data analysis and reporting

Question 1

What is the definition of an adverse event?

Answer 1

Any untoward medical occurrence associated with the use of a medicinal product, whether or not considered related.

Question 2

What is a treatment-emergent adverse event?

Answer 2

This is usually an AE that declines that occurs or worsens in the period from first dose of the drug to just after the final dose of the study drug.

Question 3

How are AEs reported?

Answer 3

They must be reported on the source documents and on the case report forms.

Question 4

What methods can you use for acquiring adverse event information?

Answer 4

1. Open-ended questions, e.g. how has your health been since I last saw you? This can unfortunately lead to under-reporting as the person may not remember if it has been a long time.
2. Symptom checklist. This can cause over-reporting due to power of suggestion.
3. Could use a subject diary that they can take home and fill out when they experience an adverse event.
4. Could use a standardised questionnaire

Question 5

Is it possible to diagnose all AEs?

Answer 5

No. AE should be diagnosed whenever possible and documented on source documents and case report forms. However, if not diagnosable (e.g. headache, etc.) then the symptoms should be described.

Question 6

What information should be obtained for reported AEs?

Answer 6

We need to establish the severity (e.g. mild, moderate, severe), if there is causality, if the event was expected or not (should be stated in protocol) and if the event was serious or non-serious (e.g. hospitalisation).

Question 7

What is causality?

Answer 7

This is determining the assessment of whether an adverse event is related to the drug and is graded from definite, probable, possible, unlikely, unrelated. If there is a reasonable causality relationship with the drug then it may be known as suspected adverse reaction.

Question 8

What does serious mean in terms of adverse events?

Answer 8

Serious indicates that death, some life-threatening experience, hospitalisation, or birth defects have been experienced after drug administration.

Question 9

What is severity of adverse events?

Answer 9

This refers to the intensity of the adverse event for the patient, e.g. was it a mild headache or a severe one? The event itself is not considered of major medical significance as it is just a headache, but to the patient it was severe.

Question 10

What does expected/unexpected mean with regards to adverse events?

Answer 10

An expected adverse event may be specified in the protocol already, based on the information that is known about the drug action, etc. An unexpected adverse event may not be consistent with the information known about the drug, e.g. a painkiller drug causing memory loss. It was not expected therefore not specified in the investigator brochure.

Question 11

If a serious AE occurs, when should it be reported?

Answer 11

Serious AEs must be reported straight away (within 24 hours of awareness) to the sponsor or clinical research officer. The relevant ethics committee must also be notified by the investigator. Investigator should then also notify other research sites involved in the same trial.

Question 12

What are the downsides to the current classifications of adverse events and their reporting?

Answer 12

Different sponsors may have different interpretations of what is considered serious (e.g. emergency room visits not considered hospitalisation) and what is considered as having a causal relationship (sponsor may not consider related but investigator might)

Question 13

What are expedited safety reports and when are they required?

Answer 13

Expedited safety reports are safety reports that are reported to regulatory authorities very quickly, and the sponsor must decide whether an adverse drug reaction meets the requirements for an ESR. If an adverse reaction is considered serious, related, and unexpected then it must be reported via an ESR. In this case it would be a SUSAR.

Question 14

What is an investigational new drug safety report?

Answer 14

This is a form of ESR which is submitted to the FDA

Question 15

Who must a SUSAR be reported to?

Answer 15

SUSARs must be reported to EudraVigilance and competent authorities.

Question 16

Why else might expedited safety reports be required?

Answer 16

ESRs may be required post-study, e.g. if a patient dies 2-months post study, the relevant authorities must be notified. Also, if new information is shed from new in vitro studies (e.g. carcinogenicity) or new epidemiological studies.

Question 17

How are SAEs documented?

Answer 17

The sponsor must document the data into a safety database, appropriate regulatory reports must be completed (e.g. MedWatch, CIOMS), then the case must be reviewed by a Medical Officer.

Question 18

When does the sponsor have 15 days to submit an ESR?

Answer 18

If an adverse reaction is considered potentially causal and unexpected, there is 15 days from awareness to submit an ESR.

Question 19

When does the sponsor have 7 days to submit an ESR?

Answer 19

If an adverse reaction is considered potentially causal, unexpected and serious, there is 7 days from awareness to submit an ESR.

Question 20

What are the possible actions by the ethics committees once a safety report is received?

Answer 20

1. No action required.
2. Protocol modifications.
3. Modification to informed consent.
4. Request for subject notification.
5. Increased frequency of EC review.
6. Study suspension/termination.

Question 21

What are the possible actions by the regulatory authorities once a safety report is received?

Answer 21

1. No action required
2. Protocol modifications
3. Study suspension or termination
4. Safety and medical alerts
5. Dear Doctor alert letters
6. Labelling implications

Question 22

What is PP analysis

Answer 22

This is per-protocol analysis in which subjects are compared to those in the treatment groups actually received, e.g. if 10 patients achieved the primary outcome, 100 people were randomised to this treatment, but 20 people withdrew. Then PPA would only look at 10/80 (the number of people getting the treatment that haven’t withdrawn).

Question 23

What is ITT analysis?

Answer 23

This is intention-to-treat analysis which compares subjects to the treatment groups they were assigned to. If the patients were randomised well, non-compliance will be balanced. E.g. in the same example, 10 patients out of 100 patients (who were randomised) achieved primary outcome. This preserves the strength of randomisation and mirrors real life situations.

Question 24

What is survival data?

Answer 24

It is data which is measured in patient time and includes the time the patient has been in the study.

Question 25

Which 2 ways can survival data be reported?

Answer 25

Descriptive analysis and survival analysis

Question 26

What is descriptive analysis of survival data?

Answer 26

This is when we use risk and odds to determine the ratio of the event occurring in 2 treatment groups. These can be compared to determine if one treatment is more likely to achieve an event. However, this does not account for how early/late an event was experienced.

Question 27

What is survival analysis of survival data?

Answer 27

This refers to the graphical representation of survival data from censored and non-censored patients. We can estimate the median survival and calculate the survivor function.

Question 28

What is the survivor function?

Answer 28

This is the probability of a patient surviving to time T.

Question 29

What is the Kaplan-Meier method?

Answer 29

This is a form of survival analysis which accounts for censored data (people never experiencing the event). It estimates the event rates at all time points, adjusting for censoring.

Question 30

What is the log-rank test?

Answer 30

This is the equivalent of the chi-squared test. It is misleading to compare curves at 1 point, therefore we do the log-rank test.