Jean Hosutt, Ph.D., Director, Medical Regulatory Writing Clinical Document Development: Planning for Accelerated Timelines clinical document development Active planning is required to facilitate the partnership between the sponsor and medical-writing contractor resulting in a report that achieves the required goals. With the current industrywide focus on compressing the timeframe for new drug development, there is increasing pressure to shorten the timeline from the last patient’s last visit to the submission of the NDA/CTD. Regardless of how protracted the data-collection process in Phase III may have been, there is almost always a desire to make up time during the reporting phase. For most drug-development programs, the rate-limiting step in this process is the production and finalization of reports for one or more pivotal efficacy and safety trials. As the foundation of the CTD pyramid, these clinical study reports (CSRs) provide the basis and focus for the integrated summaries of clinical efficacy and safety, the benefit/risk assessments, and clinical overview documents supporting the draft labeling. Although it is technically possible to produce a submission within a few weeks of the last patient’s last visit, the acceleration plan should not underestimate the thought and effort required to produce high-quality CSRs that reflect all of the key efficacy and safety messages of the study agent. Acceleration of the clinical study reporting process requires strategies to facilitate the rapid production, review, and finalization of the clinical study report without sacrificing quality or compromising the message. Further, since clinical reporting services, including medical writing, are often outsourced, active planning is required to facilitate the partnership between the sponsor and medical-writing contractor resulting in a report that achieves the required goals. Planning/Information Gathering To achieve accelerated production of the CSR, it is necessary to keep as much of the report-writing process off the critical path as possible. Shell documents comprised of complete introductory and methods sections and a detailed outline of results — including in-text table formats — can be developed, reviewed, and even signed off before database lock. Up-front planning is important to identify specific issues and develop a consensus among the review team as to how to parse the various elements into the structure/headings of an ICH report. Although these issues may have been addressed to some extent in the protocol, discussion of dose selection, explanation, and justification of nonstandard assessments or the use of surrogate endpoints often need to be amplified for adequate presentation in the CSR. In addition, there may be specific aspects of study conduct that are not described in the protocol or not described in sufficient detail to be considered unambiguous. This may be of particular importance in the case of critical endpoints that were not collected during the in-life phase of the study, for example data collected during off-site, independent assessments, adjudication processes, or other specialized core laboratory assessments. Descriptions of scoring algorithms and other mechanisms of data transformation may require clarifications that go beyond what was presented in the protocol or statistical analysis plan. Additional descriptions also may be required when new techniques or therapies are involved or if the sponsor has concerns regarding the clinical orientation or specific expertise of regulatory reviewers. Review and Revision Process In light of the challenges involved in producing a complete, accurate, and message-driven report in an accelerated timeframe, the review team should be chosen carefully. Even in large pharmaceutical companies, a given project team may lack experience or institutional knowledge regarding production of pivotal study reports and NDA/CTD summary documents. Limiting the review team to those who have the most experience and/or those who can provide definitive input for their particular functional area — for example, biostatistics, safety/pharmacovigilance, and so on — can greatly increase the efficiency and productivity of the review and revision process. It is also critical to make sure that the right reviewers are involved at the right stage. The review process also can be expedited by designating a single reviewer as the arbiter of purely format and/or style issues. Finally, there should be one member of the review team who is acknowledged as the final decision-maker. This becomes particularly important in the case of unexpected findings or marginal results, in which case the CSR can turn into a working document through which the project team obtains consensus as to what to say about the data. Another critical function of this individual during the final review stage is to prioritize reviewer comments according to those that do and those that do not need to be addressed. Planning for Publication Once the NDA is filed, planning for product launch becomes the next critical process. Since the ultimate success of a drug-development program will be determined by its impact on clinical practice, it makes sense to consider the publication process/plan while developing the CSR. A thoughtfully written CSR can function as the springboard for publications that will reach the true target audience: the practicing medical community. BioCor, Yardley, Pa., is a benchmark clinical research organization that specializes in clinical-data services and consulting to support Phase I through Phase IV programs from clinical plan design to defense of global regulatory submissions, serving pharmaceutical, biotechnology, medical-device, and venture-capital companies worldwide. For more information, visit biocor.com. June 2005 VIEW on Clinical Services

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