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.