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.
Wednesday, September 29, 2010
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.
Subscribe to:
Posts (Atom)