Adverse Reaction and Drug-Related Adverse Event

In all clinical trials, it is important to collect the adverse event information accurately. It is very common to collect the adverse events and the characteristics of these adverse events (including seriousness, severity, causality to the study drug, and so on). The causality is usually assessed by the investigator using the categories of ‘not related, unlikely related, possibly related, and related’. These categories are used in ICH E2B examples and the CDASH standards. It is also very common to define the ‘drug-related adverse events’ as any adverse events assessed by the investigators as ‘possibly related’ or ‘related’. The statistical summaries will usually include the tables for drug-related adverse events.

When it comes to the product labels or package inserts, instead of using the term ‘drug-related adverse events’,  ‘adverse drug reaction (ADR)’ or simply “adverse reaction” is used.

Is the term ‘adverse reaction’ equivalent to the term ‘drug-related adverse event’? There is no formal guidance anywhere to indicate that the ‘adverse reaction’ and ‘drug-related adverse event’ are the same thing. In Statement about “Drug-related Adverse Events” of Dr Janet Woodcock before the Senate Committee on Health, Education, Labor, and Pensions in 2000, the terms of ‘drug-related adverse events” and “adverse drug reactions” were used interchangeably.

However, if we look at the formal definition of ‘adverse reactions’ in regulatory guidelines, there seems to be some differences between these two terms and ‘adverse reactions’ seem to enable the sponsor to make the judgment whether or not an adverse event is considered as ‘adverse reaction’, especially for the product labeling purpose. If this is the case, the term ‘adverse reaction’ will be different from the ‘drug-related adverse event’ since the drug-related adverse event is based on the investigator’s assessment.

In the United States, all product labels are required to follow the new formats according to FDA’s guidance “Labeling for Human Prescription Drug and Biological Products — Implementing the New Content and Format Requirements” issued in 2006. The new format requires the reporting of adverse reactions in section 6 of the package insert.

The guidance requires the following:

“• Most frequently occurring adverse reactions
 Information under the Adverse Reactions heading must include a listing of the most frequently occurring adverse reactions, even if they are included elsewhere in Highlights, and the criteria used to determine inclusion (e.g., incidence rate).  The listing should be concise, not lengthy or comprehensive.  This listing may include adverse reactions that are important for reasons other than frequency (e.g., leading to discontinuation or dosage adjustments) unless they are included elsewhere in Highlights (e.g., under Warnings and Precautions or Contraindications).

The adverse reactions listed as most frequently occurring or most common should be selected from the table of adverse reactions from clinical trials in the FPI.  Rates of most common adverse reactions vary, but should be appropriate to the nature of a drug’s adverse reactions profile and the size and composition of the safety database.  The criteria for determining inclusion must be identified along with the listing (e.g., >2%).  If adverse reaction profiles vary significantly for different indications, list the most common adverse reactions by indication.  Also note if different criteria for determining inclusion are used for different indications.”

FDA also issued a subsequent guidance on “Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format” that attempted to provide clarifications about the adverse reactions section of labeling. This guidance provided the definition for ‘adverse reaction’ and ‘adverse event’ as following:

“Adverse Reaction (21 CFR 201.57(c)(7)): For purposes of prescription drug labeling and this guidance, an adverse reaction is an undesirable effect, reasonably associated with the use of a drug, that may occur as part of the pharmacological action of the drug or may be unpredictable in its occurrence. This definition does not include all adverse events observed during use of a drug, only those for which there is some basis to believe there is a causal relationship between the drug and the occurrence of the adverse event. Adverse reactions may include signs and symptoms, changes in laboratory parameters, and changes in other measures of critical body function, such as vital signs and ECG.
 Adverse Event (or adverse experience): For the purposes of this guidance, the term adverse event refers to any untoward medical event associated with the use of a drug in humans, whether or not considered drug-related.”

Unfortunately, the definition of ‘Adverse reaction’ did not specify who (investigator or sponsor) to make the judgment about ‘reasonably associated with the use of a drug’ and what will be considered as ‘reasonably associated with the use of a drug’. Some people think that ‘unlikely related’ adverse events should also be considered as ‘adverse reactions’ since the association with the drug can not be totally eliminated.

In EMA’s document “CLINICAL SAFETY DATA MANAGEMENT: DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING” ICH Harmonised Tripartite Guideline, the definition of ‘adverse reaction’ is also discussed. The document provided the definition of ‘adverse reaction’ in two different situation: pre-approval  and the marketed product. The same definition is also echoed in ICH GCP Glossary.

“A. Basic Terms
Definitions for the terms adverse event (or experience), adverse reaction, and unexpected adverse reaction have previously been agreed to by consensus of the more than 30 Collaborating Centres of the WHO International Drug Monitoring Centre (Uppsala, Sweden). [Edwards, I.R., et al, Harmonisation in Pharmacovigilance. Drug Safety 10(2): 93-102, 1994.] Although those definitions can pertain to situations involving clinical investigations, some minor modifications are necessary, especially to accommodate the pre-approval,
development environment.
 The following definitions, with input from the WHO Collaborative Centre, have been agreed:
1. Adverse Event (or Adverse Experience)
Any untoward medical occurrence in a patient or clinical investigation subject
administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with
the use of a medicinal product, whether or not considered related to the medicinal product.
 2. Adverse Drug Reaction (ADR)
In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established:
all noxious and unintended responses to a medicinal product related to any dose
should be considered adverse drug reactions. The phrase "responses to a medicinal products" means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out.
 Regarding marketed medicinal products, a well-accepted definition of an adverse drug reaction in the post-marketing setting is found in WHO Technical Report 498 [1972] and reads as follows:
 A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function.
 The old term "side effect" has been used in various ways in the past, usually to describe negative (unfavourable) effects, but also positive (favourable) effects. It is recommended that this term no longer be used and particularly should not be regarded as synonymous with adverse event or adverse reaction.
 3. Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not consistent with the
applicable product information (e.g., Investigator's Brochure for an unapproved
investigational medicinal product). (See section III.C.)
 B. Serious Adverse Event or Adverse Drug Reaction
During clinical investigations, adverse events may occur which, if suspected to be medicinal product-related (adverse drug reactions), might be significant enough to lead to important changes in the way the medicinal product is developed (e.g., change in dose, population, needed monitoring, consent forms). This is particularly true for reactions which, in their most severe forms, threaten life or function. Such reactions should be reported promptly to regulators.
Therefore, special medical or administrative criteria are needed to define reactions that, either due to their nature ("serious") or due to the significant, unexpected information they provide, justify expedited reporting.”

In 2006, EC issued “Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use”. It specified that the causality should be assessed by both the investigator and the sponsor.

 “All adverse events judged by either the investigator or the sponsor as having a reasonable suspected causal relationship to an investigational medicinal product qualify as adverse reactions. The causality assessment given by the investigator should not be downgraded by the sponsor. If the sponsor disagrees with the investigator’s causality assessment, both, the opinion of the investigator and the sponsor should be provided with the report.”

For now, at least we know that the ‘adverse reaction’ and ‘drug-related adverse event’ are not the same. 'Adverse reaction' concept may have different meaning in pre-marketing clinical trials and in post-marketing studies.

In the product label for ADVATE, the 'adverse reaction' has the following definition:

"ADRs are defined as any Adverse Event that occurred within 24 hours after being infused with investigational product OR all Adverse Events assessed related or possibly related to  investigational product OR Adverse Events for which the investigator's or sponsor's opinion of causality was missing or indeterminate."

where Adverse event that occurred within 24 hours belongs to the concept of 'temporally related adverse events'. The time frame of 24 hours, 48 hours, or 72 hours,...should be determined based on the nature of the drug (for example, the half life).

In a FDA's medical review memo, the reasoning for using above ADR definition was discussed:

"...That most recent information request asked the sponsor to use the following definition of adverse reaction (ADR) for the pooled analysis of ADRs in Table 3 in the ADVERSE REACTIONS section of the PI:

Any Adverse Event that began during an infusion or <= 24 hours after the end of an infusion with the investigational product OR all Adverse Events assessed by the investigator or sponsor as related, probably related, or possibly related to investigational product OR Adverse Events for which the investigator's or sponsor's opinion of causality was missing or indeterminate.

I recommend the sponsor be asked to re-title Table 3 and to use a footnote to provide the operational definition of ADR used for this pooled analysis. OBRR commonly uses temporal association to help define ADRs in clinical trials lacking a randomized parallel placebo group, since there is no assurance in such cases that the sponsor’s or investigator’s assessments of causality of AEs is necessarily accurate. Limiting ADRs in such trials to the ADRs identified by the investigator may lead to an underestimation of the true ADR incidence, but no causality assessment method is wholly satisfactory in the absence of a gold standard. Given that many of the pooled Advate trials involved routine prophylaxis given up to 4 times weekly, the 24 hour time frame for temporal association of ADRs is considered to be more useful in helping to define possibly causally related ADRs, rather than the 72 hour time frame which OBRR has often employed for parenteral biologic products given at less frequent intervals. The sponsor submitted at FDA request the results of ADR analyses as tables using timeframes of temporal association of 24, 48, and 72 hours to help define ADRs (in addition to ADRs consisting of AEs already identified as at least possibly related according to the investigator or the sponsor)."

Reference: 

• FDA (2006) Guidance for Industry Adverse Reactions Section of Labeling for Human Prescription Drug and Biological Products — Content and Format