Common Technical Document Development

Pharmaceutical and biotechnology companies are finding new innovative approaches to partnering with clinical research organizations (CROs) in order to add expertise to their internal team. In particular, smaller firms are collaborating with CROs in an effort to gain efficiency and cost effectiveness.¹ Typically, smaller firms have outsourced a higher proportion of their total clinical research portfolio in order to obtain expertise that falls outside the scope of their core capabilities.² Successful CRO partnerships can enhance the clinical development process and drug development companies recognize that speed-to-market is essential to gain advantage over their competitors.

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One particular area where smaller firms typically depend on CROs is with Common Technical Document (CTD) development. Regulatory submissions are fraught with obstacles to meeting the submission deadlines, but challenges can be anticipated and creative solutions implemented to ensure success. A CRO's experiences with previous regulatory submissions provides historical knowledge of potential pitfalls while offering the sponsor quick resolution to unforeseen barriers (Figure 1).

Figure 1. The partnership process generally goes through four stages.

Defining expectations

The first step of the partnership is to clearly define the study-specific information and scope of work between the CRO and the sponsor. This can be easily accomplished using a detailed questionnaire that captures relevant information from each study that will be included in the CTD submission (Table 1).

Studies Included in the CTD Submission

Adequate CTD submission scope descriptions are requested by the sponsor as outlined in the CTD submission checklist (Table 2). The responses provided by the sponsor are essential in order for the CRO to provide a well-defined proposal.

CTD Submission Checklist

CTD submission team development

A CRO should bring experience and expertise that creates a synergistic environment with the drug development company. Communication is critical. After defining the scope of work, the second step is to assemble a qualified CRO team that includes all necessary parties and disciplines. This should include representatives from clinical trial management, data management, programming, biostatistics, medical writing, regulatory affairs, and medical affairs. Key contacts, definitions of roles and responsibilities, escalation paths, hours of availability (including "after hour" contact information) should be compiled, maintained, and shared with the team.

The third step is to identify the larger team including the sponsor and drug development partners, electronic publishing provider, and other partners included in the submission process. Consistent, open, proactive communication between all parties is necessary for successful synergistic partnerships. Weekly conferences (e.g., telephone, video, and web) are necessary for the sponsor, the CRO, and all partnering vendors during the months preceding the submission. In the last few weeks before the submission, daily conferences are often required to ensure on-time completion of each deliverable. This communication is essential because team members typically work in different locations and time zones.

The fourth step is to identify the timelines for each step in the process. Timelines need to be identified for each clinical, data management, programming, biostatistical, medical writing, and electronic publication activity. Examples include the time to complete each planned or in progress study, data conversions (e.g., recoding for data entry, lab data/unit standardizations, etc.), SDTM specifications and dataset development, Define.xml³ document generation, integrated SAP development, and module specific medical writing deliverables. Additionally, publication strategies must be defined and developed. The sponsor must determine if the CTD will be submitted in paper or electronic (eCTD) form. Though more expensive than paper submissions, electronic submissions reduce filing time, shorten regulatory review time, eliminate handling and archiving of large volumes of paper, and allow better document management and version control. This can lead to faster drug approval and speed-to-market.

Each timeline barrier and project risk must be identified early in the process to ensure that appropriate actions are identified and implemented. Appropriate corrective measures must be indentified in advance to minimize the impact to the project timelines.

CRO project management process

Many aspects of a CTD submission can be accomplished in parallel rather than sequentially. Working in parallel ensures achievable timelines for each step of the submission process. For example, the biostatistician can develop the integrated SAP for the Integrated Summary of Safety (ISS) and Integrated Summary of Efficacy (ISE) while the data is integrated into one database by the data management and the programming teams. Define.xml documents are developed after specifications have been completed and in parallel with the SDTM dataset development and ISS/ISE integration. Draft reviews of the SDTM datasets can occur while the biostatisticians develop the SDTM specifications to produce shell tables of the Analysis Data Model (ADaM) datasets in preparation for the ISS/ISE. The primary medical writer can review the integrated draft SAP and, upon SAP finalization, create shell versions of the ISS and ISE based on the pooling strategies and shell TLGs included with the integrated SAP. Once the database is locked, the medical writer can review the draft TLGs and provide feedback to the biostatistician before the final TLGs are produced. Figure 2 summarizes CTD submission activities that can be done in parallel by data management, biostatistics, and medical writing.

Figure 2. The CTD submission activities that can be done in parallel by data management, biostatistics, and medical writing.

In addition to parallel processes, other tasks can be completed early in the submission process. For example, the nonclinical reports can be made available before the clinical data is summarized. The data is forwarded to the publishing vendor and made "submission ready." Product development rationale can be summarized and inserted in Module 2 before final integrated data is available. Each of these examples can shave weeks off the submission timelines because they are performed early in the process or in parallel rather than sequentially.

In the project management process, the team must be prepared for the unexpected and the potential impact on the project timeline. Innovative approaches can be applied to ensure that timelines are met. For example if a medical writing team includes members from the United States and Europe, the average working day can be extended from eight to 10 hours to 16 to 18 hours by partnering writers in different time zones to write and perform QC reviews of each other's work.

Potential pitfalls and solutions

As CTD's are complicated documents, potential pitfalls will arise. Each challenge must be addressed as efficiently and quickly as possible. Table 3 presents an overview of the potential pitfalls and possible solutions.

Pitfalls and Solutions

Sponsor and co-drug development partner's expectations. Drug development costs in 2009 were reported to cost anywhere from $1.3 to $1.7 billion in the United States compared to $802 million in 2003.⁴ Because of these high costs, it is not uncommon for small pharmaceutical companies to collaborate with a drug development partner to co-market their drug. During the eCTD development process, it is essential to gain alignment with each drug development partner when documenting specific submission messaging. Before each key deliverable is finalized, live web conferencing meetings can be held to gain consensus between the sponsor and their drug development partner(s) to ensure agreement in real time. During the web conferencing meetings, the CRO can guide the drug development partners toward consensus.

Vendor management. In the drug development process, pharmaceutical companies may choose to outsource various clinical developmental tasks to numerous vendors. Vendors may include Phase I units, other CROs, publishing vendors, drug supply management, or central laboratories. Roles and responsibilities are outlined for each vendor and their specific contributions during the CTD submission process to ensure successful collaboration. For example, if the CTD is outsourced to one CRO, but another CRO is responsible for writing a specific CSR (planned or in progress study), it is recommended that the medical writing team responsible for writing the submission review each planned or in-progress CSRs that will be included to ensure message uniformity across all documents. Another example might include database consistency as to how the data is captured and reported. If the lead data management CRO receives data from another vendor, the validation of the data may need to be performed to ensure data integration for the ISS, ISE, clinical summaries, and clinical overview. The sponsor plays an integral role in emphasizing the importance of vendor responsiveness when multiple vendors are involved in CTD development.

Legacy data handling. Once it is determined that some of the studies may have been acquired from other companies (legacy data), the CRO will lead the sponsor as to the best approach for legacy data handling. All data received from legacy companies (e.g., datasets, CSRs, etc.) that will be submitted as part of the CTD must be QC reviewed to ensure that the data is complete and accurate as the data is integrated into the submission. This step is imperative to prevent unacceptable datasets, and errant CSRs that may require amendments, both of which may lead to timeline delays in the development of the CTD submission. Determine if each legacy document is available electronically and if so, in what format (Microsoft Word®, Adobe PDF, etc.). Each legacy document must be "submission ready" in preparation for the publication strategy.

SDTM conversions and Define.xml document development. It is recommended that the team produce SDTM datasets and Define.xml documents, and validate those outputs against the same industry standard data checks used by the Food and Drug Administration (FDA). CROs with this experience may supplement the industry standard data checks with custom data checks based on their experience in supporting previous SDTM submissions. These custom checks ensure that there will not be major findings that could potentially result in submission delays.

Regulatory agency expectations. During the drug development process, the governing regulatory agency may propose unexpected late-game changes that may affect the CTD submission process. For example, in a recent New Drug Application submission to the Center for Drug Evaluation and Research division of the FDA, the FDA requested changes in the integration strategy. These changes impacted the data management plan, the SAP, and the integration plans for each CTD module. Although a less onerous pooling strategy was negotiated with the FDA, this development threatened to delay the planned drug submission, which would in turn have had negative implications for the sponsor's strategic goals for its compound. It is important to expect the unexpected and be ready to quickly adapt strategies to ensure an on-time regulatory filing.

Time management. Each department contributing to the CTD submission process must develop and implement measures to ensure on-time delivery of the CTD. For example, the clinical teams can expand site enrollment to finish any studies in-progress ahead of schedule. Data management, programming, biostatistics, and medical writing can complete many of the internal processes in parallel (e.g., database creation, table programming, and Modules 5 and 2 shell document generation); while some processes can only be performed sequentially (e.g., final programming to generate the TLGs used to summarize the final results).

The medical writing deliverables can be staged by delivering the ISS and ISE in Module 5 first, followed by the clinical summaries and clinical overview documents in Module 2 which allows the medical writer the ability to leverage existing text from Module 5. One appointed medical writer can review each clinical summary and overview document to ensure consistent messaging across all CTD deliverables.

Throughout the data management, programming, biostatistics, and medical writing process, if a deliverable is late by one to three days, subsequent departments must absorb the time lost to ensure an on-time regulatory filing. Support by client and vendor management to provide realistic timelines and/or adequate/additional staff is also a key component to an on-time drug submission.

Summary

Pharmaceutical companies and CROs are constantly challenged to improve the efficiency and cost effectiveness of their clinical development processes, especially the speed and efficiency of required submissions to the regulatory agency. This can be especially challenging for smaller pharmaceutical companies as they seek to gain expertise that might fall outside the scope of their core capabilities.

During the drug submission process, success can be achieved by predefining potential obstacles and providing creative solutions to each potential pitfall and challenge. This may include deploying unique approaches to parallel rather than sequential processing of tasks, creating shell documents for each medical writing deliverable, extending the work day by assembling a global team, aggressively managing document reviews in real time via web conferencing tools, and conducting frequent targeted calls with the drug development partners and each vendor involved in the drug submission process.

Communication is imperative to this process; consistent, open, proactive communication regarding project demands, timeline changes, and project issues will lead to a successful and synergistic collaboration between the CRO and the sponsor.

Mary Jane Lunsford* is Executive Director, Global Medical Writing, e-mail: MaryJane.Lunsford@Premier-Research.com, and Thomas Kalfas is Director, Global Biometrics Technical Operations both at Premier Research Group Limited, 3200 Red River, Suite 300, Austin, TX.

*To whom all correspondence should be addressed.

References

1. D. Levin, "Emerging Pharmas and CROs Need Each Other," Applied Clinical Trials Online, September 11, 2009, http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/IT/Why-Emerging-Pharmas-and-CROs-Need-Each-Other/ArticleStandard/Article/detail/664950.

2. Kenneth A. Getz and John R. Vogel, "Successful Outsourcing: Tracking Global CRO Usage," Applied Clinical Trials, 18 (6) 42-50 (2009).

3. Clinical Data Interchange Standards Consortium, "Standards and Innovations," September 24, 2010, http://www.cdisc.org/define-xml.

4. R. Collier, "Drug Development Cost Estimates Hard to Swallow," Canadian Medical Association Journal, 180 (3) 279-280 (2009).