De-challenge and Rechallenge

De-challenge and rechallenge are terms used in pharmacovigilance to describe the occurrence and recurrence of adverse drug reactions (ADRs) in relation to the administration of a particular drug.

De-challenge refers to the cessation or reduction of symptoms or adverse events after discontinuation or reduction of the drug. In other words, de-challenge occurs when the patient's symptoms improve or disappear once the drug is stopped or the dose is reduced. A positive de-challenge suggests that the drug was likely the cause of the adverse event.

Rechallenge, on the other hand, occurs when the patient's symptoms or adverse events recur after the drug is reintroduced. In other words, rechallenge occurs when the patient experiences the same symptoms or adverse events after the drug is given again. A positive rechallenge suggests a strong likelihood that the drug is the cause of the adverse event.

De-challenge and rechallenge are important components of causality assessment, which is the process of determining whether a particular drug or medical intervention is the cause of an adverse event or reaction that has occurred in a patient. De-challenge and rechallenge data can provide valuable information to help assess the likelihood of a causal relationship between the drug and the adverse event.

However, it is important to note that de-challenge and rechallenge data should be interpreted cautiously and in the context of other factors such as temporal relationship, biological plausibility, and alternative explanations. A positive de-challenge or rechallenge does not necessarily indicate a causal relationship between the drug and the adverse event, but rather provides additional evidence to support or refute the likelihood of such a relationship.

1. welcome De-challenge and Re-challenge 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 1 Name: P. Ekathmika Sarvani Qualification: B. Pharmacy Student ID: 037/022023

2. Index 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 2 Introduction Definition classification of De-challenge and Re-challenge Introduction to casuality assessement principles involved in diagnosing ADR Advantages of De-challenge and Re-challenge Definitions issued by WHO for casuality assessment Example related to De-challenge and Re-challenge Reference Acknowledgement

3. Introduction Challenge– dechallenge –rechallenge   is a medical testing  procedure  in which drug is administered, withdrawn and then re-administered while observing at each level. The protocol is used when quantitative conclusions are inappropriate due to unusual characteristic by a specific individual. This is a way of estabilishing advantages of medications while treating in specific conditions and also many ADR’s. T his is termed as one of the standard way of analysing adverse drug reactions in France. This actually falls under casuality assessment this is the most important factor for analysing whether the treatment is the reason for cause of adverse event or not. 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 3

4. Definition Challenge  – In our pharmacovigilance world, this refers to giving of the drug to the patient during the adverse event or treatment to investigate.  Let us say, a patient has started today on ampicillin orally.  This is the example for “challenge”. Dechallenge  – This refers to termination of the drug, after an adverse event or at the end of the planned treatment. F or example:- a two week course of ampicillin  Dechallenge might be complete or partial. That means the drug is completely stopped or reduced in dose and the adverse event may completely vanishes or decreases slightly. Rechallenge  – This defines to be restarting of the same drug after it has stopped, normally for an adverse events.  Rechallenge might also fall under the category of complete or partial.  Hence the patient might had resumed ampicillin a week after stopping it. 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 4

5. Classification of De-challenge and Re-challenge Positive dechallenge – it means the AE disappear after the termination of the drug.  Hence the AE which might really be the adverse reaction of diarrhea vanished a day after the patient had stopped taking the ampicillin. N egative dechallenge – it means the AE does not disappear after stopping the drug.  For example the diarrhea prolongs even after ampicillin was stopped. P ositive rechallenge – it means the AE reoccurs after restarting the drug.  To have the reoccurance , AE had to previously disappear after dechallenge in order to restart. Negative rechallenge – This is the incident where the AE does not reoccur after the drug is resumed. 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 5

6. Introduction to casuality assessment Causality assessment is defined as recognizing causal association between drug and the drug reaction. Finding the culprit drugs will be lifesaving and helpful for preventing the damage caused by that culprit drug to our body system. 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 6

7. Principles involved in diagnosing ADR. Especially 4 principles are associated with it in order to diagnoise the adverse drug reactions they are namely: Relationship of the drug with the drug reaction. Biological probability. De-challenge. Re-challenge. 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 7

8. Advantages of De-challenge and Re-challenge Major uses of De-challenge and Re-challenge are signal detection, evaluating adr reports for regulatory purpose and risk benefit assessment.   3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 8

9. Definitions issued by WHO for casuality Assessment 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 9 CERTAIN The clinical event including laboratory test abnormality, occurring in a probable time relationship to drug administration, and which cannot be explained by on going disease or other drugs or chemicals. dechallenge should be clinically probable here. R echallenge procedure is used if necessary. PROBABLE the clinical event including laboratory test abnormality, with an adequate time sequence to administration of the drug, Is unlikely to attribute to ongoing disease or other drug and which follows dechallenge. Rechallenge is not required here POSSIBLE the clinical event including laboratory test abnormality with a adequate time sequence to administration of the drug, but which can be explained by ongoing disease or other drugs. D echallenge is not clear UNLIKELY the clinical event including laboratory test abnormality with the temporal relationship to drug administration which makes a causal relationship true and in which other drugs or chemicals underlying disease provide probable explanations .

10. Example related to De-challenge and Re-challenge 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 10 There is an example in gastroenterology for the use of dechallenge /rechallenge called as Bernstein Test or the Acid Perfusion Test.  This is done sometimes when there is any doubt about whether chest pain is due to reflux esophagitis or cardiac pain.  The patient has an NG tube placed midway down to the esophagus such that the tip is several inches away from the esophageal gastric junction.  The top of the tube is connected to a “Y tube” and 2 bottles of water are hung – one on each of the “Y” tubes.  One bottle contains dilute hcl acid with a pH similar to gastric fluid in the stomach and the other has saline solution. Each bottle is clamped such that both clamp can be opened at a time to allow that fluid to pass into the esophagus .

11. bottles are covered and hung behind the patient so the person can not see them.  Then doctor informs the patient to raise his hand if he has felt any heartburn .  The doctor then changes the drips for about 1-2 minutes each without telling the patient when the drip changes from saline to acid .  The dechallenge here is that as soon as the acid touches the tender inflamed part of the esophagus pain should start if there is esophageal inflammation on the other hand saline touches the esophagus it washes away the acid and the pain should disappear within 30 to 60 seconds.  The doctor does this a few times to see  If there is any heartburn that the patient usually experiences when the acid has dripped and disappears with saline. you have made the diagnosis of esophagitis this the concept of dechallenge /rechallenge  because the adverse event here is heartburn it is treated with the saline solution so that it will disappear in a minute. D echallenge is evident in this case. 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 11

12. Reference Basic principles of Clinical Research and Methodology by SK Gupta Priniciples of PHARMACOVIGILANCE Dr. S.B. BHISE De-challenge and c 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 12

13. Acknowledgement I would like to thank the ClinoSol Research team and Ms. Shifa for the constant guidance Special thanks to, Mr. Mujeebuddin Shaik, Founder, and CEO, ClinoSol Research, Hyderabad, India Ms. Uma Priya, Director, ClinoSol Research, Hyderabad, India, for all the support and encouragement. 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 13

14. Thank You! www.clinosol.com (India | Canada) 9121151622/623/624 [email protected] 3/10/2023 www.clinosol.com | follow us on social media @clinosolresearch 14