Long ago, the concept of outsourcing clinical studies began to trend within clinical research and today, has become a customary business strategy that is widely accepted and routinely adopted within the pharmaceutical industry. Although a sponsor is permitted to transfer any, or all, the study-related duties and functions to a third-party, responsibility for the quality and integrity of the content (i.e. documents and data) ultimately resides with the sponsor1.
Content generated by the outsourced organisation is legally owned by the study sponsor (the organisation that paid for the study activities). However, it is not uncommon for questions regarding research content ownership, handling, transfer, retention and destruction to be overlooked, become an afterthought at study closure, or to even be controversial.
It is therefore important for sponsors and CROs (indeed all research partners) to define content expectations and deliverables within contracts and agreements, ideally prior to study start-up. Not only will this help ensure completeness, consistency, currency, and compliance during the conduct of the study, but also throughout the duration of archiving.
With the recent publication of guidance documents from the MHRA2, FDA3, and WHO4, data integrity has been at the forefront during inspections. What is not always noted about these guidance documents is that they require integrity to be maintained throughout the document lifecycle i.e. from creation (or capture), through processing and management, and then throughout the archiving period.
There are a number of options available to the CRO at the end of a clinical study.
1. CRO Transfers Clinical Study Content to the Sponsor
At the end of a study, CROs typically transfer all the content generated to the sponsor so that responsibility for their retention rests with them. These handovers, however, are all-too-often predicated on a number of assumptions that rarely hold true. Before transferring this content, CROs and sponsors should consider:
- Whether the sponsor has access to the file format and software required in order to access, read and use the content. The challenge is to migrate and convert the content into a format that allows for long-term access and readability.
- The impact of migration on integrity. Migration and (where necessary) conversion, risk the loss of metadata especially in relation to raw data which post-migration or conversion may be of questionable and limited (if any) evidential value or legal weight.
- The extent to which having access to original raw data may be critical in the event of regulatory findings and/or to support or refute contentions in legal actions. This applies to both the CRO and the sponsor.
- The need to protect confidentiality e.g. personal information in relation to patients or subjects will need to be anonymised, redacted, or otherwise deleted.
- The preservation of commercial interests. Raw data is the foundation of intellectual property and its protection. It is also expensive to conduct clinical research and so preserving robust, reliable and trustworthy content over time enables organisations to have ready access to historical content that:
- Proves the science/research.
- Provides valuable knowledge and experience accrued during study conduct that are of benefit to scientists and researchers in planning and conducting future research projects.
- Potentially removes or reduces the need to repeat research efforts.
2. CRO Retains Clinical Study Content
At the end of a study, the CRO might decide (or the sponsor might request the CRO) to retain the content generated during the conduct of the study meaning the CRO has responsibility for its continued retention.
The added value of this approach is that it guarantees the integrity, accessibility, readability and usability of the content but there are several practical considerations, among them the need to have written agreements:
- That the CRO will retain the content for the retention period required by the sponsor, which may exceed the legal or regulatory requirement.
- That the CRO will permit the sponsor and regulatory inspectors to have [direct] access5 to the content when required.
- Regarding stewardship, accountability and responsibility (unless these are unambiguous, misunderstandings and regulatory non-compliance may arise, particularly in relation to integrity and ready accessibility).
- That appropriate support can be provided in the event of regulatory inspection, lawsuits or disputes over intellectual property (especially access to original documentation and raw data).
- Regarding responsibility for the ongoing costs associated with long-term archiving and/or preservation.
In relation to the archiving of digital content, consideration must be given to the suitability of the application used to “archive”. It’s crucial that a CRO considers the below factors if planning to hold on to the data after the trial has finished.
Firstly, up until the point of handover or archiving, the CRO will have used applications that function as a repository for content authoring, review, approval, collaboration, verification, analysis, interpretation and day-to-day management during the conduct of the trial. Once the trial is concluded and the content is no longer active, none of that functionality is needed or relevant. Indeed, having large volumes of inactive content in these repositories potentially slows and clutters these applications.
Secondly, leaving the documents in the applications in the diverse range of technologies in which they were generated (e.g. Clinical Trial Management Systems, Clinical Data Management Systems, Pharmacovigilance Safety Databases, Electronic Data Capture applications, Clinical Data Analysis Systems, Interactive Voice Response Systems, Laboratory Information Management Systems etc) creates a fragmented environment. Each of these applications will require individual active management on an ongoing basis and their retention must be harmonised. That management relates not just to ensuring the viability of the content, but also the ongoing continuity of [licences for] the applications and any storage limitations (especially for some laboratory equipment).
Lastly, it is highly unlikely that these applications are able to actively preserve and guarantee the integrity, accessibility, readability, and usability of the documents and for the required 25- or 30-year retention period7,8.
3. CRO Transfers Copies of Clinical Study Content to the Sponsor and CRO Retains the Original Study Content
Although this option may appear to present a solution to the aforementioned issues, in reality it is a poor option because the same considerations apply. A real downside of this approach, of course, is that it creates a mass of duplication that becomes doubly burdensome to manage.
4. CRO and Sponsor Agree to Transfer Clinical Study Content to a Third-Party Digital Preservation Application
The benefit of using a third-party digital preservation application – such as Arkivum – is that this will address most (if not all) the issues above by capturing content into a single searchable repository:
- In native format to ensure integrity, immediate access, usability6, and analysis needed for operational and inspection purposes.
- In preservation format (mostly automatically) for summary and reporting purposes and to ensure long-term viability for archiving purposes.
The focus of most organisation’s archiving policies is on retention rather than ownership, the latter being rarely if ever addressed. GXP regulations permit the outsourcing of archiving. Outsourcing the archive does not confer a transfer of ownership but is an indication that both CRO and sponsor regard the third-party archive provider as the custodian of the archive. This not only satisfies any potential disputes regarding ownership, but also enhances inspection preparedness and readiness by better controlling content, better ensuring that archived content is preserved in a format that is compliant with integrity requirements, and better ensuring that content is readily available to all who require access.
If you’d like to discuss your requirements in more depth, please contact us today.
|1||MHRA Good Clinical Practice Guide 10.7.7|
|2||MHRA Guidance on GxP Data Integrity|
|3||FDA Data Integrity and Compliance With Drug CGMP (Questions and Answers) Guidance for Industry|
|4||WHO Technical Report Series No. 996, 20 Annex 5|
|5||EU Directive 2005/28/EC § Chapter 4, Article 17 & Article 20 | EudraLex Vol 10, Chapter 5 § 6 | 21CFR211.180 | Regulation (EU) No 536/2014 Art 58|
|6||EMA/15975/2016 Guideline on GCP Compliance, March 2017|
|7||Regulation (EU) No 536/2014 (57)|
|8||Regulation (EC) No 1394/2007 & EMA Guideline on GMP for ATMPs, Nov 2017|
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