DE CHALLENGES AND RE CHALLENGES
Challenge–dechallenge–rechallenge (CDR) are the medical testing protocol in which a medicine or drug is administered, withdrawn, then re-administered. When it is monitored for adverse effects at every stage. The protocol is used when statistical testing is inappropriate due to an idiosyncratic reaction by a specific individual, or a lack of sufficient test subjects and unit of analysis is the individual. During the dechallenge (withdrawal) phase, the medication is allowed to wash out of the system in order to determine what effect the medication is having on an individual.
these concepts are frequently used in the discussion of causality and regulatory agencies pay particular attention to them in assessing individual case safety reports particularly in the post-marketing setting.
Dechallenge and Rechallenge in Pharmacovigilance
Challenge – In our pharmacovigilance world, this refers to the giving of the drug to the patient during the treatment in question. That is, a patient is started today on, say, ampicillin orally. This is the “challenge”.
Dechallenge:
Dechallenge: – This refers to the stopping of the drug, usually after an adverse event (AE) or at the end of a planned treatment (e.g., a two-week course of ampicillin). Dechallenges may be complete or partial. That is, the drug is fully stopped or decreased in dose and the AE may fully disappear or only partially decrease. This term is use when the suspect drug was discontinued or withdrawn or dose reduced due to adverse event (AE).
Dechallenge (DC) can be classified into: -
Positive Dechallenge: When the suspect drug was stopped or withdrawn, or the dose was reduced, and the adverse event was improved or resolved. For example, the AE (which could actually be an adverse reaction – AR) of diarrhoea went away a day after the patient stopped taking ampicillin.
Negative Dechallenge: When the suspect drug was discontinued or withdrawn, or the dose was reduced, but the adverse event did not improve or resolve. For instance, the diarrhoea persisted even after the ampicillin was discontinued. It’s important to note that these can be a little confusing because a “positive” dechallenge refers to the problem disappearing.
Unknown: When suspect drug was discontinued or withdrawn or dose reduced but the result of dechallange was unknown.
Dechallenge not applicable: This term is used in the following situations: treatment for an adverse event, death, drug discontinuation prior to the AE, medication error, drug overdose, and drug exposure during pregnancy.
Rechallenge: -
This refers to the restarting of the same drug after having stopped it, usually for an AE. Rechallenges may also be complete or partial. Thus, the patient may have restarted ampicillin a week later after having stopped it.
A positive rechallenge – This refers to the AE recurring after restarting the drug. To have this occur, the AE had to have previously disappeared after the dechallenge in order for it to restart.
A negative rechallenge – This is the case where the AE does not recur after the drug is restarted. Note the confusion here: With a positive dechallenge the AE disappears but with a positive rechallenge the AE comes back and vice versa.
Unknown: when the suspect drug re-introduced but result of rechallenge was unknown.
Rechallenge not applicable: when the drug was not re-introduced.
Conclusion: -
So, is the dechallenge-rechallenge concept useful in assessing causality in drug safety? Yes, if good clinical judgment is also applied. This should take into account the timing of the disappearance/reappearance, the clinical setting, other comedications, the disease in question etc.
For example, if an allergic type reaction (e.g., urticarial) disappears over a few hours after stopping the drug this is consistent with a drug effect. If the urticarial reaction reappears in minutes after a rechallenge this too is consistent with a drug effect. If the urticaria occurs hours or days later it is less consistent. Similarly, many confounding comedications may make dechallenge/rechallenge hard to interpret.
Health agencies expect that questions about dechallenge and rechallenge will be asked in the work up an ICSR that is submitted. By no means should the company necessarily suggest that the patient be dechallenged and/or rechallenged just to see if the drug caused the AE. This is the judgment of the physician, investigator, patient etc. not the company. But if the dechallenge/rechallenge is done this data should be sought and included in the report.
References: -
Challenges, Prechallenges, Dechallenges and Rechallenges, Feb 06, 2013, Bart Cobert. Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert
Student Name: Prathamesh Bhaskar Golapkar
Student ID: 027/022023
Qualification: MSc (Microbiology)
e-Mail ID: golapkarpratham3112@gmail.com
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