charges a nominal up-front fee and invoices monthly. “We just had a company that cancelled the study a week before the scheduled trials. In a traditional model, they would have to throw away $175,000 in packaged inventory on the shelf or rework it at an additional cost. They spent $20,000 with us, and their unpackaged drug remained available to them,” he says.

As with traditional clinical packaging, an on-demand process must adhere to CGMP 21 CFR Part 211 processes. These include written procedures for the handling of materials through all stages of packaging and labeling and the use of pre- and postproduction batch records for process guidance and reconciliation. At CSM, a qualified reviewer reconciles the labels and components of each packaged unit before product release, says Finken.

CSM performs On-Demand for bottle packaging. For most studies using blister cards, most of the clinical material is packaged immediately for the entire program. “Traditional manufacturing methods are used for blisters to support CGMP requirements. Setting up the blister and carding machines to do only a few blister cards would be too cost-prohibitive and very timeconsuming,” Finken says.

“The quality control requirements are staggering if you are labeling product according to demand from the clinical site,” says Bilcare’s Jacobs. “You are labeling and quality checking product at the warehouse, before the product goes out the door. You have to ensure you are putting the right label on the right drug and the right drugs into the right kits.”

Bilcare packages all the actives, placebos, and comparators, then stores and labels them separately. They are then merged into patient kits, and kits are labeled. Kits are merged and labeled before they hit the warehouse. “In a highly efficient system, all you have to do is pick the right product off the shelf and ship it to the site,” Jacobs says.