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Clinical Study Reports- Medical Writing

Structure and Content of Clinical Study Reports ICH Topic E3:

Source: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/e3-eng.pdf

Commonly used Medical Dictionaries during coding- Clinical Trials

The most commonly used medical coding dictionaries used for coding medical terms are MedDRA and WHO DDE.

The other standardised medical dictionaries are:

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

Reporting to the Ethics Committee- Safety Reporting during Clinical trials

The Ethics Committee that gave a favourable opinion for the trial should routinely receive the following reports:
• Expedited reports of all SUSARs occurring in a clinical trial of an investigational medicinal product for which the sponsor is responsible. This includes SUSARs associated with active comparator drugs. Expedited reports should be sent to the relevant Ethics Committee within the timelines as stated below.
• A sponsor shall ensure that all relevant information about a suspected unexpected serious adverse reaction (SUSAR) which occurs during the course of a clinical trial in the United Kingdom and is fatal or  life-threatening is reported as soon as possible to the MHRA, the competent authorities of any EEA State, other than the United Kingdom, in which the trial is being conducted, and the relevant Ethics Committee. This needs to be done not later than seven days after the sponsor was first aware of the reaction. Any additional relevant information should be sent within eight days of the report.
• A sponsor shall ensure that a suspected unexpected serious adverse reaction (SUSAR) which is not fatal or life-threatening is reported as soon as possible, and in any event not later that 15 days after the sponsor is first aware of the reaction.
• Quarterly safety reports on all clinical trials for which the sponsor is responsible for worldwide, with a global line listing of SUSARs occurring in these trials in the reporting period.
• Annual safety reports on the safety of subjects in all clinical trials for which the sponsor is responsible worldwide, with an aggregated global line listing of all suspected serious adverse reactions (SSARs) occurring in these trials to date.
• Reports and recommendations of any independent data monitoring committee established for the trial.

Safety reports may be submitted by the sponsor, or by the sponsor’s representative, or by the chief investigator.

Case Report Form (CRF) - Clinical Trials

The ICH GCP Guidelines say: The reason for having CRFs in a study is to (collect the necessary information about:

• the patients
•  the administration of the study drug
• the outcome of the assessments.

CRFs are the official documentation of the trial for the authorities, and together with the source documents will be closely examined during audits and inspections.The data on the CRFs will be entered into a computer system and the statistical analyses will then be performed. The data on the CRFs is therefore the basis for the trial report and also for any publications, as well as making up part of the data for regulatory approval of a new drug.

When completing the form use a black ball point pen to complete the CRF. If the CRFs are printed on carbonless duplication paper, always make sure that a suitable separator is inserted under the form being completed. If for some reason you cannot complete part of the form, you shouldn’t just leave a blank space ~ this is impossible for the people doing the data entry into the computer to interpret. Instead write unknown, uncertain, missing or test not donr as appropriate, or similar unambiguous words. Avoid using the ambiguous phrase, ‘not available’.The CRFs must be signed where indicated by the Principal Investigator to indicate that
he/she believes they are complete and correct. Some Sponsors require a signature on each page of the CRF, some only a signature on the final page.

Ensure legibility of all data entries. Corrections should be made as follows:

• Cross out the incorrect entry with a single line - the incorrect entry should still be readable, on no account use liquid correcting fluid.
• Enter the correct data.
• Initial and date the correction, and give an explanation of the correction if it is not obvious why it was changed.

Informed Consent form- Signature

The consent form should be signed and dated by the following people:

• A medically qualified person providing the information, this being the Investigator
• The subject.
•  A witness, if this is possible and if required for the study. 

A witness is defined as someone who records that the subject has provided consent of their own free will and has been fully informed of the study. The best witness is a subject’s friend or family member who has sat in when the study was being explained to the patient. A witness must have no vested interest in the study; therefore a research assistant/SSC/Sub-Investigator is not suitable as a witness.All signatures should be dated by the person who is signing and under the signature or Sub-Investigator. they should write their name in block capitals.

Obtaining Personal Written Informed Consent during Clinical Trials

When describing the study the physician /SSC should cover the following:

•  That it is a research procedure, and which aspects are experimental - it may or may not be beneficial to the subject - e.g. placebo.
•   The purpose of the trial.
•  Details about the drug under investigation. If there is a placebo arm to the study, this must be carefully     explained.
• The design of the trial, for example ‘double dummy’ or ‘crossover’. Often a
•  The number of people involved.
•  Duration of the trial. If the trial is a long-term one, enthusiasm is required.
•  Number of visits involved and duration of the visits. The area where the patient will be seen and by whom.
• Procedures involved, for example blood tests, ECGs, urine samples and chest x-rays - how many and how often.
•  The responsibilities of the subject if he/she participates.
•  Out of pocket expenses and the receipt procedure. If a taxi account is set up for thestudy, then this will be explained. If payments are entailed, the details must be covered, including the arrangements for pro-rated payments.
•  The risks involved to the subject and any benefit that might be expected. If no clinical benefit is intended, the subject must be told.
• Questions about the patient’s medical history will be asked and disclosure of all medication the patient is taking, which will be kept up to date if changes occur.
• Alternative procedures or treatments.
• If the study has a specific exclusion criterion, for example a left ventricle ejection fraction <350/0, but this is measured only after the patient has given written consent, this exclusion will be carefully explained, Providing written informed consent does not mean definite progression into the study.
• The availability of compensation and treatment if needed.
• That, because it is a study, written consent is needed which is voluntary and there is no penalty for refusal.
• The right to withdraw from study medication at any time without affecting their future medical care. Similarly, if the Investigator thinks that the study medication is not suiting the patient, then the medication would be stopped.

Patient Recruitment- Clinical Trials

The first step is to define exactly what is meant by patient recruitment. This is not as straightforward as it sounds. There are several steps from the patient being identified and contacted to starting the study treatment. These include screening the patient, obtaining informed consent. randomising the patient, a possible baseline assessment and then initiation of treatment. Exactly when the patient is said to be enrolled in the trial should be
defined in the protocol.The recruitment period, i.e. starting and finishing date of recruitment for the entire study, may also be defined in the protocol.

Intention to Enrol list:For the purpose of this SOP, an ‘Intention to Enroli st’ is a record of all patients who were considered, were eligible for the study, but who, for one reason or another, were not included. This list enables a comparison of the potential patient population with the patient population actually enrolled in the study. It is helpful when questions of bias arise during evaluation of the data.

Study Files and Filing - Clinical Trials

A Study File may consist of more than one distinct file. Too many different files should be avoided. It is usually unnecessary that each individual patient has a separate file. The Investigator’s Brochure may also need to be located separately; if so, the Study File should indicate where. Each patient’s informed consent form should be filed in the patient’s medical notes.

The Study File will be sub-divided. For example:

• Correspondence.
• Protocol and Amendments.
• Investigator’s Brochure.
• Drug accountability.
• Ethics Committee.
• List of patients entered (to enable easy identification of individuals in the future. The list should also include those actively considered for the trial but not entered, with reasons for non-entry where appropriate).
• Code envelopes may be stored in the Study File, but may be stored separately, e.g. at Pharmacy. The location should be recorded.
• Where required, registration of clinical trial with the regulatory authorities and/or local management.
• Completed serious adverse event forms (if not included in the CRFs).
• Financial agreement, unless stored elsewhere.
• Records of telephone conversations and notes of study meetings should also be filed.
• The Sponsor will also keep records of telephone conversations and make written reports after each visit. During an audit, these records will be checked for consistency.
• Completed consent forms (or copies).
• Study-specific SOP checklists.
• The completed CRFs will usually be stored in a separate file.

Outline of an Standard Operating Procedures- ICH

The general outline of an SOP is as follows:

• Number and title of procedure
• Purpose (brief summary in a few lines)
• Other procedures simultaneously involved
• Personnel involved and procedure: Who is responsible for carrying out the procedure?
• When and How should the procedure be carried out?
• Date of version in use plus ‘replaces previous version of . . .’
• Name of author and person in charge who approved this version
• Each SOP has a number. Not every SOP has an accompanying checklist. Please note that the checklists are numbered according to the corresponding SOP number.

Revision and updating of Standard Operating Procedures : SOPs must be reviewed and updated on a regular basis. When they are first introduced to the department, they may need revision after a few months. However, once they have been adjusted to your needs they will probably only need revising every two years or so, but we recommend an annual review. Revision is best done as a team task. The procedures should be examined and rewritten where appropriate, then approved and signed. The old version should be archived. It should not be disposed of because it can be of use  some time after a study is completed that Regulatory Agency questions might arise, and you may be required to show the procedures you used to follow.

Standard Operating Procedures- ICH

SOPs are defined in the ICH GCP Guidelines as ‘detailed, written instructions to achieve uniformity of the performance of a specific function’.

SOPs should be detailed enough so that a procedure can be correctly carried out in a reproducible manner, but not so specific that they can only be applied to one project and then have to be rewritten for the next. It is almost always necessary to adapt SOPs to an individual department, and the SOPs here can be tailored to suit your needs,as long as the requirements of GCP are maintained.

The SOPs here can be broadly divided into the following sections:

• General study organisation
• Pre-study
• During study
• End of study

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.

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

ICH is the shortened name for The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. It works to bring together government regulators and drug industry representatives from the United States, the EU, and Japan to make the international drug regulatory process more effi cient and uniform. This work will help make new drugs available with minimum delays to both American consumers and those in other countries.

The drug regulatory systems in all three regions share the same fundamental concerns for the safety, effi cacy, and quality of drug products. However, many time - consuming and expensive clinical trials have had to be repeated in all three regions. An ICH goal is to minimize unnecessary duplicate testing during the research and development of new drugs. Another goal is to develop guidance documents that create consistency in the requirements for new drug approval. Some ICH projects include the following:

• Medical Dictionary for Regulatory Activities (MedDRA). MedDRA is a new international medical  terminology designed to improve the electronic transmission of regulatory information and data worldwide. It will be used to collect, present, and analyze information on medical products during clinical and scientifi c reviews and marketing. It will be particularly critical in the electronic transmission of adverse event reporting and coding of clinical trial data. The FDA is already using MedDRA in its Adverse Events Reporting Systems.
• Common Technical Document. This document will provide an international standard format for submitting safety and effi cacy information about a new drug.

Reporting Time Frames- ICSR

Reporting Time Frames: In general, expedited reporting of serious and unexpected ADRs refers to 15 calendar days. Time frames for other types of reports vary among countries.


Minimum Criteria for Reporting:Minimum required data elements for an ADR case are: an identifiable reporter, an identifiable patient, an adverse reaction, and a suspect product. Lack of any of these four elements means that the case is incomplete; however, MAHs are expected to exercise due diligence to collect the missing data elements. It is recommended that as much information as possible be collected at the time of the initial first report.

 Time Clock Start Point:The regulatory reporting time clock (in calendar days) starts on the date when any personnel of the MAH first receive a case report that fulfills minimum criteria as well as the criteria for expedited reporting. In general, this date should be considered as day 0.When additional medically significant information is received for a previously reported case, the regulatory reporting time clock begins again for submission of the follow-up report.

 Non-serious ADRs:Cases of non-serious ADRs are not normally reportable on an expedited basis. The spontaneous reports of non-serious ADRs should be reported in the periodic safety update report.

STANDARDS FOR EXPEDITED REPORTING- ICSR

Single Cases of Serious ADRs:Cases of adverse drug reactions from all sources that are both serious and unexpected are subject to expedited reporting. The reporting of serious expected reactions in an expedited manner varies among countries. Non-serious adverse reactions, whether expected or not, would normally not be subject to expedited reporting.For reports from studies and other solicited sources, all cases judged by either the reporting healthcare professional or the MAH as having a possible causal relationship to the medicinal product qualify as ADRs. For the purposes of reporting, spontaneous reports associated with approved drugs imply a possible causality.

Reporting Guidelines for Other Observations:In addition to single case reports, any safety information from other observations that could change the risk-benefit evaluation for the product should be promptly communicated to the regulatory authorities.

Lack of Efficacy:Reports of lack of efficacy should not normally be expedited, but should be discussed in the relevant periodic safety update report. However, in certain circumstances reports of lack of efficacy should be treated as expedited cases for reporting purposes. Medicinal products used for the treatment of life-threatening or serious diseases, vaccines, and contraceptives are examples of classes of medicinal products where lack of efficacy should be considered for expedited reporting. Clinical judgment should be used in reporting, with consideration of the approved product labeling/prescribing information.

Overdose: Reports of overdose with no associated adverse outcome should not be reported as adverse reactions. They should be routinely followed up to ensure that information is as complete as possible with regard to symptoms, treatment, and outcome. The MAH should collect any available information related to its products on overdose, and report cases of these that lead to serious adverse reactions according to expedited reporting criteria.

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.

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.

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.

Unsolicited Sources- Sources of ICSR

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.

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

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.

WHO’s Vigibase for Adverse Drug Reactions (ADRs)

Vigibase is the data repository that has accumulated about 4 million ICSRs since 1968.This international repository not only facilitates the pooling of data from different countries, but also permits comparisons among countries.A number of methods for analysis like the Bayesian approach are used for signal detection in Vigibase.

EudraVigilance database- Pharmacovigilance

The EudraVigilance database contains two reporting modules

1.The EudraVigilance Post-Authorisation module (EVPM) designed for postauthorisation Individual Case Safety Reports (ICSR) as required by Council Regulation No. 2309/93/EEC, as amended (to be replaced by Regulation (EC) No 726/2004 in November 2005), Directive 2001/83/EC, as amended, and Volume 9 of the "Rules Governing Medicinal Products in the European Union".
2.The EudraVigilance Clinical Trial (EVCTM) module designed for pre-authorisation serious unexpected suspected adverse reactions (SUSAR) (pre-authorisation Individual Case Safety Reports - ICSR) as required by Directive 2001/20/EC. As a general rule all SUSAR reports originating from any interventional clinical trial (Phase I – IV) as defined in Directive 2001/20/EC are sent electronically to the EVCTM. This includes, when applicable the comparator (active control or placebo). The database provides and facilitates an overview of SUSAR and provides for enhanced protection of clinical trial subjects.



It is closely linked for the identification of the product and clinical trial, and other clinical trial information, to the clinical trial EudraCT database. An interface is planned.

Ethics in Clinical Research- Important Dates

1803 - Thomas Percival - first code of medical ethics to include requirements concerning research
1833 - William Beaumont - ethical code specifically focussed on human experimentation
1865 - Claude Bernard, a French physiologist published ‘Introduction to the Study of Clinical Medicine’: “It is our duty and right to perform and experiment on man when it can save his life, cure him or gain him some personal benefit. The principal of medical and surgical morality, therefore, consists of never performing on man an experiment which might be harmful to him to any extent, even though the result might be highly advantageous to science, that is, to the health of others.”
1900 - Research regulations in Prussia introduced following vaccination trials performed without consent on poor and vulnerable people (abandoned children, prostitutes).
1920’s Some of the earliest and clearest pronouncements on the importance of consent in medical research are to be found in early 20th Century in Germany.
1931 - Directive from the Home Secretary of the German Reich forbids “innovative therapy” unless the “subject or his legal representative has unambiguously consented to the procedure in the light of relevant information provided in advance”
1947 - The Nuremberg Code was published following experiments in Second World War on risoners-of-War.
1964 - World Medical Associations Declaration of Helsinki revised in 1975, 1983, 1989, 1996 and 2000 replaces the Nuremberg Code.
1993, 2002 CIOMS International Ethical Guidelines for Biomedical Research Involving Human
Subjects.
1996 - ICH Tripartite Guideline on Good Clinical Practice (1996) in Clinical Trials.
1997 - European Bioethics Convention on human rights and biomedicine in Oviedo in Spain in 1997
2001 - EU Directive 2001/20/EC

WHO Key Dates & Establishments

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.

Thomas Mann urge in Medical writing

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.

Scientific texts resulting from myths and misconceptions- Medical Writing

Scientific texts resulting from myths and misconceptions:

• long and complicated sentences instead of short, 
• clear sentences (Germanic strings of words) · 
• mixing creative and scientific writing ·scientific “story” not readily apparent  
• poor structuring of text ·mixing actual results and their discussion  
• inconsistent use of technical terms and units  
• misusing or wasting specific and generic terms  
• reluctance to use first-person pronouns and overuse of passive voice  
• tendency to turn sharp and powerful verbs into weighty nouns

Vancouver Style in Medical writing

Many current journals refer to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication. This guideline was initially drawn up by a small group of editors of general medical journals in 1978. Because the group had met informally in
Vancouver, British Columbia, they became known as the Vancouver Group ( Reference Formats and the Uniform Requirements).
Subsequently, the Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE) which meets annually. The ICMJE has gradually broadened its concerns to include other aspects of scientific reporting, e.g., ethical principles related to publication in  biomedical journals.

House style- Medical writing

Publishers' style guides establish house rules for language use, such as spelling, italics and punctuation; their major purpose is consistency. They are rulebooks for writers, ensuring consistent language. Authors are asked or required to use a style guide in preparing their work for publication; copy editors are charged with enforcing the publishing house's style.

Most of the good journals provide detailed instructions for authors of manuscripts seeking publication. Such instructions are commonly referred to as the journal’s “house style.” Although individual house styles may still vary to some extent, considerable effort has gone into harmonizing standards and formats among scientific journals. The most important initiative in this respect is the generation of the document entitled Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication.

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.”

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.

Standards for drafting a scientific manuscript- Medical writing

While drafting a scientific manuscript the following standards are taken in to consideration:

Purpose The purpose of the manuscript must be obvious and unambiguous.
Conformity :Text has to conform to given formats, e.g., for health authorities, marketing, journals, books etc.
Accuracy :The wording must be grammatically correct, concise, accurate, and precise.
Consistency: Terminology should be consistent and appropriate.
Logic and flow :The manuscript should be a “story” with a clear message based on a logical train of thought.
Context :The “story” must be presented in the context of established literature or other reported work, and must be congruent with accepted institutional or regulatory values.
Structure : A logical structure (i.e., headings and subheadings, paragraphs, figures, and tables) should be chosen.
Data presentation: High-quality data should be presented clearly, using tables and figures as appropriate.

Follow-up Information- Good Case Management

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.

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.

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.

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.

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

Keep blogging to get more information about this section of study...

 

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.

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

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.

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

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.

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.

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.

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:

• Case identification
• Signal detection 

Why do we need SMQs?

• 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.

Standardised MedDRA Queries (SMQs) are created by grouping relevant MedDRA terms to represent a particular medical concept. This grouping assists in the formulation of a "case definition" and in data exploration and retrieval.
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.

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:

• 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).

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.

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.

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.

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

• Clinical Trails data
• Adverse events
• Complaints
• Product related info

The cases are processed in the following fashion:

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

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)