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Adverse Drug Reaction(s)

Adverse Event -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. Adverse Drug Reactions Are events, thought to be a response of which is both due to the drug and considered noxious and un intended.

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SAE
Serious Adverse Event or reaction - is any untoward medical occurrence that at any dose: Results in death, Is life threatening, Requires inpatient hospitalization or prolongation of existing hospitalization. Results in persistent or significant disability/incapacity. Results in a congenital anomaly/birth defect Results in other medically important conditions
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Incidence of ADRs
ADRs are always under reported ADRs are the 4th-6th largest cause for mortality ADRs account for approximately 10% of hospital admissions ADRs increase the length of hospital stay and medical costs

15-20% of hospital budget may be spent dealing with drug complications

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Possible Causes of Adverse Reactions

Intrinsic factors of the drug
Pharmacological Idiosyncratic Carcinogenicity, Mutagenicity Teratogenicity

Extrinsic factors
Adulterants Contamination

Underlying medical conditions Interactions Wrong usage

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HOW KNOWLEDGE ABOUT ADRs IS CREATED

Animal experiments Clinical trials Epidemiological methods

Observational studies
Case reports Case series

Post-Marketing Surveillance (PMS) Prescription event monitoring Cohort studies

Intensive hospital monitoring

Case-control studies Record-linkage Meta-analysis

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Limitations of Clinical Trials

Too few - Normally < than 1500 patients Too simple - Use patients without complications, other medical conditions Too narrow - Limited indications Too brief - Limited time Too median - Very old/very young patients, pregnant women not included
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Aim of Surveillance of Drug Related Adverse Reactions

Identify the suspected drug Identify factors that contributed to the occurrence of the adverse reaction such as: Multiple drug therapy, Drug-drug interactions Drug-herbal interactions Drug food interactions Excipients, colouring agents
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Aim of Surveillance of Drug Related Adverse Reactions Increase information on use in at-risk population Identify unlabeled, rare, delayed adverse reactions Identify abuse potential Follow-up cases where drugs prescribed intentionally during pregnancy Monitor outcome of pregnancy Effect of drug to the foetus/baby MAKE CHANGES TO PRODUCT INFORMATION BASED ON NEW FINDINGS

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How to Recognize ADRs

Since ADRs may act through the same physiological and pathological pathways as different disease, they are difficult and sometimes impossible to distinguish

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Drug administered

Pt develops a new condition/symptoms

Drug suspected?
Yes Check literature

Documented ? (for the product or similar class of products)

Yes Highly suggestive of ADR

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Not documented in literature

Drug continued

Drug discontinued

Worsening of symptoms

Symptoms improve (+ve dechallenge)

Any other possible causes? Concomitant therapy Underlying conditions

Drug restarted

Symptoms recur (+ve rechallenge)

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Intensity of Events
Mild events: Mild events are those, which are easily tolerated.

Moderate events: Moderate events are those, which cause sufficient discomfort to the subject which interferes with daily activity and/or require a simple dose of medication, e.g. analgesics or antiemetics. Severe events: Severe events are those, which incapacitate or prevent usual activity or require complex medication or hospitalisation.
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Severe vs Serious
The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as severe headache). This is not the same as "serious," which is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or functioning. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.
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Causal Relationship
Adverse events can be classified as : HIGHLY PROBABLE: The event follows a reasonable temporal sequence from administration of the drug and is confirmed by positive dechallenge and positive rechallenge. PROBABLE: The event follows a reasonable temporal sequence from administration of the drug is confirmed by dechallenge and is not reasonably explained by the known characterization of patients clinical state.

POSSIBLE: The event follows a reasonable temporal sequence from administration of the drug and follows a known response pattern to the suspected drug but could have been produced by the patients clinical state or other modes of therapy administered to the patient. REMOTE: Any event that does not meet the above criteria especially if the event has no temporal association with use of the drug.

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Product Safety Update Report (PSUR)

The Periodic Safety Update Report (PSUR) is required as part of the Post Marketing Drug Risk Assessment (PMDRA) program.

The PSUR report is evolving with the ICH initiatives and the February 2004 FDA Guidance for industry.

The PSUR software is designed to track the submission of Periodic Safety Update Reports by marketed product and country. The PSUR is a practical mechanism for summarizing interval safety data covering short periods of time and for conducting and overall safety evaluation.
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Product Safety Update Report (PSUR)

PSUR tracks basic information such as International Birth Date (IBD), Product license number and renewal date, and the date range of the report. Information on all indications, dosage forms, and regimens for the active substance can also be tracked as well as the affiliate requesting the report. PSUR tracks the initiation date for requests for information and the receipt of that information from the various corporate departments that contribute to the PSUR report. Besides the dates, provision is made to link the various documents and components to the PSUR tracking records for immediate retrieval of that report component.

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AE Reporting Form

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