Submitting a Monograph

Any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a proving and which is unexpected and clinically significant should be considered an Adverse Event.

Unexpected symptoms and signs have at least one of the following characteristics:

a) have duration longer than the proving period
b) have clinical severity greater than described in the Informed Consent
c) have clinical severity that falls within the definition of Serious Adverse Event
d) require medically necessary therapeutic intervention,
e) results in removal from the Proving

All AEs should be reported and managed according to the requirements of all applicable regulations and Ethics and Institutional Board Requirements.

A process for determination of likelihood of causation should be established prior to IPS administration.

Report of causation likelihood should be included for all AEs using the following labels derived from the FDA and ICH.⁽¹⁾

a) ‘Possibly related’ meaning there is evidence to suggest a ‘Reasonable possibility’ of a causal relationship between the drug and the adverse event.
b) ‘Unrelated’ meaning there is no evidence to suggest a causal relationship between the drug and the adverse event.

All AEs with a possible causal relationship to the IPS should be reported and managed as possible Adverse Drug Reactions, including:

a) Report to Pharmacopœia Revision Committee (PRC) the following information using standard reporting categorization provided in the International Conference on Harmonization tripartite guidance on Clinical Safety Data Management E2Br (R2)⁽²⁾

1. Report of causation likelihood
2. Report of adverse event timeline and outcome

i. Death: The drug may have contributed to the death.
ii. Not recovered/not resolved: The subject has not yet recovered.
iii. Recovered/resolved with sequelae: The subject recovered, but with an after effect possibly due to disease, injury, treatment, or procedure.
iv. Recovered/resolved: The subject fully recovered.
v. Unknown: The reporter did not know the outcome at the time the report was submitted.

b) Adverse Drug Reactions that potentially change the risk profile need to be reported to the relevant Competent Authority (e.g. FDA) and to the IRB in accordance with applicable regulations. Unanticipated adverse events which create a problem for the conduct of the trial should be reported to the IRB⁽¹⁾
c) Compliance with any applicable regulations
d) Reporting to the Manufacturer.

Serious adverse events are defined by the FDA ^{(3), (4), (5)} as any untoward medical occurrence that at any dose:

a) Results in death
b) Is life-threatening
c) Requires inpatient hospitalization or prolongation of existing hospitalization
d) Results in persistent or significant disability/incapacity
e) Is a congenital anomaly/birth defect
f) Or, requires medical or surgical intervention to prevent hospitalization, permanent impairment or damage

All serious adverse events must be recorded and reported:

a) To Ethics or Institutional Review board within the specified time period
b) To the Manufacturer of the IPS within 24 hours
c) And to government agency(s) in the time and manner according to any applicable legal requirements of the country(s) where the Proving is being conducted

A pre-determined written protocol should be followed for reporting and management of serious adverse events during the Proving.

A system for un-blinding of a single subject status in relation to an adverse event should be established prior to Proving initiation.

Decision to un-blind an individual Proving subject in the case of an AE should be based upon therapeutic necessity.

SAEs may require un-blinding at the time of the event.

Un-blinding protocol should comply with the following requirements:

a) Maintains blinding during the Proving unless un-blinding is required;
b) Limits the number of personnel within Proving team who will have access to un-blinding information to those absolutely necessary;
c) Controls which personnel have authority to access data;
d) If individual blind is broken, records any data access including specific personnel who obtained or viewed this information, information that was obtained, date in which it was obtained, and reason for un-blinding;
e) Includes protocol for when un-blinding should occur;
f) And contains adequate “fail-safe” procedures to assure immediate access to subject data during the Proving.

All subjects with an AE, where the therapeutic intervention has been determined by the Investigator to potentially affect the Proving, should be discontinued from the Proving. A complete record of the discontinuance and reasons should be part of the study record.

If subject is withdrawn/ discontinued due to symptom reliability concerns, no further data from that subject should be included in the Proving analysis.

A flow chart for new symptom assessment to guide Study Personnel in the recognition and management of suspected adverse drug reactions (including SUSARs) should be developed. Chart 1 (below) may be used as a template.