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  5. Guidance Recap Podcast | E19 A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-approval or Post-approval Clinical Trials
  1. Guidances | Drugs

Guidance Recap Podcast | E19 A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-approval or Post-approval Clinical Trials

Thank you for joining us for another episode of the Guidance Recap Podcast. The Guidance Recap Podcast provides highlights for FDA guidance documents straight from the authors. My name is Kylie Haskins, and I am the host for today’s podcast. In today’s episode, I am excited to be talking with Dr. Mary Thanh Hai, the Deputy Director for Clinical Science in CDER’s Office of New Drugs. She will be sharing some thoughts with us on the newly published final guidance titled, “E19 A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-approval or Post-approval Clinical Trials.” Welcome, Dr. Thanh Hai! Thank you for speaking with us today.

Podcast

For listeners less familiar with this topic, what is selective safety data collection and how can it be useful in drug development?

Selective Safety Data Collection, or SSDC, is essentially the purposeful planned collection of certain types of data in a clinical trial, based on a thorough understanding of a drug’s risk profile, and what data should be collected to meet the study objectives while ensuring trial participant safety. The focus is on relevant safety data. If some information doesn't add to our understanding of safety in the clinical investigation, it should not be collected. But this doesn't mean patients are not carefully monitored or that safety is ignored; safety data are still gathered judiciously. It's about making clinical trials more efficient by customizing the approach to safety data collection. This can be particularly helpful in large-scale efficacy and safety trials with many participants and long-term follow-up. It's crucial to understand, though, that in SSDC, we never compromise on participant welfare.

This guidance was developed from an ICH guideline. What is ICH, and what prompted the development of the E19 guideline?

The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use, or ICH, is a global initiative with the goal of bringing multiple drug regulatory authorities and the pharmaceutical industry together to establish global regulatory standards that achieve greater harmonization worldwide to streamline the development, registration, and maintenance of effective and safe medicines.

The development of the E19 ICH guideline was prompted by FDA, which had previously issued a guidance on SSDC in late-stage and post-approval trials in 2016. FDA proposed the development of an ICH guideline on this topic because drug development and clinical trials are conducted globally and application of the principles of SSDC in the 2016 FDA guidance would require adoption by other regulatory agencies. Global endorsement of SSDC by multiple regulatory agencies and industry representatives facilitates how these trials can be operationalized.

What was FDA’s role in the development of the ICH E19 Guideline?

FDA played a pivotal role in the development of the E19 guideline. FDA proposed the concept topic of developing an ICH guideline on SSDC, which was then endorsed by the ICH assembly. Next, an expert working group was convened of which I was designated the Rapporteur.

As the Rapporteur, I led the scientific discussions of the expert working group, ensuring that different opinions across many ICH participants were considered to help reach alignment. The expert working group consisted of representatives from each ICH regulatory body and also members from the pharmaceutical industry. Together we worked on developing E19 guideline, which was a labor-intensive 5-year process that went from the issuance of the draft form of the guideline, to receiving and responding to public comments, to the publication of the final E19 Guideline in Sept 2022. Development of the guideline was a lengthy effort and required a subset of the expert working group members be assigned key roles supporting the development process. Of these roles, in addition to Rapporteur, the topic lead and the project manager were from CDER, and the deputy topic lead was from CBER.

FDA subsequently published the E19 guidance. What are the objectives of issuing the E19 Guideline as FDA Guidance?

The final E19 ICH Guideline was published in September 2022. After its publication each regulatory agency begins its process for implementation of the ICH Guideline. FDA published the E19 guideline as a final FDA guidance on December 5, 2022, signaling the Agency’s implementation of the principles of SSDC outlined in the E19 ICH guideline. Since then, other regulatory agencies have also implemented E19 in accordance with their respective procedures. Each regulatory agency’s implementation of E19 fulfills the objective of endorsing and promoting international harmonization of SSDC processes.

What is the scope of the E19 Guidance?

FDA’s E19 guidance mainly focuses on the selective collection of safety data in interventional clinical trials, particularly in the post-approval setting, though it can be considered in pre-approval situations as well. It's important to note that this guidance isn't meant for gene therapy or rare/orphan disease clinical trials, where comprehensive data collection is essential due to the limited availability of participants or novelty of the intervention.

How does the E19 Guidance ensure the safety of trial participants?

Safety in trials under SSDC is ensured through several measures. Only trials where there's a substantial understanding of the drug's safety profile should be considered for SSDC. Additionally, SSDC doesn't reduce the responsibility of trial and healthcare administrators to monitor participant safety rigorously to ensure patient safety. Lastly, it’s important to remember that SSDC is a prospectively planned approach, agreed upon with regulatory authorities after careful evaluation of benefits and risks, with clear protocols for handling safety concerns. And it is important to note that since there is ongoing monitoring throughout the conduct of a clinical trial, should unexpected events occur, conversion to a more comprehensive safety data collection can be implemented.

In what situations can SSDC be considered?

The guidance discusses several circumstances where SSDC might be considered. The first is in post-approval settings for drugs seeking new indications. This is particularly relevant if the new population is similar to the one previously studied. For example, if a company wants to evaluate an approved drug with extensive pre- and post-market safety data in a new population because there is evidence that it could help this population, FDA will consider how much data is available for the new population in the original studies. If there are a lot of data in the original studies, then using an SSDC may be considered, but if the original studies do not have much safety data in the new population, then SSDC is likely not appropriate.

SSDC can also be considered is in pre-approval settings. However, this decision involves more discussion with the Agency. If there's already extensive safety data available for the drug seeking approval or a thorough understanding of risks associated with the drug class, it might be possible to scale back on routine safety tests like EKGs and some blood tests if it’s deemed this information is not necessary for safety monitoring, which could reduce the burden on patients, study site personnel, and sponsors.

When is a drug's safety profile considered well understood?

There are a variety of factors that contribute to determining whether a drug's safety profile is considered well understood. If the drug is already approved, that’s a strong indicator it might be considered well understood because the safety profile was reviewed and deemed safe enough for the approved population. Other factors include the similarity of the new population to the approved population, insights from post-marketing reports, and a thorough understanding of the drug’s mechanism of action, how it is metabolized, eliminated from the body, impact of different levels of organ function – such as kidney impairment - and drug-drug interactions.

What are possible approaches to implementing SSDC in a clinical trial?

There are several approaches to implementing SSDC in clinical trials. Sponsors can conduct selective data collection for all patients, they can conduct a combination of comprehensive and selective data collection for different patient populations or subsets, or sponsors can start with comprehensive data collection and then switch to selective data collection after meeting certain predetermined safety criteria. These approaches can be flexible but need to be well-planned and clearly described in the protocol to obtain agreement from regulatory authorities.

What are key considerations before implementing SSDC?

Key considerations before implementing SSDC include understanding the potential impacts on patients, trial conduct, data analysis, and interpretation. It's essential to discuss the feasibility and plans for implementation with regulatory authorities in advance and reach an agreement on the approach. Sponsors should be aware of potential disadvantages of SSDC, such as the inability to explore certain questions retrospectively because certain safety data were never collected, and challenges that might arise if safety concerns necessitate a change in the monitoring approach during the trial.

Do you have a sense for why a sponsor might or might not consider implementing SSDC?

A sponsor might consider SSDC for a variety of reasons, including streamlining the clinical trial process, reducing costs, and lessening participant burden. However, they might also be hesitant due to concerns about possible complexity of implementation, regulatory acceptance, and the potential need for more detailed monitoring if new safety issues arose. Ultimately, the decision to implement SSDC depends on the drug's safety profile, the stage of development, and the specific context of the clinical trial.

For our final question, what are a couple of key items that you would like listeners to remember?

Drug development is a lengthy process that collects data over the lifespan of a drug where knowledge of benefits and risks evolves over time. Getting important safe and effective therapies to market is costly and the evidence to support approval is patient-derived, placing a demand on their time and commitment to trial participation. It's in this context that streamlining safety data collection to information that is necessary will facilitate the conduct of clinical trials designed to answer important scientific questions about many therapeutic interventions. The goal of SSDC is to focus on what matters most in order to bring safe and effective treatments to market.

Dr. Thanh Hai, thank you for taking the time to share your thoughts on the E19 guidance. We have learned so much from your insights on this document. We would also like to thank the ICH expert working group for developing the E19 guideline and FDA for subsequently publishing the E19 guidance.

To the listeners, we hope you found this podcast useful. We encourage you to look at the snapshot and to read the guidance.

 
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