Regulatory Considerations for Digitally Driven Trials

Within the domain of clinical trials, the goals of quality by design (QbD) are to assure that the outcome data are fit for their intended purpose and that there is an absence of errors that could impact decision-making. Since all products and services within a clinical trial are subject to regulatory oversight, all sponsors, vendors, and clinical research sites must always be prepared for that knock on the door when your administrator says, as mine said to me a few years ago, “The FDA has arrived and would like to speak to the person responsible for the clinical trial.”

A frequently asked question is what have been the barriers to entry preventing pharmaceutical and medical device companies from widely adopting and implementing paperless and digitally based clinical trials? Ironically, for more than a decade, technologies allowing for paperless and digital clinical trials have been encouraged by regulators. Fortunately, the time has finally come for the transition to a global acceptance by the pharmaceutical industry and regulators of the use of paperless and digital technologies to collect clinical trial data both within the clinic and remotely.

The FDA and others have issued multiple guidance documents addressing the use of digital technology tools when used in clinical trials. Now that the electronic world has finally entered the clinical trials space, as part of routine pre-approval inspections, there must be stakeholder assessments of the impacts of digital systems on 1) informed consent; 2) data collected to determine effectiveness; 3) patient safety by assuring that all safety events are accurately collected and reported 4) data integrity and accountability; 5) protocol compliance; 6) monitoring of the study, including risk-based monitoring; and 7) drug/device accountability etc.

Since digital-based companies have not been routinely subject to FDA laws, rules, and regulations, the following are key elements to be addressed and assessed by these organizations choosing to enter the clinical trials space.

Software validation. The basic goal of software validation is to assure that configured applications act as intended when used in clinical trials. Therefore, when regulators inspect software products, it is critical to document that the trial software applications are validated. Fortunately, starting in 2002, the FDA has provided validation guidelines for software supporting regulated products. For new products hitting the market, an assessment should also be made if FDA clearance of the software would be required through the device 510(k) or PMA regulatory approval routes. For global programs, local regulatory requirements must also be addressed.

Human factors and end-user usability. These are elements that must be considered during development of digital devices for use in clinical trials. FDA has issued a guidance document to assist the industry on how to follow appropriate human factors and usability engineering processes so that new medical devices will be safe and effective for the intended users, uses, and use environments. It is recommended that these studies focus specifically on the user interface, including displays, controls, packaging, product labels, and instructions for use. As part of their design controls, manufacturers must also conduct a risk analysis that includes the risks associated with device use and the measures designed to mitigate those risks.

Source records management. Some of those fully committed to using paper records often ask the question, if a system is fully electronic how do we know that the data are real if there are no paper source records to compare with the electronic record? To assuage some of these concerns, as part of a company’s SOPs, there must be supporting documentation that the vendor has been qualified and that the software is in a validated state. It is also critical that all roles and responsibilities are properly identified, as well as how the original source data are controlled. This includes the presence of date and time stamps for all transactions, and an audit trail of changes cannot be overwritten.

Regulatory pre-approval inspections. One of the first things the inspectors may request is to talk to the head of quality as well as who was directly responsible for the trial. Be prepared to share your organizational chart as it relates to the study and copies of relevant contracts/agreements, although inspectors are usually not concerned about financial matters. The inspectors may also ask for the documents supporting vendor qualifications, software validation/testing, and risk mitigation plans.