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ADVERSE EVENTS AND NON-COMPLIANT PRODUCTS Presented by Nazarita T. Lanuza, R. Ph., M. M. COSMETO-VIGILANCE Adverse event reporting and Causality Cosmeto-vigilance ● There is no definition worldwide of cosmeto-vigilance and adverse events on cosmetics. ● Pharmacovigilance is being done in most countries Why Pharmacovigilance? Pharmacovigilance is the science of collecting, monitoring, researching and evaluating data on the effects of medicinal drugs, biological products, herbals and traditional medicines with a view to identifying new information about adverse reactions and preventing harm to patients. The information collected during the pre-marketing phase of a medicinal drug is inevitably incomplete with regard to possible adverse reactions: ● Test in animals are insufficiently predictive of human safety. ● In clinical trials patients are selected and limited in number, the conditions of use differ from those in clinical practice and the duration of trials is limited. ● Information about rare but serious adverse reactions, chronic toxicity, use in special groups (such as children, the elderly or pregnant women) or drug interactions is often incomplete or not available Pharmacovigilance is needed in every country, because there are differences between countries (and even within countries) in the occurrence of adverse drug reactions and other drug-related problems. This may be because of differences in: ● Drug production ● Distribution and use (e.g. indication, dose, availability) ● Genetics, diet, traditions of the people ● Pharmaceutical quality and composition (excipients) of locally produced pharmaceutical products ● The use of non-orthodox drugs (e.g. herbal medicines) which may pose special toxicological problems, when used alone or in combination with other drugs. Pharmacovigilance is needed for the prevention of drug-induced human suffering and to avoid financial risks associated with unexpected adverse effects. Definition of Adverse Drug Reaction Any response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function. ● Thalidomide incident in the 1960’s An adverse reaction may result from effects of the drug, of illness, and their interaction with each other. Causality between the clinical event and the drug may not always be present although with a reaction (ADR), causality is more definite. For adverse reactions during therapy, remember that they: ● ● ● ● Are undesirable Are unintentional Are suspected (not necessarily proven) May develop as a consequence of therapy or other procedures Key Points in ADR Reporting: * Identifying rare adverse effects * Monitoring newly introduced drugs where their safety profile is relatively unknown * Hypothesis generating and raising of signals or flags * Supporting the regulatory policies in the promotion of drug safety * Contributing to improvement in health policies and practices such as rational drug prescribing It should be emphasized that such reports are neither proof nor admission of causality. ADR monitoring teaches us what we do not know and how to become better healers. ADR ON ALLOPURINOL COSMETO-VIGILANCE ● Cosmetic products are consumer goods that are basically conceived to make people feel comfortable and happy after its use. ● But there are possibilities that the expected result turns to opposite: it is called an adverse event. Some allergic reaction to cosmetics such as poorly formulated antiperspirant COSMETO-VIGILANCE ● An adverse event may be encountered by consumers in the course or after the use of cosmetic products and can be originated by a misuse or by a faulty product (quality defect). Skin reaction ● Adverse effect can also originate from a physiological reaction to the chemicals 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 COSMETO-VIGILANCE ● Products are conceived to be safe for health when used in normal condition. Regulation contains many disposition in that direction. Some allergic reaction to cosmetics such as hair dye COSMETO-VIGILANCE ● But safety studies conducted with ingredients cannot provide an exhaustive guaranty of innocuity to all cosmetics for all consumers. Testing for allergic sensitivity, using progressively more dilute solutions on forearm skin COSMETO-VIGILANCE ● Despite important safety precaution, the use of cosmetic products present on the market, may some time reveal inadequate for certain people who are specifically sensitive to certain chemicals, adverse effect remains possible on these consumers. Skin reactions to irritants : irritated skin around the eyes, caused by a poorly formulated cosmetic product COSMETO-VIGILANCE ● Regulation trend is to make the monitoring of adverse effects related to health of consumers, a mandatory task for manufacturers. ● In the EU before the 7th amendment of the cosmetic Directive, there was no regulatory disposition for the monitoring of health related adverse effects generated by products on the market. COSMETO-VIGILANCE ● Some companies have however set up their own system allowing the gathering of such data. Such is also true in the United States. ● 7th Amendment makes the collection of information on health adverse effects mandatory. In addition, companies have to allow consumers a free access to these information. Information is limited only to health related events. COSMETO-VIGILANCE ● Free access to information are possible by electronic means (telephone or Internet) ● Collection of information is shared responsibility of the manufacturer, regulatory and users Example of organization set by companies: Consumers affected by an adverse event can have access to company through company address or <<A Phone Number>> usually printed on product label. Company receives and put on record the consumer’s complaint and other details and redirect the information to the person in charge of cometovigilance inside the company. cont. . . . The Person in charge of cosmetovigilance contacts the consumer back (by visit/phone/mail) and starts an investigation following a specific questionnaire in order to classify the type of effect encountered by the customer, its causality and the necessity to eventually have this consumer examined by a dermatologist. cont. . . . Companies set up a network of affiliated dermatologists is ready to diagnose specific cases and to inform the company on the health issues linked to the use of their products. COSMETO-VIGILANCE ● Data are collected in a data base and regularly reviewed. ● In case of a relation linking the adverse effect to the product composition, the causality is further investigated. ● Patch test with suspected ingredients in the product are conducted on consumers under the supervision of the dermatologist to help in identifying the substance that may have caused the adverse event. Data are fed back to the Research and Development laboratory of the company for statistical analysis. Confirming allergies: the results of a patch test on the skin of patients back Post Marketing Quality Compliance Programme (PMQCP) Objectives: PMQCP involves the active systematic scientifically valid collection, analysis and interpretation of data or other information about a marketed product. The data can reveal unforeseen adverse events, the actual rate of anticipated adverse events or other information necessary to protect the public health. Sampling: The approach shall be based on risk assessment. ● Adulterated ● Misbranded Criteria for sampled collection: ● Cosmetic products intended for use around the eye and genital regions, those that may come into contact with the conjunctiva or mucosa respectively. Criteria for sampled collection: ● Products where certain amount of the product may be ingested, inhaled or absorbed through the mucous membranes such as oral hygiene products and products used on lips. ● Hair colouring products that may contain prohibited or restricted colour additives. Criteria for sampled collection: ● Adulterated or misbranded cosmetic products. A cosmetic product is misbranded if its labeling is false or misleading, if it does not bear the required labeling information. Inspection of establishments: Factors to determine when an inspection is warranted: • Type and risk-level of products • Significance of market information and feedback from consumer or industry • Company’s history of compliance • Regulatory Authority’s surveillance and compliance activities Examples of Post Marketing Surveillance 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. ii. a market quality surveillance programme, 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 Marketing Surveillance Systems The PMS may be connected to a manual or electronicbased ACR reporting System. Manual System Electronic System Voluntary System *(Non-compliance) to Pre-Licensing Adverse Cosmetic Reaction Reporting Formal Programme Post-Marketing Surveillance Response-based Feedback / Complaints Safety Alerts / Public Notification Risk-based Suspension Of Sale *(Batch/Product) Recall/Withdrawal Guidelines on Cosmetic Product Adverse Reporting System Report 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 Guidelines on Cosmetic Product Adverse Reporting System Electronic ACR System 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. Guidelines on Cosmetic Product Adverse Reporting System 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: 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; and c. Facilitation of regulatory processes and decisions in each Member State through sharing of regulatory expertise and ideas. Guidelines on Cosmetic Product Adverse Reporting System cont. . . . . . . The development and implementation of the information exchange network may take effect in 2 phases: Phase 1 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 Guidelines on Cosmetic Product Adverse Reporting System cont. . . . . . . b. Identified scope of regulatory responsibility c. Types of information to be exchanged Phase 2 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) Guidelines on Cosmetic Product Adverse Reporting System cont. . . . . . . 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 dissemination e. Other trade information such as: i. ASEAN Cosmetic Directives and new updates ii. Guidelines (e.g. GMP Guidelines, PMS / SE Guidelines, etc iii. Test methodology iv. Cosmetic Ingredients and nomenclature v. Scientific review of cosmetic products Guidelines on Cosmetic Product Adverse Reporting System cont. . . . . . . A diagrammatic depiction of the Information Exchange Network is shown below: Enquiries (Products, Dealers Sharing of Regulatory Information / Expertise Information / Alerts on ACR, Recall, Risks, etc. Forum on new Regulatory Initiatives, Projects Information Exchange Network ASEAN MEMBER STATES Guidelines on Management of Adverse Information on Cosmetic Products Evaluation of Adverse Report 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. Guidelines on Management of Adverse Information on Cosmetic Products Outcomes • Action by the Regulatory Authority: Each Member State shall have full authority to determine and impose the remedial actions and legal penalties under the situation of product noncompliance of the company to the requirements of the ASEAN Cosmetic Directives. • Withdrawal or suspension of sale: 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. Guidelines on Management of Adverse Information on Cosmetic Products Cont . . . . . . • Issuance of safety alert / product notification: 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. • Recall 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. Guidelines on Management of Adverse Information on Cosmetic Products Cont . . . . . . The information to be provided should include but not limited to the following: a) Details of Defect • 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 Guidelines on Management of Adverse Information on Cosmetic Products Cont . . . . . . b) Details of Defective Product • 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) Guidelines on Management of Adverse Information on Cosmetic Products Cont . . . . . . c) Details of Manufacturer / Product Owner / Company Responsible • Name of Company • Name of person responsible • Telephone No. / Fax No. of person responsible Guidelines on Management of Adverse Information on Cosmetic Products • Assessment of Recall The recall classification and recall level are determined by consultation between the Company and the Regulatory Agency. a) Recall Classification Class 1 recall This is initiated when the problem or defect poses a life-threatening situation to users. Class 2 recall This is initiated when the problem or defect is unlikely to cause serious harm to users. Guidelines on Management of Adverse Information on Cosmetic Products • 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. Guidelines on Management of Adverse Information on Cosmetic Products cont . . . . . . 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 Guidelines on Management of Adverse Information on Cosmetic Products 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 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. Guidelines on Management of Adverse Information on Cosmetic Products 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. Guidelines on Management of Adverse Information on Cosmetic Products • 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 I. Company Particulars Name of Company Person Responsible Tel. No. II. Product Particulars Product Name including strength Dosage Form Product Licence No. (if any) Batch No. Pack Size Expiry Date Manufacturer Country of Manufacture Active Ingredient(s) and Strength Type of product e.g. medicinal product, cosmetic Example of Defective Products Notification Form III. Product Defect Particulars INFORMATION ON PRODUCT DEFECTS 1 Date of occurrence of defect 2 Nature and cause of defect 3 Number of occurrence of similar defects 4 Results of tests or investigations on suspected products or other products 5 Assessment of risk to user 6 Proposed action by company including recall classification and level 7 Other relevant details Example of Defective Products Notification Form IV. Import / Manufacture and Sales Particulars INFORMATION ON IMPORT / MANUFACTURE / SALE 1 Date and quantity imported or manufactured (for locally manufactured product) 2 Date and quantity sold or supplied 3 Date and quantity remaining in the warehouse 4 Date and quantity exported and to which country 5 Names and addresses of purchasers of product *6 (Quantity recalled from purchasers) Signature Name of person making report Date THANK YOU ! ! !