Adaptive Clinical Trials and the TMF
January 9, 2013
- eTMF Resources
Since the FDA published “Guidance for Industry: Adaptive Design Clinical Trials for Drugs and Biologics” in February 2010, the pharmaceutical industry has viewed adaptive trials as providing a methodology to run studies that are more efficient, more likely to succeed in meeting their objectives, and yield improved understanding of a treatment’s effect. A November research report conducted by Industry Standard Research found that “91% of respondents indicated adaptive trials are gaining momentum within their organization”* .
Though adaptive trials continue to spur considerable industry dialog, with companies examining their R&D processes and discussing the incorporation of these trial designs into their permanent practices, there has been very little discussion around requirements for support of adaptive clinical trials in eClinical systems.
In this posting, we’ll look at how an adaptive trial may impact a paper or electronic Trial Master File.
Planning for Documentation to Support an Adaptive Trial
Due to the nature of adaptive trials, additional documents will need to be added to every study to ensure the clarity of the trials. Documentation is important to any clinical trial, but careful structuring and enhanced information to provide clarity on trial design are essential in the early stages of an adaptive clinical trial. Since many documents such as protocols, Statistical Analysis plans, etc. will change compared to those used in standard trials, often new document templates must be developed and authors trained on their use.
It’s likely that new documents will be required for adaptive trials. For example, trial simulations are usually required for adaptive trials, and should be fully documented in a report, including an executive summary, a background of the trial, design features, design models, evaluations of proposed adaptions, types of simulation tools, and sponsor contact information. To maintain data integrity (minimize operational bias), some details of the adaptive design may best be deferred to IRB and SAP supplements to be included in the TMF as additional, blinded documents.
For a paper TMF, the trial Table of contents must be updated to include the new documents. eTMF software will need a mechanism to manage the new documents. Preferably the eTMF will prompt for the documents automatically based on the identification of the trial as adaptive.
The Need for a New Committee and its Corresponding Documentation Set
According to the FDA’s “Guidance of Industry: Adaptive Design Clinical Trials for Drugs and Biologics”, “the role of monitoring a study’s conduct and addressing its issues is a separate role from the Data Monitoring Committee (DMC) will have if it is used to implement a prospective adaption plan”. Instead, the FDA proposes that an independent and external DMC steering committee should be created as an organization blinded to interim treatment results and therefore able to decide to alter a study design. This committee will encompass monitoring responsibilities in addition to those responsibilities related to the adaption, and will have an ongoing role throughout the adaptive trial.
In addition to the plans of conduct for an adaptive clinical trial, all analysis, results, modifications, and decisions discussed or created by this new committee should be wholly and clearly documented. The normal documentation such as charter, member list, etc. must also be collected for this committee.
eTMF Changes at Trial Adaptation
When the adaptation occurs, the TMF must be updated. Therefore, a sponsor should have a predefined list of new, updated, or amended documents that are needed for each potential adaptation. Aspects of a study that may result in a revised or new document could vary due to the nature of the adaptation: for example, adjusted study duration or readjusted sample size. Both examples might affect dependent study items, such as monitoring visits, study plans, study milestones, enrollment goals, statistical progress, and overall study events.
Because of this need for strict and all-encompassing documentation in adaptive clinical trials, there should be comprehensive written Standard Operating Procedures (SOPs) outlining who will implement the interim analysis, who will implement the adaptation plan, and who will monitor all study-related procedures regarding an adaptive implementation. These will be more complex than of SOPs for standard trials.
Interim Analysis Means Special Security Requirements
Strict security requirements must also be in place for adaptive clinical trials. Whether it be through blinding external DMC meetings, blinded interim analysis, or through enforced written minutes of all committee minutes, security regarding the study should be upheld. As stated by the FDA:
“Shielding the investigators as much as possible from knowledge of the chosen adaptive changes is important because knowledge of the interim unblended data used to make the adaptation decision, or even knowledge only of the specified adaptive choices, has the potential to introduce operational bias into the treatment-effect estimates”.
Therefore, documents that reveal significant information about interim results and analyses, such as external DMC committee minute meetings, must be treated as having the potential to unblind a study.
With the pharmaceutical industry’s embracement of adaptive clinical trials, it’s important for sponsors to understand the implications this trial type will have in managing TMFs. Here are a few key steps in the preparation of a TMF for adaptive clinical trials:
- Identify new artifacts and their proper location within the eTMF/ paper TMF
- Update the document templates and train authors on the new document format
- For each trial adaption, a specific list of new, modified or amended documents is identified, and the eTMF must be able to handle these in-progress adaptions
- Determine whether business processes and eTMF security configurations are sufficient to safeguard blinded documents in order to preserve trial integrity
- Update all SOPs for processes specific to adaptive trials
In order for adaptive clinical trials to truly become successful in a TMF, the TMF itself must mirror the trial’s flexibility, and the best way to accomplish this is to be prepared as a sponsor; Being armed with proper documentation steps, enforced security requirements, and strict SOPs are all important ways to ensure an easy and effective integration of the trial into an existing TMF.