Overview and application

R.RAJESH M.Pharm

What is Pharmacovigilance? Pharmacovigilance is defined as the science and activities concerned with the detection, assessment, understanding and prevention of adverse reactions to medicines (i.e. adverse drug reactions or ADRs). The ultimate goal of this activity is to improve the safe and rational use of medicines, thereby improving patient care and public health.

Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems.

Recently, its concerns have been widened to include: herbals traditional and complementary medicines blood products biologicals medical devices vaccines.

 Many

other issues are also of relevance to the science:

substandard medicines medication errors lack of efficacy reports use of medicines for indications that are not approved and for which there is inadequate scientific basis case reports of acute and chronic poisoning assessment of drug-related mortality abuse and misuse of medicines adverse interactions of medicines with chemicals, other medicines, and food.

improve patient care and safety in relation to the use of medicines and all medical and paramedical interventions. improve public health and safety in relation to the use of medicines.

contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use.
promote understanding, education and clinical training in pharmacovigilance and its effective communication to the public.

There are differences among countries (and even regions within countries) in the occurrence of ADRs and other drugrelated problems. This may be due to differences in diseases and prescribing practices, genetics, diet, traditions of the people, drug manufacturing processes used which influence pharmaceutical quality and composition, drug distribution and use including indications, dose and availability. The use of traditional and complementary drugs (e.g. herbal remedies) may also pose specific toxicological problems, when used alone or in combination with other drugs.

Therefore, Pharmacovigilance is needed for detecting ADRs and specifically to combat counterfeit and substandard quality products. ADR monitoring ensures that patients obtain safe and efficacious products.

Pharmacovigilance Why?
At

the time of approval, clinical trial data are available on limited numbers of patients treated for relatively short periods Once a product is marketed, large numbers of patients may be exposed, including:

Patients with co-morbid illnesses Patients using concomitant medications Patients with chronic exposure

Type A and Type B by Rawlins and Thompson

Type A Qualitatively normal but augmented responses to drugs Predictable from the pharmacology of concerned drug Effects are dose dependent Do not generally cause serious illness, rarely fatal Resolve when the dose is reduced Relatively common Identified during premarketing phase Type B Bizzare effects Unpredictable on the basis of known pharmacology of drug Effects are unrelated to dose Can cause serious illness and death Warrant complete withdrawal of drug Comparatively rare Continuous PMS necessary for identification

Type A (Augmented) These include the common,

pharmacologically predictable dose related reactions which improve when the medicine is withdrawn.
with the microorganisms. Eg: sugar containing medicines promoting dental caries, broad spectrum antibiotics causing oral thrush. to drug concentrations. Eg: phlebitis, pain at the site of injection, contact dermatitis and gastric mucosal damage by local irritant action. used or the nature of formulation. Eg: particles in the injection causing thrombosis or infection due to contamination of injection solution with microorganism.

Type B (Bugs) similar type-A but they involve interaction

Type C (Chemical) These involve irritant actions related

Type D (Delivery) caused by the method of administration

Type E (Exit) These reactions are pharmacologically

predictable but they begin only when the medicine is withdrawn or the dose is reduced. They improve when the medicine is reintroduced. Eg: established reactions with opioids, benzodiazepines, tricyclic antidepressants.
susceptible individuals with genetically determined, inherited, metabolic disorders. Eg: patients suffering from G6PD deficiency may experience hemolysis when exposes to quinine. irreversible genetic damage in humans. Some teratogenic agents damage genetic material with the foetus.

Type F (Familial) These reactions occur only in

Type G (Genotoxicity) A number of drugs can produce

Type H (Hypersensitivity) These reactions require

activation of immune system. Eg: anaphylaxis, allergic skin rashes Type U (Unclassified) produced by mechanism which are still not understood. Eg: drug induced taste disturbance.

 There

are three major determinants to drug response; the drug itself, the patient and the extrinsic factors. related to these determinants serve as criteria for selective clinical monitoring of patients as they often predispose the patients to ADRs.

Factors

1)

Dose Ingestion of excessive amount of drug will cause more

intense pharmacological response and a greater likelihood of adverse effects. Eg: arthritic and asthmatic patients may consume larger dose of NSAIDs.

2)

Formulation Particle size, tablet disintegration time and

dissolution rate, presence of excipients in dosage form and degree of purity influence drug absorption and thus the potential for adverse effects. Eg: macrocrystals of nitrofurantoin are associated with less GI adverse effects than microcrystalline formulation, presence of preservatives (products that contain parabens).

3)

Physiochemical Properties including Ph, degree of ionization,

lipid solubility, protein binding and extent of first pass metabolism can alter the bioavailability of a drug.

4)

Rate and Route of Administration The IV route provides

complete bioavailability while the IM and rectal routes have slower and more erratic absorption patterns. BA from oral route depend on certain factors.

1)

Age - Geriatrics: misuse of medications, non compliance, use of non prescribed drugs, errors in dosage timing or due to forgetfulness, bad eyesight and lack of comprehension about the drug regimen

- Pediatrics: incomplete physiological development can predispose, incompletely developed intrinsic defense mechanism
2)

Pregnancy teratogenic effect. Eg: drugs like phenytoin, haloperidol, some anti cancer drugs, diazepam, phenytoin Concurrent Diseases - Hepatic Diseases - Renal Diseases Genetics Hereditary factors have been shown to predispose individuals to increases toxicity to drugs. Patients vary in their ability to biotransform these drugs and these may result in increased serum conc and toxicity.

3)

4)

5) 6)

Gender Nutrition The nutritional status of a patient is another

factor predisposing to ADRs. Eg: salt substitute containing potassium can cause hyperkalemia in the presence of potassium sparing diuretics (spiranolactone), Benzodiazepines when taken with grape juice causes inhibition of cytochrome P450 enzyme system causing high serum level of drug and respiratory depression.

7)

Extrinsic factors environmental temperature has been

cited as a predisposing factor to ADRs. Eg: Diuretics such as thiazides may also cause photosensitivity and also excessive loss of fluid and salt which has negative implications for persons in hot environment.

Signal Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or in completely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information.
The discovery of adverse effects is a stepwise process consisting of:

Hypothesis generation Hypothesis strengthening Preliminary assessment of available data Signal testing, evaluation and detection

The discovery of new ADRs may be hindered by a number of reaction such as:
When

frequency of the adverse effect is low When frequency of exposure to the drug is relatively low When there is no suggestive time or dose relationship

Signals in Pharmacovigilance are usually derived from observations in individual patients or in population or from experimental studies and have a Qualitative and Quantitative dimension.
Observation in Patients (Qualitative Signals) Spontaneous reporting systems Anecdotal literature reporting Intensive hospital monitoring Prescription event monitoring Follow up studies

Observations In Populations (Quantitative signals) Large Data Resources on Morbidity Drug Use Case control studies : case control surveillance Follow- up studies Prescription Event Monitoring Intensive hospital monitoring Large Spontaneous reporting system (eg. WHO, US FDA)
Experimental Findings Clinical Trials In Vitro Experiments Animal Toxicology

 Causality

Assessment of Suspected Adverse

Reactions Criteria for determining causative drugs relationship to ADR Naranjo Algorithm Criteria for determining preventability of an ADR Modified Schumock and Thornton ADR severity assessment scale Modified Hartwig and Siegel

Causality assessment is the method by which the extent of relationship between a drug and a suspected reaction is established Currently wide variety of causality assessment scales exist, to attribute clinical events to drugs in individual patients or in case reports, each with their own advantages and limitations. These scales include
- Karch & Lasagna scale

Naranjo's scale WHO probability scale Spanish quantitative imputation scale Kramer's scale Jones scale European ABO system Bayesian system.

 Are Did Did

there previous conclusive reports on this reaction? the ADR appear after the suspected drug was administered? the ADR improve when the drug was discontinued or a specific antagonist was administered? the ADR reappear when the drug was readministered? the ADR confirmed by objective evidence

Did

Was

 Are Did

there alternative causes that could on their own have caused the reaction?

the ADR reappear when a placebo was given?

the drug detected in the blood (or other fluids) in concentrations known to be toxic? the ADR more severe when the dose was increased or less severe when the dose was decreased?

Was Was

Did

the patient have a similar ADR to the same or similar drugs in any previous exposure?

question Are there previous conclusion reports on this reaction?

Yes +1

No 0 -1

Don't know 0 0

Did the adverse event appear after the suspect drug was administered? +2 Did the AR improve when the drug was discontinued or a specific antagonist was administered? Did the AR reappear when drug was readministered? Are there alternate causes [other than the drug] that could solely have caused the reaction? Did the reaction reappear when a placebo was given? Was the drug detected in the blood [or other fluids] in a concentration known to be toxic? Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? Did the patient have a similar reaction to the same or similar drugs in any previous exposure? Was the adverse event confirmed by objective evidence?

+1

+2

-1

-1

+2

-1

+1

+1

+1

+1

+1

SCORING FOR NARANJO's ALGORITHM > 9 = definite ADR 5-8 = probable ADR 1-4 = possible ADR 0 = doubtful ADR

WHO SCALE OF ASSESSMENT

1.CERTAIN A clinical event, including laboratory test abnormality, occurring in a plausible time relationship to drug administration, and which cannot be explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be clinically plausible. The event must be definitive pharmacologically, using a satisfactory rechallenge procedure if necessary. A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is not required to fulfil this definition. A clinical event, including laboratory test abnormality, with a reasonable time sequence to administration of the drug, but which could also be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. A clinical event, including laboratory test abnormality, with a temporal relationship to drug administration which makes a causal relationship improbable, and in which other drugs, chemicals or underlying disease provide plausible explanations. A clinical event, including laboratory test abnormality, reported as an adverse reaction, about which more data is essential for a proper assessment or the additional data are under examination. A report suggesting an adverse reaction which cannot be judged because information is insufficient or contradictory, and which cannot be supplemented or verified.

2.PROBABLE/ LIKELY

3.POSSIBLE

4.UNLIKELY

5.CONDITIONAL/ UNCLASSIFIED

6.UNASSESSIBLE/ UNCLASSIFIABLE

Objective: The guideline describes a method for

summarizing the important - identified risks - potential risks - missing information Including the potentially at-risk populations and situations where the product is likely to be used that have not been studied pre-approval.

The purpose of this guideline is to propose a structure for a Pharmacovigilance Plan, and a Safety Specification that summarizes the identified and potential risks of the product to be addressed in the plan. The guideline is divided into the following sections:

Safety Specification; Pharmacovigilance Plan; Pharmacovigilance Methods.

The following principles underpin this guideline:

Planning of pharmacovigilance activities throughout the product life-cycle; Science-based approach to risk documentation Effective collaboration between regulators and industry; Applicability of the Pharmacovigilance Plan across the three ICH region

The Safety Specification should be a summary of the important identified risks, potential risks, missing information. It should also address the population potentially at-risk (where the product is likely to be used), and outstanding safety questions which warrant further investigation to refine understanding of the benefit-risk profile during the post approval period. The Safety Specification is intended to help industry and regulators identify any need for specific data collection and also to facilitate the construction of the Pharmacovigilance Plan.

It is recommended that sponsors follow the structure of elements provided when compiling the safety specification
1)

Non-Clinical Within the specification, this section should present non-clinical safety findings that have not been adequately addressed by clinical data, for example: - Toxicity - General pharmacology - Drug interactions - Other toxicity-related information or data

Note: If the product is intended for use in special populations, consideration should be given to whether specific non-clinical data needs exist.

2)
a)

Clinical
Limitations of the Human Safety Database It should be considered and the implications of such limitations w.r.t predicting the safety of the product in the marketplace should be explicitly discussed. Population not studied in the Pre-approval phase Such population includes: - Children - The elderly - Pregnant or lactating women - Patients with relevant co-morbidity such as hepatic or renal disorders - Patients with disease severity different from that studied in clinical trials - Sub-populations carrying known and relevant genetic polymorphism - Patients of different racial and/or ethnic origins.

b)

c) Adverse Events (AEs)/Adverse Drug Reactions (ADRs)

- Identified risks that require further evaluation - those that are serious or frequent and that
also might have an impact on the balance of benefits and risks of the product

- Potential risks that require further evaluation - Important potential risks should be described

in this section. It is anticipated that for any important potential risk, there should be further evaluation to characterize the association.

d) Identified and Potential Interactions, Including food-drug

and drug-drug interactions

e) Epidemiology The epidemiology of the indication(s) should

be discussed. This discussion should include incidence, prevalence, mortality and relevant co-morbidity, and should take into account whenever possible different stratifications f) Pharmacological class effects The safety specification should identify risks believed to be common to the pharmacological class

The pharmacovigilance plan should be based on the safety specification. The specification and plan can be written as two parts of the same document. The plan would normally be developed by the sponsor and can be discussed with regulators during product development , prior to approval (i.e., when the marketing application is submitted) of a new product or when a safety concern arises postmarketing. The plan should be updated as important information on safety becomes available.

1)

Summary of ongoing safety issues- At the beginning of the PP a summary should be provided. This is important if the PP is a separate document from the safety specification. Routine pharmacovigilance practices- which should include: - Systems and process that ensure that information about all suspected adverse reactions that are reported to the personnel of the company are collected and collated in an accessible manner - The preparation of reports for regulatory authorities: - Expedited ADR reports - PSURs

2)

- Continuous monitoring of the safety profile of approved products including signal detection, issue evaluation, updating of labeling, and liaison with regulatory authorities
- Other requirements, as defined by local regulations.

3) Action plan for safety issues:- it should be presented and justified according to the following: - safety issue - Objective of proposed action(s) - Action(s) proposed - Rationale for proposed action(s) - Monitoring by the sponsor for safety issue and proposed action(s) - Milestones for evaluation and reporting 4) Summary of actions to be completed, including milestones: - The reason for this is that one proposed action could address more than one of the identified issues.

Withdrawn Drugs (in the US, since 2000)

Drug Lumiracoxib Aprotinin Tegaserod Ximelagatran Valdecoxib Pemoline Rofecoxib Levomethadyl Rapacuronium Cerivastatin Trovafloxacin Amineptine Cisapride Troglitazone Year 2008 2008 2007 2006 2005 2005 2004 2003 2001 2001 2001 2000 2000 2000 Reason Hepatotoxicity Kidney and cardiovascular toxicity Cardiovascular ischemic events Hepatotoxicity Dermatology adverse events Hepatotoxicity Thrombotic cardiovascular events Fatal Arrhytmia Risk of fatal bronchospasm Rhabdomyolosis Hepatotoxicity Hepatotoxicity, dermatological side effects, abuse potential Cardiac arrhythmias Hepatotoxicity

Report all suspected ADRs YOU DO NOT NEED TO BE CERTAIN. JUST BE SUSPICIOUS !

DISCUSSION

Facts
Generic

drugs are safe and effective alternatives to brand name prescriptions drugs can help both consumers and the government reduce the cost of prescription drugs

Generic

Original Drug NDA Requirements 1. Chemistry 2. Manufacturing 3. Controls 4. Labeling 5. Testing 6. Animal Studies 7. Clinical Studies (Bioavailability/Bioeq uivalence)

Generic Drug ANDA Requirements 1. Chemistry 2. Manufacturing 3. Controls 4. Labeling 5. Testing 6. Bioequivalence Study (In Vivo, In vitro)

Note: Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the original drug).

A drug product that is comparable to a brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use.
Prior to this, companies had to independently establish the safety and efficacy of their generics.
When can a Generic Drug be Marketed? After patent & exclusivity protection ends, or Patent owner waives its rights, and FDA requirements are met

The extent and rate at which its active moiety is delivered from pharmaceutical form and becomes available in the systemic circulation
Pharmacokinetics
conc. vs time

Conc.(mg/L)

0.0 0

Time (h)

25

Specific studies performed with two or more different formulations of a given drug and designed to identify if the blood levels, the time course of these blood levels and the elimination of the drug from body are the same or different between formulations.

The true dose is not the drug swallowed; BUT is the drug available to exert its effect. - Dissolution - Absorption - Survive metabolism May have a drug with very low bioavailability - Dosage form or drug may not dissolve readily - Drug may not be readily pass across biological membranes (i.e.be absorbed) - Drug may be extensively metabolized during absorption process (first-pass, gut wall, liver) Important component of overall variability - Variable bioavailability may produce variable exposure

Extent of absorption is reflected by AUC Rate of absorption, ka, is reflected by Tmax Both Rate and Extent of absorption affect Cmax
Leads to 4 possible relative scenarios:
(R) Rapid, (E) Complete Absorption yields a short Tmax, high Cmax, high AUC yields a short Tmax, low Cmax, low AUC

Pharmacokinetics
conc. vs time
Conc.(mg/L)
0.0 0

(R) Rapid, (E) incomplete absorption (R) Slow, (E) complete absorption yields a long Tmax, high Cmax, high AUC (R) Slow, (E) incomplete absorption yields a long Tmax, low Cmax, low AUC

Time (h)

25

the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
A generic drug is considered to be bioequivalent to the brand name drug if:
The rate and extent of absorption do not show a significant difference from listed drug, or The extent of absorption does not show a significant difference and any difference in rate is intentional or not medically significant

A bioavailability study conducted using the same drug that has been manufactured by two different companies. The aim of the study is to show that two drugs have the same bioavailability profile (i.e. they are bioequivalent)

No clinical studies have been performed in patients with the Generic Product to support its Efficacy and Safety.
With data to support similar in vivo performance (= Bioequivalence) Efficacy and Safety data can be extrapolated from the Innovator Product to the Generic Product.