Common Terminology Criteria for Adverse Events (CTCAE)

The NCI’s Common Terminology Criteria for Adverse Events (CTCAE; http://ctep.cancer.gov/reporting/ctc.html) is a longstanding empirically developed “dictionary” or lexicon, designed for use in clinical trials to aid clinicians in detecting and documenting an array of adverse events (AEs) commonly encountered in oncology.

An AE is a term that is a unique representation of a specific event used for medical documentation and scientific analyses. Each AE is graded on a scale of 1 (mild) to 5 (death related to AE).

There is growing awareness that collecting symptom data directly from patients using patient-reported outcome (PRO) tools can improve the accuracy and efficiency of symptomatic AE data collection.

The NCI’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) system provides a web-based platform to collect patient reports of symptoms they are experiencing while undergoing treatment for the purpose of enhancing adverse event (AE) reporting http://outcomes.cancer.gov/tools/pro-ctcae.html). To date, 81 symptoms of the CTCAE (version 4) have been identified to be amenable to patient reporting. These symptoms have been converted to patient terms (e.g., CTCAE term “myalgia” converted to “aching muscles”).


Source: http://outcomes.cancer.gov/tools/pro-ctcae_fact_sheet.pdf

How to Monitor new medicines and vaccines- MHRA

New chemicals and vaccines are effectively put on probation for up to two years and labelled with a black triangle to ensure prescribers are aware of the need to monitor them carefully. The black triangle symbol accompanies new medicines and vaccines in prescribing manuals, product information, and advertising material. It prompts healthcare professionals to report any potential side effects to the MHRA. This information helps to build up a broader picture of how the treatment works in the general population and enables the MHRA to act promptly, should a previously unrecognised and serious side effect come to light. The black triangle may also be assigned to a medicine that has already been licensed if it contains a new combination of active chemicals or if it is being used in a new way or for a different condition. The black triangle is not removed until the MHRA is satisfied that the medicine works safely in large numbers of people. Additionally, the MHRA also asks manufacturers to keep a close watch on side effects that may be associated with newly marketed products.

Source: MHRA Guidelines

Dictionary - Clinical Research

http://www.michr.umich.edu/tools/dictionary/G-I.htm

Understand the SAE process

When an SAE report is sent by an investigator, health worker, or employee (clinical research associate or pharm center), it is immediately assigned a number and reviewed to determine whether the event is a reportable SAE. If it is reportable, the company needs to send the SAE to FDA by one of the following methods.
• Form 3500A only (can be filed manually or electronically via the AERS system)
•A narrative report
• VAERS form (vaccines only)
• CIOMS I form (foreign reports only).

A company’s culture and experience dictate the way it meets these reporting requirements. Whatever the method it uses, a company must keep an audit trail, either manual or electronic, that shows
• the initial receipt date of the SAE
• all changes made to the original SAE by any personnel.
• all supporting documentation requested and sent in from the site.
• any internal or external correspondence.
• any internal notes, such as medical review.
• all attempts to get additional information regarding the event.
• whether the event is open or closed.

We need to code the SAEs in such a way that they become categorical in nature, such as assigning a code for the event and a MedDRA term

Source: FDA Guidelines

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.

Source: FDA and EMEA Guidelines

Single Case Processing- Pharmacovigilance

The various sources from where we may get information :
a) Spontaneous reports
b) Clinical trial reports, including SAE case narrative writing
c) Special reports (legal, literature)

Following established guidelines, source documents sent to Drug Safety Unit are entered (MedDRA coding) on to a Drug Safety/Pharmacovigilance database, after a duplicate search, on behalf of those clients. This may involve an initial triage and a subsequent medical review/assessment of the report by physicians.

a) Spontaneous reports :These can be serious or non-serious event reports from the following sources, originating after a product has been marketed by the Marketing Authorization Holder (MAH):

Government agencies, Industry, Hospitals, Academia, Medical and Pharmaceutical Associations, Poisons and Medicines Information Centers, Health Professionals, Patients,Consumers,Media

b) Clinical trial reports :These are adverse event reports originating from clinical trials involving investigational products. Only serious events and non-serious events of special interest are reportable to the health authorities. Such events may be considered related or unrelated to the investigational product by the investigator/client.

c) Special reports :
i)Legal reports : These are case reports originating from filed lawsuits. These cases are forwarded to Drug safety typically by the MAH's legal department and contain a list of damages (events that are the subject of the legal action). The source documents includes plaintiff fact sheets, medical records, e-mail communications, jury trial demand notifications, deficiency letters and summons etc.
ii)Literature reports : These are all case reports where an adverse event associated with a marketed or investigational product has been generated from a systematic search of commercial scientific databases of published peer-reviewed journal articles. In these, only a generic name of the marketed or investigational product may have been reported, and quite often the manufacturer cannot be determined.

Source: ICH Guidelines

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:

•   Evidence of previously unidentified toxicity.
•   Increased frequency of known toxicity or expected undesirable effects,e.g. incidence greater than 1 in  10,000 animals treated.
•   Drug interactions.
•   Adverse reactions associated with off-label use including overdose.
•   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.

Source: ICH Guidelines

Product Monograph

Product Monograph should have the information which can communicate with the sections described below:

Health Professional Information: This particular area  covers essential prescribing information, including dosage and strength, indications and clinical uses, warnings and precautions, adverse reactions and drug interactions.

Scientific Information:The Scientific Information section contains more detailed scientific information including toxicology and data from animal studies, clinical trials, pharmaceutical information and pharmacology.

Patient Information: Such a section may or may not be included. It is informative about how to use the medicine safely and most effectively.

Contents of a Product Monograph:

Contents of a product monograph:

1. Pharmacology of the drug
2. Clinical Trials
3. Indications and Clinical Uses
4. Contraindications
5. Warnings and Precautions
6. Adverse Reactions
7. Toxicology and Drug Interactions
8. Dosage and Administration
9. Special Handling Instructions
10. Glossary

Source: http://www.chillibreeze.com/articles/Product-Monograph.asp
Product Monograph Sample: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/monograph/pmappe_mpanne-eng.php
http://www.janssen-ortho.com/JOI/pdf_files/Elmiron_E.pdf

Difference between Protocol Deviation and Protocol Violation

Protocol Deviation- A protocol deviation is any change, divergence, or departure from the study design or procedures of a research protocol that is under the investigator’s control and that has not been approved by the IRB. Upon discovery, the Principal Investigator is responsible for reporting protocol deviations to the IRB using the standard reporting form.

Protocol Violation- A protocol violation is a deviation from the IRB approved protocol that may affect the subject's rights, safety, or well being and/or the completeness, accuracy and reliability of the study data.

If the deviation meets any of the following criteria, it is considered a protocol violation.

I. The deviation has harmed or posed a significant or substantive risk of harm to the research subject.
Examples:
• A research subject received the wrong treatment or incorrect dose.
• A research subject met withdrawal criteria during the study but was not withdrawn.
• A research subject received an excluded concomitant medication.

II. The deviation compromises the scientific integrity of the data collected for the study.
Examples:
• A research subject was enrolled but does not meet the protocol's eligibility criteria.
• Failure to treat research subjects per protocol procedures that specifically relate to primary efficacy outcomes. (if it involves patient safety it meets the first category above)

III. The deviation is a willful or knowing breach of human subject protection regulations, policies, or procedures on the part of the investigator(s).
Examples:
• Failure to obtain informed consent prior to initiation of study-related procedures

IV. The deviation involves a serious or continuing noncompliance with federal, state, local or institutional human subject protection regulations, policies, or procedures.
Examples:
• Working under an expired professional license or certification

V. The deviation is inconsistent with the NIH Human Research Protection Program’s research, medical, and ethical principles.
Examples:
• A breach of confidentiality.

Source: http://www.genome.gov/Pages/Research/Intramural/IRB/Deviation_Violation_examples8-07.pdf

ICH Guidances

The ICH process results in guidance documents that create consistency in the requirements for new drug approval. Guidance documents represent the Agency ’ s current thinking on a particular subject. These documents provide guidance on the processing, content, evaluation, and approval of applications. They also establish policies intended to achieve consistency in the Agency ’ s regulatory approach and establish inspection and enforcement procedures. Because guidances are not regulations or laws, they are not enforceable, eitherthrough administrative actions or through the courts. An alternative approach may be used if such an approach satisfi es the requirements of the applicable statutes, regulations, or both.

ICH guidances are developed through a fi ve - step process: (1) consensus building, (2) start of regulatory action, (3) regulatory consultation, (4) adoption of text, and (5) implementation.

When a guidance document reaches Step 2 or Step 4 in the ICH process, the FDA publishes a notice of
availability in the Federal Register . Guidances are posted on the Internet and placed in the Docket for viewing and public comment. Notices for Step 2 guidances include a date for receipt of written comment. Because Step 2 documents are drafts, they do not conform with the Agency ’ s Good Guidance Practices (GGP) policy. Step 4 guidances must be reformatted and edited to be consistent with the GGPs. This is because the 1997 U. S. Food, Drug and Cosmetic Act required the Agency to make GGPs the law.

Source: ICH Guidelines

PLAIN LANGUAGE MOVEMENT- Medical Writing

Joanne Locke, Senior Policy Advisor and Plain Language Coordinator at the U.S. Food and Drug Administration (FDA), reviewed an initiative termed “The Plain Language Movement” The movement dates back to the 1970s when the U.S. federal government began encouraging its regulation writers to be less bureaucratic.

 

The plain language movement is an attempt to demonstrate the benefits of writing clearly and concisely, in a reader-focused style. In short, the plain language movement may be called a recipe to use

• logical organization of your text,  
• common, everyday words (except for necessary technical terms),  
• “we” and other personal pronouns, 
• the active voice, and 
• short sentences.

Source: ICH Guidelines

Regulatory Authority Sources- Sources of Individual Case Safety Report

Individual serious unexpected adverse drug reaction reports originating from foreign regulatory authorities are always subject to expedited reporting. Re-submission of serious ADR cases without new information to the originating regulatory authority is not usually required, unless otherwise specified by local regulation.

Source: ICH Guidelines

Licensor -Licensee Interaction- Sources of ICSR

When companies co-develop, co-market, or co-promote products, it is considered very important that explicit contractual agreements specify the processes for exchange of safety information, including timelines and regulatory reporting responsibilities. Whatever the contractual arrangement, the MAH is ultimately responsible for regulatory reporting.

It is particularly important to ensure that processes are in place to avoid duplicate reporting to the regulatory authority, e.g. assigning responsibility to one company for literature screening. The time frame for expedited regulatory reporting should normally be no longer than 15 calendar days from the first receipt of a case meeting minimum criteria by any of the partners, unless otherwise specified by local regulation. Any subsequent follow-up information sent to the regulators should be submitted by the same MAH that reported the case originally.

Source: ICH Guidelines 

Sources of Individual Case Reports- Pharmacovigilance

Sources:

• Unsolicited Sources: Spontaneous Reports,Consumer reports, Literature, Internet, Other Sources.
• Solicited Sources: data collection systems, which include clinical trials, post-approval named patient use programs, other patient support and disease management programs, surveys of patients or healthcare providers, or information gathering on efficacy or patient compliance.
• Licensor-Licensee Interaction
•  Regulatory Authority Sources

Source: ICH Guidelines 

Solicited Sources

Solicited reports are those derived from organized data collection systems, which include clinical trials, post-approval named patient use programs, other patient support and disease management programs, surveys of patients or healthcare providers, or information gathering on efficacy or patient compliance. Adverse event reports obtained from any of these should not be considered spontaneous.

For the purposes of safety reporting, solicited reports should be handled as if they were study reports, and therefore should have an appropriate causality assessment. Further guidance on study-related issues such as managing blinded therapy cases can be found in ICH E2A.

Source: ICH Guidelines 

Sources of ICSR: Unsolicited Sources

Unsolicited Sources:

Spontaneous Reports: A spontaneous report is an unsolicited communication by healthcare professionals or consumers to a company, regulatory authority or other organization (e.g. WHO, Regional Centers, Poison Control Center) that describes one or more adverse drug reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organized data collection scheme. Stimulated reporting may occur in certain situations, such as a notification by a "Dear Healthcare Professional" letter, a publication in the press, or questioning of healthcare professionals by company representatives. These reports should be considered spontaneous.

Consumer reports:Consumer adverse reaction reports should be handled as spontaneous reports irrespective of any subsequent "medical confirmation", a process required by some authorities for reportability. Even if reports received from consumers do not qualify for regulatory reporting, the cases should be retained. Emphasis should be placed on the quality of the report and not on its source.

Literature:The Marketing Authorisation Holder (MAH) is expected to regularly screen the worldwide scientific literature, by accessing widely used systematic literature reviews or reference databases. Cases of ADRs from the scientific and medical literature, including relevant published abstracts from meetings and draft manuscripts, might qualify for expedited reporting. A regulatory reporting form with relevant medical information should be provided for each identifiable patient. The publication reference(s) should be given as the report source; additionally a copy of the article might be requested by the local regulatory authority to accompany the report. All company offices are encouraged to be aware of publications in their local journals and to bring them to the attention of the company safety department as appropriate. The regulatory reporting time clock starts once it is determined that the case meets minimum criteria for reportability. MAHs should search the literature according to local regulation or at least once a month. If the product source, brand, or trade name is not specified, the MAH should assume that it was its product, although reports should indicate that the specific brand was not identified.

Internet:MAHs are not expected to screen external websites for ADR information. However, if an MAH becomes aware of an adverse reaction on a website that it does not manage, the MAH should review the adverse reaction and determine whether it should be reported. Unsolicited cases from the Internet should be handled as spontaneous reports. MAHs should regularly screen their websites for potential ADR case reports. MAHs and regulators should consider utilising their websites to facilitate ADR data collection, e.g. by providing ADR forms for direct reporting or by providing appropriate contact details for direct communication. For the determination of reportability the same criteria should be applied as for cases provided via other ways.

Other Sources:If MAHs become aware of a case report from non-medical sources, it should be handled as a spontaneous report.

Source: ICH Guidelines 

Terminologies: Vigimed,Vigiflow,Vigibase and Vigisearch.

Vigibase: The name for the WHO International ADR Database

Vigiflow: is a sophisticated case report management system created by the UMC, complying with GxP requirements.

Vigisearch : is a custom search offered by the UMC to third –party inquirers for which several types of standard presentation are available.

Vigimed: E-mail conferencing facility, exclusive to member countries of the WHO Programme for International Drug Monitoring.

Source: www.who-umc.org/graphics/15338.pdf

Causality assessment

The evaluation of the likelihood that a medicine was the causative agent of an observed adverse reaction.
Causality assessment is usually made according established algorithms.

Methods of causality assessment:

• WHO assessment scale
• Naranjo’s scale
• European ABO system
• Karch and Lasagna’s scale
• Kramer scale
• Bayesian network
• Yale Algorithm
• Spanish Imputation System

WHO Causality categories:

1. Certain
2. Probable
3. Possible
4. Unlikely
5. Conditional/Unclassified
6. Unassessable/Unclassifiable.

Reference: WHO

Adverse Event Types

Adverse Events are categorized in to 4 different types based on the following criteria:

• Intensity: Based on intensity it is again categorized in to Mild ,Moderate, Severe.

• Seriousness: Based on its seriousness it is again categorized in to Non Serious and Serious.

• Expectedness: Based on its seriousness it is again categorized in to Expected and Unexpected.

• Causality: Based on the causality assessment  it is again categorized in to Related and Un-related.

Glossary of Important Terms in Pharmacovigilance

PharmacovigilanceWHO, 2002 :The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem.

Adverse reactionWHO, (1972):'A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function'.

Adverse event: Unintended effect occurring at normal dose related to the pharmacological properties.

Serious adverse event or reaction: Any untoward medical occurrence that at any dose;
Results in death; Requires inpatient hospitalization or prolongation of existing hospitalization; Results in persistent of significant disability or incapacity.

Unexpected adverse reaction: Not consistent with applicable product information or characteristics of drug.

Signal: Reported information on possible causal relationship between an adverse event and drug Previously unknown or incompletely documented; More than one report is needed.

BASO pyramid in Medical writing

Baseline: correct grammar and spelling, accepted terminology in the field

Style: personal sty l e,language styles,type of manuscript,“house style” of specific journal,conventions, traditions

Opinion: It is important to realize that there is, in fact, room for personal opinion even in the context of scientific writing. This implies that certain issues are not simply “correct” or “incorrect.”

Medical writing- Thomas Mann urge

Many scientific authors hold a firm belief that sentences crowded with information add value to their scientific message, and yet they achieve the opposite. Although this problem is evident across the entire
scientific literature, it is clearly more pronounced among authors with a language background other than English, for example, German or French. The temptation to use ample decoration also comes from the mixing of creative and scientific writing is termed as Thomas Mann urge.

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).

Reference: MSSO

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

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.

Source: EMEA Guidelines

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: ICH E2F

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%)

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

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.

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.

Literature Database- Difference between Medline and Embase Database

MEDLINE (Medical Literature Analysis and Retrieval System Online) is a bibliographic database of life sciences and biomedical information.It is compiled by the United States National Library of Medicine (NLM).MEDLINE uses Medical Subject Headings (MeSH) for information retrieval. Engines designed to search MEDLINE (such as Entrez and PubMed) generally use a Boolean expression combining MeSH terms, words in abstract and title of the article, author names, date of publication.It mainly covers US journals.

Embase(Excerpta Medica), is a biomedical and pharmacological database produced by Elsevier.It tends to be more comprehensive with inclusion of more EU journals (plus US journals) as well as abstracts of scientific meetings, which you would not find in MedLine.

Investigator’s Brochure

The investigator’s brochure is a “compilation of the clinical and nonclinical data on the investigational product(s) that is relevant to the study of the investigational product(s) in human subjects.” (ICH E6). In general, the investigator’s brochure provides more complete background information on the investigational product than is provided in the protocol. The investigator’s brochure assists the investigator in interpreting and implementing the study protocol, and may be of particular importance in helping the investigator determine whether specific adverse events are unanticipated, and accordingly, when and how such events should be reported to the sponsor, IEC/ IRB, and regulators.

Source: ICH E6

What is the ideal approach to pharmacovigilance- Signal Detection

Various methods are used throughout the life cycle of the product (from all phases of clinical trials and post-marketing) to evaluate new information that comes in routinely. This is called signal detection. Signal detection is one of the most important objectives of pharmacovigilance. The whole process of risk/benefit evaluation depends on effective detection of signals. Methods for signal detection include observations by clinicians and patients, case reports in the literature, assessment of individual case reports or clusters of reports that are received from healthcare professionals, patients and consumers etc, data from formal studies, e.g. clinical trials, epidemiological studies like cohort studies and case control studies.

The detection of signals require clinical assessment assisted by epidemiological and statistical analysis. Information technology tools also help in the generation of signals and enhancing its effectiveness. Automated signal generation is used by many MNCs, where reported safety profile of a particular product is compared with other products in the database using simple statistical methods like proportional reporting rates (PRR). Apart from PRR, which is very popular, there are other statistical tools used for signal detection that are used like incidence rates, frequency of adverse events and trend analysis.

Understand the SAE process

When an SAE report arrives in-house from an investigator, health worker, or employee (clinical research associate or customer service representative, for example), it is immediately assigned a number and reviewed to determine whether the event is a reportable SAE. If it is reportable, the company needs to send the SAE to FDA by one of the following methods.
• Form 3500A only (can be filed manually or electronically via the AERS system)
•A narrative report
• VAERS form (vaccines only)
• CIOMS I form (foreign reports only).

A company’s culture and experience dictate the way it meets these reporting requirements. Whatever the method it uses, a company must keep an audit trail, either manual or electronic, that shows
• the initial receipt date of the SAE
• all changes made to the original SAE by any personnel.
• all supporting documentation requested and sent in from the site.
• any internal or external correspondence.
• any internal notes, such as medical review.
• all attempts to get additional information regarding the event.
• whether the event is open or closed.

We need to code the SAEs in such a way that they become categorical in nature, such as assigning a code for the event and a MedDRA term

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.

Source:  EU Guidelines

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.

Source: FDA and EU Guidelines

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

MedDRA

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).

Reference: ICH Guidelines

ICH - Multidisciplinary Topics

Multidisciplinary topics are categorized in to five types:

ICH M1: MedDRA(Medical Dictionary)

ICH M2: ESTRI(Electronic Standards for the Transfer of Regulatory Information)

ICH M3:  Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorisation for Pharmaceuticals

ICH M4: CTD(Common Technical Document)

ICH M5: Data Elements and Standards for Drug Dictionaries

Source: http://www.ich.org/UrlGrpServer.jser?@_ID=2196&@_FORCETEMPLATE=272

ICH(International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use)

 ICH topics are divided in to 4 major types:

1. "Quality" Topics, i.e., those relating to chemical and pharmaceutical Quality Assurance (Stability Testing, Impurity Testing, etc.)

 2."Safety" Topics, i.e., those relating to in vitro and in vivo pre-clinical studies (Carcinogenicity Testing, Genotoxicity Testing, etc.)

3."Efficacy" Topics, i.e., those relating to clinical studies in human subject (Dose Response Studies, Good Clinical Practices, etc.)

4."Multidisciplinary" Topics, i.e., cross-cutting Topics which do not fit uniquely into one of the above categories (MedDRA, ESTRI, M3, CTD, M5)

 Source: https://www.ich.org/cache/html/250-272-1.html

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.