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May 15, 2005 (Vol. 25, No. 10)

Preparation of Clinical Trials Materials

Guidelines, Frequently Asked Questions, and Tips from Industry Veterans

  • Contract preparation of clinical trial materials has been a growing business since the mid 1980s in Europe and the 1990s in the U.S., explains Gary Sutterlin, director of clinical trial project management at Cardinal Health (Philadelphia).

    Prior to the outsourcing trend in the U.S., the preparation of clinical trial materials was typically done internally by pharma companies, Sutterlin maintains. Due to the ebb and flow of projects it is hard for an internal department to maintain a steady state and be cost efficient.

    With increasing revenues at biotech companies and consolidation within big pharma continuing, the demand for the outsourcing of the preparation of materials for clinical trials is predicted to keep growing.

    Joseph Urban, Pharm.D., senior director at Proclinical Pharmaceutical Services (Phoenixville, PA), predicts that growth will continue for a good five years for several reasons. One key reason is the problem in recent years of newly approved drugs being pulled off the market.

    The FDA is going to want to look at more, larger, and longer clinical trials. Sutterlin reports that Cardinal Health's recent investment in a 400 palet and additional -20C refrigerator reflects its expectation that business will continue to grow, particularly from smaller and mid-size biotechs and pharma.

  • Services Provided

    Clinical trial supply contractors offer a wide variety of services. Some offer a continuum of service from a new chemical entity (NCE) to a contract sales force, "just short of a CRO," says Sutterlin. Services can include analytical testing, manufacturing, open-labeling versus blinding, packaging, quality control release, and testing, storage, distribution, and interactive voice response system (IVRS) patient registration.

    The customers can be divided into two broad groups. According to Sutterlin, the established companies know what they want and have their plan all laid out; the virtual companies come in wanting more instruction and guidance.

    Jeff Hallquist, sales director at Fisher Clinical Services (Allentown, PA), classifies the first group as "transactional and tactical" with a specific task to be done in a short time period of say six weeks. The second group's needs are more in the line of "strategic management" that occurs over a longer timeline requiring multiple project or program management.

    Providing services for preparing clinical trial materials is like "being a hotel," says Hallquist. "Whether you are staying for one night or one week, you expect a clean room, a good restaurant, and a friendly concierge."

    No matter who the customer is, Hallquist recommends evaluating, auditing, and selecting a clinical supply management organization earlier, as opposed to later. A good partner can help evaluate the protocol and the drug supply needs that might be required in future trials.

  • Planning

    Planning for clinical trial material preparation can sometimes be done a couple of months in advance or occasionally as long as a year. Focusing on the clinical trial packaging aspect late in the development life cycle is "the biggest mistake we see," says Sutterlin.

    Companies need to focus on the end product in parallel with the initial development of the clinical protocol.

    There are many factors to consider in the complex process of preparing materials for clinical trials. According to Sutterlin, in addition to providing the clinical protocol, the sponsor should be prepared to provide samples of drug product, MSDS, proposed label text, and defined expectations at the outset of the project. Keeping the goals and endpoints in focus is particularly important, Hallquist maintains.

    Monte Maroevich, senior manager of clinical labeling at Dow Pharmaceutical Sciences (Petaluma, CA), adds that the management and conservation of drug product is crucially important for domestic and EU trials, particularly for longer running trials using multiple batches that are manufactured over the course of the study.

    For most Ex-U.S. trials, the expiration date printed on the label can make this logistically challenging. In addition to the expiration date, the projected patient enrollment, early implementation of IVRS, and manufacturing schedule are all factors to consider when planning the labeling, packaging, and distribution portion of the program.

  • Regulatory Requirements

    U.S. and EU regulatory requirements are also important aspects to keep in mind when planning for a clinical trial. In the U.S., the FDA, DEA, and state agencies provide guidelines, while in the EU, Annex 13, the EMEA, and other specific country requirements are the guidelines.

    Regulations require that the preparation of all materials meet GMP and GCP requirements, Dr. Urban explains. Sutterlin notes that the clinical supply contractor should be flexible and have a full set of standard operating procedures (SOPs) in place. In addition, clinical supply contractors should be able to provide guidance when selecting packaging components.

    Some companies lock themselves into obscure components at the stability phase of a product's life cycle, which translates into long lead times due to custom manufacturing requirements. Most companies like to review all the necessary SOP documentation, which is currently paper and will probably become electronic in the future, Dr. Urban notes.

    According to Maroevich, the most important regulatory requirements are the complete segregation and traceability of all drug lots during preparation and 100% accountability for all materials and labels.

    The most significant recent change in regulations is the May 2004 EU Clinical Trial Directive. One important component of the directive requires that a Qualified Person (QP) certify that investigational materials manufactured and packaged outside of the EU are GMP compliant before use in EU countries.

    The review may also include an audit of the facilities that performed the manufacturing and packaging. The directive is on top of existing export and import regulations and taxes. The directive is important because so many trials are global, explains Halquist.

    In addition, he says that there are nearly 400 virtual companies with supplies not only coming from the U.S., but from all over the globe including India, Japan, and Australia.

    Maroevich reports that advice from the April 2005 Pacific Region Clinical Support Discussion Group recommends getting a QP involved as early as possible. Late contacting of QPs results in rushing of the clinical trial preparation process.

  • Common Mistakes

    Learning from mistakes and previous experiences is critical. Maroevich cites three equally problematic common mistakes:

    Making protocol changes late in the game, such as text on a label or a request from a statistician for additional patients. This can affect the packaging and labeling design, causing possible delays in the timeline, and be a "killer."

    Underestimating the amount of labeled supplies that will be necessary in global multicenter trials due to higher than estimated patient drop-outs. Additional supplies are then needed for new patients.

    Over-shipment of initial drug supplies to individual clinic sites. If a site is having difficulty recruiting subjects, drug cannot be transferred to another "good enroller," and thus the over-supply of drug is returned for destruction. Maroevich reminds companies that shipping today is fast, and getting drug supply somewhere quickly is usually not a problem.

    The last two common problems of over- and under-supply, indicate that managing the supply at different clinic sites and throughout a trial is a juggling act.

    As clinical trials continue to grow and become more complex, the continuing emergence, evaluation, and implementation of technologies give companies new options to improve the process.

    In the early 2000s, child-resistant (CR) and senior-effective blister card packaging options arrived, partially in response to the U.S. requirement for CR packaging on all outpatient material.

    According to Hallquist, blister cards are more common in Europe. The cards are more expensive up front, but offer more control and accountability resulting in a better record of drug not taken.

    MEM chips that record when a bottle of a drug is opened and closed have been used for years. Studies show that compliance with this technology is good initially, but is reduced over time.

  • RFID

    Today, radio-frequency identification microprocessor chips (RFIDs) are permeating different consumer end-user industries, including clinical trials. RFID tags are in cars recording driving information. Companies like Walmart are exploring the use of RFID technology for tracking products from suppliers. The clinical trial business is exploring the use of RFIDs to account for patient compliance to a clinical trial protocol drug-dosing regimen.

    An RFID offers the advantage of concealing the tracking device from the patient for improved compliance. However, there are problems with the technology. One issue is not being able to scan the chip through all materials, for example foil, lamination, plastic, and liquid. "That is why RFID isn't used in supermarkets on cans of Hi-C punch, for example," Sutterlin explains.

    The proper application of this technology is being explored. Even though the use of RFID technology will add an incremental cost to a clinical trial, "when it costs $1.7 billion dollars to bring a new drug to market, the value of tracking patient compliance is high in comparison to the cost," Hallquist asserts.



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