Presented by Nazarita T. Lanuza, R. Ph., M. M. ADVERSE EVENTS AND NON-COMPLIANT PRODUCTS

Presented byNazarita T. Lanuza, R. Ph., M.

M.

ADVERSE EVENTSAND

NON-COMPLIANT PRODUCTS

COSMETO-VIGILANCECOSMETO-VIGILANCE

Adverse event reporting Adverse event reporting andand

CausalityCausality

● There is no definition worldwide of There is no definition worldwide of cosmeto-vigilance and adverse cosmeto-vigilance and adverse events on events on cosmetics. cosmetics.

Cosmeto-vigilanceCosmeto-vigilance

● Pharmacovigilance is being done in Pharmacovigilance is being done in most most countries countries

Pharmacovigilance is the science Pharmacovigilance is the science of collecting, monitoring, researching of collecting, monitoring, researching and evaluating data on the effects of and evaluating data on the effects of medicinal drugs, biological products, medicinal drugs, biological products, herbals and traditional medicines with herbals and traditional medicines with a view to identifying new information a view to identifying new information about adverse reactions and about adverse reactions and preventing harm to patients.preventing harm to patients.

The information collected during The information collected during the pre-marketing phase of a medicinal the pre-marketing phase of a medicinal drug is inevitably incomplete with drug is inevitably incomplete with regard to possible adverse reactions:regard to possible adverse reactions:

Why Pharmacovigilance?Why Pharmacovigilance?

● Test in animals are insufficiently Test in animals are insufficiently predictive of human safety. predictive of human safety.

● Information about rare but serious Information about rare but serious adverse reactions, chronic toxicity, adverse reactions, chronic toxicity, use in use in special groups (such as children, the special groups (such as children, the

elderly or pregnant women) or drug elderly or pregnant women) or drug interactions is often incomplete or interactions is often incomplete or not not available available

● In clinical trials patients are In clinical trials patients are selected and selected and limited in number, the conditions of limited in number, the conditions of use use differ from those in clinical practice differ from those in clinical practice and and the duration of trials is limited. the duration of trials is limited.

Pharmacovigilance is needed in Pharmacovigilance is needed in every country, because there are every country, because there are differences between countries (and differences between countries (and even within countries) in the even within countries) in the occurrence of adverse drug reactions occurrence of adverse drug reactions and other drug-related problems. This and other drug-related problems. This may be because of differences in:may be because of differences in:

● Drug productionDrug production

● Genetics, diet, traditions of the Genetics, diet, traditions of the peoplepeople

● Distribution and use (e.g. indication, Distribution and use (e.g. indication,

dose, availability) dose, availability)

● Pharmaceutical quality and Pharmaceutical quality and composition composition (excipients) of locally produced (excipients) of locally produced pharmaceutical products pharmaceutical products

● The use of non-orthodox drugs (e.g. The use of non-orthodox drugs (e.g. herbal herbal medicines) which may pose special medicines) which may pose special toxicological problems, when used toxicological problems, when used alone or alone or in combination with other drugs. in combination with other drugs.

Pharmacovigilance is needed for the Pharmacovigilance is needed for the prevention of drug-induced human prevention of drug-induced human suffering suffering and to avoid financial risks associated and to avoid financial risks associated with with unexpected adverse effects. unexpected adverse effects.

Any response to a drug which is Any response to a drug which is noxious and unintended and which noxious and unintended and which occurs at doses normally used in man occurs at doses normally used in man for prophylaxis, diagnosis or therapy for prophylaxis, diagnosis or therapy of disease, or for the modification of of disease, or for the modification of physiological function.physiological function.

● Thalidomide incident in the Thalidomide incident in the 1960’s1960’s

Definition of Adverse Drug Definition of Adverse Drug ReactionReaction

An adverse reaction may result from An adverse reaction may result from effects of the drug, of illness, and their effects of the drug, of illness, and their interaction with each other. Causality interaction with each other. Causality between the clinical event and the between the clinical event and the drug may not always be present drug may not always be present although with a reaction (ADR), although with a reaction (ADR), causality is more definite. For adverse causality is more definite. For adverse reactions during therapy, remember reactions during therapy, remember that they:that they:

● Are undesirable● Are unintentional● Are suspected (not necessarily proven)● May develop as a consequence of therapy or other procedures

* * Identifying rare adverse effectsIdentifying rare adverse effects

* * Monitoring newly introduced drugs Monitoring newly introduced drugs where where their safety profile is relatively their safety profile is relatively unknownunknown

** Hypothesis generating and raising of Hypothesis generating and raising of

signals or flags signals or flags

* * Supporting the regulatory policies in Supporting the regulatory policies in the the promotion of drug safety promotion of drug safety

Key Points in ADR Reporting:Key Points in ADR Reporting:

It should be emphasized that It should be emphasized that such reports are neither proof nor such reports are neither proof nor admission of causality. ADR admission of causality. ADR monitoring teaches us what we do monitoring teaches us what we do not know and how to become better not know and how to become better healers.healers.

* * Contributing to improvement in health Contributing to improvement in health

policies and practices such as rational policies and practices such as rational drug prescribingdrug prescribing

ADR ON ALLOPURINOL

● Cosmetic products are consumer Cosmetic products are consumer goods goods that are basically conceived to make that are basically conceived to make people feel comfortable and happy people feel comfortable and happy after after its use. its use.


● But there are possibilities that the But there are possibilities that the expected result turns to opposite: it expected result turns to opposite: it is is called an adverse event. called an adverse event.

Some allergic reaction to cosmetics such as poorly formulated antiperspirant


● An adverse event may be An adverse event may be encountered by encountered by consumers in the course or after the consumers in the course or after the use use of cosmetic products and can be of cosmetic products and can be originated by a misuse or by a faulty originated by a misuse or by a faulty

product (quality defect). product (quality defect). Skin reaction

● Adverse effect can also originate from Adverse effect can also originate from a a physiological reaction to the chemicals physiological reaction to the chemicals present in the product (health concern). present in the product (health concern).

Some allergic reaction to cosmetics such as beach sunscreen

Skin allergies to a plant (Primula)

Skin reactions to irritants : exfoliation of hand skin by cleansing liquid


● Products are conceived to be safe Products are conceived to be safe for for health when used in normal health when used in normal condition. condition. Regulation contains many Regulation contains many disposition in disposition in that direction. that direction.

Some allergic reaction to cosmetics such as hair dye


● But safety studies conducted with But safety studies conducted with ingredients cannot provide an ingredients cannot provide an exhaustive exhaustive guaranty of innocuity to all guaranty of innocuity to all cosmetics for cosmetics for all consumers. all consumers.

Testing for allergic sensitivity, using progressively more dilute solutions on forearm skin


● Despite important safety precaution, Despite important safety precaution, the the use of cosmetic products present on use of cosmetic products present on the the market, may some time reveal market, may some time reveal inadequate inadequate for certain people who are for certain people who are specifically specifically sensitive to certain chemicals, sensitive to certain chemicals, adverse adverse effect remains possible on these effect remains possible on these consumers. consumers.

Skin reactions to irritants : irritated skin around the eyes, caused by a poorly formulated cosmetic product


● Regulation trend is to make the Regulation trend is to make the monitoring of adverse effects monitoring of adverse effects related to related to health of consumers, a mandatory health of consumers, a mandatory task task for manufacturers. for manufacturers.● In the EU before the 7th amendment In the EU before the 7th amendment of of the cosmetic Directive, there was no the cosmetic Directive, there was no regulatory disposition for the regulatory disposition for the monitoring monitoring of health related adverse effects of health related adverse effects generated by products on the market. generated by products on the market.


● Some companies have however set Some companies have however set up up their own system allowing the their own system allowing the gathering gathering of such data. Such is also true in the of such data. Such is also true in the United States. United States.● 7th Amendment makes the 7th Amendment makes the collection of collection of information on health adverse information on health adverse effects effects mandatory. In addition, companies mandatory. In addition, companies have have to allow consumers a free access to to allow consumers a free access to these these information. Information is limited information. Information is limited only only to health related events. to health related events.


● Free access to information are Free access to information are possible by possible by electronic means (telephone or electronic means (telephone or Internet)Internet)● Collection of information is shared Collection of information is shared responsibility of the manufacturer, responsibility of the manufacturer, regulatory and users regulatory and users

Example of organization set by Example of organization set by companies:companies:

Consumers affected by an adverse event Consumers affected by an adverse event can have access to company through can have access to company through company address or <<A Phone company address or <<A Phone Number>> usually printed on product Number>> usually printed on product label. Company receives and put on label. Company receives and put on record the consumer’s complaint and record the consumer’s complaint and other details and redirect the other details and redirect the information to the person in charge of information to the person in charge of cometovigilance inside the company.cometovigilance inside the company.

The Person in charge of The Person in charge of cosmetovigilance contacts the cosmetovigilance contacts the consumer back (by visit/phone/mail) consumer back (by visit/phone/mail) and starts an investigation following and starts an investigation following a specific questionnaire in order to a specific questionnaire in order to classify the type of effect classify the type of effect encountered by the customer, its encountered by the customer, its causality and the necessity to causality and the necessity to eventually have this consumer eventually have this consumer examined by a dermatologist.examined by a dermatologist.

cont. . . .cont. . . .

Companies set up a network of Companies set up a network of affiliated dermatologists is ready to affiliated dermatologists is ready to diagnose specific cases and to inform diagnose specific cases and to inform the company on the health issues the company on the health issues linked to the use of their products.linked to the use of their products.

cont. . . .cont. . . .


● Data are collected in a data base Data are collected in a data base and and regularly reviewed. regularly reviewed.● In case of a relation linking the In case of a relation linking the adverse adverse effect to the product composition, effect to the product composition, the the causality is further investigated. causality is further investigated.

● Patch test with suspected Patch test with suspected ingredients in ingredients in the product are conducted on the product are conducted on consumers consumers under the supervision of the under the supervision of the dermatologist to help in identifying dermatologist to help in identifying the the substance that may have caused the substance that may have caused the adverse event. Data are fed back to adverse event. Data are fed back to the the Research and Development Research and Development laboratory of laboratory of the company for statistical analysis.the company for statistical analysis.

Confirming allergies: the results of a patch test on the skin of patients back

PMQCP involves the active systematic PMQCP involves the active systematic scientifically valid collection, analysis scientifically valid collection, analysis and interpretation of data or other and interpretation of data or other information about a marketed product.information about a marketed product.

The data can reveal unforeseen The data can reveal unforeseen adverse events, the actual rate of adverse events, the actual rate of anticipated adverse events or other anticipated adverse events or other information necessary to protect the information necessary to protect the public health.public health.

Post Marketing Quality Post Marketing Quality Compliance Programme (PMQCP)Compliance Programme (PMQCP)

ObjectivesObjectives::

The approach shall be based on The approach shall be based on risk assessment.risk assessment.

Sampling:Sampling:

● Cosmetic products intended for use Cosmetic products intended for use around the eye and genital regions, around the eye and genital regions, those those that may come into contact with the that may come into contact with the conjunctiva or mucosa respectively. conjunctiva or mucosa respectively.

Criteria for sampled Criteria for sampled collection:collection:

● AdulteratedAdulterated● MisbrandedMisbranded

● Products where certain amount of Products where certain amount of the the product may be ingested, inhaled or product may be ingested, inhaled or absorbed through the mucous absorbed through the mucous membranes such as oral hygiene membranes such as oral hygiene products products and products used on lips. and products used on lips.

Criteria for sampled collection:Criteria for sampled collection:

● Hair colouring products that may Hair colouring products that may contain contain prohibited or restricted colour prohibited or restricted colour additives.additives.

● Adulterated or misbranded cosmetic Adulterated or misbranded cosmetic

products. A cosmetic product is products. A cosmetic product is misbranded if its labeling is false or misbranded if its labeling is false or misleading, if it does not bear the misleading, if it does not bear the required labeling information. required labeling information.

Criteria for sampled collection:Criteria for sampled collection:

• Regulatory Authority’s surveillance Regulatory Authority’s surveillance and and compliance activities compliance activities

Factors to determine when an Factors to determine when an inspection is warranted:inspection is warranted:

Inspection of establishments:Inspection of establishments:

• Type and risk-level of productsType and risk-level of products

• Significance of market information Significance of market information and and feedback from consumer or industry feedback from consumer or industry• Company’s history of complianceCompany’s history of compliance

Examples of Post MarketingSurveillance Systems

.

A few Member States have implemented either a formal or response-based PMS system that include one or a combination of the following:

i. a market quality surveillance programme,ii. random and / or systematic checks through

sampling of products from the market and / or from

manufacturers and importers store, iii. checks in response to Adverse Cosmetic

Report (ACR) or complaints

Examples of Post MarketingSurveillance Systems

The PMS may be connected to a manual or electronic-based ACR reporting System.

Manual System

Electronic System

Voluntary System

*(Non-compliance)to Pre-Licensing

Adverse CosmeticReaction Reporting

Feedback /Complaints

Post-MarketingSurveillance

Formal Programme

Risk-based

Response-based

Safety Alerts/ Public

Notification

SuspensionOf Sale

*(Batch/Product)Recall/

Withdrawal

Guidelines on Cosmetic ProductAdverse Reporting System

.

Adverse information on cosmetic products can be made on prescribed forms, either manually or electronically. Information on ACR may come from the following sources:

• Consumer complaints• Feedback from health professionals• Product manufacturer and/or

importers, distributor• Regulatory Authorities of other

countries• ASEAN ACR Database

Report


A centralized ASEAN ACR Database to collect and document adverse reports from each ASEAN member through an Internet (World Wide Web) system is recommended.

The advantages and benefits of a centralized electronic database include the rapid retrieval of information so that prompt and effective actions could be taken to protect public health and safety.

Electronic ACR System


Information exchange among the regulators in ASEAN is a key factors in the successful implementation of PMS/SE. The objectives of the information Exchange Network include:

Electronic ACR System

a. Provision of a formal process of transfer of information across ASEAN Member States;b. Provision of a rapid, accurate and secure

channel for information flow to key regulatory agencies;

andc. Facilitation of regulatory processes and

decisions in each Member State through sharing of

regulatory expertise and ideas.


The development and implementation of the information exchange network may take effect in 2 phases:

cont. . . . . . .

A formal but simple system of communication network arrangement for Immediate implementation with the following features:

a. Contract points established within each ASEAN Member State

Phase 1


cont. . . . . . .

Enhancement of communication network established in Phase 1 by the hosting of an Internet-based website database management system with the following features:

a. Notifications, announcements and reports of the ASEAN Cosmetic Committee (ACC)

Phase 2

b. Identified scope of regulatory responsibilityc. Types of information to be exchanged


b. Reports on review of new cosmetic ingredients by the ASEAN Cosmetic Scientific Body (ACSB)c. Database could be maintained for information on defective cosmetic products, fraudulent companies, cosmetic products sold in the various ASEAN countries, GMP Audit reports, etc.d. Adverse Cosmetic Reaction reports – information uploaded in the website for rapid disseminatione. Other trade information such as:

i. ASEAN Cosmetic Directives and new updatesii. Guidelines (e.g. GMP Guidelines, PMS / SE Guidelines, etciii. Test methodologyiv. Cosmetic Ingredients and nomenclaturev. Scientific review of cosmetic products

cont. . . . . . .


A diagrammatic depiction of the Information Exchange Network is shownbelow:

cont. . . . . . .

Enquiries(Products, Dealers

Sharing of RegulatoryInformation / Expertise

Information / Alerts onACR, Recall, Risks, etc.

Forum on new RegulatoryInitiatives, Projects

InformationExchangeNetwork

ASEANMEMBERSTATES

Guidelines on Management of AdverseInformation on Cosmetic Products

On receipt of an adverse report, an evaluation of the health hazard presented

by a cosmetic product shall include but not limited to the following:

• Severe or unusual skin irritation or allergic reaction, eye irritation, urogenital tract or respiratory tract irritation, or apparent toxicity;

• Reports of unusually large numbers of adverse events, even when the event is less severe;

• Mislabelling because they contain unlisted ingredients, lack instructions for safe use, or lack of any necessary warning statements which may constitute health hazards;

• Suspectec microbiological contamination; or• Exposure to high levels of toxic heavy metals.

Evaluation of Adverse Report


Outcomes

Each Member State shall have full authority to determine and impose the remedial actions and legal penalties under the situation of product non-compliance of the company to the requirements of the ASEAN Cosmetic Directives.

• Action by the Regulatory Authority:

Remedial actions shall include mandatory and voluntary removal / suspension from sale by a company. The removal / suspension may be either a permanent or temporary removal of the affected product from the market for product correction, after which the corrected product may be returned to the market use.

• Withdrawal or suspension of sale:


Cont . . . . . .

The company may be required to provide advice to the public regarding a specific situation with respect to a product which, while performing to meet all specifications and therapeutic indications, might present an unreasonable risk of substantial harm if certain specified precautions in regard to its use are not observed.

• Issuance of safety alert / product notification:

A recall may either be a permanent removal of the affected products from the market or a temporary removal for product correction, after which the corrected products are returned to the market for use. The type of recall to be initiated will depend on the nature of the defect involved.

• Recall


Cont . . . . . .

• Date of occurrence of defect• Nature of defect• Cause of defect• Number of occurrence of similar defects• Results of tests or investigations on suspected products or other products• Assessment of risk to user• Proposed action by Company (in the local and ASEAN markets, where product is sold)• Proposed recall classification• Proposed recall level• Other relevant details

a) Details of Defect

The information to be provided should include but not limited to the following:


Cont . . . . . .

• Product name and its description, including strength, dosage form, pack size and identification number, if applicable• Batch number• Expiry date• Manufacturer• Country of manufacture• *(Quantity manufactured/imported)• *(Quantity sold, quantity of stocks held)• *(Quantity recalled from market (submitted after consolidation of recall report)

b) Details of Defective Product


Cont . . . . . .

• Name of Company• Name of person responsible• Telephone No. / Fax No. of person responsible

c) Details of Manufacturer / Product Owner /

Company Responsible


• Assessment of Recall

a) Recall Classification

The recall classification and recall level are determined by consultation between the Company and the Regulatory Agency.

Class 1 recallThis is initiated when the problem or defect poses a life-threatening situation to users.Class 2 recallThis is initiated when the problem or defect is unlikely to cause serious harm to users.


• Responsibilities of Manufacturer / Product Owner

The manufacturer / product owner has responsibility in the following 2 areas:

•Maintain sales records and establish proper procedures for effective recall of

product in the event that such action becomes necessary; and

•Take the prime responsibility in carrying out the product recalls, including

notification of recall to all affected parties, recovery of product, institution of corrective action and implementation of follow-up checks to ensure that recalls are successful and completed.

a) Records

The manufacturer / product owner must maintain and keep relevant records, to enable prompt and effective recall of affected products. All records should be readily to the Regulatory Authority available so as to expedite recall when necessary.


a) Implementation of Recall

When there is a recall initiated, the manufacturer / product owner should immediately place an embargo on the remaining stock of the product and notify all its customers to do likewise pending further investigation.

Recall letters to be sent out by manufacturer / product owner should contain factual information on the defective product. They should include but not limited to the following:

• Name of defective product• Active ingredients and strength• Pack size• Dosage form

cont . . . . . .


• Batch number• Manufacturer / Country of manufacture• Other details for easy identification• Reason(s) for recall – nature and cause of defect• Assessment of risk to user• Necessity to identify, cease sale and quarantine product• Method of recovery / collection of defective product by company• Date of recall letter• Name of person and company responsible and the contact numbers for inquiry• Signature of person responsible for the recall

cont . . . . . .

If the hazard to user is serious, indication of clinical symptoms and advice to consult a medical practitioner is warranted to be included in the recall letter.


cont . . . . . .

When there is a risk of significant hazard to consumers and the distribution has been extensive, the manufacturer / product owner responsible is required to employ all possible mass communication media available including newspaper, radio and television broadcast to disseminate the recall information to the consumers.

The manufacturer / product owner is also responsible for recovering the defective product from all affected parties, instituting corrective actions, if necessary and ensuring that the product recall is completed.

The manufacturer / product owner is required to submit a final report to the Regulatory Authorities of the country where the product is marketed, upon completion of the recall.


• Conclusion

Manufacturers, product owners and sellers are responsible for the quality, safety and efficacy of their products. All efforts must be made to ensure that recall operations are carried out as efficiently and effectively as possible. Appropriate follow-up actions must also be taken to prevent future recurrence of similar problem.

Example of Defective Products Notification Form

Name of CompanyName of Company

Person ResponsiblePerson Responsible Tel. No.Tel. No.

Product Name including Product Name including strengthstrength

Dosage FormDosage Form

Product Licence No. (if any)Product Licence No. (if any) Batch No.Batch No.

Pack SizePack Size Expiry DateExpiry Date

ManufacturerManufacturer Country of Country of ManufactureManufacture

Active Ingredient(s) and Active Ingredient(s) and StrengthStrength

Type of Type of product e.g. product e.g. medicinal medicinal product, product, cosmeticcosmetic

II. Product Particulars

I. Company Particulars


III. Product Defect Particulars

INFORMATION ON PRODUCT DEFECTSINFORMATION ON PRODUCT DEFECTS

11 Date of occurrence of defectDate of occurrence of defect

22 Nature and cause of defectNature and cause of defect

33 Number of occurrence of similar defectsNumber of occurrence of similar defects

44 Results of tests or investigations on suspected Results of tests or investigations on suspected products or other productsproducts or other products

55 Assessment of risk to userAssessment of risk to user

66 Proposed action by company including recall Proposed action by company including recall classification and levelclassification and level

77 Other relevant detailsOther relevant details


IV. Import / Manufacture and Sales Particulars

INFORMATION ON IMPORT / MANUFACTURE / SALEINFORMATION ON IMPORT / MANUFACTURE / SALE

11 Date and quantity imported or manufactured (for locally Date and quantity imported or manufactured (for locally manufactured product)manufactured product)

22 Date and quantity sold or suppliedDate and quantity sold or supplied

33 Date and quantity remaining in the warehouseDate and quantity remaining in the warehouse

44 Date and quantity exported and to which countryDate and quantity exported and to which country

55 Names and addresses of purchasers of productNames and addresses of purchasers of product

*6*6 (Quantity recalled from purchasers)(Quantity recalled from purchasers)

Signature Name of person making report Date

THANK YOU ! ! !THANK YOU ! ! !

Documents

Presented by Nazarita T. Lanuza, R. Ph., M. M. ADVERSE EVENTS AND NON-COMPLIANT PRODUCTS