Submitting a Monograph

All monograph sponsors must demonstrate an adequate safety and reporting process while acquiring clinical data. The process may vary according to the type of clinical study being conducted.

The safety and reporting process must be evaluated and approved by an Ethics Committee or IRB.

An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.ⁱⁱⁱ

Expected events specific to homeopathy are described in Section 6.1.3. of these guidelines and shall be managed as described in that section.

All shall be reported and managed according to the requirements of the AEs applicable regulations, and Ethics Committee or IRB requirements.

In addition to the FDA/ICH-GCP defined events, there are two expected events specific to homeopathy that can occur during the treatment with an IHMP.

a) Proving Symptoms
Proving Symptoms are expected, mild, transient signs or symptoms occurring within an expected time period after IHMP administration. Such signs or symptoms must be consistent with the current understanding of the homeopathic clinical picture of the IHMP as derived from and supported by prior proving, toxicological, and/or clinical data
b) Homeopathic Aggravations
Homeopathic Aggravations are expected, mild, transient increases of pre-existing signs or symptoms that occur shortly after IHMP administration, quickly resolve, and are associated with an improvement in clinical complaints and / or general health

The occurrence of either of these types of events given in Section 6.1.3. shall be recorded in the monograph submission as potentially significant to the clinical understanding of the IHMP and form part of the source data of the study.

If, however, either a homeopathic aggravation or proving symptom occurs with an unexpected degree of severity, duration, or frequency, this would also be assessed and managed as an AE (see Flowchart 1 Adverse Event Determination While Acquiring Clinical Data located in Section 6.5).

A process for determination of causation likelihood shall be established prior to IHMP administration (for prospective studies) or data analysis (for all studies).

a) Report of causation likelihood shall be included for all AEs using the following labels derived from the FDA^iv and ICH guidance^v.

i. Possibly related – there is sufficient evidence to suggest a reasonable possibility of a causal relationship between the drug and the AE
ii. Unrelated – there is no evidence to suggest a causal relationship between the drug and the AE

b) Process for determination of causation likelihood must include consideration of all of the following:

i. Temporal relation to IHMP administration
ii. Strength of association
iii. Consistency over repeated dosing (if applicable)
iv. Coherence with known facts on the biology of disease

An ADR is any AE that is deemed to be possibly related to the IHMP (see Section 6.1.5 a)).

Therefore, all AEs deemed to be possibly related to the IHMP shall be managed as ADRs. This process must include:

d) Report of causation likelihood
e) Report of AE timeline and outcome using the following categories:

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

f) Compliance with all applicable regulatory requirements

SAEs are defined¹⁷,^{ix, x} as any untoward medical occurrence, associated with the use of a drug in humans, whether or not considered drug related, 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 SAEs must be recorded and reported to the following bodies:

a) Ethics Committee or IRB within the specified time period
b) The manufacturer of the IHMP (within 24 hours for prospective studies)
c) Government agency(s) in the time and manner according to any applicable legal requirements of the country

A pre-determined written protocol shall be followed for reporting and management of SAE’s (prospective studies only).

A SUSAR is a SAE (see Section 6.1.7), that is suspected to have a causal relationship with the IHMP.

All SUSARS must be recorded and reported to all of the following:

a) Ethics Committee or IRB within the specified time period
b) The manufacturer of the IHMP (within 24 hours for prospective studies)
c) Government agency(ies) in the time and manner according to any applicable legal requirements of the country

Figure 1 delineates the various categories and relationships of AEs. The scale of the figure does not reflect actual frequencies of the various events.

All ADRs, AEs, proving symptoms, and Homeopathic Aggravations shall be included and delineated in the Monograph Report.

If ADRs, AEs, proving symptoms, or Homeopathic Aggravations do not occur during data acquisition, this must be stated.

A specific AE handling process is not required for retrospectively collected cases.

Monograph sponsor shall report what reasonable efforts were made to collect and assess safety information on the IHMP (including AEs, homeopathic specific reactions, and ADRs), despite the inherent challenges with collecting this type of data retrospectively.

Sponsors collecting data from prospective cases shall include a process for AE handling by the healthcare providers involved in the investigational use of the IHMP. This process must follow the requirements listed in Section 6.1.

Because subjects receive therapy with unknown or unconfirmed therapeutic action, this form of study requires a detailed Safety Management plan with specific personnel designated to manage the plan.

A safety management plan shall contain standard operating procedures (SOPs) for AE handling, treatment if necessary, and reporting.

The plan shall define the process of handling and managing of AEs, including SUSARs and SAEs – taking into account any applicable regulatory requirements with regards to reporting timelines.

For all studies except retrospective case studies, a clear plan for the recording, assessment and reporting, of AEs, approved by the Ethics Committee or IRB, shall form part of the study protocol.

Trial monitoring is required to conform to the ICH-GCP guidelines.

Monograph sponsors shall submit a detailed report of the monitoring process with any controlled trial data.

For experimental trials with blinded allocation, a system for un-blinding of a single subject status in relation to an AE shall be established prior to trial initiation.

Requirements for procedures un-blinding are given in Section 5.4.3.

All subjects with an AE, where the therapeutic intervention related to the IHMP that has been determined by the PI to potentially affect the clinical outcome, safety, or well-being of the subject, shall be discontinued from the experimental trial.

Requirements for procedures subject discontinuation are given in Section 5.4.5.

If a trial is prematurely discontinued, the Ethics Committee or IRB, monograph sponsor, and any relevant regulatory authorities must be notified promptly including the reason for termination or suspension of the trial.