The information from ADR cases when first received is generally incomplete. Ideally, comprehensive information would be available on all cases, but in practice efforts should be made to seek additional information on selected reports. In any scheme to optimize the value of follow-up, the first consideration should be prioritization of case reports by importance.
The priority for follow-up should be as follows: cases which are 1) both serious and unexpected, 2) serious and expected, and 3) non-serious and unexpected. In addition to seriousness and expectedness as criteria, cases "of special interest" also deserve extra attention as a high priority (e.g., ADRs under active surveillance at the request of the regulators), as well as any cases that might lead to a labeling change decision.
Follow-up information should be obtained, via a telephone call and/or site visit and/or via a written request. Efforts should be tailored toward optimising the chances to obtain the new information. Written confirmation of details given verbally should be obtained whenever possible. In exceptional circumstances, a regulatory authority might be able to assist an MAH to obtain follow-up data if requests for information have been refused by the reporter. The company should provide specific questions it would like to have answered.
In order to facilitate the capture of clinically relevant and complete information, use of a targeted questionnaire is encouraged, preferably at the time of the initial report. Ideally, healthcare professionals with thorough pharmacovigilance training and therapeutic expertise should be involved in the collection and the direct follow up of reported cases (particularly those of medical significance). For serious ADRs, it is important to continue follow-up and report new information until the outcome has been established or the condition is stabilized. How long to follow-up such cases will require judgment.MAHs should collaborate on follow-up if more than one MAH's drug is suspected as a causal agent in a case.
It is important that, at the time of the original report, sufficient details about the patient and reporter be collected and retained to enable future investigations, within the constraints imposed by local data privacy legislation.
Thursday, September 30, 2010
Single Case Evaluation- Good Case Management
The purpose of careful medical review is to ensure correct interpretation of medical information. Regardless of the source of an ADR report, the recipient should carefully review the report for the quality and completeness of the medical information. This should include, but is not limited to, consideration of the following:
Is a diagnosis possible?
Have the relevant diagnostic procedures been performed?
Were alternative causes of the reaction(s) considered?
What additional information is needed?
ADR terms should be used consistently and in accord with recommended standards for diagnosis. The report should include the verbatim term, which quotes the reporter. Staff receiving reports should provide an unbiased and unfiltered report of the information from the reporter. While the report recipient is encouraged to actively query the reporter to elicit the most complete account possible, inferences and imputations should be avoided in report submission. However, clearly identified evaluations by the MAH are considered acceptable and, for some authorities, required. Encouraging good communication on medical information with the reporter will serve to improve the quality of case documentation.
When a case is reported by a consumer, his/her description of the event should be retained, although confirmatory or additional information from any relevant healthcare professionals should also be sought and included. Ideally, supplemental information should be obtained from the healthcare professional directly involved in the care of the patient.
Is a diagnosis possible?
Have the relevant diagnostic procedures been performed?
Were alternative causes of the reaction(s) considered?
What additional information is needed?
ADR terms should be used consistently and in accord with recommended standards for diagnosis. The report should include the verbatim term, which quotes the reporter. Staff receiving reports should provide an unbiased and unfiltered report of the information from the reporter. While the report recipient is encouraged to actively query the reporter to elicit the most complete account possible, inferences and imputations should be avoided in report submission. However, clearly identified evaluations by the MAH are considered acceptable and, for some authorities, required. Encouraging good communication on medical information with the reporter will serve to improve the quality of case documentation.
When a case is reported by a consumer, his/her description of the event should be retained, although confirmatory or additional information from any relevant healthcare professionals should also be sought and included. Ideally, supplemental information should be obtained from the healthcare professional directly involved in the care of the patient.
Role of the Narratives
The objective of the narrative is to summarize all relevant clinical and related information, including patient characteristics, therapy details, medical history, clinical course of the event(s), diagnosis, and ADR(s) (including the outcome, laboratory evidence and any other information that supports or refutes an ADR). The narrative should serve as a comprehensive, stand-alone "medical story". The information should be presented in a logical time sequence; ideally this should be presented in the chronology of the patient's experience, rather than in the chronology in which the information was received. In follow-up reports, new information should be clearly identified.
Abbreviations and acronyms should be avoided, with the possible exception of laboratory parameters and units. Key information from supplementary records should be included in the report, and their availability should be mentioned in the narrative and supplied on request. Any autopsy or other post-mortem findings (including a coroner's report) should also be provided when available if allowed by local privacy protection laws. Terms in the narrative should be accurately reflected by appropriate coding.
Abbreviations and acronyms should be avoided, with the possible exception of laboratory parameters and units. Key information from supplementary records should be included in the report, and their availability should be mentioned in the narrative and supplied on request. Any autopsy or other post-mortem findings (including a coroner's report) should also be provided when available if allowed by local privacy protection laws. Terms in the narrative should be accurately reflected by appropriate coding.
Assessing Patient and Reporter Identifiability
Patient and reporter identifiability is necessary to avoid case duplication, detect fraud, and facilitate follow-up of appropriate cases. The term identifiable in this context refers to the verification of the existence of a patient and a reporter.
One or more of the following automatically qualifies a patient as identifiable: age (or age category, e.g., adolescent, adult, elderly), gender, initials, date of birth, name, or patient identification number. Additionally, in the event of second-hand reports, every effort should be made to verify the report source. All parties supplying case information (or approached for case information) are subject to the notion of identifiability: not only the initial reporter (the initial contact for the case), but also others supplying information.
In the absence of qualifying descriptors, a report referring to a definite number of patients should not be regarded as a case until the minimum four criteria for case reporting are met. For example, "Two patients experienced." or " a few patients experienced" should be followed up for patient-identifiable information before regulatory reporting.
One or more of the following automatically qualifies a patient as identifiable: age (or age category, e.g., adolescent, adult, elderly), gender, initials, date of birth, name, or patient identification number. Additionally, in the event of second-hand reports, every effort should be made to verify the report source. All parties supplying case information (or approached for case information) are subject to the notion of identifiability: not only the initial reporter (the initial contact for the case), but also others supplying information.
In the absence of qualifying descriptors, a report referring to a definite number of patients should not be regarded as a case until the minimum four criteria for case reporting are met. For example, "Two patients experienced." or " a few patients experienced" should be followed up for patient-identifiable information before regulatory reporting.
Good Case Management
Accurate, complete and bonafide information is very important for MAHs and regulatory agencies identifying and assessing ADR reports. Both are faced with the task of acquiring sufficient information to help ensure that the reports are authentic, accurate, as complete as possible, and non-duplicative.
- Assessing Patient and Reporter Identifiability
- Role of Narratives
- Single Case Evaluation
- Follow up Information
Pharmacovigilance software
The EMEA or the European Medicines Agency in Europe develops and maintains the pharmacovigilance database of probable serious adverse effect medicines in the market. This system is called EudraVigilance.
Similarly, the US medical society has its own pharmacovigilance branches namely; the FDA; the academic and non-profit organizations like RADAR and Public Citizen and the pharmaceutical manufacturers. Several companies like Aris Global, Relsys and Workflow have developed pharmacovigilance software to keep track of safety applications in the market.
Kinds of pharmacovigilance software:
PV Works for example is a pharmacovigilance software system that records report safety data keeping track of adverse event reporting. It is a commercial workflow engine providing management control of pharmacovigilance processes. Flexible data entry, risk management, safety system assessment, evaluation and submission of regulatory reports are some of its important features.
PV Works (Vet) is another software system made to support veterinary pharmacovigilance business and technical processes meeting the necessary safety standards. Data entry, reporting, audit trail are some of its main features.
The outsourced pharmacovigilance software develops drug development expertise, safety rules and regulatory necessities, securing client access to data and regular tracking and status updates to clients or to the authority. It is an economical project development process making using of the electronic medium for handling management purposes.
The Assured pharmacovigilance software provides Internet access to the server for the client’s use and operation of the system for management and customer use. This software meets the standards of pharmaceutical companies, regulatory authorities and medical personnel.
How effective is pharmacovigilance software?
- Pharmacovigilance software minimizes the risk of adverse events (ADR) by using genetic profiles.
- It makes accurate determinations as to whether a product is safe or not.
- It determines the benefit-risk ratio quickly
- It overcomes the challenges that small firms face as far as limited financial and personnel resources are concerned.
- Pharmacovigilance software helps maintain regulatory compliance and improve operational efficiency.
- Global information can be easily shared by means of this software.
- In the age of safety concerns, more need is being felt for software that can avert probable risks and also help in worldwide networking in the medical field. Pharmacovigilance software is designed just for this.
Adverse event reporting system(AERS)
(AERS) is a computerized database of adverse events that is designed to help drug regulation authority. Adverse event reporting systemrities in drug manufacturing and post-marketing safety surveillance program for all medicines and biological products produced. AERS can be used in monitoring activities such as looking for new safety concerns that might be related to a marketed product, evaluating a manufacturer's compliance to reporting regulations and responding to requests for drug information from consumers, medical practitioners or authorities.
AERS can be used to compile and enhance the set of standards set for manufacturing and marketing drugs. The pharmaceutical industry will be in turn notified about the revised drug standardizations. Based on this, they can manufacture products that do not cause any of the reported adverse drug reactions. This helps pharmaceutical industries produce safer products that in turn generates greater demand and increases sales.
AERS can be used to compile and enhance the set of standards set for manufacturing and marketing drugs. The pharmaceutical industry will be in turn notified about the revised drug standardizations. Based on this, they can manufacture products that do not cause any of the reported adverse drug reactions. This helps pharmaceutical industries produce safer products that in turn generates greater demand and increases sales.
FDA issues final rule on safety information during clinical trials
FDA is announcing a final rule that will improve the quality of safety reports and better protect people participating in clinical trials for drugs. The final rule clarifies the safety information that drug sponsors (drug manufacturers) must report to FDA for investigational new drug applications (INDs).
The final rule will help sponsors decide whether an adverse event that occurs in a participant during a clinical trial is related to the investigational drug being tested, or if it is related to other health problems in the trial participants. Reports that focus on the most significant adverse events help FDA, sponsors, and clinical investigators better understand how to use the drug safely.
The final rule defines new terms that help clarify when an adverse event should be reported to FDA rapidly - within 7 to 15 days. The rule explains that adverse events should be reported to FDA in an expedited manner only when there is a reasonable possibility that the drug caused the adverse event. The final rule also makes clear what information should not be reported to FDA because the information would not help the agency assess the safety of the drug being studied.
The final rule enhances the protection of clinical trial participants by requiring rapid reports to FDA of certain safety information that had not previously been required. For example, findings from clinical or epidemiological studies that suggest a significant risk or serious, suspected adverse reactions that occur more frequently than anticipated must now be reported rapidly to FDA.Another new requirement is that serious adverse events from bioavailability and bioequivalence studies, which are typically conducted for generic drugs, need to be reported rapidly to FDA.
Many clinical trials are conducted in countries outside the United States, so the revised definitions and reporting standards in this final rule are designed to be as consistent as possible with international definitions and standards. This should help lead to consistent, harmonized reporting for globally conducted clinical trials. Safety information from clinical studies conducted outside the United States can be evaluated along with information from U.S. clinical trials.
Reference:http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm227386.htm
The final rule will help sponsors decide whether an adverse event that occurs in a participant during a clinical trial is related to the investigational drug being tested, or if it is related to other health problems in the trial participants. Reports that focus on the most significant adverse events help FDA, sponsors, and clinical investigators better understand how to use the drug safely.
The final rule defines new terms that help clarify when an adverse event should be reported to FDA rapidly - within 7 to 15 days. The rule explains that adverse events should be reported to FDA in an expedited manner only when there is a reasonable possibility that the drug caused the adverse event. The final rule also makes clear what information should not be reported to FDA because the information would not help the agency assess the safety of the drug being studied.
The final rule enhances the protection of clinical trial participants by requiring rapid reports to FDA of certain safety information that had not previously been required. For example, findings from clinical or epidemiological studies that suggest a significant risk or serious, suspected adverse reactions that occur more frequently than anticipated must now be reported rapidly to FDA.Another new requirement is that serious adverse events from bioavailability and bioequivalence studies, which are typically conducted for generic drugs, need to be reported rapidly to FDA.
Many clinical trials are conducted in countries outside the United States, so the revised definitions and reporting standards in this final rule are designed to be as consistent as possible with international definitions and standards. This should help lead to consistent, harmonized reporting for globally conducted clinical trials. Safety information from clinical studies conducted outside the United States can be evaluated along with information from U.S. clinical trials.
Reference:http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm227386.htm
Pharmacovigilance- various inputs,processes and outputs
INPUTS: Safety data: spontaneous ADRs, epidemiology studies, clinical trials, pre-clinical data.
PROCESSES : Signal generation, Signal evaluation, Risk–benefit review, Expert advice, Decision-making
OUTPUTS:Decision, Communication, revised SPC, revised PIL, bulletin article.
PROCESSES : Signal generation, Signal evaluation, Risk–benefit review, Expert advice, Decision-making
OUTPUTS:Decision, Communication, revised SPC, revised PIL, bulletin article.
Essential activities in Pharmacovigilance
There are five broad activities that are essential to pharmacovigilance. These are:
- suspected ADR signal generation and formation of hypotheses,
- analysis of all issues around the signal, particularly confirmation (or refutation) of hypotheses,estimation of the size of the risk and whether susceptible patients exist,
- consideration of possible changed benefit-to risk issues in therapy,
- communication of information to health professionals and patients in a useful way and possible regulatory action;
- consequence evaluation.
CENTRAL DRUGS STANDARD CONTROL ORGANIZATION(CDSCO)- Pharmacovigilance In India
Under the Drug and Cosmetics Act, the regulation of manufacture, sale and distribution of Drugs is primarily the concern of the State authorities while the Central Authorities are responsible for approval of New Drugs, Clinical Trials in the country, laying down the standards for Drugs, control over the quality of imported Drugs, coordination of the activities of State Drug Control Organisations and providing enforcement of the Drugs and Cosmetics Act.
Drug Controller General of India is responsible for approval of licenses of specified categories of Drugs such as blood and blood products, I. V. Fluids, Vaccine and Sera.
Medicines in India are regulated by CDSCO - Central Drugs Standard Control Organization Under Ministry of Health and Family Welfare. Headed by Directorate General of Health Services CDSCO regulates the Pharmaceutical Products through DCGI - Drugs Controller General of India at Chair. Under Retail and Distribution:- Drugs classified under 5 heads
1. Schedule X drugs - Narcotics
2. Schedule H and L - Injectables, Antibiotics, Antibacterials
3. Schedule C and C1- Biological Products-example Serums and Vaccines
Under Manufacturing Practice: Schedule N
List of the equipment for the efficient running of manufacturing wing, Qualified personnel: Schedule M
Drug Controller General of India is responsible for approval of licenses of specified categories of Drugs such as blood and blood products, I. V. Fluids, Vaccine and Sera.
Medicines in India are regulated by CDSCO - Central Drugs Standard Control Organization Under Ministry of Health and Family Welfare. Headed by Directorate General of Health Services CDSCO regulates the Pharmaceutical Products through DCGI - Drugs Controller General of India at Chair. Under Retail and Distribution:- Drugs classified under 5 heads
1. Schedule X drugs - Narcotics
2. Schedule H and L - Injectables, Antibiotics, Antibacterials
3. Schedule C and C1- Biological Products-example Serums and Vaccines
Under Manufacturing Practice: Schedule N
List of the equipment for the efficient running of manufacturing wing, Qualified personnel: Schedule M
Uppsala Monitoring Centre
The principal function of the Uppsala Monitoring Centre is to manage the international database of ADR reports received from National Centres. In 2002 this database held nearly three million case reports. The majority of national contributing centres have easy electronic access to these. The UMC has established standardized reporting by all National Centres and has facilitated communication between countries to promote rapid identification of signals.
A sophisticated Bayesian confidence propagation neural network (BCPNN) programme was created in 1998, which partly automates the signal detection system, and provides earlier alert signals than previous methods.The effectiveness of this system depends on:
• the size of the database
• the quality of the reports received from the contributing centres
• the timeliness of such reporting
• an active and reliable reporting culture within participating countries.
An international advisory panel of clinical experts determines the validity and clinical importance of the signals generated. In recent years the UMC has expanded its role as a communications and training centre and clearing-house for information on drug safety. Through
• mail discussion groups,
• website development,
• newsletters
• annual National Centre meetings,
The UMC team, in collaboration with the WHO, facilitates and encourages the international collaboration, which was identified in 1972 as being vital for the success of pharmacovigilance. The terminologies developed within the WHO programme for coding adverse reactions and medicines have been widely adopted by National Centres, manufacturers and drug regulators. In recent years, the introduction of a new terminology known as MedDRA (Medical Dictionary for Drug Regulatory Activities) has replaced the World Health Organization Adverse Reaction Terminology (WHO-ART) in developed countries. WHO-ART remains the mainstay of communicating adverse reactions in most developing countries within the International Programme.
Another project at the UMC is the creation of an ADR monitoring system for herbal and traditional medicines.While the UMC has achieved much in improving the activities, support and recognition of individual National Centres, much more could still be done in providing training and encouraging expertise at a national level. There needs to be better consultation and communication between developed and developing countries when discussions on international harmonization of pharmacovigilance issues are taking place. More effective communication of information is being promoted and encouraged through the WHO International Drug Monitoring Programme and the UMC. They are working towards playing a more pro-active role in working together with countries in addressing specific safety concerns and establishing a system that would make possible an evaluation of safety concerns of international importance by a supranational body of experts.
A sophisticated Bayesian confidence propagation neural network (BCPNN) programme was created in 1998, which partly automates the signal detection system, and provides earlier alert signals than previous methods.The effectiveness of this system depends on:
• the size of the database
• the quality of the reports received from the contributing centres
• the timeliness of such reporting
• an active and reliable reporting culture within participating countries.
An international advisory panel of clinical experts determines the validity and clinical importance of the signals generated. In recent years the UMC has expanded its role as a communications and training centre and clearing-house for information on drug safety. Through
• mail discussion groups,
• website development,
• newsletters
• annual National Centre meetings,
The UMC team, in collaboration with the WHO, facilitates and encourages the international collaboration, which was identified in 1972 as being vital for the success of pharmacovigilance. The terminologies developed within the WHO programme for coding adverse reactions and medicines have been widely adopted by National Centres, manufacturers and drug regulators. In recent years, the introduction of a new terminology known as MedDRA (Medical Dictionary for Drug Regulatory Activities) has replaced the World Health Organization Adverse Reaction Terminology (WHO-ART) in developed countries. WHO-ART remains the mainstay of communicating adverse reactions in most developing countries within the International Programme.
Another project at the UMC is the creation of an ADR monitoring system for herbal and traditional medicines.While the UMC has achieved much in improving the activities, support and recognition of individual National Centres, much more could still be done in providing training and encouraging expertise at a national level. There needs to be better consultation and communication between developed and developing countries when discussions on international harmonization of pharmacovigilance issues are taking place. More effective communication of information is being promoted and encouraged through the WHO International Drug Monitoring Programme and the UMC. They are working towards playing a more pro-active role in working together with countries in addressing specific safety concerns and establishing a system that would make possible an evaluation of safety concerns of international importance by a supranational body of experts.
WHO Quality Assurance and Safety
The Quality Assurance and Safety: Medicines team is responsible for providing guidance and support to countries on drug safety matters. The team is part of the Department of Essential Drugs and Medicines Policy, within the WHO Health Technology and Pharmaceuticals cluster. The purpose of the department is:
to help save lives and improve health by closing the huge gap between the potential that essential drugs have to offer and the reality that for millions of people – particularly the poor and disadvantaged – medicines are unavailable, unaffordable, unsafe or improperly used.
WHO works towards fulfilling this mission by providing global guidance on essential drugs and medicines, and working with countries to implement national drug policies.These are designed to ensure:
• equity of access to essential drugs
• drug quality and safety
• rational use of drugs.
The explicit objectives of the Quality Assurance and Safety: Medicines team are:
• to ensure the quality, safety and efficacy of all medicines by strengthening and putting into practice regulatory and quality assurance standards.
For this policy to meets its objectives, the scope of pharmacovigilance needs to be extended to include the safety of all related health technologies, including medicines, vaccines, blood products, biotechnology, herbal medicines and traditional medicines.
Functions of the WHO Programme for International Drug Monitoring include: • Identification and analysis of new adverse reaction signals from the case report information submitted to the National Centres, and from them to the WHO database. A data-mining approach (BCPNN) is used at the UMC to support the clinical analysis made by a panel of signal reviewers.
Provision of the WHO database as a reference source for signal strengthening and ad hoc investigations. Web-based search facilities and customized services are available • Information exchange between WHO and National Centres, mainly through 'Vigiflow', an e-mail information exchange system • Publication of periodical newsletters , (WHO Pharmaceuticals Newsletter and Uppsala Reports), guidelines and books in the pharmacovigilance and risk management area • Supply of tools for management of clinical information including adverse drug reaction case reports. The main products are the WHO Drug Dictionary and the WHO Adverse Reaction Terminology • Provision of training and consultancy support to National Centres and countries establishing pharmacovigilance systems • Computer software for case report management designed to suit the needs of National Centres (VigiFlow) • Annual meetings for representatives of National Centres at which scientific and organizational matters are discussed • Methodological research for the development of pharmacovigilance as a science.
to help save lives and improve health by closing the huge gap between the potential that essential drugs have to offer and the reality that for millions of people – particularly the poor and disadvantaged – medicines are unavailable, unaffordable, unsafe or improperly used.
WHO works towards fulfilling this mission by providing global guidance on essential drugs and medicines, and working with countries to implement national drug policies.These are designed to ensure:
• equity of access to essential drugs
• drug quality and safety
• rational use of drugs.
The explicit objectives of the Quality Assurance and Safety: Medicines team are:
• to ensure the quality, safety and efficacy of all medicines by strengthening and putting into practice regulatory and quality assurance standards.
For this policy to meets its objectives, the scope of pharmacovigilance needs to be extended to include the safety of all related health technologies, including medicines, vaccines, blood products, biotechnology, herbal medicines and traditional medicines.
Functions of the WHO Programme for International Drug Monitoring include: • Identification and analysis of new adverse reaction signals from the case report information submitted to the National Centres, and from them to the WHO database. A data-mining approach (BCPNN) is used at the UMC to support the clinical analysis made by a panel of signal reviewers.
Provision of the WHO database as a reference source for signal strengthening and ad hoc investigations. Web-based search facilities and customized services are available • Information exchange between WHO and National Centres, mainly through 'Vigiflow', an e-mail information exchange system • Publication of periodical newsletters , (WHO Pharmaceuticals Newsletter and Uppsala Reports), guidelines and books in the pharmacovigilance and risk management area • Supply of tools for management of clinical information including adverse drug reaction case reports. The main products are the WHO Drug Dictionary and the WHO Adverse Reaction Terminology • Provision of training and consultancy support to National Centres and countries establishing pharmacovigilance systems • Computer software for case report management designed to suit the needs of National Centres (VigiFlow) • Annual meetings for representatives of National Centres at which scientific and organizational matters are discussed • Methodological research for the development of pharmacovigilance as a science.
WHO Key Dates & Establishments - Pharmacovigilance
1968 WHO Programme established. International ADR terminology and drug dictionary
1969 Definition of ADR
1978 Operations transferred to the UMC; setting-up of relational ADR database. Regular WHO Programme member meetings
1981 Computerised version of WHO Drug Dictionary available to all
1982 ATC classification coding of all medicinal products
1985 International expert review panel created
1991 On-line WHO database search programme available to national centres
1991 Definitions of adverse event, side effect and causality assessment terms
1993 Windows-based client server program for online database searches
1993 Regular training and educational activities
1994 Methodology for use of denominator data for calculation of ADR reporting rates
1997 Knowledge-detection tool for automated signal detection (BCPNN)
1997 Promotion of communication as a necessary discipline
1998 Internet discussion group for national centres
2001 Start of Vigibase Online project
2002 New database system (Vigiflow)
2003 New Drug Dictionary with expanded data fields; agreement with IMS Health to increase information in DD
2004 Pattern recognition using the BCPNN on health databases to find safety information.
1969 Definition of ADR
1978 Operations transferred to the UMC; setting-up of relational ADR database. Regular WHO Programme member meetings
1981 Computerised version of WHO Drug Dictionary available to all
1982 ATC classification coding of all medicinal products
1985 International expert review panel created
1991 On-line WHO database search programme available to national centres
1991 Definitions of adverse event, side effect and causality assessment terms
1993 Windows-based client server program for online database searches
1993 Regular training and educational activities
1994 Methodology for use of denominator data for calculation of ADR reporting rates
1997 Knowledge-detection tool for automated signal detection (BCPNN)
1997 Promotion of communication as a necessary discipline
1998 Internet discussion group for national centres
2001 Start of Vigibase Online project
2002 New database system (Vigiflow)
2003 New Drug Dictionary with expanded data fields; agreement with IMS Health to increase information in DD
2004 Pattern recognition using the BCPNN on health databases to find safety information.
MedDRA Changes - General Remarks
There are two possible types of changes in the MedDRA terminology: simple changes and complex changes. Simple changes are changes to the existing terminology that involve terms at the PT and LLT levels. There are two types of Simple changes: (1) changes introduced by subscribers request and (2) Maintenance changes (also referred to as Associate changes). Maintenance changes are generated as a by-product of other changes requested by subscribers, or changes introduced by the MedDRA Management Board to preserve consistency within the dictionary. Complex changes involve modifications within the entire hierarchy, including the HLT, HLGT, and SOC terminology. Currently, the initial MedDRA terminology version release in one specific year (12.0, 13.0) includes both simple and complex changes, and the subsequent release in the same year (12.1, 13.1) represents a simple change of terminology. These changes are based on MedDRA subscribers' terminology change requests and on MedDRA terminology maintenance needs identified by MedDRA's maintenance organization reviewers. Please note that as a consequence of implementing some of these changes (e.g. demoting a multi-axial PT, adding a new HLT, etc.) it may be necessary to break the multiaxial links, to re-link the replacement terms, and/or to enable additional terms to be included within a particular SOC. All these changes may require modifications to your existing MedDRA coding, guideline development, and data retrieval practices. Keep in mind that changes involve both MedDRA terminology updates as well as Standardized MedDRA Queries (SMQ).
Definition of SMQ(Standard MedDRA Queries)
Result of cooperative effort between CIOMS and ICH (MSSO).Groupings of terms from one or more MedDRA System Organ Classes (SOCs) related to defined medical condition or area of interest. Included terms may relate to signs, symptoms, diagnoses, syndromes, physical findings, laboratory and other physiologic test data, etc., related to medical condition or area of interest intended to aid in case identification.
SMQ – an additional analytical tool for MedDRA-coded data, it is used for:
Other than data presentation by SOCs, data retrieval was initially also addressed with 13 Special Search Categories (SSCs). These are simple groupings of associated PTs which pertain to the same medical concept. To better address the need for standardization of data retrieval queries, Council for International Organizations of Medical Sciences (CIOMS) and MSSO have been working together on developing an extensive set of SMQs. These are retrieval groupings with a more complex and thus useful structure, a narrow and broad scope, some with an inherent hierarchy, and some with an algorithm. MedDRA version 13.1 contains 8 SMQs in development or testing and 82 in production.
- Case identification
- Signal detection
- Potential scenarios:Regulators to monitor a newly-marketed product with a certain potential safety issue from late Phase III
- Safety monitors (pre- or post-marketing) could set up “surveillance” parameters in safety system to alert them to incoming cases whose events “belong” to an SMQ of interest
- Co-development/marketing safety issues (or potential issues) can be shared and compared readily
- PSURs (overdose, pregnancy exposure, drug abuse, etc.)
- Identify cases based on PSUR findings
- Volume 9A recommends using SMQs for signal detection and retrieving cases of interest
- EMEA and PMDA (Japan) currently testing SMQs for signal detection
- FDA exploring the use of SMQs in new drug review process.
Other than data presentation by SOCs, data retrieval was initially also addressed with 13 Special Search Categories (SSCs). These are simple groupings of associated PTs which pertain to the same medical concept. To better address the need for standardization of data retrieval queries, Council for International Organizations of Medical Sciences (CIOMS) and MSSO have been working together on developing an extensive set of SMQs. These are retrieval groupings with a more complex and thus useful structure, a narrow and broad scope, some with an inherent hierarchy, and some with an algorithm. MedDRA version 13.1 contains 8 SMQs in development or testing and 82 in production.
MSSO(Maintenance and Support Services Organization)
MedDRA is managed by the MSSO (Maintenance and Support Services Organization-as the repository, maintainer, and distributor of MedDRA as well as the source for the most up-to-date information regarding MedDRA and its application within the bio-pharmaceutical industry and regulators. MedDRA subscribers submit proposed changes to the terminology. The MSSO includes a group of internationally based physicians who review all proposed subscriber changes and provide a timely response directly to the requesting subscriber.), an organization that reports to the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). MedDRA is free for regulators and priced according to company revenue for industry. MedDRA is also available in Japanese. The Japanese counterpart for MSSO is called JMO. The process of change requests is performed within 7 calendar days from initial receipt by the MSSO. Approved Change Requests are designated as supplemental changes to MedDRA and are posted on the MSSO Web site for review by all subscribers. It should be noted that supplemental releases are not considered “official” MedDRA releases. Supplemental terms, however, will be included in the “official”, scheduled version release.
The MSSO updates MedDRA from subscriber change requests to add a new medical concept that is yet to be in MedDRA or to change an existing concept. The decisions are made by international medical officers on how to map the terminology within the grouping categories according to a general consensus based on language considerations internationally.
The MSSO releases updated MedDRA versions twice a year - in March and September. The March release is the main annual release and contains LLT and PT changes, and changes at the HLT level and above. The September release typically contains changes only at the LLT and PT level. The September 2010 Version 13.1 release is the current version.
The MedDRA dictionary is organized by System Organ Class (SOC), divided into High-Level Group Terms (HLGT), High-Level Terms (HLT), Preferred Terms (PT) and finally into Lower-Level Terms (LLT). In addition, the MedDRA dictionary includes Standardized MedDRA Queries (SMQs). SMQs are groupings of terms that relate to a defined medical condition or area of interest. “The MedDRA dictionary itself poses significant challenges. It is new, complex, and roughly 10 times larger than COSTART or WHO-ART.” MedDRA also brings its own challenges concerning the performing of autoencoding failure resolution, dictionary updates, and version control.
The MSSO updates MedDRA from subscriber change requests to add a new medical concept that is yet to be in MedDRA or to change an existing concept. The decisions are made by international medical officers on how to map the terminology within the grouping categories according to a general consensus based on language considerations internationally.
The MSSO releases updated MedDRA versions twice a year - in March and September. The March release is the main annual release and contains LLT and PT changes, and changes at the HLT level and above. The September release typically contains changes only at the LLT and PT level. The September 2010 Version 13.1 release is the current version.
The MedDRA dictionary is organized by System Organ Class (SOC), divided into High-Level Group Terms (HLGT), High-Level Terms (HLT), Preferred Terms (PT) and finally into Lower-Level Terms (LLT). In addition, the MedDRA dictionary includes Standardized MedDRA Queries (SMQs). SMQs are groupings of terms that relate to a defined medical condition or area of interest. “The MedDRA dictionary itself poses significant challenges. It is new, complex, and roughly 10 times larger than COSTART or WHO-ART.” MedDRA also brings its own challenges concerning the performing of autoencoding failure resolution, dictionary updates, and version control.
Purposes of using MedDRA
To code (classify) ADR/AEs, history, indication, investigations, procedures, etc.Verbatim/reported information is linked to a MedDRA Lowest Level Term (LLT),LLTs have a parent concept Preferred Term (PT) Grouping terms and System Organ Classes (SOCs) logically group concepts for later retrieval and analysis.Used for coding, assessment, and reporting of safety data for both marketed products and clinical studies.
Purpose:
Purpose:
- To aggregate reported terms in medically meaningful groupings for the purpose of reviewing and/or analyzing safety data
- To facilitate identification of common data sets for evaluation of clinical and safety information
- To facilitate consistent retrieval of specific cases or medical conditions from a database
- To improve consistency in comparing and understanding “safety signals” and aggregated clinical data
- To facilitate electronic data interchange of clinical safety information
- To report adverse reaction/adverse event (ADR/AE)2 terms via individual case safety reports
- To include ADR/AEs in tables, analyses, and line listings for reports
- To identify frequency of medically similar ADR/AEs
- To capture and present product indications, investigations, medical history, and social history data
MedDRA or Medical Dictionary for Regulatory Activities
MedDRA or Medical Dictionary for Regulatory Activities is a clinically validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry throughout the entire regulatory process, from pre-marketing to post-marketing activities, and for data entry, retrieval, evaluation, and presentation. In addition, it is the adverse event classification dictionary endorsed by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). MedDRA is used in the US, European Union, and Japan. Its use is currently mandated in US, Europe and Japan for safety reporting.
MedDRA was developed by the International Conference on Harmonisation (ICH) and is owned by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) acting as trustee for the ICH steering committee.
MedDRA is managed by the MSSO (Maintenance and Support Services Organization).
MedDRA was developed by the International Conference on Harmonisation (ICH) and is owned by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) acting as trustee for the ICH steering committee.
MedDRA is managed by the MSSO (Maintenance and Support Services Organization).
Why Is Medical Coding Necessary during processing a case
The need for coding however, continues and the reason being that in order to perform statistical analysis, clinical trial data needs to be structured in such as way that a computer program or human being are able to count data items that are “identical” (in clinical terms) and to be able to group items that are “similar” (in categorical terms). One of the requirements for being able to do this is found in the labeling that must be provided for all prescription medications. The labeling provides the consumer with information concerning possible adverse reactions they might experience in terms of probabilities, that is, the percentage of people that have experienced a particular reaction. In order to calculate these percentages, it is necessary to be able to count “identical” experiences and divide them by the total number of subjects that were in the clinical trial(s) that collected this safety information.
Counting these unintended reactions (i.e., experiences) is hard to do when data are collected in “free text” form. It is perhaps unfortunate that, by and large, the descriptions of unintended reactions or experiences incurred during a clinical trial need to be captured and entered into the clinical trial database in “free text” form. Adverse events such as “Slight headache”, “Very bad headache”, “Debilitating Migraine”, “Sinus headache”, “Stress headache”, “Earache”, “Achy right knee” may not be a description of the same thing in clinical terms, but how does one report on the occurrence of headaches, infections, and muscle and/or joint pains (as in our example) given the wide variety and variations in reporting adverse events? The answer is to code the verbatim terminology using a medical terminology dictionary that gives synonymous terms the same code (known as “equivalence”) and provides a mechanism whereby grouping and classification of terms can be performed.
Furthermore, it is necessary to provide a preferred wording for synonymous terms to use for reporting purposes, for example, “Headache” might be used for “Slight headache”, “Very bad headache”, and “Debilitating Migraine”. At a higher level, one might want to classify these terms based on the body system (or organ class) that they impact. For “Headache”, this might be the central nervous system. Coding, of course, is not limited to adverse event verbatim terminology. It is desirable to code other medical terminology such as medication names, medical procedures such as surgeries, and physical conditions.
Counting these unintended reactions (i.e., experiences) is hard to do when data are collected in “free text” form. It is perhaps unfortunate that, by and large, the descriptions of unintended reactions or experiences incurred during a clinical trial need to be captured and entered into the clinical trial database in “free text” form. Adverse events such as “Slight headache”, “Very bad headache”, “Debilitating Migraine”, “Sinus headache”, “Stress headache”, “Earache”, “Achy right knee” may not be a description of the same thing in clinical terms, but how does one report on the occurrence of headaches, infections, and muscle and/or joint pains (as in our example) given the wide variety and variations in reporting adverse events? The answer is to code the verbatim terminology using a medical terminology dictionary that gives synonymous terms the same code (known as “equivalence”) and provides a mechanism whereby grouping and classification of terms can be performed.
Furthermore, it is necessary to provide a preferred wording for synonymous terms to use for reporting purposes, for example, “Headache” might be used for “Slight headache”, “Very bad headache”, and “Debilitating Migraine”. At a higher level, one might want to classify these terms based on the body system (or organ class) that they impact. For “Headache”, this might be the central nervous system. Coding, of course, is not limited to adverse event verbatim terminology. It is desirable to code other medical terminology such as medication names, medical procedures such as surgeries, and physical conditions.
Wednesday, September 29, 2010
What happens to the safety data once it is captured in the database in the Pharmacovigilance unit:
Safety data collected from the original reporting sources (i.e apart from partners’ exchange safety data and reports from regulatory authorities) is like raw material and it requires further processing and evaluation in order to determine the reporting criteria and further identify its safety signals.
To ensure complete and correct data is captured in the database, regulatory authorities require single cases and follow-up information to be processed. An important tool for a pharmacovigilance department is, therefore, an efficient follow up system, equipped with reminders and instant retrieval of contact/reporter details. It helps keep track of the development of patients’ health conditions as well as detecting potential safety signals.
The pharmacovigilance department needs to systematically and periodically review the cumulative safety data for signals, and generate periodic reports for regulatory reporting. Coding and assessment are key to identifying a reliable safety signal (for signal detection, incomplete reports containing less than the four minimum criteria also count). This process can be improved by designing a system that prioritizes specific safety issues based on medical significance and highlights new safety trends in the collected data.
To ensure complete and correct data is captured in the database, regulatory authorities require single cases and follow-up information to be processed. An important tool for a pharmacovigilance department is, therefore, an efficient follow up system, equipped with reminders and instant retrieval of contact/reporter details. It helps keep track of the development of patients’ health conditions as well as detecting potential safety signals.
The pharmacovigilance department needs to systematically and periodically review the cumulative safety data for signals, and generate periodic reports for regulatory reporting. Coding and assessment are key to identifying a reliable safety signal (for signal detection, incomplete reports containing less than the four minimum criteria also count). This process can be improved by designing a system that prioritizes specific safety issues based on medical significance and highlights new safety trends in the collected data.
Sources and collection of safety information
The core of any pharmaceutical company’s pharmacovigilance process is the safety data. This data is collected through multiple sources, including spontaneous reports, clinical trials, observational studies, registries and surveys of patients or healthcare providers.
The safety data from a product may be collected from thousands of clinical trial patients before it is approved for the market; however, the signal will become more profound and new signals will arise when the product finally reaches millions of consumers. Post-marketing surveillance studies and observations are a significant source of safety signals in drug safety. But contrary to the clinical safety data, the collection of postmarketing safety data is less structured and more diverse, so pharmaceutical companies need to proactively seek and acquire safety data through multiple media and sources.
Collecting post-marketing safety data is complex, largely because of the amount of communication required to reach multiple media, sources and destinations. By identifying an effective communication system that channels the knowledge of the safety profile and the importance of product risk surveillance to the targeted media, the pharmaceutical company can enhance the quality of the safety data it receives, while extending the risk management programme outwards.
Safety data collection can be proactively planned through the implementation of product-driven web forums and patient registry programmes that promote direct lines of safety surveillance to capture the rational and desirable data.
The safety data from a product may be collected from thousands of clinical trial patients before it is approved for the market; however, the signal will become more profound and new signals will arise when the product finally reaches millions of consumers. Post-marketing surveillance studies and observations are a significant source of safety signals in drug safety. But contrary to the clinical safety data, the collection of postmarketing safety data is less structured and more diverse, so pharmaceutical companies need to proactively seek and acquire safety data through multiple media and sources.
Collecting post-marketing safety data is complex, largely because of the amount of communication required to reach multiple media, sources and destinations. By identifying an effective communication system that channels the knowledge of the safety profile and the importance of product risk surveillance to the targeted media, the pharmaceutical company can enhance the quality of the safety data it receives, while extending the risk management programme outwards.
Safety data collection can be proactively planned through the implementation of product-driven web forums and patient registry programmes that promote direct lines of safety surveillance to capture the rational and desirable data.
Various elements required in a Pharmacovigilance Set-up
Data can come from different sources like:
IVRS(Interactive Voice Reporting System),,Patient registries,,Clinics,,CRO, Letters, Press, Sales contacts;
Literature, Calls, Company, Customers web forums/sites, Databanks, Reports, Journals, Emails.
Pharmacovigilance team is involved in collecting data related to
Data entry/Coding/Medical review: The safety data is prepared and then submitted to the respective regulatory authority.
IVRS(Interactive Voice Reporting System),,Patient registries,,Clinics,,CRO, Letters, Press, Sales contacts;
Literature, Calls, Company, Customers web forums/sites, Databanks, Reports, Journals, Emails.
Pharmacovigilance team is involved in collecting data related to
- Clinical Trails data
- Adverse events
- Complaints
- Product related info
Data entry/Coding/Medical review: The safety data is prepared and then submitted to the respective regulatory authority.
Why postmarketing surveillance and reporting ADR is needed:
The information collected during the pre-marketing phase of drug development is inevitably incomplete with regard to possible ADRs. This is mainly because :
❖ Tests in animals are insufficient to predict human safety;
❖ Patients used in clinical trials are selected and limited in number, the conditions of use differ from those in clinical practice and the duration of trials is limited;
❖ By the time of licensing exposure of less than 5000 human subjects to a drug allows only the more common ADR to be detected;
❖ At least 30,000 people need to be treated with a drug to be sure that you do not miss at least one patient with an ADR which has an incidence of 1 in 10,000 exposed individuals;
❖ 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;
Thus, post-marketing surveillance is important to permit detection of less common, but sometimes very serious ADRs. Therefore health professionals worldwide should report on ADRs as it can save lives of their patients and others.
❖ Tests in animals are insufficient to predict human safety;
❖ Patients used in clinical trials are selected and limited in number, the conditions of use differ from those in clinical practice and the duration of trials is limited;
❖ By the time of licensing exposure of less than 5000 human subjects to a drug allows only the more common ADR to be detected;
❖ At least 30,000 people need to be treated with a drug to be sure that you do not miss at least one patient with an ADR which has an incidence of 1 in 10,000 exposed individuals;
❖ 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;
Thus, post-marketing surveillance is important to permit detection of less common, but sometimes very serious ADRs. Therefore health professionals worldwide should report on ADRs as it can save lives of their patients and others.
Why pharmacovigilance is needed in every country:
There are differences among countries (and even regions within countries) in the occurrence of ADRs and other drug-related problems.This may be due to differences in e.g.:
❖ 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) which may pose specific toxicological problems,when used alone or in combination with other drugs.
Data derived from within the country or region may have greater relevance and educational value and may encourage national regulatory decision-making. Information obtained in one country (e.g. the country of origin of the drug) may not be relevant to other parts of the world, where circumstances may differ. Therefore, drug monitoring is of tremendous value as a tool for detecting ADRs and specifically in relation to counterfeit and substandard quality products. ADR monitoring is to help ensure that patients obtain safe and efficacious products. The results of ADR monitoring have also a very important educational value.
❖ 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) which may pose specific toxicological problems,when used alone or in combination with other drugs.
Data derived from within the country or region may have greater relevance and educational value and may encourage national regulatory decision-making. Information obtained in one country (e.g. the country of origin of the drug) may not be relevant to other parts of the world, where circumstances may differ. Therefore, drug monitoring is of tremendous value as a tool for detecting ADRs and specifically in relation to counterfeit and substandard quality products. ADR monitoring is to help ensure that patients obtain safe and efficacious products. The results of ADR monitoring have also a very important educational value.
How to recognize ADRs
Since ADRs may act through the same physiological and pathological pathways as different diseases, they are difficult and sometimes impossible to distinguish. However, the following step-wise approach may be helpful in assessing possible drug-related ADRs:
1. Ensure that the medicine ordered is the medicine received and actually taken by the patient at the dose advised;
2. Verify that the onset of the suspected ADR was after the drug was taken, not before and discuss carefully the observation made by the patient;
3. Determine the time interval between the beginning of drug treatment and the onset of the event;
4. Evaluate the suspected ADR after discontinuing the drugs or reducing the dose and monitor the patient’s status. If appropriate, restart the drug treatment and monitor recurrence of any adverse events.
5. Analyse the alternative causes (other than the drug) that could on their own have caused the reaction;
6. Use relevant up-to-date literature and personal experience as a health professional on drugs and their ADRs and verify if there are previous conclusive reports on this reaction. The National Pharmacovigilance Centre and Drug Information Centres are very important resources for obtaining information on ADR.The manufacturer of the drug can also be a resource to consult;
7. Report any suspected ADR to the person nominated for ADR reporting in the hospital or directly to the National ADR Centre.
1. Ensure that the medicine ordered is the medicine received and actually taken by the patient at the dose advised;
2. Verify that the onset of the suspected ADR was after the drug was taken, not before and discuss carefully the observation made by the patient;
3. Determine the time interval between the beginning of drug treatment and the onset of the event;
4. Evaluate the suspected ADR after discontinuing the drugs or reducing the dose and monitor the patient’s status. If appropriate, restart the drug treatment and monitor recurrence of any adverse events.
5. Analyse the alternative causes (other than the drug) that could on their own have caused the reaction;
6. Use relevant up-to-date literature and personal experience as a health professional on drugs and their ADRs and verify if there are previous conclusive reports on this reaction. The National Pharmacovigilance Centre and Drug Information Centres are very important resources for obtaining information on ADR.The manufacturer of the drug can also be a resource to consult;
7. Report any suspected ADR to the person nominated for ADR reporting in the hospital or directly to the National ADR Centre.
How to report ADRs?
There are different Case Report Forms in different countries. But all of them have at least four sections which should be completed :
1. Patient information:patient identifier, age at time of event or date of birth, gender , weight
2. Adverse event or product problem: description of event or problem, date of event, date of this report , relevant tests/laboratory data (if available) other relevant patient information/history, outcomes attributed to adverse event
3. Suspected medication(s):name (INN and brand name), dose, frequency & route used , therapy date, diagnosis for use, event abated after use stopped or dose reduced, batch number, expiration date, event reappeared after reintroduction of the treatment, concomitant medical products and therapy dates
4. Reporter:name, address and telephone number, speciality and occupation.
1. Patient information:patient identifier, age at time of event or date of birth, gender , weight
2. Adverse event or product problem: description of event or problem, date of event, date of this report , relevant tests/laboratory data (if available) other relevant patient information/history, outcomes attributed to adverse event
3. Suspected medication(s):name (INN and brand name), dose, frequency & route used , therapy date, diagnosis for use, event abated after use stopped or dose reduced, batch number, expiration date, event reappeared after reintroduction of the treatment, concomitant medical products and therapy dates
4. Reporter:name, address and telephone number, speciality and occupation.
Literature Search
Pharmacovigilance staff perform literature search on behalf of clients. Currently, in the EU and in accordance with the regulations such searches are conducted weekly and they set up weekly search streams that are generated automatically for clients and are approved by the clients for their content to ensure capture of all types of articles involving the safety of the Company products. Literature searching is performed using Medical subject Headings( MeSH) terms to enhance possible ADR identification. Literature cases are used to perform expedited reporting; signal detection; benefit risk assessments and analyse Class related events (which may be used in PSURs).Literature search is usually carried out to find:
- Adverse Drug Reactions
- Cases of lack of efficacy
- Cases of overdose, abuse and misuse
- Cases of medication errors
Individual Safety Case (ICSR) Processing
This involves data entry; data QC check; medical review; reportability assessment; electronic/paper reporting; follow up; case closure; case file archiving.
This can be performed for post-marketing and clinical trial cases (SAEs and SUSARs) and captured within the validated and password protected adverse event safety database. Reports can be generated electronically (or paper format) to the Regulatory Agencies from this database and compliance metrics produced for Companies for notification of adherence to the regulations.
Similarly the database can generate, periodic summary tabulations; line-listings and perform analyses for identifying potential signals and tabulations and specialized queries used in safety reviews.
They are responsible for obtaining follow up information to adverse reaction (ADR) reports to obtain comprehensive information that will allow a proper determination of both causality and the possible mechanism by which the reaction occurred thereby looking to prevent or minimize its appearance.
This can be performed for post-marketing and clinical trial cases (SAEs and SUSARs) and captured within the validated and password protected adverse event safety database. Reports can be generated electronically (or paper format) to the Regulatory Agencies from this database and compliance metrics produced for Companies for notification of adherence to the regulations.
Similarly the database can generate, periodic summary tabulations; line-listings and perform analyses for identifying potential signals and tabulations and specialized queries used in safety reviews.
They are responsible for obtaining follow up information to adverse reaction (ADR) reports to obtain comprehensive information that will allow a proper determination of both causality and the possible mechanism by which the reaction occurred thereby looking to prevent or minimize its appearance.
Basic Activities carried out in Pharmacovigilance Unit
To name a few of the activities carried out by a PV professional:
- Individual Safety Case (ICSR) Processing
- Aggregate Reporting(PSUR, PADER,IND ASR, DSUR etc..)
- Literature Search
- Electronic Reporting to Regulatory Authorities
- Risk Management
- Signal Detection
Guidance on the Preparation of PSURs
A PSUR should include the following:
1. Details of the MA holder and product (to include names and MA number), and the period covered by the PSUR.
2. An update on any regulatory or MA holder actions taken for safety reasons, if applicable, since the last PSUR.
3. The latest version of the Summary of Product Characteristics (SPC) for the MA concerned.
4. The number of doses or the amount of the product sold in the UK within the period of the report. The sales volume should be expressed per presentation in an appropriate form, e.g. liquid in litres, powder in kilograms, etc. (see Volume 9 guideline above). For PSURs covering more than one year, sales volume should be broken down by calendar year or part year.
5. An estimation of the number of animals treated in the UK within the period of the report. It should be explained how the number of animals treated is derived from the volume sold. For products authorised for use in more than one species, the approximate percentage use per species should be included.
6. The incidence of suspected adverse reactions (SAR) during the period of the PSUR expressed as a percentage. The incidence (%) of adverse reactions (reports assigned a causality of A, B, O or O1) should be calculated by dividing the total number of animals reacting during the period by an estimate of the number of animals treated during the period of the report and multiplying by 100. Adverse reactions (A, B, O and O1) that occur after recommended and off-label use in the
target species should be included in the calculation.
7. For products authorised for use in more than one species, if more than 50% of the adverse reactions are reported in one of the target species, a separate incidence for that species.
8. The incidence of suspected lack of expected efficacy (SLEE) for the period of the PSUR (see 6 above), if there have been any such reports.
9. Individual case histories should be presented as line listings in an appendix to the PSUR,.
For PSURs submitted electronically, the line listings should be provided separately in a format suitable for sorting and analysis, e.g. Excel, to assist assessment of the PSUR.
For PSURs submitted as paper copies, it is helpful if the line listings are first sorted by country.
In addition, adverse reactions considered to have involved the off-label use of a product should be clearly indicated in the column headed ‘Was product used as recommended?’ An explanation as to why the use was off-label should be provided, either in the same column or in the column for the MA holder’s conclusions .
Competent Authority (CA) reference numbers, where they are known by the company. This includes CA references that were sent with acknowledgements of company reports, as well as where the original reports
were received by the CA and copied to the company.
10. A narrative review of individual or group case histories in the overall summary, if more information or explanation is appropriate. For example, discussion of a lack of expected efficacy problem.
11. Reports from other sources, if appropriate. For example, post-authorisation studies or published adverse reaction reports.
12.A literature review for the period covered by the PSUR based on the product.
13. An overall analysis of the data and a critical evaluation of the benefit-risk balance of the product, written by the Qualified Person for Pharmacovigilance (QPPV). This section should include the following:
i. Evidence of previously unidentified toxicity.
ii. Increased frequency of known toxicity or expected undesirable effects,e.g. incidence greater than 1 in 10,000 animals treated.
iii. Drug interactions.
iv. Adverse reactions associated with off-label use including overdose.
v. Urgent safety issues that occurred during the period.
13.Any important information received after the data lock point, e.g. a serious adverse reaction which could have an impact on the overall safety evaluation.
1. Details of the MA holder and product (to include names and MA number), and the period covered by the PSUR.
2. An update on any regulatory or MA holder actions taken for safety reasons, if applicable, since the last PSUR.
3. The latest version of the Summary of Product Characteristics (SPC) for the MA concerned.
4. The number of doses or the amount of the product sold in the UK within the period of the report. The sales volume should be expressed per presentation in an appropriate form, e.g. liquid in litres, powder in kilograms, etc. (see Volume 9 guideline above). For PSURs covering more than one year, sales volume should be broken down by calendar year or part year.
5. An estimation of the number of animals treated in the UK within the period of the report. It should be explained how the number of animals treated is derived from the volume sold. For products authorised for use in more than one species, the approximate percentage use per species should be included.
6. The incidence of suspected adverse reactions (SAR) during the period of the PSUR expressed as a percentage. The incidence (%) of adverse reactions (reports assigned a causality of A, B, O or O1) should be calculated by dividing the total number of animals reacting during the period by an estimate of the number of animals treated during the period of the report and multiplying by 100. Adverse reactions (A, B, O and O1) that occur after recommended and off-label use in the
target species should be included in the calculation.
7. For products authorised for use in more than one species, if more than 50% of the adverse reactions are reported in one of the target species, a separate incidence for that species.
8. The incidence of suspected lack of expected efficacy (SLEE) for the period of the PSUR (see 6 above), if there have been any such reports.
9. Individual case histories should be presented as line listings in an appendix to the PSUR,.
For PSURs submitted electronically, the line listings should be provided separately in a format suitable for sorting and analysis, e.g. Excel, to assist assessment of the PSUR.
For PSURs submitted as paper copies, it is helpful if the line listings are first sorted by country.
In addition, adverse reactions considered to have involved the off-label use of a product should be clearly indicated in the column headed ‘Was product used as recommended?’ An explanation as to why the use was off-label should be provided, either in the same column or in the column for the MA holder’s conclusions .
Competent Authority (CA) reference numbers, where they are known by the company. This includes CA references that were sent with acknowledgements of company reports, as well as where the original reports
were received by the CA and copied to the company.
10. A narrative review of individual or group case histories in the overall summary, if more information or explanation is appropriate. For example, discussion of a lack of expected efficacy problem.
11. Reports from other sources, if appropriate. For example, post-authorisation studies or published adverse reaction reports.
12.A literature review for the period covered by the PSUR based on the product.
13. An overall analysis of the data and a critical evaluation of the benefit-risk balance of the product, written by the Qualified Person for Pharmacovigilance (QPPV). This section should include the following:
i. Evidence of previously unidentified toxicity.
ii. Increased frequency of known toxicity or expected undesirable effects,e.g. incidence greater than 1 in 10,000 animals treated.
iii. Drug interactions.
iv. Adverse reactions associated with off-label use including overdose.
v. Urgent safety issues that occurred during the period.
13.Any important information received after the data lock point, e.g. a serious adverse reaction which could have an impact on the overall safety evaluation.
Cumulative Safety Report
Preapproval reports include IND Annual Reports in the U.S. and Annual Safety Reports (ASRs) in Europe. Some of these documents may provide cumulative information, while others contain aggregate information specific to the reporting period. Postapproval cumulative reports of safety include NDA Periodic Adverse Drug Experiences Reports (PADERs) in the U.S. And Periodic Safety Update Reports (PSURs) in many other countries, including in Europe.
Main focus of a cumulative safety report is serious, unexpected adverse events. All spontaneously reported adverse events are included in a cumulative safety report. For clinical study and literature cases, only those judged to be related to the medicine by the reporter and the pharmaceutical company are typically included. PSURs and NDA Periodic Adverse Drug Experiences Reports (PADERs) submitted to FDA differ considerably in terms of content.
The reporting and regulatory environment in which these efforts occur is not uniform worldwide:
• The U. S. Food and Drug Administration (FDA) generally requires NDA Periodic Reports quarterly during the first 3 years after the medicine is approved, and annual reports thereafter.
• The European Medicines Evaluation Agency (EMEA) requires PSURs every 6 months for 2 years, annually for the 3 following years, and then every 5 years (at the time of renewal of registration).
• In Japan, the authorities require a survey on a cohort of a few thousand patients established by a certain number of identified institutions during the 6 years following approval, with systematic information reported annually on this cohort. Regarding other post approval experience, adverse reactions that are nonserious, but both mild in severity and unlabeled,must be reported every 6 months for 3 years and annually thereafter.
Although the frequency of reporting may diminish with time as the benefit-risk profile of the product becomes better understood, cumulative safety reports are submitted to regulators for as long as the medicine is marketed anywhere in the world.
Main focus of a cumulative safety report is serious, unexpected adverse events. All spontaneously reported adverse events are included in a cumulative safety report. For clinical study and literature cases, only those judged to be related to the medicine by the reporter and the pharmaceutical company are typically included. PSURs and NDA Periodic Adverse Drug Experiences Reports (PADERs) submitted to FDA differ considerably in terms of content.
The reporting and regulatory environment in which these efforts occur is not uniform worldwide:
• The U. S. Food and Drug Administration (FDA) generally requires NDA Periodic Reports quarterly during the first 3 years after the medicine is approved, and annual reports thereafter.
• The European Medicines Evaluation Agency (EMEA) requires PSURs every 6 months for 2 years, annually for the 3 following years, and then every 5 years (at the time of renewal of registration).
• In Japan, the authorities require a survey on a cohort of a few thousand patients established by a certain number of identified institutions during the 6 years following approval, with systematic information reported annually on this cohort. Regarding other post approval experience, adverse reactions that are nonserious, but both mild in severity and unlabeled,must be reported every 6 months for 3 years and annually thereafter.
Although the frequency of reporting may diminish with time as the benefit-risk profile of the product becomes better understood, cumulative safety reports are submitted to regulators for as long as the medicine is marketed anywhere in the world.
Tuesday, September 28, 2010
Archival of Site Master File and ‘Essential’ Documents in the Clinical Trial Secnario
1. When an investigator receives confirmation that a study can be archived,reference should be made to the clinical trials agreement that should specify whether the investigator or sponsor is responsible for archiving the
study.
2. All documentation as defined in ICH-GCP guidelines (section 8.2, 8.3, 8.4) as ‘essential documents which individually and collectively permit the evaluation of the conduct of a study and the quality of the data produced’’ must be retained until notification from the sponsor.
3. Where electronic copies of documents exist, these should be backed up and retained alongside the paper documents.
4. Files and documents relating to a study may be held in other departments,such as Pharmacy or Clinical Radiology. These should be collated with the master site file when the study is archived.
5. One copy of each document should be kept and filed in a bankart box and stored within the clinical trials archives store.
6. All archived material should be stored in a suitable place. The archival location should be restricted to only appropriately delegated individuals,and appropriate quality checks should be in place to ensure the
preservation of the archive. This would include a Risk Assessment for fire,environmental damage, pest control, and ongoing monitoring of these risks. This store may be an internal storage area or a commercial archiving
store.
7. The Trust will nominate an archivist for Clinical trials; this will usually be the R&D Manager.
8. The master site file and other research documents will be held by the PI,or delegate, for 3 years following the last day of the patient’s active followup period.
9. Study documentation will be consolidated to ensure that only one copy of any document is held in the archive store
10. Archived documents should be packed securely in archival boxes. Staples, plastic wallets and paper clips must be removed as these will degrade the records over time.
11. Paper documents must be suitable for long term archiving. For example,faxes or ECG results should be photocopied since the inks used may be prone to fading.
12.The file should be clearly labelled with the name and reference number of the study, sponsor, investigator and date to be archived until. See Appendix A for a copy of label to be used.
13.For commercial studies it is the lead investigators role to identify the storage area. If it is the sponsor’s responsibility, arrange for them to archive study contents as soon as possible.
14. Access to the material should be restricted to the investigator, his/her delegate and the regulatory authorities.
15.Details of the archiving location should be recorded in a location register stored in the R&D Office. See Appendix B. This register should record the name and reference number of the study, Sponsor, Investigator and date to be archived until as well as where the documents are located.
16.Whenever an item is retrieved from archive, the date, item and person retrieving the item should be documented, together with the date returned to archive.
Medical Records:
17. A check should be made that all enrolled patients are flagged before the study is archived.
18. A destruction date will be recorded on the archiving box: the notes should not be destroyed until at least 20 years after the completion of the trial.
study.
2. All documentation as defined in ICH-GCP guidelines (section 8.2, 8.3, 8.4) as ‘essential documents which individually and collectively permit the evaluation of the conduct of a study and the quality of the data produced’’ must be retained until notification from the sponsor.
3. Where electronic copies of documents exist, these should be backed up and retained alongside the paper documents.
4. Files and documents relating to a study may be held in other departments,such as Pharmacy or Clinical Radiology. These should be collated with the master site file when the study is archived.
5. One copy of each document should be kept and filed in a bankart box and stored within the clinical trials archives store.
6. All archived material should be stored in a suitable place. The archival location should be restricted to only appropriately delegated individuals,and appropriate quality checks should be in place to ensure the
preservation of the archive. This would include a Risk Assessment for fire,environmental damage, pest control, and ongoing monitoring of these risks. This store may be an internal storage area or a commercial archiving
store.
7. The Trust will nominate an archivist for Clinical trials; this will usually be the R&D Manager.
8. The master site file and other research documents will be held by the PI,or delegate, for 3 years following the last day of the patient’s active followup period.
9. Study documentation will be consolidated to ensure that only one copy of any document is held in the archive store
10. Archived documents should be packed securely in archival boxes. Staples, plastic wallets and paper clips must be removed as these will degrade the records over time.
11. Paper documents must be suitable for long term archiving. For example,faxes or ECG results should be photocopied since the inks used may be prone to fading.
12.The file should be clearly labelled with the name and reference number of the study, sponsor, investigator and date to be archived until. See Appendix A for a copy of label to be used.
13.For commercial studies it is the lead investigators role to identify the storage area. If it is the sponsor’s responsibility, arrange for them to archive study contents as soon as possible.
14. Access to the material should be restricted to the investigator, his/her delegate and the regulatory authorities.
15.Details of the archiving location should be recorded in a location register stored in the R&D Office. See Appendix B. This register should record the name and reference number of the study, Sponsor, Investigator and date to be archived until as well as where the documents are located.
16.Whenever an item is retrieved from archive, the date, item and person retrieving the item should be documented, together with the date returned to archive.
Medical Records:
17. A check should be made that all enrolled patients are flagged before the study is archived.
18. A destruction date will be recorded on the archiving box: the notes should not be destroyed until at least 20 years after the completion of the trial.
Archiving documents in Clinical Trials Scenario
Clinical trial documentation can be archived by the Principal investigator /designee or the Sponsor. The Principal Investigator must agree with the sponsor the exact requirements for local archiving and make or assist in making the necessary arrangements. The investigator has a responsibility to allow the sponsor and regulators access to the archived data on request. The Management of trial documentation and study file is the responsibility of the Principal Investigator however this role may be delegated to the clinical trials co-ordinator or research nurse or other member of the research team. This procedure should be carried out in accordance with local hospital policies. All data should be made available if requested by relevant authorities. The Trust Archivist will consolidate the research files and manage the clinical trials archives store. For local studies not involving investigational medicinal products it will be the responsibility of the Principal Investigator to
store the data.
Archiving occurs as soon as possible after completion of a study, typically the end of the follow-up stage for treatment and multicentre studies, and at close down of study for all other studies. Regulations state that the documentation for clinical trials involving medicinal products should be archived for at least five years after the last licence application. Patients’ medical records should be retained for a minimum of twenty years after the completion of a trial. Three years following the Principal Investigator’s close down of the study the archivist will gather all of the trial documents from all the areas across the Trust, including Pharmacy, and undertake the consolidation process.
store the data.
Archiving occurs as soon as possible after completion of a study, typically the end of the follow-up stage for treatment and multicentre studies, and at close down of study for all other studies. Regulations state that the documentation for clinical trials involving medicinal products should be archived for at least five years after the last licence application. Patients’ medical records should be retained for a minimum of twenty years after the completion of a trial. Three years following the Principal Investigator’s close down of the study the archivist will gather all of the trial documents from all the areas across the Trust, including Pharmacy, and undertake the consolidation process.
Anatomical Therapeutic Chemical Classification(ATC) - WHO DD
The Anatomical Therapeutic Chemical (ATC) Classification System is used for the classification of drugs. It is controlled by the WHO Collaborating Centre for Drug Statistics Methodology (WHOCC), and was first published in 1976.
The classification system divides drugs into different groups according to the organ or system on which they act and/or their therapeutic and chemical characteristics. Each bottom-level ATC code stands for a pharmaceutically used substance in a single indication (or use). This means that one drug can have more than one code: acetylsalicylic acid (aspirin), for example, has A01AD05 as a drug for local oral treatment, B01AC06 as a platelet inhibitor, and N02BA01 as an analgesic and antipyretic. On the other hand, several different brands share the same code if they have the same active substance and indications.
First level
The first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups:
Code Contents
A Alimentary tract and metabolism
B Blood and blood forming organs
C Cardiovascular system
D Dermatologicals
G Genito-urinary system and sex hormones
H Systemic hormonal preparations, excluding sex hormones and insulins
J Antiinfectives for systemic use
L Antineoplastic and immunomodulating agents
M Musculo-skeletal system
N Nervous system
P Antiparasitic products, insecticides and repellents
R Respiratory system
S Sensory organs
V Various
Second level
The second level of the code indicates the therapeutic main group and consists of two digits.
Example: C03 Diuretics
Third level
The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter.
Example: C03C High-ceiling diuretics
Fourth level
The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter.
Example: C03CA Sulfonamides
Fifth level
The fifth level of the code indicates the chemical substance and consists of two digits.
Example: C03CA01 Furosemide
The classification system divides drugs into different groups according to the organ or system on which they act and/or their therapeutic and chemical characteristics. Each bottom-level ATC code stands for a pharmaceutically used substance in a single indication (or use). This means that one drug can have more than one code: acetylsalicylic acid (aspirin), for example, has A01AD05 as a drug for local oral treatment, B01AC06 as a platelet inhibitor, and N02BA01 as an analgesic and antipyretic. On the other hand, several different brands share the same code if they have the same active substance and indications.
First level
The first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups:
Code Contents
A Alimentary tract and metabolism
B Blood and blood forming organs
C Cardiovascular system
D Dermatologicals
G Genito-urinary system and sex hormones
H Systemic hormonal preparations, excluding sex hormones and insulins
J Antiinfectives for systemic use
L Antineoplastic and immunomodulating agents
M Musculo-skeletal system
N Nervous system
P Antiparasitic products, insecticides and repellents
R Respiratory system
S Sensory organs
V Various
Second level
The second level of the code indicates the therapeutic main group and consists of two digits.
Example: C03 Diuretics
Third level
The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter.
Example: C03C High-ceiling diuretics
Fourth level
The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter.
Example: C03CA Sulfonamides
Fifth level
The fifth level of the code indicates the chemical substance and consists of two digits.
Example: C03CA01 Furosemide
Main Files in WHO-DD
1)Medicinal Products :
# This is the main file in which most information about the product is recorded. This file contains the unique identifier and the Trade name.
# It also contains information about the company responsible for the product internationally, and the company that markets the product.
2)Pharmaceutical Product :
# The WHO-DD allows for the use of a two-level structure of the product information.
# The two-level structure makes it possible to record both the Medicinal Product – the product name and the pharmaceutical products with their individual ingredient.
3)Therapeutic Group :
# Each medicinal product can be coded to one or several Therapeutic groups.
# The therapeutic grouping uses the Anatomical Therapeutic Chemical classification (ATC).
4)Ingredient :
# Each Pharmaceutical Product contains one or several Ingredients.
# Only active substances are included (no excipients, colouring agents, filling agents etc.
# This is the main file in which most information about the product is recorded. This file contains the unique identifier and the Trade name.
# It also contains information about the company responsible for the product internationally, and the company that markets the product.
2)Pharmaceutical Product :
# The WHO-DD allows for the use of a two-level structure of the product information.
# The two-level structure makes it possible to record both the Medicinal Product – the product name and the pharmaceutical products with their individual ingredient.
3)Therapeutic Group :
# Each medicinal product can be coded to one or several Therapeutic groups.
# The therapeutic grouping uses the Anatomical Therapeutic Chemical classification (ATC).
4)Ingredient :
# Each Pharmaceutical Product contains one or several Ingredients.
# Only active substances are included (no excipients, colouring agents, filling agents etc.
Drug Code in detail
# The term drug code refers to the unique numeric key in the B format of the dictionary. A drug code identifies a name, either a trade name or a generic Preferred Name.
# A Drug Code is aggregated from Drug Record Number (Drecno),Sequence number 1 and Sequence number 2.
# The code differs from the Medicinal Product ID in that it has a meaning.
# The code is not only a unique identifier of a name – it also gives information about the active ingredients and salt/ester form of the substance.
For example:
A Drecno identifies a generic identification level. In most cases the generic identification level is the one active ingredient, but it can also identify a unique combination of active
ingredients.
Sequence number 1 : It identifies the salt or the ester of the active ingredient.
Sequence number 2 : It identifies the trade names and in some cases a synonym to a generic name. Eg ; Acetaminophen as a synonym to Paracetamol.
Combination products : Products with more than one active ingredient – needs to have a separate coding
principle. It is not possible to include the names of all active ingredients in the name field, so the first trade name with the unique combination of ingredients will be the preferred name though it is not a generic name.
Use of Codes in Data analysis and Retrievals :
The identification levels are useful for querying and analysis of aggregate data.
# The Drecno can be used to identify all products with the same active ingredient(s)
# The Drecno + Sequence number 1 to identify different salts.
# The Drecno + Sequence number 1 + Sequence number 2 to identify a trade name.
# A Drug Code is aggregated from Drug Record Number (Drecno),Sequence number 1 and Sequence number 2.
# The code differs from the Medicinal Product ID in that it has a meaning.
# The code is not only a unique identifier of a name – it also gives information about the active ingredients and salt/ester form of the substance.
For example:
A Drecno identifies a generic identification level. In most cases the generic identification level is the one active ingredient, but it can also identify a unique combination of active
ingredients.
Sequence number 1 : It identifies the salt or the ester of the active ingredient.
Sequence number 2 : It identifies the trade names and in some cases a synonym to a generic name. Eg ; Acetaminophen as a synonym to Paracetamol.
Combination products : Products with more than one active ingredient – needs to have a separate coding
principle. It is not possible to include the names of all active ingredients in the name field, so the first trade name with the unique combination of ingredients will be the preferred name though it is not a generic name.
Use of Codes in Data analysis and Retrievals :
The identification levels are useful for querying and analysis of aggregate data.
# The Drecno can be used to identify all products with the same active ingredient(s)
# The Drecno + Sequence number 1 to identify different salts.
# The Drecno + Sequence number 1 + Sequence number 2 to identify a trade name.
Proposed Coding Rules- WHO DD
Proposed Coding Rules
# Code the drug term to the appropriate drug name level of the dictionary (generic/generic and trade/trade)
# Do not change, add, or subtract to the original verbatim in a way that modifies its original meaning or content.
# Abbreviations should be avoided at all costs.
# Misspellings are never assumed as it is dangerous. Eg; PRAZAC (prazosin hydrochloride) and PROZAC (fluoxetine hydrochloride)
# Verbatim terms with symbols – Trade marks, accent marks etc are not appropriate and should be queried and removed while coding clinical data and ignored in post marketing data.
# Verbatim terms with procedures – Code the drug regardless of procedure information.
# Code the drug term to the appropriate drug name level of the dictionary (generic/generic and trade/trade)
# Do not change, add, or subtract to the original verbatim in a way that modifies its original meaning or content.
# Abbreviations should be avoided at all costs.
# Misspellings are never assumed as it is dangerous. Eg; PRAZAC (prazosin hydrochloride) and PROZAC (fluoxetine hydrochloride)
# Verbatim terms with symbols – Trade marks, accent marks etc are not appropriate and should be queried and removed while coding clinical data and ignored in post marketing data.
# Verbatim terms with procedures – Code the drug regardless of procedure information.
WHO Drug Dictionary (WHO-DD)
Introduction
# The WHO-DD is administered and licensed by the World Health Organization’s Uppsala Monitoring Center (UMC). The UMC collaborates with regulators, researchers and other professionals from healthcare and pharmaceutical industry in practice of pharmacovigilance.
#A drug dictionary proves useful when tabulating medication usage because it classifies the same medication, often known by different names, into a single name.
#For example – Tylenol, acetaminophen and paracetamol all refer to the same active ingredient, and WHO-DD uses the ingredient name paracetamol.
CODES AND IDs
# The WHO-DD dictionary contains a large number of data fields that contain information about the Medicinal Products. This information is used to identify a product that should be coded in a database, eg.For clinical trial data or drug safety data.
#The WHO Drug Dictionary enhanced contains two types of IDs that can be used as links between the case report in the clinical trials database/Drug Safety database and the WHO-DD.
#The medicinal product ID identifies an entry in the dictionary.
Medicinal Product ID (MP ID):
The Medicinal Product ID identifies a unique entry in the WHO-DD. The ID is just a “numeric name” of the medicinal product and it has no intrinsic meaning.
The MP ID constitute:
# Medicinal Product Name (generic name)
# Drug code (drug record number + sequence 1 + sequence 2)
# Name specifier
# Market Authorization Holder
# Country
# Dosage form (available as Pharmaceutical form in pharmaceutical product table)
# Strength (available as amount and unit of active ingredients in the ingredient table)
# The WHO-DD is administered and licensed by the World Health Organization’s Uppsala Monitoring Center (UMC). The UMC collaborates with regulators, researchers and other professionals from healthcare and pharmaceutical industry in practice of pharmacovigilance.
#A drug dictionary proves useful when tabulating medication usage because it classifies the same medication, often known by different names, into a single name.
#For example – Tylenol, acetaminophen and paracetamol all refer to the same active ingredient, and WHO-DD uses the ingredient name paracetamol.
CODES AND IDs
# The WHO-DD dictionary contains a large number of data fields that contain information about the Medicinal Products. This information is used to identify a product that should be coded in a database, eg.For clinical trial data or drug safety data.
#The WHO Drug Dictionary enhanced contains two types of IDs that can be used as links between the case report in the clinical trials database/Drug Safety database and the WHO-DD.
#The medicinal product ID identifies an entry in the dictionary.
Medicinal Product ID (MP ID):
The Medicinal Product ID identifies a unique entry in the WHO-DD. The ID is just a “numeric name” of the medicinal product and it has no intrinsic meaning.
The MP ID constitute:
# Medicinal Product Name (generic name)
# Drug code (drug record number + sequence 1 + sequence 2)
# Name specifier
# Market Authorization Holder
# Country
# Dosage form (available as Pharmaceutical form in pharmaceutical product table)
# Strength (available as amount and unit of active ingredients in the ingredient table)
Drug Coding
Drug coding is the process of identifying a particular medications pharmacological classification for the intended use in adverse event evaluation, drug/drug interaction study, drug-herbal interaction study, or drug-food interaction study (hereto referred as drug-substance interaction).
# In a clinical trial, concomitant and historical/prior medications are usually recorded for this purpose.
# While data-mining and initial detection of drug-substance issues can be determined using the ATC levels, true drug-substance analysis requires active ingredient retrieval from the dictionary.
WHY IS DRUG CODING IMPORTANT ?
# Drug interactions account for 3-5% of preventable in-hospital Adverse Drug Reactions (ADRs)
# Drug interactions contribute to a number of emergency room (ER) visits and hospital admissions
# Drugs are removed/restricted from marketplace due to drug/drug interactions
Examples of drug interactions with other drugs …
Cordarone (amiodarone): FDA issued an alert in August 2008, warning patients about taking Cordarone to correct abnormal rhythms of the heart and the cholesterol-lowering drug Zocor (Simvastatin). Patients taking Zocor in doses higher than 20 mg while also taking Cordarone run the risk of developing a rare condition of muscle injury called rhabdomyolysis, which can lead to kidney failure or death. "Cordarone also can inhibit or reduce the effect of the blood thinner Coumadin (warfarin)," . "So if you're using Cordarone, you may need to reduce the amount of Coumadin you're taking."
Lanoxin (digoxin): "Lanoxin has a narrow therapeutic range. So other drugs, such as Norvir (ritonvair), can elevate the level of Lanoxin,". "And an increased level of Lanoxin can cause irregular heart rhythms." Norvir is a protease inhibitor used to treat HIV, the virus that causes AIDS.
Antihistamines: Over-the-counter (OTC) antihistamines are drugs that temporarily relieve a runny nose, or reduce sneezing, itching of the nose or throat, and itchy watery eyes. If you are taking sedatives, tranquilizers, or a prescription drug for high blood pressure or depression, you should check with a doctor or pharmacist before you start using antihistimines. Some antihistamines can increase the depressant effects (such as sleepiness) of a sedative or tranquilizer. The sedating effect of some antihistamines combined with a sedating antidepressant could strongly affect your concentration level. Operating a car or any other machinery could be particularly dangerous if your ability to focus is impaired. Antihistamines taken in conjunction with blood pressure medication may cause a person's blood pressure to increase and may also speed up the heart rate.
Reference: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm096386.htm
Will discuss more about the WHO DD in my next post.So keep blogging.
# In a clinical trial, concomitant and historical/prior medications are usually recorded for this purpose.
# While data-mining and initial detection of drug-substance issues can be determined using the ATC levels, true drug-substance analysis requires active ingredient retrieval from the dictionary.
WHY IS DRUG CODING IMPORTANT ?
# Drug interactions account for 3-5% of preventable in-hospital Adverse Drug Reactions (ADRs)
# Drug interactions contribute to a number of emergency room (ER) visits and hospital admissions
# Drugs are removed/restricted from marketplace due to drug/drug interactions
Examples of drug interactions with other drugs …
Cordarone (amiodarone): FDA issued an alert in August 2008, warning patients about taking Cordarone to correct abnormal rhythms of the heart and the cholesterol-lowering drug Zocor (Simvastatin). Patients taking Zocor in doses higher than 20 mg while also taking Cordarone run the risk of developing a rare condition of muscle injury called rhabdomyolysis, which can lead to kidney failure or death. "Cordarone also can inhibit or reduce the effect of the blood thinner Coumadin (warfarin)," . "So if you're using Cordarone, you may need to reduce the amount of Coumadin you're taking."
Lanoxin (digoxin): "Lanoxin has a narrow therapeutic range. So other drugs, such as Norvir (ritonvair), can elevate the level of Lanoxin,". "And an increased level of Lanoxin can cause irregular heart rhythms." Norvir is a protease inhibitor used to treat HIV, the virus that causes AIDS.
Antihistamines: Over-the-counter (OTC) antihistamines are drugs that temporarily relieve a runny nose, or reduce sneezing, itching of the nose or throat, and itchy watery eyes. If you are taking sedatives, tranquilizers, or a prescription drug for high blood pressure or depression, you should check with a doctor or pharmacist before you start using antihistimines. Some antihistamines can increase the depressant effects (such as sleepiness) of a sedative or tranquilizer. The sedating effect of some antihistamines combined with a sedating antidepressant could strongly affect your concentration level. Operating a car or any other machinery could be particularly dangerous if your ability to focus is impaired. Antihistamines taken in conjunction with blood pressure medication may cause a person's blood pressure to increase and may also speed up the heart rate.
Reference: http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm096386.htm
Will discuss more about the WHO DD in my next post.So keep blogging.
Medication guide- Product Labeling
A Medication Guide or other patient labeling may be required for certain medicines. This printed document contains FDA-approved information that may be included at the end of the PI, but must be made available separately.
A Medication Guide or other patient labeling may provide:
• Certain information that is necessary to prevent serious side effects.
• Information about a known serious side effect with a medicine to help patients to make an informed decision about whether the benefits of taking the medicine outweigh the risks.
• Directions for the use of a product that are essential to its effectiveness.
Refer this site: http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm
A Medication Guide or other patient labeling may provide:
• Certain information that is necessary to prevent serious side effects.
• Information about a known serious side effect with a medicine to help patients to make an informed decision about whether the benefits of taking the medicine outweigh the risks.
• Directions for the use of a product that are essential to its effectiveness.
Refer this site: http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm
Precautions and Information for patients/patient counseling information- Product Labeling
Precautions:
Actions required to make sure a medicine is properly and safely used are included under Precautions if not covered in other sections of the PI (for example, under Warnings, Dosage and Administration,Indications and Usage, or Contraindications).Precautions for health care professionals are covered separately from precautions for patients. For example, health care professionals might be instructed to ensure that certain preexisting medical
conditions are treated prior to using the medicine because of the risk of the medicine exacerbating those conditions, or to test the levels of certain enzymes in the patient that might affect the activity of the medicine.
This section also may include information for the prescriber concerning certain laboratory tests that may be necessary or helpful to the practitioner to ensure the medication is being used safely or to help predict when possible adverse reactions might occur.
[Note: The Information for Patients subsection, within the Precautions section under the old labeling rules, has been deleted under the new PI labeling format. It may still appear in older labels, but not in the newer labels. That section has been replaced by the Patient Counseling Information section (see
below).]
Information for patients/patient counseling information:
This section explains to health care professionals the information about the medicine that they should discuss with their patients. Such information might include precautions about operating machinery when using the medicine, or instructions on when to take the medicine relative to mealtimes.Note that this section may have different titles and locations within the product label according to when the medicine and/or its labeling was approved. Whether in the newer or older format, however, the same types of information are provided.
• Information for Patients is found in PIs for older medicines. You will find it as a subsection under the Precautions section near the middle of the PI.
• Patient Counseling Information, on the other hand, is a separate section at the very end of the PIs for newer medicines.
If a medication has information designed specifically for patients (Patient Package Insert or Medication Guides), that information would be contained in a separate document that may be printed at the end of the PI, or provided separately. That kind of labeling is not always necessary or required, so not all medications will have such a document
Actions required to make sure a medicine is properly and safely used are included under Precautions if not covered in other sections of the PI (for example, under Warnings, Dosage and Administration,Indications and Usage, or Contraindications).Precautions for health care professionals are covered separately from precautions for patients. For example, health care professionals might be instructed to ensure that certain preexisting medical
conditions are treated prior to using the medicine because of the risk of the medicine exacerbating those conditions, or to test the levels of certain enzymes in the patient that might affect the activity of the medicine.
This section also may include information for the prescriber concerning certain laboratory tests that may be necessary or helpful to the practitioner to ensure the medication is being used safely or to help predict when possible adverse reactions might occur.
[Note: The Information for Patients subsection, within the Precautions section under the old labeling rules, has been deleted under the new PI labeling format. It may still appear in older labels, but not in the newer labels. That section has been replaced by the Patient Counseling Information section (see
below).]
Information for patients/patient counseling information:
This section explains to health care professionals the information about the medicine that they should discuss with their patients. Such information might include precautions about operating machinery when using the medicine, or instructions on when to take the medicine relative to mealtimes.Note that this section may have different titles and locations within the product label according to when the medicine and/or its labeling was approved. Whether in the newer or older format, however, the same types of information are provided.
• Information for Patients is found in PIs for older medicines. You will find it as a subsection under the Precautions section near the middle of the PI.
• Patient Counseling Information, on the other hand, is a separate section at the very end of the PIs for newer medicines.
If a medication has information designed specifically for patients (Patient Package Insert or Medication Guides), that information would be contained in a separate document that may be printed at the end of the PI, or provided separately. That kind of labeling is not always necessary or required, so not all medications will have such a document
Boxed warning- Product Labeling
This term refers to a specially formatted warning that is the strongest level of safety warning that may be required by FDA for an approved medicine. Specifically, a boxed warning gives a brief explanation of any contraindications or serious warnings that may be associated with death or serious injury, with a cross-reference to more detailed information covered in the Warnings and/or
Contraindications sections of the PI. If a boxed warning is required, it will be found at the beginning of the PI, with the text surrounded by a thick black border, with the heading WARNING. For this reason, it is often referred to as a “black box” or “black box warning.”
Contraindications sections of the PI. If a boxed warning is required, it will be found at the beginning of the PI, with the text surrounded by a thick black border, with the heading WARNING. For this reason, it is often referred to as a “black box” or “black box warning.”
Warnings- Product Labeling
Information about a medicine’s important side effects and what to do about them is provided in the Warnings section. Clinically significant adverse events are described, along with other potential safety hazards, limitations in the medicine’s use due to those reactions and hazards, and steps to take if they occur. The defining criterion for inclusion under Warnings is that a reasonable association must have been established between the adverse event or risk and the medicine—although a definitive causal relationship need not be established.
The Warnings section may also provide information about nonapproved uses of the medicine. This would be the case if the medicine either has been commonly used for a condition, or there is a common belief that the medicine is effective for a condition, but the preponderance of evidence demonstrates that the medicine is not effective and this usage of the medicine is associated with a clinically significant risk or hazard. Note that, because such situations involve nonapproved uses of the medicine, they would not be covered in other sections of the PI such as Indications and Usage or Contraindications.
The Warnings section may also provide information about nonapproved uses of the medicine. This would be the case if the medicine either has been commonly used for a condition, or there is a common belief that the medicine is effective for a condition, but the preponderance of evidence demonstrates that the medicine is not effective and this usage of the medicine is associated with a clinically significant risk or hazard. Note that, because such situations involve nonapproved uses of the medicine, they would not be covered in other sections of the PI such as Indications and Usage or Contraindications.
Contraindication- Product Label
By contrast, a “contraindication” for a medicine refers to a specific situation in which the medicine should NOT be taken or administered—defined as circumstances under which using the medicine entails a substantial risk of harm that clearly outweighs any possible therapeutic benefit. To put this another way, the Contraindications section describes the kinds of cases where patients would have a substantial risk of being harmed by a medicine without the potential for sufficient benefit to make that risk acceptable. The Warnings section of the PI will also include a brief mention of any contraindications (with cross-references to this section), and will provide more detail about any
specific adverse reaction that is involved.
Various criteria can be considered for determining when a medicine is contraindicated:
• Patient age (especially infants or young children, or elderly individuals, for whom the demonstrated effectiveness might be less, or the risk of harmful adverse reactions greater,than for other ages).
• Patient gender (a risk may be higher, or the effectiveness of the medicine less, for male versus female individuals).
• Concomitant therapy (other medicines or treatments already being taken might lead to harmful adverse reactions if this medicine were taken at the same time).
• Disease state (the risk-benefit relationship might be different for different severities or stages of the disease to be treated).
• Other condition (a specific coexisting disease or the general condition of a patient might make use of a medicine potentially more hazardous, or less effective against a disease).
• Patient hypersensitivity to the medicine.
A contraindication is a judgment by regulators—after reviewing the available medical evidence—about the benefit-risk relationship of using that medicine under specific circumstances. For example,
a medicine may be approved for treatment of advanced stages of a life-threatening disease, despite
a known risk of serious adverse reactions, if a sufficient level of effectiveness has been demonstrated and no safer effective treatment options exist. In contrast, that same medicine may be contraindicated for patients in whom the same treated disease is less advanced, if it can be treated with other medicines that are equally effective but have a lower risk of serious side effects. It is important to remember that whether a medicine is right for you, at the right time, and for your condition, is always a decision ultimately made by you and your doctor. Note that, according to FDA regulations,contraindications are issued regarding medicine hazards that are known—because they have been demonstrated in studies and/or clinical experience—not for hazards that are simply theoretically possible.
specific adverse reaction that is involved.
Various criteria can be considered for determining when a medicine is contraindicated:
• Patient age (especially infants or young children, or elderly individuals, for whom the demonstrated effectiveness might be less, or the risk of harmful adverse reactions greater,than for other ages).
• Patient gender (a risk may be higher, or the effectiveness of the medicine less, for male versus female individuals).
• Concomitant therapy (other medicines or treatments already being taken might lead to harmful adverse reactions if this medicine were taken at the same time).
• Disease state (the risk-benefit relationship might be different for different severities or stages of the disease to be treated).
• Other condition (a specific coexisting disease or the general condition of a patient might make use of a medicine potentially more hazardous, or less effective against a disease).
• Patient hypersensitivity to the medicine.
A contraindication is a judgment by regulators—after reviewing the available medical evidence—about the benefit-risk relationship of using that medicine under specific circumstances. For example,
a medicine may be approved for treatment of advanced stages of a life-threatening disease, despite
a known risk of serious adverse reactions, if a sufficient level of effectiveness has been demonstrated and no safer effective treatment options exist. In contrast, that same medicine may be contraindicated for patients in whom the same treated disease is less advanced, if it can be treated with other medicines that are equally effective but have a lower risk of serious side effects. It is important to remember that whether a medicine is right for you, at the right time, and for your condition, is always a decision ultimately made by you and your doctor. Note that, according to FDA regulations,contraindications are issued regarding medicine hazards that are known—because they have been demonstrated in studies and/or clinical experience—not for hazards that are simply theoretically possible.
Product Label :Medicines Approved in U.S. After June 2006
Highlights of Prescribing Information:
• Product Names, Other Required Information
• Boxed Warning
• Recent Major Changes
• Indications and Usage
• Dosage and Administration
• Dosage Forms and Strengths
• Contraindications
• Warnings and Precautions
• Adverse Reactions
• Drug Interactions
• Use in Specific Populations
Full Prescribing Information:
Boxed Warning (if required)
1. Indications and Usage
2. Dosage and Administration
3. Dosage Forms and Strengths
4. Contraindications
5. Warnings and Precautions
6. Adverse Reactions
7. Drug Interactions
8. Use in Specific Populations
− 8.1 Pregnancy
− 8.2 Labor and delivery
− 8.3 Nursing mothers
− 8.4 Pediatric use
− 8.5 Geriatric use
9. Medicine Abuse and Dependence
− 9.1 Controlled substance
− 9.2 Abuse
− 9.3 Dependence
10. Overdosage
11. Description
12. Clinical Pharmacology
− 12.1 Mechanism of action
− 12.2 Pharmacodynamics
− 12.3 Pharmacokinetics
13. Nonclinical Toxicology
− 13.1 Carcinogenesis, mutagenesis, impairment of fertility
− 13.2 Animal toxicology and/or pharmacology
14. Clinical Studies
15. References
16. How Supplied/Storage and Handling
17. Patient Counseling Information
• Product Names, Other Required Information
• Boxed Warning
• Recent Major Changes
• Indications and Usage
• Dosage and Administration
• Dosage Forms and Strengths
• Contraindications
• Warnings and Precautions
• Adverse Reactions
• Drug Interactions
• Use in Specific Populations
Full Prescribing Information:
Boxed Warning (if required)
1. Indications and Usage
2. Dosage and Administration
3. Dosage Forms and Strengths
4. Contraindications
5. Warnings and Precautions
6. Adverse Reactions
7. Drug Interactions
8. Use in Specific Populations
− 8.1 Pregnancy
− 8.2 Labor and delivery
− 8.3 Nursing mothers
− 8.4 Pediatric use
− 8.5 Geriatric use
9. Medicine Abuse and Dependence
− 9.1 Controlled substance
− 9.2 Abuse
− 9.3 Dependence
10. Overdosage
11. Description
12. Clinical Pharmacology
− 12.1 Mechanism of action
− 12.2 Pharmacodynamics
− 12.3 Pharmacokinetics
13. Nonclinical Toxicology
− 13.1 Carcinogenesis, mutagenesis, impairment of fertility
− 13.2 Animal toxicology and/or pharmacology
14. Clinical Studies
15. References
16. How Supplied/Storage and Handling
17. Patient Counseling Information
Indications in Prescribing Information - Product Label
It states what diseases or conditions a medicine should be used for, by which patients, and under what situations.
An indication will specify:
• The recognized disease or condition for which the medicine’s use is approved, or the important manifestation of a disease or condition, such as:
i. Hypertension.
ii. Edema in patients with congestive heart failure.
• Whether the medicine is approved to treat, prevent, or diagnose the disease or condition, or to relieve the symptoms associated with a disease or syndrome, such as:
i.Penicillin is indicated for the treatment of pneumonia due to susceptible pneumococci.
ii.Chlorpheniramine is indicated for the symptomatic relief of nasal congestion in patients with vasomotor rhinitis.
• Whether the medicine may be used by itself (often referred to as “monotherapy”), should be used as the primary therapy (ie, without first trying another medicine) versus secondary/tertiary therapy (ie, used only if another medicine has been found not to be sufficiently effective or to have unacceptable side effects), or in conjunction with another mode of therapy (such as surgery, diet, etc—often referred to as “adjunctive therapy”) or in combination with another medicine.
• Whether the medicine is only approved for certain subgroups of patients with the disease or
symptom, such as:
i. Patients with mild disease.
ii. Patients in certain age groups.
iii.
• Whether use of the medicine should be reserved for certain situations, such as:
i.Cases where other therapy has not been effective (often referred to as “refractory” to other therapy).
ii.Patients who are not able to tolerate the adverse effects they experience with another therapy or medicine.
You will get more information about the Prescribing Information including Highlights of Prescribing Information and Full Prescribing Information in my next post.
An indication will specify:
• The recognized disease or condition for which the medicine’s use is approved, or the important manifestation of a disease or condition, such as:
i. Hypertension.
ii. Edema in patients with congestive heart failure.
• Whether the medicine is approved to treat, prevent, or diagnose the disease or condition, or to relieve the symptoms associated with a disease or syndrome, such as:
i.Penicillin is indicated for the treatment of pneumonia due to susceptible pneumococci.
ii.Chlorpheniramine is indicated for the symptomatic relief of nasal congestion in patients with vasomotor rhinitis.
• Whether the medicine may be used by itself (often referred to as “monotherapy”), should be used as the primary therapy (ie, without first trying another medicine) versus secondary/tertiary therapy (ie, used only if another medicine has been found not to be sufficiently effective or to have unacceptable side effects), or in conjunction with another mode of therapy (such as surgery, diet, etc—often referred to as “adjunctive therapy”) or in combination with another medicine.
• Whether the medicine is only approved for certain subgroups of patients with the disease or
symptom, such as:
i. Patients with mild disease.
ii. Patients in certain age groups.
iii.
• Whether use of the medicine should be reserved for certain situations, such as:
i.Cases where other therapy has not been effective (often referred to as “refractory” to other therapy).
ii.Patients who are not able to tolerate the adverse effects they experience with another therapy or medicine.
You will get more information about the Prescribing Information including Highlights of Prescribing Information and Full Prescribing Information in my next post.
Prescribing information (PI)
This document includes a great deal of technical medical detail intended to inform health care professionals who might prescribe or dispense a medicine. The PI of any approved medicine is publicly available and anybody may obtain it (from the manufacturer or from FDA, for example), but a PI is written for a professional audience. Whatever your level of scientific and/or mathematical
training, reading the PI cannot substitute for a discussion with a health care professional regarding the risks and benefits and appropriateness of a medicine in your individual circumstances.
Manufacturers typically make the PIs of their medicines available on the Web, and must include the PI as a printed “package insert” with any medicine that is sold in a box or other type of package. Note that a package insert may also include other material in addition to the PI (although you may see the
terms “package insert” and “prescribing information” referred to interchangeably in general discussion).
Given the large amount of information to be provided, newer medicines must now have a two-part PI to make it easier to find and review the information. The first part, titled Highlights of the Prescribing Information, usually takes up less than one page, but may be longer, depending on the complexity and extent of the relevant information. This section excludes much of the technical detail,
charts/graphs, and less broadly applicable information about the medicine. The second part is the full PI, with specifically labeled and numbered sections.
Although PIs for the older products cover the same types of information as for new products, some of the sections are arranged and labeled a bit differently. For instance, in PIs of older medicines, the topics Medicine Interactions, Use in Special Populations, and Patient Counseling Information are subsections of a separate Precautions section. In PIs of newer medicines, each of these three topics is presented as a separate section, and Precautions is part of a combined Warnings and Precautions section, rather than being its own section.
Some of the more important sections of the PI relating to the safe and effective use of a medicine are:
a)Indications
b)Contraindications
c)Warnings
d)Boxed Warning
e)Precautions
f)Information for patients/patient counseling information
g)Medication Guide
training, reading the PI cannot substitute for a discussion with a health care professional regarding the risks and benefits and appropriateness of a medicine in your individual circumstances.
Manufacturers typically make the PIs of their medicines available on the Web, and must include the PI as a printed “package insert” with any medicine that is sold in a box or other type of package. Note that a package insert may also include other material in addition to the PI (although you may see the
terms “package insert” and “prescribing information” referred to interchangeably in general discussion).
Given the large amount of information to be provided, newer medicines must now have a two-part PI to make it easier to find and review the information. The first part, titled Highlights of the Prescribing Information, usually takes up less than one page, but may be longer, depending on the complexity and extent of the relevant information. This section excludes much of the technical detail,
charts/graphs, and less broadly applicable information about the medicine. The second part is the full PI, with specifically labeled and numbered sections.
Although PIs for the older products cover the same types of information as for new products, some of the sections are arranged and labeled a bit differently. For instance, in PIs of older medicines, the topics Medicine Interactions, Use in Special Populations, and Patient Counseling Information are subsections of a separate Precautions section. In PIs of newer medicines, each of these three topics is presented as a separate section, and Precautions is part of a combined Warnings and Precautions section, rather than being its own section.
Some of the more important sections of the PI relating to the safe and effective use of a medicine are:
a)Indications
b)Contraindications
c)Warnings
d)Boxed Warning
e)Precautions
f)Information for patients/patient counseling information
g)Medication Guide
Product label
The product label is developed during the formal process of review and approval by regulatory agencies of any medicine or medical product. There are specific regulations concerning what must be included in a medicine label regarding its content, and how it works, as well as its proper administration and handling, its side effects, and its proven effectiveness and safety. The content and
presentation of any medicine’s specific labeling—originally drafted and submitted by the manufacturer—are reviewed and approved by regulatory agencies, which may require changes or additions to the label before approving the use of the medicine.
In the U.S., the complete label of a prescription medicine is made up of several documents that are approved and required by FDA—some professionally oriented and some intended for patients and consumers. The first and most comprehensive of these documents is always the professional Prescribing Information. Others may include Patient Counseling Information and a patient-oriented Medication Guide.
presentation of any medicine’s specific labeling—originally drafted and submitted by the manufacturer—are reviewed and approved by regulatory agencies, which may require changes or additions to the label before approving the use of the medicine.
In the U.S., the complete label of a prescription medicine is made up of several documents that are approved and required by FDA—some professionally oriented and some intended for patients and consumers. The first and most comprehensive of these documents is always the professional Prescribing Information. Others may include Patient Counseling Information and a patient-oriented Medication Guide.
Development Safety Update Report( DSUR)
The main focus of the DSUR is data from interventional clinical trials (referred to in this document as “clinical trials”) of investigational drugs including biologicals, with or without a marketing approval, whether conducted by commercial or non-commercial sponsors.It presents an annual review and evaluation of pertinent safety information collected during the reporting period to:
1)summarise the current understanding and management of identified and potential risks;
2)describe new safety issues that could have an impact on the protection of clinical trial subjects;
3)examine whether the information obtained by the sponsor during the reporting period is in accord with previous knowledge of the product’s safety; and
4)provide an update on the status of the clinical investigation/development programme. This guideline defines the content and format of a DSUR and provides an outline of points to be considered in its preparation and submission.
DSUR cannot be considered as:
a)An evaluation of the benefit-risk relationship for the product
b)An interim integrated safety summary (ISS) as submitted for marketing applications
c)A repository or discussion of individual adverse experience cases, unless by exception
d)A signal detection tool
e)An “expert report”
Reference: E2F
1)summarise the current understanding and management of identified and potential risks;
2)describe new safety issues that could have an impact on the protection of clinical trial subjects;
3)examine whether the information obtained by the sponsor during the reporting period is in accord with previous knowledge of the product’s safety; and
4)provide an update on the status of the clinical investigation/development programme. This guideline defines the content and format of a DSUR and provides an outline of points to be considered in its preparation and submission.
DSUR cannot be considered as:
a)An evaluation of the benefit-risk relationship for the product
b)An interim integrated safety summary (ISS) as submitted for marketing applications
c)A repository or discussion of individual adverse experience cases, unless by exception
d)A signal detection tool
e)An “expert report”
Reference: E2F
Differences between IND Annual Report and Annual Safety Report
IND ANNUAL REPORT :
purpose- progress report
Timing- IND anniversary date
Frequency- annual
Recipients- FDA
Content- study data and summary information
Feedback by may be requested regulators: may be requested
Short term end of study report safety report within trials end of study report safety report within trials for all trials within 90 days 1 year of end
Adverse events included: all serious ± associated± expected
Format and Summary: Content, Tabular summary of most frequent and most serious AEs by body system. Summary of all IND expedited reports for the period. Lists of deaths (w/ cause) and dropouts. List of completed non-clinical studies and result summary.
Annual Safety Report:
Purpose-benefit-risk assessment
Timing- Date of 1st authorization of a clinical trial of IMP by authority in member state
Frequency-annual, or on request
Recipients- EMEA, Member States, Ethics Committees
Content- benefit-risk assessment;
Content- supporting tables
Feedback by may be requested regulators:not mentioned
Short term end of study report safety report within trials: safety report within trials for all trials within 90 days
Adverse events included SUSARs; serious,associated; ± expected
Format and Summary Content: Concise global analysis; benefit-risk evaluation; implications for trial subjects; proposed measures to minimize risk; rationale for updates of study documents and procedures; supporting results of non-clinical studies; other considerations
purpose- progress report
Timing- IND anniversary date
Frequency- annual
Recipients- FDA
Content- study data and summary information
Feedback by may be requested regulators: may be requested
Short term end of study report safety report within trials end of study report safety report within trials for all trials within 90 days 1 year of end
Adverse events included: all serious ± associated± expected
Format and Summary: Content, Tabular summary of most frequent and most serious AEs by body system. Summary of all IND expedited reports for the period. Lists of deaths (w/ cause) and dropouts. List of completed non-clinical studies and result summary.
Annual Safety Report:
Purpose-benefit-risk assessment
Timing- Date of 1st authorization of a clinical trial of IMP by authority in member state
Frequency-annual, or on request
Recipients- EMEA, Member States, Ethics Committees
Content- benefit-risk assessment;
Content- supporting tables
Feedback by may be requested regulators:not mentioned
Short term end of study report safety report within trials: safety report within trials for all trials within 90 days
Adverse events included SUSARs; serious,associated; ± expected
Format and Summary Content: Concise global analysis; benefit-risk evaluation; implications for trial subjects; proposed measures to minimize risk; rationale for updates of study documents and procedures; supporting results of non-clinical studies; other considerations
Monday, September 27, 2010
Professional Diploma in Clinical Research
FDA ESG (Electronic Submission Gateway)
The FDA ESG is the central transmission point for sending information electronically to the FDA. The FDA ESG is a conduit, or "highway", along which submissions travel to reach their final destination. It does not open or review submissions; it merely routes them to the proper destination. A single point of entry for receiving and processing all electronic submissions in a highly secure environment.Automating current electronic processes such as the electronic acknowledgment of submissions.Supporting the electronic Common Technical Document (eCTD).
The electronic submission process is defined as the receipt, acknowledgment, routing, and notification to a receiving Center of the receipt of an electronic submission. Each of these terms denotes a step in the process of electronic submission delivery, and together, these steps comprise the whole scope of electronic submission delivery.
"Receipt" means transfer of a submission from a sender’s system to a temporary storage area in the FDA ESG."Acknowledgment" to the sender that the submission was sent from the sender’s system and received by the Gateway."Routing" refers to delivering a submission to a Center-level storage area and initiating a load process to place a submission into a Center receiving system."Notification" of a submission’s arrival is made to those individuals responsible for the Center’s receiving system.
The electronic submission process is defined as the receipt, acknowledgment, routing, and notification to a receiving Center of the receipt of an electronic submission. Each of these terms denotes a step in the process of electronic submission delivery, and together, these steps comprise the whole scope of electronic submission delivery.
"Receipt" means transfer of a submission from a sender’s system to a temporary storage area in the FDA ESG."Acknowledgment" to the sender that the submission was sent from the sender’s system and received by the Gateway."Routing" refers to delivering a submission to a Center-level storage area and initiating a load process to place a submission into a Center receiving system."Notification" of a submission’s arrival is made to those individuals responsible for the Center’s receiving system.
Differences between PSUR and PADER
Preapproval reports include IND Annual Reports in the U.S. and Annual Safety Reports (ASRs) in Europe. Some of these documents may provide cumulative information, while others contain aggregate information specific to the reporting period. Postapproval cumulative reports of safety include NDA Periodic Adverse Drug Experiences Reports (PADERs) in the U.S. and Periodic Safety Update Reports (PSURs) in many other countries, including in Europe. Their purpose is to update and evaluate the worldwide safety experience with a medicine at defined time points after approval.
These reports provide succinct summary information together with an evaluation of the benefit-risk
profile of approved medicines in the light of new or changing postapproval information.This evaluation is designed to help ascertain whether further investigations need to be carried out and whether changes should be made to the approval and/or to the medicine’s labeling.
In summary, the aim of cumulative reports of safety is to:
• Report all the relevant new information from appropriate sources.
• Relate these data to patient exposure to the medicine.
• Summarize the medicine’s approval status in different countries and any significant variations related to safety.
• Create periodically the opportunity for an overall reevaluation of safety.
• Indicate whether changes should be made to an approved medicine’s label in order to optimize the use of the product.
These reports provide succinct summary information together with an evaluation of the benefit-risk
profile of approved medicines in the light of new or changing postapproval information.This evaluation is designed to help ascertain whether further investigations need to be carried out and whether changes should be made to the approval and/or to the medicine’s labeling.
In summary, the aim of cumulative reports of safety is to:
• Report all the relevant new information from appropriate sources.
• Relate these data to patient exposure to the medicine.
• Summarize the medicine’s approval status in different countries and any significant variations related to safety.
• Create periodically the opportunity for an overall reevaluation of safety.
• Indicate whether changes should be made to an approved medicine’s label in order to optimize the use of the product.
Common Terminology for Adverse Events (CTCAE)- National Cancer Institute
Grading adverse events : By this grading scale, all adverse events are classified as follows:
0=No adverse event or within normal limits
1=Mild adverse event
2=Moderate adverse event
3=Severe and undesirable adverse event
4=Life-threatening or disabling adverse event
5=Death related to adverse event
0=No adverse event or within normal limits
1=Mild adverse event
2=Moderate adverse event
3=Severe and undesirable adverse event
4=Life-threatening or disabling adverse event
5=Death related to adverse event
Adverse Drug Reactions Classifcations: Based on Severity
a)Mild : No antidote or treatment is required; hospitalization is not prolonged
b)Moderate: A change in treatment (e.g., modified dosage, addition of a drug), but not necessarily discontinuation of the drug, is required; hospitalization may be prolonged, or specific treatment may be required
c)Severe: An ADR is potentially life threatening and requires discontinuation of the drug and specific treatment of the ADR
d)Lethal : An ADR directly or indirectly contributes to a patient's death
b)Moderate: A change in treatment (e.g., modified dosage, addition of a drug), but not necessarily discontinuation of the drug, is required; hospitalization may be prolonged, or specific treatment may be required
c)Severe: An ADR is potentially life threatening and requires discontinuation of the drug and specific treatment of the ADR
d)Lethal : An ADR directly or indirectly contributes to a patient's death
Adverse Drug Reactions Classifcations
Classification based on frequency :
a)Very common
> 1/10 ( > 10%)
b)Common (frequent)
> 1/100 and < 1/10 ( > 1% and < 10%)
c)Uncommon (infrequent)
> 1/1,000 and < 1/100 ( > 0.1% and < 1 %)
d)Rare
> 1/10,000 and < 1,000 ( > 0.01% and < 0.1%)
e)Very rare
< 1/10,000 (< 0.01%)
a)Very common
> 1/10 ( > 10%)
b)Common (frequent)
> 1/100 and < 1/10 ( > 1% and < 10%)
c)Uncommon (infrequent)
> 1/1,000 and < 1/100 ( > 0.1% and < 1 %)
d)Rare
> 1/10,000 and < 1,000 ( > 0.01% and < 0.1%)
e)Very rare
< 1/10,000 (< 0.01%)
Wednesday, September 22, 2010
Quality Assurance
Each pharmaceutical sponsor company should have a quality assurance unit that is independent of the operational area that is, outside the company’s clinical research group. The function of the QA unit is to conduct independent assessments and audits to ensure that appropriate clinical research processes are in place and that clinical operations are being conducted according to relevant regulations and guidelines, and in conformance with the sponsor’s corporate policies, procedures, and trial protocol. QA is to report any variations or deviations it finds to the operational area staff and management and, periodically, to the company’s senior management.
Although organizationally separate from the clinical research component, QA personnel work closely with clinical operations to understand its internal processes and activities and to learn the locations of trial sites and site-related activities. It is important for the QA department to know “where the action is,” and to be there frequently enough to ensure that things are done properly. This means compiling a list of clinical operations group activities and conducting a formal or informal risk assessment to determine which processes and areas are best under control. Examples of risk factors are investigators new to clinical research who require further
training and sites with high staff turnover, which can lead to uncertainties and mistakes in clinical trial practice. QA personnel can then conduct planned audits of sites and medical processes and write reports for QA management review. The management and staff of the audited group receive final reports of the audit
findings, as do designated senior managers throughout the company.
In some cases, “special alert” notations may be marked on audits to trigger specific and prompt action by senior corporate managers. In fact, all audit findings require some response, such as who will address the issue, what the action plans are, and when they will be completed. The QA department tracks the action plans to completion with the goal of continual improvement in quality, compliance, and safety reporting.
Although organizationally separate from the clinical research component, QA personnel work closely with clinical operations to understand its internal processes and activities and to learn the locations of trial sites and site-related activities. It is important for the QA department to know “where the action is,” and to be there frequently enough to ensure that things are done properly. This means compiling a list of clinical operations group activities and conducting a formal or informal risk assessment to determine which processes and areas are best under control. Examples of risk factors are investigators new to clinical research who require further
training and sites with high staff turnover, which can lead to uncertainties and mistakes in clinical trial practice. QA personnel can then conduct planned audits of sites and medical processes and write reports for QA management review. The management and staff of the audited group receive final reports of the audit
findings, as do designated senior managers throughout the company.
In some cases, “special alert” notations may be marked on audits to trigger specific and prompt action by senior corporate managers. In fact, all audit findings require some response, such as who will address the issue, what the action plans are, and when they will be completed. The QA department tracks the action plans to completion with the goal of continual improvement in quality, compliance, and safety reporting.
Sponsor monitoring- Clinical Trials
It is an important oversight process to ensure quality, compliance,and subject safety. Monitors may be employees of the sponsor’s medical staff or a contract research organization, or may be independent contractors. In each case, they represent the sponsor, and visit investigator sites regularly, perhaps every four to eight weeks. They examine subject records in detail and verify that the correct information was transferred to the clinical trial case report forms a process called source data verification. During their site visits, monitors also examine administrative and regulatory documents, including drug supply and dosing records, adverse events documentation and reporting, the informed consent process,and communications between the sponsor company and investigator and between the investigator and IRB. In short, the activities of clinical trial monitors are designed to ensure that all elements of the protocol are being followed. In addition, monitors examine the appropriateness of the qualifications, training, and training records of all site staff involved with the trial, and they communicate changes in site personnel to the sponsor company’s oversight team. Following the completion of a site monitoring visit, the monitor meets with the site staff to review findings and discuss (agree upon) corrections in data or improvements in processes, if needed. Monitors are expected to write a formal
monitoring report promptly after each visit. Reports are sent to the sponsor company’s medical department, which reviews the reports. When necessary, that department’s clinical research associates and physicians recommend remedial action. Regular monitoring ensures continued contact with an investigator site to keep
the sponsor company aware of the site’s safety and compliance status. Periodically, information from many monitoring visits and reports is gathered and analyzed for common problems. When problems are detected, special site- or trial-specific counseling and training is initiated.
monitoring report promptly after each visit. Reports are sent to the sponsor company’s medical department, which reviews the reports. When necessary, that department’s clinical research associates and physicians recommend remedial action. Regular monitoring ensures continued contact with an investigator site to keep
the sponsor company aware of the site’s safety and compliance status. Periodically, information from many monitoring visits and reports is gathered and analyzed for common problems. When problems are detected, special site- or trial-specific counseling and training is initiated.
Tuesday, September 21, 2010
CCSI(Company Core Safety Information)
All relevant safety information contained in the company core data sheet (CCDS) prepared by the marketing authorization / licence holder and which the MA holder requires to be listed in all countries where the company markets the drug, except when the local regulatory authority specifically requires a modification
The CCSI is the reference information by which listed and unlisted are determined for the purpose of periodic reporting for marketed products, but not by which expected and unexpected are determined for expedited reporting.
For the purpose of periodic Safety Update Report, the CCSI forms the basis for determining whether an ADR is already listed or is still unlisted.
For a clinical trial, the CCSI is the company core data sheet, prepared by the MAH of a marketed product when it is used as an investigational medicinal product, except when the local regulatory authority specifically requires a modification. For investigational products the CCSI is the Development Core Safety Information.
The CCSI is the reference information by which listed and unlisted are determined for the purpose of periodic reporting for marketed products, but not by which expected and unexpected are determined for expedited reporting.
For the purpose of periodic Safety Update Report, the CCSI forms the basis for determining whether an ADR is already listed or is still unlisted.
For a clinical trial, the CCSI is the company core data sheet, prepared by the MAH of a marketed product when it is used as an investigational medicinal product, except when the local regulatory authority specifically requires a modification. For investigational products the CCSI is the Development Core Safety Information.
Company Core Data Sheet(CCDS)
A document prepared by the marketing authorization holder containing, in addition to safety information, material relating to indications, dosing, pharmacology and other information concerning the product.
The CCDS is required to judge whether an adverse event or adverse drug reaction is labeled / listed or unlabelled / unlisted and is therefore always included in a periodic safety update report (PSUR).
In many countries involved in the international conference on harmonization (ICH) as members or observers, this kind of document is similar to the labelling approved as part of the marketing authorisation, although there are often differences because of differences in the scope of the document, principles for inclusion, indications and / or recommended dosage of the drug, experience drawn from pre-registration studies and from the market, local habits for concomitant drugs and local or ethnic sensitivity. The classification ‘labeled’ or ‘unlabelled’ has many more consequences for expedited reporting than for periodic reporting. The CCDS must be dated, including the date of last revision (or all revision dates).
CCDS are usually prepared by an applicant for a drug substance (active ingredient) rather than a drug product because post-marketing PSUR’s and IPSR’s would be based on a drug substance.
The CCDS is required to judge whether an adverse event or adverse drug reaction is labeled / listed or unlabelled / unlisted and is therefore always included in a periodic safety update report (PSUR).
In many countries involved in the international conference on harmonization (ICH) as members or observers, this kind of document is similar to the labelling approved as part of the marketing authorisation, although there are often differences because of differences in the scope of the document, principles for inclusion, indications and / or recommended dosage of the drug, experience drawn from pre-registration studies and from the market, local habits for concomitant drugs and local or ethnic sensitivity. The classification ‘labeled’ or ‘unlabelled’ has many more consequences for expedited reporting than for periodic reporting. The CCDS must be dated, including the date of last revision (or all revision dates).
CCDS are usually prepared by an applicant for a drug substance (active ingredient) rather than a drug product because post-marketing PSUR’s and IPSR’s would be based on a drug substance.
Investigator Brochure Update
An IB is usually revised and updated to include new information at least annually, if not more frequently, depending on the stage of development and the volume of new relevant information generated. If the clinical trial is not sponsored by the pharmaceutical company, but is sponsored by the investigator, the sponsor-investigator is responsible for obtaining any updates to the brochure from the commercial manufacturer and distributing the updates to the clinical sites. If the investigational product is provided by the sponsor-investigator, then he or she should provide the necessary information to the trial personnel. If a formal IB is impractical, the sponsor-investigator should provide an expanded background information section in the trial protocol as a substitute. This section must contain the minimum current information described in the ICH guideline.
The Principal Investigator conducting the study at each site is responsible for ensuring the current IB has been provided to the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) while the study is ongoing at their site. The IEC or IRB reviews the IB as part of its responsibilities in reviewing and approving the clinical trial protocol and the investigators conducting the study. New information may be so important that it should be communicated to the investigators, and possibly to the IRBs/IEBs before it is included in a revised IB.
When providing an updated IB to the IEC/IRB, it is common practice to provide a listing of the changes made between the previous and current version. It is often helpful to the study sites to provide the change history to help ensure the study staff are aware of the changes. It is important, therefore, to have a document control system in place to manage the editing and publishing process.
As part of the site management process for regulated studies, it is common practice to have the site sign and return a document indicating the updated IB has been received and reviewed. Documentation of IRB approval is also required to be maintained in the study files both at the study site and by the study sponsor.
The Principal Investigator conducting the study at each site is responsible for ensuring the current IB has been provided to the Independent Ethics Committee (IEC) or Institutional Review Board (IRB) while the study is ongoing at their site. The IEC or IRB reviews the IB as part of its responsibilities in reviewing and approving the clinical trial protocol and the investigators conducting the study. New information may be so important that it should be communicated to the investigators, and possibly to the IRBs/IEBs before it is included in a revised IB.
When providing an updated IB to the IEC/IRB, it is common practice to provide a listing of the changes made between the previous and current version. It is often helpful to the study sites to provide the change history to help ensure the study staff are aware of the changes. It is important, therefore, to have a document control system in place to manage the editing and publishing process.
As part of the site management process for regulated studies, it is common practice to have the site sign and return a document indicating the updated IB has been received and reviewed. Documentation of IRB approval is also required to be maintained in the study files both at the study site and by the study sponsor.
MedDRA
MedDRA is used for coding medical terms generated during all phases of clinical trial, excluding animal toxicology,therapeutic indications which include signs, symptoms,diseases, diagnosis, or prophylaxis of disease, and modification of functions, coding names and quantitative results of investigations,surgical procedures and medical/social/family history.
MedDRA releases 2 versions in a year - one in March and the second in September. One can obtain access to the MedDRA terminology annually, by renewable subscription.Each subscription brings all MedDRA updates that incorporate approved changes and additions .
MedDRA has five hierarchical levels as listed below
Low Level Term (LLT),
Preferred Tem (PT),
High Level Term (HLT),
High Level Group Term (HLGT),
System Organ Class (SOC)
MedDRA releases 2 versions in a year - one in March and the second in September. One can obtain access to the MedDRA terminology annually, by renewable subscription.Each subscription brings all MedDRA updates that incorporate approved changes and additions .
MedDRA has five hierarchical levels as listed below
Low Level Term (LLT),
Preferred Tem (PT),
High Level Term (HLT),
High Level Group Term (HLGT),
System Organ Class (SOC)
Medical Coding in Clinical Trials
All data generated in Clinical trials are ultimately subjected to further analysis. It is very essential that this data gets interpreted uniformly in a standardized format.Medical coding is performed in clinical trial using Standardised medical coding dictionaries.Data listed above like AEs, SAEs, MH , CM and any other category generally are coded. However coding AEs, SAEs and CM is mandate in any given clinical trial.
There are several standardized medical coding dictionaries in the market; however five dictionaries listed below are used for coding:
1. COSTART - Coding Symbols for Thesaurus of Adverse Reaction Terms
2. ICD9CM - International Classification of Diseases 9 Revision Clinical Modification
3. MedDRA – Medical Dictionary for Regulatory Activities
4. WHO-ART – World Health Organisation Adverse Reactions Terminology
5. WHO-DDE– World Health Organisation Drug Dictionary Enhanced
Out of the above five, two widely used medical coding dictionaries used for coding medical terms generated in clinical trials are MedDRA and WHO-DDE.
There are several standardized medical coding dictionaries in the market; however five dictionaries listed below are used for coding:
1. COSTART - Coding Symbols for Thesaurus of Adverse Reaction Terms
2. ICD9CM - International Classification of Diseases 9 Revision Clinical Modification
3. MedDRA – Medical Dictionary for Regulatory Activities
4. WHO-ART – World Health Organisation Adverse Reactions Terminology
5. WHO-DDE– World Health Organisation Drug Dictionary Enhanced
Out of the above five, two widely used medical coding dictionaries used for coding medical terms generated in clinical trials are MedDRA and WHO-DDE.
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