- INTRODUCTION
1.1. Objectives of the Guideline
This guidance is intended to provide internationally harmonized guidance on the use of selective safety data collection that may be applied in specific pre-approval or post-approval late-stage clinical trials. Selective safety data collection refers to the reduced collection of certain types of data in a clinical trial after thorough consideration of factors that would justify such an approach. By tailoring the method and streamlining the approach to safety data collection, it may be possible to carry out clinical trials with greater efficiency. This may facilitate the conduct of large-scale efficacy and safety clinical trials with large numbers of participants and long-term follow-up. In all circumstances in which the use of selective safety data collection is considered, it is important that the welfare of every trial participant is safeguarded.
- Background
A robust safety database is the basis upon which the safety profile of a drug is characterized. Knowledge about a medicinal product’s safety profile continually evolves as safety data accumulates over time. Throughout the course of medicinal product development sponsors collect extensive safety-related data that may include vital signs and other physical examination data, laboratory data, and all adverse events. In specific phase 3 or post-approval clinical trials, if the safety profile of a drug is well-understood and documented, collection of comprehensive safety data may provide only limited additional knowledge of clinical importance. In such circumstances, a more selective approach to safety data collection may be adequate. With the growing complexity and size of clinical trials, it is recognized that a uniform approach no longer applies to all clinical trials. In some instances, a selective, i.e., risk proportionate, approach to safety data collection may be acceptable. This document describes circumstances in which it may be appropriate to reduce the collection of safety data in late-stage pre-approval and post-approval clinical trials, e.g., long term outcome trials, when appropriate and with agreement from regulatory authorities.
- Scope of the Guideline
This guidance is intended to apply mainly to collection of safety data from interventional clinical trials primarily in the post-approval setting. In some circumstances, it may be considered for use in the pre-approval setting.
Pre-approval Setting
In the pre-approval setting, comprehensive safety data collection is generally expected to elucidate the frequency, severity, seriousness, and dose-response of adverse events, including potential differences across subsets, e.g., demographic; medical history; and/or concomitant therapy.
Post-approval Setting
Once a drug has been approved, comprehensive collection of all safety data may provide only limited additional knowledge of clinical importance. In such circumstances, a more selective approach to safety data collection may be adequate as long as the trial objectives and the welfare of trial participants are not compromised.
With limited numbers of prospective participants for such trials, the collection of comprehensive safety data, from every participant, is warranted.
2. GENERALPRINCIPLES (2)
A. Ensuring Safety of Trial Participants (2.1)
Safety monitoring in a clinical trial serves two purposes: (1) to protect the safety and wellbeing of individual trial participants; and (2) to obtain safety information to be used in the assessment of the risk profile of the investigational medicinal product. The selective safety data collection approach described in this guidance refers to the recording of certain data (see section II.E (2.5)) by investigators in case report forms, as well as to their reporting to sponsors for subsequent evaluation and submission to regulatory authorities. Importantly, this approach does not affect the responsibilities of investigators, as health care professionals, to monitor trial participants and ensure they are treated according to prevailing standards of care. Specifically, selective safety data collection does not affect the monitoring and clinical care of individual trial participants or documentation of their adverse events in medical records. Moreover, selective safety data collection does not obviate other reporting obligations of health care professionals, such as safety reporting in accordance with local/regional requirements.
A strategy for sample collection and processing for genomic testing must consider several pre-analytical variables to ensure sample suitability. Variations in procedures across different clinical study sites can influence test performance, affecting data interpretability and reliability. Thus, all staff must be adequately trained in standardized procedures, and specimens should be collected and labeled following biosafety practices, privacy regulations, and informed c
For example, consider a drug where the safety data are well characterized, where hypoglycaemia is a known adverse drug reaction and routine blood glucose monitoring is recommended in labelling. In a clinical trial utilising selective safety data collection, blood glucose should be monitored in the same way it would be monitored in clinical practice; however, the data do not need to be recorded in the case report form or reported to the sponsor as long as they are not stipulated in the protocol and not associated with a serious adverse event. Blood glucose levels and hypoglycaemia would be recorded in the case report form, however, if they are stipulated in the protocol, e.g., as an adverse event of special interest, deemed to be clinically relevant, or associated with serious adverse events. onsent guidelines.
B.Factors That Contribute to a Conclusion That the Safety Profile of a Drug Is Sufficiently Characterized To Justify Selective Safety Data Collection (2.2)
The factors listed below can contribute to the conclusion that the safety profile of a drug is sufficiently characterized to justify selective safety data collection in a proposed clinical trial.
Regulatory Status
1. The regulatory status of the product, i.e., whether the drug has received marketing authorization from a regulatory authority.
Mechanistic Factors
- Understanding of the drug’s mechanism of action; characterization of off-target effects (untoward effects mediated through targets other than the target of interest, e.g., mineralocorticoids and gynecomastia; minoxidil and hirsutism).
- Knowledge of the safety profile of drugs in the same pharmacologic class, e.g., support for selective safety data collection would be stronger for a member of a well-established pharmacologic class of drugs than for a drug that is the only member of its class.
Clinical Safety Database
- The number of drug-exposed trial participants who contributed to the characterization of the drug’s safety. In general, the larger the number, the greater the confidence in the prior characterization of safety.
- The consistency of the safety profile across clinical trials where comprehensive safety data collection was used.
- The intensity of safety monitoring in the previous clinical trials used to characterize the drug’s safety. For example, the number and type of safety parameters monitored (e.g., laboratory measures, vital signs), thoroughness of assessment, and frequency and duration of monitoring can be important.
Similarity of the Planned Clinical Trial to Previous Trials
7. The planned dose and dosing frequency in the proposed clinical trial. In general, the planned dose or dosing frequency of the drug should not exceed what was studied in previous clinical trials used to characterize the drug’s safety.
8. The duration of exposure. The duration of exposure in previous clinical trials should beadequate to support the duration in the proposed trial.
9. Comparability of the drug product (e.g., pharmaceutical form, drug substance, excipients) and route of administration. The drug product and route of administration for the proposed clinical trial should be comparable to those used in previous trials to characterize safety.
10 To ensure feasible selective safety data collection in planned clinical trials, it is crucial that the trial population closely resembles previous trial populations in terms of demographics, health conditions, therapies, and other relevant factors, such as cytochromeP450 CYP phenotype. Disparities, particularly in age or health status (e.g., renal impairment or increased cardiovascular risk), may result in greater susceptibility to adverse drug effects, complicating safety assessments.
Clinical Pharmacology
11. Drug-drug interactions have been well characterized.
12. Drug metabolism and excretion are well described and understood.
13. Nonclinical toxicology data have been well characterized.
Post-authorization Data
14 Quantity and quality of post-approval safety data. Sufficiency of data is related to several factors, e.g., duration of marketing, number of participants exposed, method of data collection.
CBaseline Data (2.3)
Use of a selective safety data collection approach does not change considerations for baseline data collection determined by the clinical trial objectives. Baseline data are essential to ensure that prospective trial participants are eligible for trial enrolment. Furthermore, baseline data are needed for assessment of efficacy and safety in subgroups based on, for example, demographics, baseline disease characteristics, concurrent and previous illnesses, and concomitant therapies.
D. Data That Should Generally Be Collected (2.4)
In line with ICH guidance’s E2A and E6, an adverse event is defined as any unfavourable and unintended sign, symptom, or disease associated with a medicinal product, regardless of its relation to the product. A list of generally recommended data elements for collection is provided, though it is not exhaustive.
- Serious adverse events (see ICH E2A; ICH E6)
- Important medical events (see ICH E2A)
- Medication error/overdose (intentional or unintentional)
- Adverse event that led to study drug discontinuation
- Pregnancy and lactation exposure and outcomes
- Adverse events of special interest, including laboratory abnormalities, identified in the protocol as critical to safety evaluations.
A selective collection of some of the aforementioned data may be taken into consideration in certain places if permitted by local or regional rules and backed up by sufficient justification in the protocol.
Serious adverse events that are deemed safety or effectiveness endpoints should be prospectively agreed upon with the regulatory authority or authorities and detailed in the clinical trial protocol. These events would not be subject to unblinding and expedited reporting (see ICH E2A). An impartial data monitoring committee set up by the sponsor shall be in charge of regularly gathering and observing them (see ICH E6).
The entire text of ICH E19 could not be presented in this article due to space constraints. To properly grasp,A SELECTIVE APPROACH TO SAFETY DATA COLLECTION IN SPECIFIC LATE-STAGE PRE APPROVAL OR POST-APPROVAL CLINICAL TRIALS E19it is advised that you read the entire guideline. The link is provided below
Reference:
https://database.ich.org/sites/default/files/E19_Guideline.pdf
–Dr Subramanian S Iyer
