Adverse drug reaction detection (pre-and post-marketing studies) and reporting methods. ADR reporting form.

1. ADVERSE DRUG REACTION
PRAJJWAL
20PPC013
M.Pharmacy (Pharmacology)

2. INTRODUCTION
• Adverse drug reaction is an unwanted or harmful reaction experienced following the
administration of a drug or combination of drugs under normal conditions of use and is
suspected to be related to the drug. An ADR usually require the drug to be discontinued
or the dose reduced.
• In US, 3 to 7% of all hospitalizations are due to adverse drug reaction.
• Incidence and severity of adverse drug reactions vary by patient characteristics e.g., age,
sex, genetic factors etc. and by drug factors e.g., type of drug, route of administration,
treatment duration, bioavailability.
• According to WHO, “a response to a drug which is noxious and unintended and which
occurs at doses normally used in man for diagnosis, or therapy of disease or for the
modification of physiologic function.
• Adverse drug event is, any unexpected medical occurrence that may present during
treatment with medicine, but which may not have casual relationship with the
treatment.

3. TYPES OF ADR
• On the basis of the duration:
I. Acute – less than 60 minutes
II. Subacute – 1-24 hours
III. Latent – for around 2 days
IV. Chronic – more than 2 days
• On the basis of severity:
i. Minor – no therapy, antidote or prolongation of hospitalization is required.
ii. Moderate – requires change in therapy, prolongation of hospitalization is required.
iii. Severe – life threatening, can cause permeant damage, require intensive medical care.
iv. Lethal - death

4. CONT.…
• On the basis of types of reaction: also known as Wills and Brown classification.
I. Type A (augmented) – dose related
II. Type B (bizarre) – non-dose related
III. Type C (chronic) – dose and time related
IV. Type D (delayed) – time related
V. Type E (end of use) - withdrawal
VI. Type F (failure of drug) – failure of therapy
VII.Type G (genotoxicity)
VIII.Type H (hypersensitivity) – immune medicated
IX. Type U (unclassified) - unclear

5. Type A augmented
• It is predictable and dose related reaction which predict from the known pharmacology of the drug.
• This can be counter by reducing the dose.
• It occurs in high incidence but has low mortality.
• Most ADRs of this type are attributable to differences in drug disposition that results in higher plasma and
tissue drug concentration arising from dysfunction of organs of metabolism and excretion, or inappropriate
dose.
• Example – dry mouth, blurry vision, hypoglycemia, headache etc.
Type B bizarre
• Type B is also predictable where mechanism is know but it does not depend on the dose of the drug. It is
unrelated to the drug’s pharmacological effect.
• It is more serious and may be requires drug withdrawal.
• It has low incidence but with high mortality.
• Example – anaphylactic reaction due to penicillin G, and haemolysis.

6. Type C chronic
• They are not pharmacologically predicable, by may be seen based on the knowledge of
physiochemical characteristic of drug.
• It is related to the dose and the duration of therapy.
• Example – nephrotoxicity due to use of NSAIDs
Type D delayed
• They are not dependent to the chemical or pharmacological properties of drug.
• They occurs due to method of administration or nature of the drug formulation.
• It occurs after years of the treatment.
• Example - chemotherapy – secondary tumors, carcinogenesis, teratogenicity.

7. Type E withdrawal
• Occurs in specific situations when drug treatment is terminated suddenly. The condition of the
patient improves when the drug therapy is reintroduced.
• Example – withdrawal seizure when anticonvulsants like phenytoin is withdrawn.
Type F failure
• ADRs occur when the expected response to treatment is not achieved.
• Due to underdosing of medication.
• Occur in genetically predisposed patient or due to interaction of drugs. It can be improved if
medicine withdrawn.
• Example – hemolytic anemia with primaquine, inadequate dosage of an oral contraceptive
with enzyme inducer.

8. Type G Genotoxicity
• Reaction that cause the irreversible genetic damage. Ex. Thalidomide caused genetic damage
to the developing fetus.
Type H hypersensitivity
• Also known as drug allergy and is often immune mediated response.
• It occurs when sensitized individuals are re-exposed to same drug again.
Type U unclassified
• This includes those reactions in which the mechanism is unclear.
• Example – taste disturbance associated with simvastatin.

9. DETECTION OF ADRs
• Detection of an ADR is crucial in the management of any patient. It can be detect by patient
interview, reviewing prescription, and obtaining previous medical history.
• Detection of ADR in hospitals offers the chance to detect serious ADRs resulting in
hospitalization and ADRs occurring in hospitalized patients.
• Detection of ADRs can be done by these methods;
i. Pre-marketing studies
ii. Post-marketing surveillance

10. Pre-marketing studies
• During the development of new medicines, their safety is tested in animal models.
• Different animal models are available for different type of studies e.g., carcinogenicity,
teratogenicity, and mutagenicity.
• Pre-marketing studies conducted to evaluate safety and efficacy of the new compound.
• If all performed tests shows favorable results than further studies performed in human
subjects.
• Clinical trials are carried out in 3 different phases prior to the submission of a marketing
authorization application. Clinical trials normally identifies ADRs of frequency greater than
0.5-1.0%.

11. Post-marketing studies
• Pharmacovigilance methodologies are used for detection of risk and for the collection of risk
information.
• Spontaneous adverse drug reaction reporting is a powerful and cost effective tool for the
identification of unknown drug-related risk.
• Two epidemiological methods are most commonly used for studies; cohort studies and case-
control studies.
1. Cohort studies – are design where two groups are compared, one with the exposure of the
specific drug and other without exposure factor, for differences in the incidence of
outcome.
Cohort study designs are used to study outcomes from a single exposure factor. They are
classified into prospective and retrospective.

12. Prospective studies follows subjects from the presence of risk factors to the development of
disease.
Retrospective, identify a population with and without the risk factor based on past records
and then assess if they had developed the disease at the time of the study.
2.Case-control studies – An observational study that compares patient who have a disease of
interest with patient who don’t have the disease. Medical history of both the groups are
traced for the comparison.
It is less expensive and time-consuming than cohort studies. These studies are usually
retrospective.

13. REPORTING AN ADR
• All types of suspected ADRs irrespective of whether they are known or unknown, serious or
non-serious, frequent or rare and regardless of a established casual relationship.
• Pharmacovigilance centers involved in the study of the safety of marketed drugs under the
practical conditions of clinical use in large communities. The ultimate goal is to improve the
safe and rational use of medicines.
• Pharmacovigilance centers available in hospitals to report adverse drug reactions. They are
centrally governed by Uppsala Monitoring Centre (UMC), Sweden.
• In UK yellow card scheme is used to report adverse drug reactions by MHRA (Medical and
Healthcare products Regulatory Agency).
• All health care professionals and non-healthcare professionals including consumers can report
suspected adverse drug reaction.
• ADRs can be reported to Local/Regional/National pharmacovigilance centers, WHO
collaborating centre, manufacturers.

14. ADR reporting form
A case report should contain information on the following elements;
• The patient – age, sex and brief medical history.
• Adverse event – description, results of investigation tests, start date, course and outcome.
• Suspected drugs – name, dose, route, administered and withdrawal date.
• Other used drugs name, routes, and dose.
• Risk factors
• Name and address of reporter used for data verification.

17. THANK YOU