| Within the biopharmaceutical industry, one of the most critical tasks in the clinical lifecycle of drug development is the authoring and review of clinical study reports. It is a complex process that involves numerous contributors from various functional areas. It is also a process that has changed significantly in recent years as organizations focus on optimizing the document and submission lifecycle. This is most effectively accomplished through the application of enabling technologies. However, technology alone does not provide the highest degree of efficiency. Process reengineering is the link that connects a new technology to a business problem and provides a competitive advantage.
Input and review of study documentation usually includes representatives from the Medical Affairs, Clinical Operations, Biostatistics, Pharmacokinetics, Regulatory and Quality Assurance areas, at a minimum. Each reviewer evaluates the content from a different perspective, thus, each may require access to numerous pieces of supporting documentation at different points in the review. Once multiple reviewers offer comments, a designated individual usually evaluates the comments, conducts a review meeting and then incorpor- ates combined comments into a new draft. The development of the new draft sometimes signals another iteration of re-view and comment generation. Once the documentation is finalized, it is approved and an "official copy" is secured for future use in regulatory submissions and distributed to appropriate recipients.
The traditional scenario described above is fraught with inefficiencies that have begun to be addressed in recent years through technology advances and process improvements. These changes typically go hand-in-hand as new technologies are employed and processes are optimized to take full advantage of them. The shift from paper to electronic processes in support of clinical study report development usually affects a large group of people with varying roles in the process. These stakeholders play critical roles in the development of efficient, streamlined processes. There are also external factors that impact the move to electronic processes. Two critical shifts in industry have greatly impacted this scenario.
First, the advent and acceptance of electronic document management systems (eDMS) has enabled organizations to transition from paper processes. This transition has required a substantial organizational shift that includes the implementation of new technology, process reengineering, and training in both of these fields. Many companies have spent substantial amounts of money developing and implementing global repositories of study documentation. Immediate, simultaneous access to supporting documentation supports the increasingly global approach that multinational companies must take to remain competitive. In addition, it has also enabled collaborative activities with CROs and licensing partners.
The second shift is the move to electronic regulatory submissions. This initiative has made great strides in recent years and has enabled organizations to introduce electronic processes with the goal of new electronic deliverables. This movement has seen noteworthy progress through the activities of the International Conference on Harmonization (ICH). The development of global standards such as the ICH E3 Format for Clinical Study Reports and the Common Technical Document (CTD) and Electronic Common Technical Document (eCTD) have provided a vision for industry to strive for efficiencies that can be multiplied across regions.
The clinical study report authoring process has been impacted by electronic processes in four key areas: authoring, collaboration, packaging and distribution/access. These four aspects span the clinical study report lifecycle and must be viewed in terms of other integrated processes such as electronic regulatory submissions.
The term "authoring" refers to the creation of content. Changes in electronic authoring processes have altered the way medical writers do their jobs and will continue to evolve as we see organizations looking to XML technologies to support content creation. This technology allows content and electronic links between content to be tagged for use in different contexts. The introduction of XML editors into document-authoring processes will also have a substantial impact on document management and publishing processes.
As document management and electronic publishing systems have been developed and implemented across the industry, the need for standards emerged very early. These standards, such as authoring templates and style guides, provide a mechanism for creating a consistent approach to study report development. Corporate authoring standards are often difficult to enforce, especially across multiple sites and multiple functional areas.
Templates are often designed as report "shells" that provide a framework for authoring. These shells offer consistency among users and can significantly decrease authoring time by providing a predefined structure as well as boilerplate content. Such standards facilitate electronic search and retrieval capabilities and can actually automate later publishing activities. For example, most authors of study reports use word-processing packages to create the text of the report. During the finalization process, the report must be rendered to the current electronic submission format, PDF. In the case when a templated word-processing document is published as a component of an electronic submission, most PDF publishing tools can generate bookmarks in an automated fashion, based on template information. Automatic application of navigation aids significantly reduces the manual effort of applying navigation and maintaining quality control standards. This is particularly helpful as organizations grow and more authors and reviewers share information and contribute to the process.
Electronic processes combined with enforceable standards have also enabled flexibility in developing cross-referencing strategies in preparation for electronic submissions. Tools now enable users to create internal document links as well as cross-document links. Competitive organizations are reevaluating their processes to make sure that appropriate individuals have responsibility for these activities. Influencing factors include the degree of content knowledge required to create accurate links and the degree of automation that can be consistently expected from a tool. Often, the degree of automation that is possible directly correlates to the authoring standards that have been imposed. Many tools offer the user the ability to identify a text string and create a link to a predefined target location for each occurrence of the string. If authors are consistent in creation of text, the degree of automation will increase significantly.
One of the biggest benefits of electronic authoring process is the ability to version documents. Typically this is a function of a document management system that is incorporated into the process to track and manage multiple iterations throughout the document lifecycle. This seems like common sense, but if you have ever experienced the frustration of coordinating reviews of a document where versions weren't controlled and tracked, you know how quickly a simple process can become extremely complex.
Global repositories of supporting documentation have also enabled authors to access information more quickly and efficiently. Most organizations that have put forth the effort and Resources to create a global repository have also developed global processes and standards so that authors are trained on where and how to access the documentation required for writing the clinical study report. For example, an author should have easy access to the original protocol as well as any amendments. These documents are not only used for reference but are also included as appendices to the final report.
The biggest changes in study report creation processes are currently occurring in support of collaborative processes. Most document management solutions provide standard capabilities such as versioning. However, now that organizations have developed architectures that support the storage of the clinical documentation, they are now looking to improve collaboration of team members who are contributing to the development of the documentation. Collaboration tools are sometimes available functions of a document management system but are often separate tools that integrate with an eDMS. The implementation of collaboration tools requires detailed process analysis to determine the most efficient route the information should take throughout the process. Once this is defined, technology can be used in multiple ways to add efficiency. For example, as a review cycle for a clinical study report is developed and documented, an automated workflow process can be defined (often within the eDMS) to routinely route a document for review to a predefined set of contributors or reviewers. Once these recipients access the information and complete their reviews, the document is automatically forwarded back to the originator. If a particular reviewer fails to access the document during the review period, reminder notifications are triggered to ensure that the process is not hindered. This same process may also utilize technology throughout the approval cycles of a document when electronic signature capabilities are implemented.
Collaborative tools also enable simultaneous reviews by providing different views of the information. Some tools provide reviewers the ability to access other reviewers' comments along with the document text. In essence, this allows reviewers to have on-line discussions of the study report text and the ability to note their agreement or disagreement with another reviewer's comments during the authoring and review cycles. This greatly facilitates team reviews because important topics that "bubble up" through the comment period can be quickly captured for further discussion. It also allows the individual coordinating the review to minimize duplicate comments when updating the documentation for the next round of reviews. This parallel review model shaves significant time from the traditional, serial paper review process and promotes early access to information. When these processes are de-ployed in an international setting, virtual teams from all over the globe are able to review, comment and contribute to the process in real time. Some tools also provide views of the original documentation that highlight only the changed portions of the document or provide summaries of changed elements. These views are particularly beneficial during multi-cycle draft reviews since they enable reviewers to focus on the modified content of the report.
These collaborative technologies also facilitate quality assurance and quality control activities throughout the organization. Versioning of draft documents and the ability to view comments and changes to a document in the context of a document audit trail are features that are beneficial to quality assurance reviewers. This document information can be as important to the process as the actual content.
Another key benefit of electronic processes employed in clinical study report development is the ability to associate supporting information with a particular document. This can be implied through a storage metaphor where standards dictate the location for report documentation. However, if an organization looks at the bigger picture of electronic submissions that occur later in the process, they can build efficiencies into the report process. For example, electronic submission standards include various bookmarking and hyperlinking requirements within a report. These requirements facilitate navigation through volumes of information by simply clicking on links that take the reviewer to a referenced point on another page in the document or to a completely separate document. Internal reviewers can benefit from these same capabilities. By inserting links in the documentation prior to internal review, contributors can quickly access supporting documentation rather than conducting searches and questioning the author.
Capabilities exist, but the deployment of the capabilities in a formal process is the key to success. The organization must consider who should apply navigation and links, at what point it should occur, and how automated it can be. This is another example where the opportunity exists for automation but it relies heavily on the development and enforcement of standards.
For electronic submission purposes, the de facto standard for publishing is PDF. The generation of a compliant electronic clinical study report requires the compilation of various components of the report that usually exist in multiple formats (TIFF, MS WORD, ASCII, and PDF). Electronic publishing packages provide the ability to render all the components to PDF. Once all components are in a common format, navigation across components is applied. Additional links to supporting data in other formats such as SAS are also applied. Sometimes the supporting data itself must be converted to a compliant format or a particular version of an acceptable format for submission to an agency. This packaging of the study report and supporting information links report text to corresponding data sets and offers transparent navigation across multiple files.
From a process perspective, most companies have implemented electronic publishing capabilities to support electronic submissions, traditionally within the realm of the Regulatory Affairs function. These capabilities were not initially integrated with contributing upstream processes. Now that the capabilities have been brought in-house, many companies are pushing the electronic publishing function upstream to the contributing departments.
There are several good reasons for this shift. First, internal reviewers can take advantage of the same efficiencies that agency reviewers have seen when accessing, reviewing and navigating through the substantial amounts of documentation associated with a clinical study report. Second, this shift allows for a smoother resource curve and eliminates the spike in resources that is traditionally required to support submission compilation. Reports can be finalized and published for submission months in advance of the submission date. Finally, it offers full accountability for the final report content and format to the subject matter experts. The clinical study report can exist as an entity that can be reused in other submissions and can be stored in an eDMS for future reference before, during and after the submission.
Electronic processes can facilitate the distribution of information across an organization, and can extend that reach to partnering entities. Once content is available electronically, it can be transported to other recipients in multiple methods. The development of portals and electronic document management systems provide targeted, realtime access to critical information. They eliminate the dependencies on traditional paper distribution methods that add significant delays to review process. Time and cost savings can be realized because reams of paper are no longer being shipped across country borders, possibly to be detained by international customs offices. This also mitigates the traditional concerns of paper being incorrectly duplicated, damaged or destroyed.
In order to ensure that only the "appropriate individuals" have access to critical study information, access control lists are defined that assign permissions (read only, write, etc.) to team members. These permissions can be modified based on the status of the information (draft, approved). Access control lists and document statuses must be developed based on a clearly defined process. Otherwise, authors and contributors will be frustrated in their attempts to participate in electronic processes.
Access to particular information can also be modified based on milestones in a project. For example, members of a CRO can be given access to project documentation for the life of the project. Once the project is complete, access can be modified or restricted completely. Procedures must be set in place to review contractor/partner access to study documentation to ensure the security of the environment.
The availability of final study documentation in electronic format does not preclude printing of the information to paper. In fact, many organizations store electronic documentation in PDF format so that their affiliates or partners can access the PDF records to support global paper filings. The electronic access and download of information replaces shipment of paper and all of the delays and costs associated with it.
With appropriate standards in place, pharmaceutical and biotechnology companies can save significant time in the development and delivery of clinical study reports. New tools provide quicker, earlier access to study information, but this access must be focused and managed through well-designed electronic processes. As technologies evolve, processes must also evolve to take advantage of both human expertise and powerful emerging technologies.
Processes must also evolve to integrate with the larger regulatory submission process. As electronic regulatory submission initiatives progress, changes will be required to support new deliverables. Companies that design their clinical study report processes with these deliverables in mind will be well positioned to realize the benefits of the electronic processes across the organization.
How have they changed clinical study report development?
By Monique Garrett
Published August 23, 2005
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