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Martin Dittmer and Brooke Cox

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FDA Compliance

Overcoming the Global Challenges

Clinical-trial label approvals

Published: Tuesday, May 22, 2007 - 21:00

Despite the best efforts of pharmaceutical manufacturers, drug labeling is one of the greatest challenges in clinical trials, involving a complex, time-consuming process to meet strict regulatory requirements and obtain wide-ranging approvals from individual countries. That labels must contain a diverse range of information used by investigators, subjects and pharmaceutical companies alike compounds the problem.

Fortunately, a number of leading industrial automation companies are moving forward with new solutions and programs designed to ease the label-creation and -approval process for pharmaceutical manufacturers. Following is a closer look at the clinical-trials label processes, along with innovative technology tips like Web-based label approvals that hold promise for improving the current system.

How labels are used
In clinical trials, labels are used by pharmaceutical manufacturers to provide doctors, subjects and trial sponsors with information such as batch numbers, directions for use, the strength or potency of the drug, expiration date, package numbers, storage requirements and unique subject identifiers. Each clinical-trial label identifies the packaged drug, the study and the subject participant. Extra care is required in blind studies, where the labeling for placebos must look identical to the labeling for active drugs and yet be identifiable in some way to the pharmaceutical company conducting the trial.

Each label is unique to the individual subject, in addition to being trial and country-specific. If side effects occur—particularly severe side effects—it’s imperative that the pharmaceutical manufacturer know exactly what it delivered to the subject. Thus, a unique identifier, such as a barcode or RFID tag, provides full traceability.

The U.S. Food and Drug Administration and other regulatory authorities require that every drug be correctly labeled and, when possible, permanently affixed to the container. Labels are generally affixed to a number of different locations. For example, a clinical trial for a new tablet would likely require labels on the blister package, visit box and shipping box. Moreover, the label design will need to comply with the regulatory requirements of each country participating in the trial.

When a new drug is ready for testing, clinicians compile the requirements for clinical trials in a study protocol, determining the materials required, needed supplies, the countries involved and the languages into which label text must be translated. Pharmaceutical representatives must understand clinical-trial regulations for each country where trials are conducted and work to submit labels and obtain approvals from quality assurance and regulatory reviewers in each country.

For each clinical trial phase, new labels must be created and approved,a process that gets more complex with each step. Typically, the first phase of a clinical trial includes 10 to 20 people to test side effects and dosage. Phase two usually involves a larger sample size, from 100 to 200 people, to determine drug efficacy. In phase three, the drug is retested for efficacy and side effects among a larger test group, generally involving from 1,000 to as many as 10,000 subjects.

Because clinical trials often run in several countries at the same time, they generally require packaging with multiple languages, which means that labels need to be reviewed and approved by multiple regulatory bodies.

Challenges in gathering label approvals
To attain regulatory approval for labels in countries where trials will be conducted, the majority of pharmaceutical manufacturers today will print out a sample label and fax it to the appropriate regulatory agency. Each country’s quality assurance representative then reviews the label and approves or denies it. If a label isn’t approved, the pharmaceutical manufacturer and regulatory representative work together—faxing labels back and forth—until requirements are met and the label is approved.

Once approved, the country’s regulatory representative signs a form and faxes it back to the manufacturer, who in turn manually marks the label in their system as approved—it can now be used for packaging. The pharmaceutical manufacturer then stores physical files of the approval request and signed approval form.

While simple on the surface, the fax-based approval process is time-consuming and prone to errors, creating a pile of papers to be shuffled from location to location, physically or via fax lines. A mix-up in the paper trail can delay the label approval process, which can affect a manufacturer’s bottom line by delaying time-to-market. It can also be difficult to track a label’s approval status once a request has been faxed. Similarly, a faxed request has no trigger requiring a review, running the risk that a faxed request may sit unattended—or be lost in the shuffle—until the manufacturer calls the appropriate pharmaceutical representative in that country to follow up.

Clinical trial labeling and alternatives
As an alternative to the fax-based approval process, a growing number of pharmaceutical manufacturers are exploring the benefits of Web-based label approvals, with sample copies and final approvals gathered and handled electronically. For manufacturers and approval groups, Web-based approvals offer a simple alternative that speeds the approval process and transmits secure, accurate label versions among all parties involved in the approval process.

Using Web-based clinical trial management systems such as Rockwell Automation’s RS PMX CTM software tool, drug companies can design a label, designate countries to receive a label proof and e-mail approval requests simultaneously to all appropriate approvers worldwide.

Once an approval request has been sent by a clinical-trial management system, reviewers from each country simply click a hyperlink that directs them to a secure Web page. After logging in with a user name and password, the reviewer can view the customized label design and instantly approve (or deny) the label. Using his or her user name and password as an electronic signature, the reviewer’s comments are recorded and sent via e-mail to the initiator. The Web-based software displays a status column showing which reviewers have approved the label and a complete history of label development and revisions.

Benefits of Web-based label approvals
Obtaining approvals electronically makes the process easier for the approver and the initiator, and eliminates the risk of mismatched approval information. The label approval process is completely integrated and accurately tracks all activity for each label. If a pharmaceutical manufacturer plans to conduct German clinical trials on 10 different drugs, Web-based software can track each label through each phase of the trial and approval process. Pharmaceutical manufacturers can assign a language and label layout to each subject, so any specific labels can be dynamically updated to match each subject’s record.

More secure than the traditional fax method, Web-based label approval helps ensure that only the intended eyes see trial labels. The system provides electronic signatures and audit trails that are compliant with FDA 21 CFR Part 11 in the United States. Furthermore, the Web-based approach adds an extra layer of protection for drug safety, because the system will not print labels until it receives approvals from regulatory representatives within the pharmaceutical company.

Maintaining an archive of approved labels in the Web-based system is limited only by the size of the electronic database and server space, and additional databases and servers can easily be added. Saving time and improving costs, such systems provide benefits that grow exponentially, often depending on the number of clinical trials a drug manufacturer conducts and how many countries are involved in trials. In general, manufacturers can expect Web-based systems to improve efficiency by up to 400 percent.

Outlook for clinical trial labeling
Though Web-based approval solutions have been available for years, many companies have focused on getting other systems online, and pharmaceutical manufacturers haven’t yet made a full-scale shift to the process. Those companies that have invested in Web-based approval software solutions are already realizing significant time and cost savings using software to submit approvals as well as design, track and archive clinical-trial labels.

In an industry where documentation and organization are paramount, using a clinical-trial management system for Web-based approvals looks to be a logical approach to quickly, securely and conveniently obtaining clinical-trial label approvals.

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About The Author

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Martin Dittmer and Brooke Cox

Martin Dittmer is the life sciences industry commercial marketing manager for Rockwell Automation. He has a decade of experience in the design, implementation and deployment of global enterprise management solutions for the life sciences industry. Brooke Cox is a life sciences application engineer for Rockwell Automation and has helped provide the world’s top pharmaceutical companies with solutions for improved cost competitiveness throughout the product cycle. Cox received the Rockwell Automation superior leadership award for her efforts in leading the company’s Web-labeling functionality efforts.