Clinical trials must meet different regulatory requirements at every step of their lifecycle. Perhaps the most impactful of these is the final marketing authorisation process.
Obtaining this authorisation will enable biopharmaceutical companies to provide a new therapeutic avenue for patients – as well as a form to recoup their investment. At this stage, regulatory agencies have a final chance to send back documents for extra clarification, or to raise questions about a product’s safety and efficacy.
The chances of these are minimised by following three basic strategies: first, by ensuring best practices for clinical data management throughout the trial; second, by seeking expert advice from the regulatory agencies themselves; and finally, by working with experts who understand the regulatory nuances of each specific country or region.
Clinical Data Management and Regulatory Compliance
Both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) enforce basic quality standards when it comes to clinical data management. These encompass the entry, verification and validation of all the information gathered throughout the study1.
A solid clinical data management system should also include:
• Automatic time-stamps for each entry
• The opportunity to record any variations done on the protocol, as well as their rationale
• A process to handle missing data
• Built-in mechanisms to ensure the participant’s confidentiality.
The last point often entails going beyond clinical trial regulations: the anonymization of data will need to uphold the standards of either the US’s HIPAA (Health Insurance Portability and Accountability Act) or the European Union’s GDPR (General Data Protection Regulation).
Seeking Scientific Advice from Regulatory Agencies
When trial sponsors need expert guidance on specific aspects of a clinical trial, they can approach their regulatory agency. This opinion, known as Scientific Advice (SA), usually carries a fee, but it is an entirely voluntary step of the marketing authorisation process2.
Possible topics for Scientific Advice requests
A request for Scientific Advice addressed to the EMA, or FDA may involve:
• Specific queries related to study design
• Opinion on the suitability of a trial’s endpoint
• A draft summary of the product characteristics
• Advice on possible new indications for a new drug
• A preliminary review on safety guidelines
• Other non-clinical issues
Application process for Scientific Advice
A request for Scientific Advice will require significant preparations from the Sponsor’s side. First, an initial brief of the overall trial, and its investigational medicinal product, should be prepared. This should be thorough enough to prevent misunderstandings between Sponsor and Agency. An experienced medical writer should verify the brief and all attached presentations before submitting them.
It is possible to approach several regulatory agencies simultaneously with the same question, or to do file a request for joint advice3. However, each request should be clearly defined and narrow in scope: it is not possible to address several issues in one request. In such cases, any new requests will incur an additional fee.
In some cases, the fee for Scientific Advice may be waived, as part of larger incentives for specific types of trials. For example, the EMA waives this fee for any trials involving pediatric and orphan disease indications4.
Advantages of requesting Scientific Advice
A request for Scientific Advice provides a good opportunity to smooth out the trickiest parts of a clinical trial. This will shorten the trial’s total life cycle, enabling patients to access the drug in less time.
At the trial-planning stage, queries on trial design can also be used to better plan the use of resources, estimate budget allocations, and recruit patients more effectively. By choosing more appropriate endpoints, clinical investigators will gain access to more significant data that showcases the possible benefits for patients.
Finally, a Scientific Advice request can often act as an introduction between the investigating team, and the relevant decision-makers within a regulatory agency. Although requesting Scientific Advice does not guarantee that a marketing authorisation will be approved, acknowledging and incorporating its recommendations will strengthen an application.
Enlisting Help from Regulatory Affairs Experts
The final strategy to facilitate an uneventful approval process is to ally with a regulatory affairs CRO that has a good track record with the local regulatory agency.
For this process, it is important to look at their existing relationships with local universities and Key Opinion Leaders who can lend weight to the application. Biopharmaceutical companies who would like to request Scientific Advice services should also be able to approach their CRO for help. The latter can arrange an interview between their medical writer and one of the investigators, or potentially point out the right times in which external advice should be sought.
A close and transparent communication between Sponsor and CRO will also help identify possible challenges ahead of time. In these cases, the CRO can act as a “third eye” that can prevent the possibility of a rejection or a request for resubmission.