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Finding a strategic approach to writing clinical study reports.
As you may have read in Robin Whitsell’s, “RESCUE Medical Writing,” in Applied Clinical Trial's April issue -“An experienced medical writer will employ certain techniques to make even the messiest situations provide meaningful CSR [clinical study reports].” The following case study reveals that while the hefty data and information required for a CSR may be discouraging, where there’s a strategic approach there’s potential for a completed study report.
Case Study: Out of bounds
Company C had data from a large Phase II study from a foreign partner that they wanted to summarize and file to their IND. Though the study was run under GCP circumstances using an analogous demographic that Company C planned on targeting, the protocol itself was not written to incorporate ICH principles or standard formats.
A draft clinical study report (CSR) provided by the foreign partner was also not in the ICH recommended format.
Findings. The writer discovered that certain sections of the protocol and draft CSR missed components required to make these documents compliant with ICH guidelines. Among the potentially missing data were the elements of demographics (Section 10 or Section 11 of the CSR), specifications for the statistical plan (Section 9), and specifications for the randomization code and treatment compliance (also found in Section 9).
Though the demographics data appeared to be well-organized, it seemed somewhat incomplete for the subject population that Company C was targeting.
It was unknown whether protocol deviations had been tracked. Whether the randomization code had been appropriately implemented was also questionable.
Though there had been no prespecified Statistical Analysis Plan, the Company believed their partner did have a prospective statistical section. They thought this plan had been filed as an addendum to the protocol though they were not certain if a translation of this had been provided. Much of the information on how the study had been implemented had not been translated into English.
Solutions. In March 2001 FDA finalized a guidance document specifying that foreign clinical studies were acceptable for submission-even if they were not conducted under an IND-if they conformed to whichever gave the human subject greater protection: the ethical principles outlined in the 1989 version of the Declaration of Helsinki or the local regulations of the country where the research was completed.
The keys to resolving the issues with this CSR were:
-Evaluating the sum of the information to determine if enough information was available to create a CSR and summarizing what was incomplete (or not translated)
-Communicating with Company C about the missing information and if it was available from other sources or if translations could be obtained
-Strategizing how to present the foreign partner’s data in a CSR format that reflected ICH guidelines.
Fortunately, Company C’s foreign partner was willing to translate their study manuals and supplemental study forms. Between the supplemental forms and the protocol, the missing statistical plan emerged.
Though protocol deviations had not been tracked in the case report forms, a tracking log had been maintained by study monitors. This log was suitable to complete Section 10.2 (Protocol Deviations) and to be added, in its entirety, to the appendix of the CSR.
Maintenance of the randomization code had also been specified in a separate study manual. It appeared that the study procedures had been strict about randomization and maintenance of the study blind. It also appeared from drug administration logs and PK data, that the level of compliance had been very high. For this particular study and therapeutic area, a more complete subject demographic profile was able to be created by harvesting information from detailed narratives in the physical examination and comment log sections of the database. The final CSR was ICH-compliant and allowed Company C to file a significant amount of safety data and robust efficacy data from a well-controlled clinical trial to their IND.
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