The following general guidelines are proposed by FDA in reference in Computerized systems in clinical trials, the complete document is available at http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm
A. Each study protocol should identify at which steps a computerized system will be used to create, modify, maintain, archive, retrieve, or transmit data.
Comment : This means that the study protocol has to receive input from the data manager. Most of the companies include these steps as SOPs so that they can be referenced in the study protocol.
B. For each study, documentation should identify what software and, if known, what hardware is to be used in computerized systems that create, modify, maintain, archive, retrieve, or transmit data. This documentation should be retained as part of study records.
Comment : This level of detail is not mandatory, and is often missed out in most study protocols.
C. Source documents should be retained to enable a reconstruction and evaluation of the trial.
Comment : This requirement is fulfilled via a Audit trial so that FDA/ independent audits can be performed.
D. When original observations are entered directly into a computerized system, the electronic record is the source document.
Comment : The specific condition where this rule will not apply is for lab data, the source data is obtained electronically from the lab. The data is then batch loaded into the CDM system, still the source data is the lab data.
E. The design of a computerized system should ensure that all applicable regulatory requirements for recordkeeping and record retention in clinical trials are met with the same degree of confidence as is provided with paper systems.
Comment : 21 CFR Part 11 and ER/ES are two common regulatory requirements. The "degree of confidence" is set via a validation process for each CDM system.
F. Clinical investigators should retain either the original or a certified copy of all source documents sent to a sponsor or contract research organization, including query resolution correspondence.
Comment : Though this sounds simple, it is complicated for investigators to maintain a source data archive.
G. Any change to a record required to be maintained should not obscure the original information. The record should clearly indicate that a change was made and clearly provide a means to locate and read the prior information.
Comment : All updates on source data will include a reason for change, data and time of change, person initiating the change, data value before change and data value after change. Sometimes the change in data may require sign-off by a study manager.
H. Changes to data that are stored on electronic media will always require an audit trail, in accordance with 21 CFR 11.10(e). Documentation should include who made the changes, when, and why they were made.
Comment : Refer to above
I. The FDA may inspect all records that are intended to support submissions to the Agency, regardless of how they were created or maintained.
Comment : Refer to above
J. Data should be retrievable in such a fashion that all information regarding each individual subject in a study is attributable to that subject.
Comment : Refer to above
K. Computerized systems should be designed: (1) So that all requirements assigned to these systems in a study protocol are satisfied (e.g., data are recorded in metric units, requirements that the study be blinded); and, (2) to preclude errors in data creation, modification, maintenance, archiving, retrieval, or transmission.
Comment : Refer to above
L. Security measures should be in place to prevent unauthorized access to the data and to the computerized system.
Tuesday, August 5, 2008
Electronic Health Records (EHR) in clinical trials
Electronic Health Records (EHR) are standard instruments used to capture patient encounter data in clinical practice. They offer some key benefits in relation to clinical trials by supporting : 1. Increased patient recruitment, 2. Increased physician participation.
Study Set-up
Query EHR database to establish number of potential study candidates.
Incorporate study manual or special instructions into EHR “clinical content”for study encounters
Study execution
Incorporate study-specific data capture (just as you would do with a CRF in a clinical trial) as part of routine clinical care / clinical documentation workflow.
Auto-populate study data elements (for example demographics) into CRFs from other parts of the EHR database.
Embed study-specific data requirements (modules not already included in the EHR) as special tabs/documentation templates using structured data entry.
Implement rules/alerts to ensure compliance with study data collection requirements (EHR systems have inbuilt validation checks)
Create range checks and structured documentation checks to ensure valid data entry
Study Enrollment
Implement study screening parameters into patient registration and scheduling.
Query EHR database to contact/recruit potential candidates and notify the patient’s provider(s) of potential study eligibility.
Submission & Reporting
Provide data extraction formats that support data exchange standards (for example CDISC)
Document and report adverse events (Note : EHRs often use ICD-9/10 coding, while CRFs would need MedDRA codes)
Study Set-up
Query EHR database to establish number of potential study candidates.
Incorporate study manual or special instructions into EHR “clinical content”for study encounters
Study execution
Incorporate study-specific data capture (just as you would do with a CRF in a clinical trial) as part of routine clinical care / clinical documentation workflow.
Auto-populate study data elements (for example demographics) into CRFs from other parts of the EHR database.
Embed study-specific data requirements (modules not already included in the EHR) as special tabs/documentation templates using structured data entry.
Implement rules/alerts to ensure compliance with study data collection requirements (EHR systems have inbuilt validation checks)
Create range checks and structured documentation checks to ensure valid data entry
Study Enrollment
Implement study screening parameters into patient registration and scheduling.
Query EHR database to contact/recruit potential candidates and notify the patient’s provider(s) of potential study eligibility.
Submission & Reporting
Provide data extraction formats that support data exchange standards (for example CDISC)
Document and report adverse events (Note : EHRs often use ICD-9/10 coding, while CRFs would need MedDRA codes)
xml
XML or extensible markup language is exactly what the acronym says. XML is a non-proprietary textual representation of data/strings and atributes.XML structure is defined by a schema or a DTD (document type definition). There are a number of clinical research/health care standards based on xml such as HL7, CDISC, JANUS etc.,XML basically defines content/data as tags and attributes and data elements can be defined in namespaces. The intention of this post is not to teach you xml but to give some basics of why you should be aware of xml in relation to Clinical Research.Recently Microsoft has been in conflict with many open source groups in relation to their OOXML standard, There has been complaints and concerns that this standard has been rigged
CDISC
CDISC
CDISC mission statement from CDISC website says "CDISC is a global, open, multidisciplinary, non-profit organization that has established standards to support the acquisition, exchange, submission and archive of clinical research data and metadata. The CDISC mission is to develop and support global, platform-independent data standards that enable information system interoperability to improve medical research and related areas of healthcare. CDISC standards are vendor-neutral, platform-independent and freely available via the CDISC website."
We will cover each CDISC standard in detail in the coming posts, here is a summary table with links to the current standard specification at http://www.cdisc.org. To give an overview the different parts of the CDISC standard are related as below to the clinical trial process
CDISC Standards in Production
Submission Data Standards Team(For submission of data-sets to regulatory)
(SDTM IG V3.1.1)(SDTM V1.1)(SDTM IG V3.1)
WebSDM edit checks for (SDTM 3.1.1)
Operational Data Modeling Team(ODM V1.3) (ODM V1.2.1) See also (eSDI Document)
Analysis Dataset Model Team(ADAM)
Laboratory Standards Team(LAB)
Standard for Exchange of Non-clinical Data(SEND V2.3)
Case Report Tabulation Data Definition Specification (define .xml)(CRT-DDS V1.0)
Terminology(Terminology)
Standards in Development
Submission Data Standards Team
SDTM IG V3.1.2 DraftSDTM V1.2 DraftMetadata Submission Guidelines, Appendix to the SDTM IG V3.1.1
Protocol Representation Group(PRG)
Clinical Data Acquisition Standards Harmonization (CDASH)(CDASH)
Terminology(Terminology)
Cardiovascular and Tuberculosis Data Standards(Cardiovascular and Tuberculosis Data Standards)
CDISC SDTM standard
Inline with the Critical Path Initiative CDISC has developed three main standards to improve the efficiency of clinical trial projects, namely : Operational Data Model (ODM), the Study Data Tabulation Model (SDTM) and the Analysis Data Model (ADaM).
The SDTM defines a standard structure for study data tabulations. These are to be submitted as part of a product application to a regulatory authority such as FDA.
The SDTM was prepared by the CDISC Submission Data Standards (SDS) Team to guide the organization, structure, and format of tabulation data sets for study data submitted to regulatory authorities. Data tabulation data sets are one of four ways to represent the human subject Case Report Tabulation (CRT) and equivalent animal data submitted to the FDA.
The SDTM is composed of 30+ defined domains within six broad categories. Each domain represents a file structure and contains a particular type of data associated with clinical trials, such as demographics, vital signs or adverse events.
The model also provides the ability to create custom-defined domains with sets of standard variable definitions. Variables in common across domains all have similar name extensions, and the standard specifies the beginning prefix of all variables be a (typically) two-letter domain abbreviation.
CDISC ODM Standard
The Operational Data Model (ODM) provides a format for representing the study metadata, study data and administrative data associated with a clinical trial.
It represents only the data that would be transferred among different software systems during a trial, or archived after a trial.
It need not represent any information internal to a single system, for example, information about how the data would be stored in a particular database.
The ODM model assumes that a study's clinical data will consist of several kinds of entities. These include:
subjects
study events (a series of forms connected to an event)
forms (aggregations of item groups)
item groups (groups of items that will be analyzed together)
items (single data item such as Hb%)
annotations (comment applied to any of the above)
CDISC ADaM standard
ADaM is a CDISC standard to submit analysis data to FDA. Key is to understand that ADaM is a SDTM model for providing analysis data, programs and data definitions. The principles of ADaM is aimed at providing a clear and unambiguous communicationof the content, source and quality of the datasets submitted in support of the statistical analysis performed by the sponsor. This in turn would support the machine-readable description for the JANUS data repository.
Analysis datasetsAnalysis datasets are datasets created to support specific analyses.
Each dataset is provided as a SAS Transport (XPORT) file.
Programs should be provided as both ASCII text and PDF files and should include sufficient documentation to allow a reviewer to understand the submitted programs. ProgramsPrograms are scripts used with selected software to produce reported analyses based on these datasets.Analysis-level Metadata
ANALYSIS NAME –A unique identifier for this analysis. May include a table number or other sponsor- specific reference.
DOCUMENTATION –A text description documenting the analysis performed.
REASON –The reason for performing this analysis. Examples may include Pre-specified, Data-driven, Exploratory, and Regulatory Request.
DATASET –the name of the analysis dataset used should be linked to the analysis dataset used for this analysis. In most cases, this will be a single dataset. If multiple datasets are used, they should all be listed here.
PROGRAM –Analysis programs using the DATASET above as input can be described or included here.
define.xml and SDTM
Define.xml is the document which specifies the standard for providing Case Report Tabulations Data Definitions in an XML format for submission to regulatory authorities (e.g., FDA).
The XML schema used to define the expected structure for these XML files is based on an extension to the CDISC Operational Data Model (ODM).
CDISC mission statement from CDISC website says "CDISC is a global, open, multidisciplinary, non-profit organization that has established standards to support the acquisition, exchange, submission and archive of clinical research data and metadata. The CDISC mission is to develop and support global, platform-independent data standards that enable information system interoperability to improve medical research and related areas of healthcare. CDISC standards are vendor-neutral, platform-independent and freely available via the CDISC website."
We will cover each CDISC standard in detail in the coming posts, here is a summary table with links to the current standard specification at http://www.cdisc.org. To give an overview the different parts of the CDISC standard are related as below to the clinical trial process
CDISC Standards in Production
Submission Data Standards Team(For submission of data-sets to regulatory)
(SDTM IG V3.1.1)(SDTM V1.1)(SDTM IG V3.1)
WebSDM edit checks for (SDTM 3.1.1)
Operational Data Modeling Team(ODM V1.3) (ODM V1.2.1) See also (eSDI Document)
Analysis Dataset Model Team(ADAM)
Laboratory Standards Team(LAB)
Standard for Exchange of Non-clinical Data(SEND V2.3)
Case Report Tabulation Data Definition Specification (define .xml)(CRT-DDS V1.0)
Terminology(Terminology)
Standards in Development
Submission Data Standards Team
SDTM IG V3.1.2 DraftSDTM V1.2 DraftMetadata Submission Guidelines, Appendix to the SDTM IG V3.1.1
Protocol Representation Group(PRG)
Clinical Data Acquisition Standards Harmonization (CDASH)(CDASH)
Terminology(Terminology)
Cardiovascular and Tuberculosis Data Standards(Cardiovascular and Tuberculosis Data Standards)
CDISC SDTM standard
Inline with the Critical Path Initiative CDISC has developed three main standards to improve the efficiency of clinical trial projects, namely : Operational Data Model (ODM), the Study Data Tabulation Model (SDTM) and the Analysis Data Model (ADaM).
The SDTM defines a standard structure for study data tabulations. These are to be submitted as part of a product application to a regulatory authority such as FDA.
The SDTM was prepared by the CDISC Submission Data Standards (SDS) Team to guide the organization, structure, and format of tabulation data sets for study data submitted to regulatory authorities. Data tabulation data sets are one of four ways to represent the human subject Case Report Tabulation (CRT) and equivalent animal data submitted to the FDA.
The SDTM is composed of 30+ defined domains within six broad categories. Each domain represents a file structure and contains a particular type of data associated with clinical trials, such as demographics, vital signs or adverse events.
The model also provides the ability to create custom-defined domains with sets of standard variable definitions. Variables in common across domains all have similar name extensions, and the standard specifies the beginning prefix of all variables be a (typically) two-letter domain abbreviation.
CDISC ODM Standard
The Operational Data Model (ODM) provides a format for representing the study metadata, study data and administrative data associated with a clinical trial.
It represents only the data that would be transferred among different software systems during a trial, or archived after a trial.
It need not represent any information internal to a single system, for example, information about how the data would be stored in a particular database.
The ODM model assumes that a study's clinical data will consist of several kinds of entities. These include:
subjects
study events (a series of forms connected to an event)
forms (aggregations of item groups)
item groups (groups of items that will be analyzed together)
items (single data item such as Hb%)
annotations (comment applied to any of the above)
CDISC ADaM standard
ADaM is a CDISC standard to submit analysis data to FDA. Key is to understand that ADaM is a SDTM model for providing analysis data, programs and data definitions. The principles of ADaM is aimed at providing a clear and unambiguous communicationof the content, source and quality of the datasets submitted in support of the statistical analysis performed by the sponsor. This in turn would support the machine-readable description for the JANUS data repository.
Analysis datasetsAnalysis datasets are datasets created to support specific analyses.
Each dataset is provided as a SAS Transport (XPORT) file.
Programs should be provided as both ASCII text and PDF files and should include sufficient documentation to allow a reviewer to understand the submitted programs. ProgramsPrograms are scripts used with selected software to produce reported analyses based on these datasets.Analysis-level Metadata
ANALYSIS NAME –A unique identifier for this analysis. May include a table number or other sponsor- specific reference.
DOCUMENTATION –A text description documenting the analysis performed.
REASON –The reason for performing this analysis. Examples may include Pre-specified, Data-driven, Exploratory, and Regulatory Request.
DATASET –the name of the analysis dataset used should be linked to the analysis dataset used for this analysis. In most cases, this will be a single dataset. If multiple datasets are used, they should all be listed here.
PROGRAM –Analysis programs using the DATASET above as input can be described or included here.
define.xml and SDTM
Define.xml is the document which specifies the standard for providing Case Report Tabulations Data Definitions in an XML format for submission to regulatory authorities (e.g., FDA).
The XML schema used to define the expected structure for these XML files is based on an extension to the CDISC Operational Data Model (ODM).
Safety Reporting to FDA
We have received lot of requests to write about Safety related reporting, coding and regulation. This blog will feature these aspects for the next 10 days, if you wish us to write on a specific topic please email us at contact@clinnovo.com. Thanks for your interest.
Pre-Approval - To IND
Unexpected fatal or life-threatening experience associated with the use of the drug
7 calendar day reports (telephone or fax)
From All Studies Worldwide (Serious, Drug-Related and Unexpected)
15 calendar day reports (telephone or fax)
Findings from long term tox tests in laboratory animals suggesting a significant risk to humans (mutagenicity, teratogenicity, carcinogenicity)
15 calendar day reports (telephone or fax)
Spontaneous Reports from Marketing Outside the U.S. (Serious and Unexpected)
15 calendar day reports (telephone or fax)
Reports in the scientific literature including unpublished manuscripts (Serious and Unexpected)
15 calendar day reports (telephone or fax)
Reports from foreign regulatory authorities (Serious and Unexpected)
15 calendar day reports (telephone or fax)
From Studies Worldwide (Serious)
Annual IND reports
Post-Approval - To IND
From IND Studies (Serious, Drug-Related and Unexpected)
15 calendar day reports (telephone or fax)
From IND Studies (Serious)
15 calendar day reports (telephone or fax)
Post-Approval - To NDA
From All Studies Worldwide (Serious, Drug-Related and Unexpected)
15 calendar day reports (telephone or fax)
Spontaneous Reports Worldwide (Serious and Unexpected)
Spontaneous and Periodic
Consequences of not following the schedule
Pre-Approval - Termination of IND
21 CFR 312.44 in Phase 1, 2 or 3 : (b)(1)(vii) “The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of serious and unexpected adverse experiences in accordance with part 312 section 32 or fails to make any other report required under this part.
Post-Approval- Withdrawal of NDA
21 CFR 314.80 (K) : "If an applicant fails to establish and maintain records and make reports required under this section FDA may withdraw approval of the application and, thus, prohibit continued marketing of the drug product that is the subject of the application.”
Pre-Approval - To IND
Unexpected fatal or life-threatening experience associated with the use of the drug
7 calendar day reports (telephone or fax)
From All Studies Worldwide (Serious, Drug-Related and Unexpected)
15 calendar day reports (telephone or fax)
Findings from long term tox tests in laboratory animals suggesting a significant risk to humans (mutagenicity, teratogenicity, carcinogenicity)
15 calendar day reports (telephone or fax)
Spontaneous Reports from Marketing Outside the U.S. (Serious and Unexpected)
15 calendar day reports (telephone or fax)
Reports in the scientific literature including unpublished manuscripts (Serious and Unexpected)
15 calendar day reports (telephone or fax)
Reports from foreign regulatory authorities (Serious and Unexpected)
15 calendar day reports (telephone or fax)
From Studies Worldwide (Serious)
Annual IND reports
Post-Approval - To IND
From IND Studies (Serious, Drug-Related and Unexpected)
15 calendar day reports (telephone or fax)
From IND Studies (Serious)
15 calendar day reports (telephone or fax)
Post-Approval - To NDA
From All Studies Worldwide (Serious, Drug-Related and Unexpected)
15 calendar day reports (telephone or fax)
Spontaneous Reports Worldwide (Serious and Unexpected)
Spontaneous and Periodic
Consequences of not following the schedule
Pre-Approval - Termination of IND
21 CFR 312.44 in Phase 1, 2 or 3 : (b)(1)(vii) “The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of serious and unexpected adverse experiences in accordance with part 312 section 32 or fails to make any other report required under this part.
Post-Approval- Withdrawal of NDA
21 CFR 314.80 (K) : "If an applicant fails to establish and maintain records and make reports required under this section FDA may withdraw approval of the application and, thus, prohibit continued marketing of the drug product that is the subject of the application.”
standardized MedDRA Queries
Definition
Groupings of MedDRA terms from one or more System Organ Classes (SOCs) that relate to a defined medical condition or area of interest.
Purpose
To support the retrieval of potentially relevant safety reports that includes a broad selection of terms that may relate to signs, symptoms, diagnoses, syndromes, physical findings, laboratory and other physiologic test data, etc., that are associated with a given medical condition or area of interest
Benefits
Uniformity of search strategies and results across organizations
Reproducibility of search strategies and results from regulatory perspective
Convenience of pre-defined grouping based on a medical condition of interest
Maintenance by MSSO and standard frame of reference
Example
SMQs combine narrow and broad search strategies allowing as much safety related information as relevant to be tagged to the query.
Acute Renal Failure definition : Acute renal failure is a syndrome characterized by a relatively rapid decline in renal function that leads to the accumulation of water, crystalloid solutes, and nitrogenous metabolites in the body.
Acute Renal Failure Narrow SMQ: Acute prerenal failure, Anuria, Azotemia, Dialysis, Hemodialysis, Neonatal anuria, Nephropathy toxic, Oliguria, Peritoneal dialysis, Renal failure acute, Renal failure neonatal, Renal impairment neonatal, and Renal impairment, and Renal insufficiency.
Acute Renal Failure Broad SMQ: Albuminuria, Blood creatinine abnormal, Blood creatinine increased, Blood urea abnormal, Blood urea increased, Blood urea nitrogen/creatinine ratio increased, Creatinine renal clearance decreased, Edema due renal disease, Hepatorenal failure, Nephritis, Nephritis interstitial, Proteinuria, Renal clearance decreased, Renal function tests abnormal, Renal transplant, Renal tubular disorder, Renal tubular necrosis, Tubulointerstitial nephritis.
Development of SMQs
SMQs are developed by consortium of swiss based Council For International Organization Of Medical Sciences (CIOMS) and MSSO. They are tested on one instance of federal safety database and one industrial partner database.
MedDRA unleashed
MedDRA stands for Medical Dictionary for Regulatory Activities
WHO-ART would be WHO's Adverse Reaction Terminology
ICD-9CM is International Classification of Diseases, 9th Revision Clinical Modification
A more rarer abbreviation : MSSO stands for Maintenance Service and Support Organization
History
Just as they did with James Bond 007, MedDRA was originally developed by UK's regulatory authority. Medicines Control Agency (MCA), and is a terminology for classifying adverse effects and medical history.
Applications of MedDRA
Data Capture and Coding : mainly efficacy data and post-market safety surveillance
Data Retrieval : Safety data reporting and pharmacovigilance, periodic safety reports
Data Analysis : End of trial safety data tabulation, thresholding (as a cut-off)
Regulatory Actions : Product label creating and maintenance
MedDRA hierarchy
The dictionary is structured into 5 levels namely : System Organ Class (SOC) > High level term group (HLGT) > High Level Term (HLT) > Preferred Term (PT) > Lowest Level Term (LLT). The association between PT and LLT is one to one, and for the rest it is many to one.
How to get MedDRA
MedDRA is a licensed software for non-regulators, and comes as a ASCII text file separated by $ signs. The data can be then easily fed into any relational database system such as mysql, oracle etc.,
What is the role of MSSO ?
MedRA is handled by www.meddramsso.com which is responsible change requests, help desk and handling the user group. One of the early issues with MedDRA adoption was the need to translate from COSTART or WHO-ART to MedDRA. The more recent issue has been the need to keep up with the new updates in MedDRA. MSSO tries to soothe the pain felt by companies in this process of changes and updates.
Groupings of MedDRA terms from one or more System Organ Classes (SOCs) that relate to a defined medical condition or area of interest.
Purpose
To support the retrieval of potentially relevant safety reports that includes a broad selection of terms that may relate to signs, symptoms, diagnoses, syndromes, physical findings, laboratory and other physiologic test data, etc., that are associated with a given medical condition or area of interest
Benefits
Uniformity of search strategies and results across organizations
Reproducibility of search strategies and results from regulatory perspective
Convenience of pre-defined grouping based on a medical condition of interest
Maintenance by MSSO and standard frame of reference
Example
SMQs combine narrow and broad search strategies allowing as much safety related information as relevant to be tagged to the query.
Acute Renal Failure definition : Acute renal failure is a syndrome characterized by a relatively rapid decline in renal function that leads to the accumulation of water, crystalloid solutes, and nitrogenous metabolites in the body.
Acute Renal Failure Narrow SMQ: Acute prerenal failure, Anuria, Azotemia, Dialysis, Hemodialysis, Neonatal anuria, Nephropathy toxic, Oliguria, Peritoneal dialysis, Renal failure acute, Renal failure neonatal, Renal impairment neonatal, and Renal impairment, and Renal insufficiency.
Acute Renal Failure Broad SMQ: Albuminuria, Blood creatinine abnormal, Blood creatinine increased, Blood urea abnormal, Blood urea increased, Blood urea nitrogen/creatinine ratio increased, Creatinine renal clearance decreased, Edema due renal disease, Hepatorenal failure, Nephritis, Nephritis interstitial, Proteinuria, Renal clearance decreased, Renal function tests abnormal, Renal transplant, Renal tubular disorder, Renal tubular necrosis, Tubulointerstitial nephritis.
Development of SMQs
SMQs are developed by consortium of swiss based Council For International Organization Of Medical Sciences (CIOMS) and MSSO. They are tested on one instance of federal safety database and one industrial partner database.
MedDRA unleashed
MedDRA stands for Medical Dictionary for Regulatory Activities
WHO-ART would be WHO's Adverse Reaction Terminology
ICD-9CM is International Classification of Diseases, 9th Revision Clinical Modification
A more rarer abbreviation : MSSO stands for Maintenance Service and Support Organization
History
Just as they did with James Bond 007, MedDRA was originally developed by UK's regulatory authority. Medicines Control Agency (MCA), and is a terminology for classifying adverse effects and medical history.
Applications of MedDRA
Data Capture and Coding : mainly efficacy data and post-market safety surveillance
Data Retrieval : Safety data reporting and pharmacovigilance, periodic safety reports
Data Analysis : End of trial safety data tabulation, thresholding (as a cut-off)
Regulatory Actions : Product label creating and maintenance
MedDRA hierarchy
The dictionary is structured into 5 levels namely : System Organ Class (SOC) > High level term group (HLGT) > High Level Term (HLT) > Preferred Term (PT) > Lowest Level Term (LLT). The association between PT and LLT is one to one, and for the rest it is many to one.
How to get MedDRA
MedDRA is a licensed software for non-regulators, and comes as a ASCII text file separated by $ signs. The data can be then easily fed into any relational database system such as mysql, oracle etc.,
What is the role of MSSO ?
MedRA is handled by www.meddramsso.com which is responsible change requests, help desk and handling the user group. One of the early issues with MedDRA adoption was the need to translate from COSTART or WHO-ART to MedDRA. The more recent issue has been the need to keep up with the new updates in MedDRA. MSSO tries to soothe the pain felt by companies in this process of changes and updates.
21 CFR Part 11 : Basics
Title 21 CFR Part 11 deals with the FDA guidelines on electronic records and electronic signatures in the United States. Title 21 itself is part of the Code of Federal Regulations. Part 11, defines the criteria under which electronic records and electronic signatures are considered to be trustworthy, reliable and equivalent to paper records.Part 11 requires drug makers, medical device manufacturers, biotech companies, biologics developers, and other FDA-regulated industries, with some specific exceptions, to implement controls, including audits, system validations, audit trails, electronic signatures, and documentation for software and systems involved in processing many forms of data as part of business operations and product development.The rule also applies to submissions made to the FDA in electronic format (i.e. a NDA) but not to paper submissions by electronic methods (i.e. faxes). It specifically does not require the 21CFR requirement for record retention for tracebacks by food manufacturers. Most food manufacturers are not otherwise explicitly required to keep detailed records, but electronic documentation kept for HACCP (Hazard Analysis and Critical Control Points) and similar requirements must meet these requirements.Most of the regulation is excessive, and the FDA has stated in guidance that it will exercise enforcement discretion on many parts of the rule. This has led to confusion on exactly what is required, and the rule is being revised. In practice, the requirements on access controls are the only part routinely enforced. The "predicate rules" which required the records to be kept in the first place are still in effect. If electronic records are illegible, inaccessible, or corrupted the manufacturers are still subject to those requirements.If a regulated firm keeps "hard copies" of all required records, the paper documents are considered to be the authoritative document for regulatory purposes and the computer system need not meet these requirements.Subpart A – General Provisions
Scope
Implementation
Definitions
Subpart B – Electronic Records
Controls for closed systems
Controls for open systems
Signature manifestations
Signature/record linking
Subpart C – Electronic Signatures
General requirements
Electronic signatures and controls
Controls for identification codes/passwords
Title 21 CFR Part 11 deals with the FDA guidelines on electronic records and electronic signatures in the United States. Title 21 itself is part of the Code of Federal Regulations. Part 11, defines the criteria under which electronic records and electronic signatures are considered to be trustworthy, reliable and equivalent to paper records.Part 11 requires drug makers, medical device manufacturers, biotech companies, biologics developers, and other FDA-regulated industries, with some specific exceptions, to implement controls, including audits, system validations, audit trails, electronic signatures, and documentation for software and systems involved in processing many forms of data as part of business operations and product development.The rule also applies to submissions made to the FDA in electronic format (i.e. a NDA) but not to paper submissions by electronic methods (i.e. faxes). It specifically does not require the 21CFR requirement for record retention for tracebacks by food manufacturers. Most food manufacturers are not otherwise explicitly required to keep detailed records, but electronic documentation kept for HACCP (Hazard Analysis and Critical Control Points) and similar requirements must meet these requirements.Most of the regulation is excessive, and the FDA has stated in guidance that it will exercise enforcement discretion on many parts of the rule. This has led to confusion on exactly what is required, and the rule is being revised. In practice, the requirements on access controls are the only part routinely enforced. The "predicate rules" which required the records to be kept in the first place are still in effect. If electronic records are illegible, inaccessible, or corrupted the manufacturers are still subject to those requirements.If a regulated firm keeps "hard copies" of all required records, the paper documents are considered to be the authoritative document for regulatory purposes and the computer system need not meet these requirements.Subpart A – General Provisions
Scope
Implementation
Definitions
Subpart B – Electronic Records
Controls for closed systems
Controls for open systems
Signature manifestations
Signature/record linking
Subpart C – Electronic Signatures
General requirements
Electronic signatures and controls
Controls for identification codes/passwords
Clinical Research Coordinator - Tasks
Often the job titles are vague in clinical research, one example is the role of a clinical research coordinator.Clinical Research Coordinators provide support, coordination and leadership for drug/device studies for Phase I, II, III, and IV clinical trials. Responsibilities :
Ensure progress of clinical studies from the planning and approval stages through completion of study and post-study closure.
Prepare documentation for submission for review by the IRB, recruit and screen study participants, coordinate their clinical treatment and follow-up care, and help facilitate their compliance to trial
Abstract data from medical records and other sources
Collect, submit and maintain study data and regulatory documents
Develop and ensure compliance with study protocol
Participate in the planning, development, and budgeting for clinical studies.
Required skill and training
Knowledge of Medical Terminology such as Body Systems & Diseases
Legal Aspects of Health Information (ex: confidentiality)
Project Management
Intro to Clinical Research
Intro to Health Records
Legal and Regulatory Research Compliance
Research Design
Data Management
Clinical Research Site Management
Often the job titles are vague in clinical research, one example is the role of a clinical research coordinator.Clinical Research Coordinators provide support, coordination and leadership for drug/device studies for Phase I, II, III, and IV clinical trials. Responsibilities :
Ensure progress of clinical studies from the planning and approval stages through completion of study and post-study closure.
Prepare documentation for submission for review by the IRB, recruit and screen study participants, coordinate their clinical treatment and follow-up care, and help facilitate their compliance to trial
Abstract data from medical records and other sources
Collect, submit and maintain study data and regulatory documents
Develop and ensure compliance with study protocol
Participate in the planning, development, and budgeting for clinical studies.
Required skill and training
Knowledge of Medical Terminology such as Body Systems & Diseases
Legal Aspects of Health Information (ex: confidentiality)
Project Management
Intro to Clinical Research
Intro to Health Records
Legal and Regulatory Research Compliance
Research Design
Data Management
Clinical Research Site Management
Quality in Clinical Trials
After all the complaining that "quality" is not great in Indian CRO's we often miss the whole poing about quality. Lets break this discussion into two levels : 1. How is quality measured, 2. How to improve quality in your clinical trials ?Quality in clinical trials is a product of reliability & credibility and compliance to the protocol/process specified by sponsor/client. The customer or client is looking at fulfilling requirements such as : budget, legal regulations, ethical guidelines, study protocol, time frame and GXP. Most of the large MNCs have Quality Management Systems (QMS) toestablish and consistently achieve quality objectives. QMS are structured into training, SOP/procedures, Quality Control and Quality Assurance.Procedures and SOPs can be specific to a sponsor or to an investigator site. SOPs clearly define the timeframe, specifications of input and output and most importantly the role of each team member. They also serve as tools for training and for change management.Quality control : systematic checks on the compliance of the trial process & reliability and credibility of dataQuality Assurance : independent audits of all trial-related processess & functions. Can be trial or project specific or system audits.
After all the complaining that "quality" is not great in Indian CRO's we often miss the whole poing about quality. Lets break this discussion into two levels : 1. How is quality measured, 2. How to improve quality in your clinical trials ?Quality in clinical trials is a product of reliability & credibility and compliance to the protocol/process specified by sponsor/client. The customer or client is looking at fulfilling requirements such as : budget, legal regulations, ethical guidelines, study protocol, time frame and GXP. Most of the large MNCs have Quality Management Systems (QMS) toestablish and consistently achieve quality objectives. QMS are structured into training, SOP/procedures, Quality Control and Quality Assurance.Procedures and SOPs can be specific to a sponsor or to an investigator site. SOPs clearly define the timeframe, specifications of input and output and most importantly the role of each team member. They also serve as tools for training and for change management.Quality control : systematic checks on the compliance of the trial process & reliability and credibility of dataQuality Assurance : independent audits of all trial-related processess & functions. Can be trial or project specific or system audits.
Drug Safety and Pharmacovigilance
The ground truth of how pharmaceutical industry has evolved over the past decade is the large surge in increased specialization and sophistication. In this series we will focus on specialist careers in pharmaceutical industry, lets start with pharmacovigilance.
No medicine which is effective is 100% safe, but the adverse/side effects of a drug have to be weighed against the benefits of the drug. For example a drug treating terminal disease like cancer can have some adverse effects like vomiting and hair loss, but still it would be approved given the gravity of disease it is used to treat. Drug safety function focuses on measurement, prediction, reporting and evaluating safety signals. There are several roles in this domain namely :
Drug safety physician
Safety specialist
Safety informatics expert
Safety information expert If you are good at either synthesising medical information/research finding or have great analytical capabilities to drill down into complex safety data this area of specialization is very suitable and lucrative for you.
The ground truth of how pharmaceutical industry has evolved over the past decade is the large surge in increased specialization and sophistication. In this series we will focus on specialist careers in pharmaceutical industry, lets start with pharmacovigilance.
No medicine which is effective is 100% safe, but the adverse/side effects of a drug have to be weighed against the benefits of the drug. For example a drug treating terminal disease like cancer can have some adverse effects like vomiting and hair loss, but still it would be approved given the gravity of disease it is used to treat. Drug safety function focuses on measurement, prediction, reporting and evaluating safety signals. There are several roles in this domain namely :
Drug safety physician
Safety specialist
Safety informatics expert
Safety information expert If you are good at either synthesising medical information/research finding or have great analytical capabilities to drill down into complex safety data this area of specialization is very suitable and lucrative for you.
Certified Clinical Data Manager (CCDM) Certification
If you are keen on a career in CDM you should seriously consider CCDM certification exam. You will find the details on the exam at this link SCDM websiteHowever this exam is not an easy one, we will do a series of post discussing how to get certified and what you need to learn for this exam.The very basic knowledge you need is how clinical process work, mainly the phases in clinical research and what happens in each phase of drug development. The key aspect is that you should understand how data is collected and what data is important and the relevance of quality of the data you deal with. Also you should be familiar with regulatory and other guidelines such as GCP, ICH guidelines. For example knowledge of 21 CFR Part 11 is critical.
If you are keen on a career in CDM you should seriously consider CCDM certification exam. You will find the details on the exam at this link SCDM websiteHowever this exam is not an easy one, we will do a series of post discussing how to get certified and what you need to learn for this exam.The very basic knowledge you need is how clinical process work, mainly the phases in clinical research and what happens in each phase of drug development. The key aspect is that you should understand how data is collected and what data is important and the relevance of quality of the data you deal with. Also you should be familiar with regulatory and other guidelines such as GCP, ICH guidelines. For example knowledge of 21 CFR Part 11 is critical.
Indian clinical trials market is growing at a CAGR of 40% for the last 3 years. India is fast emerging as a favoured destination for clinical trials outsourcing.
Clinical trials conducted in India are estimated to grow upto $1-1.5 billion in 2010.
Offshoring clinical trials to emerging markets around the world is receiving increasing attention as a very attractive alternative in the clinical development process.
Its an era of Science Graduates to work on computers,novel system of study in inventing drugs.
Clinical trials conducted in India are estimated to grow upto $1-1.5 billion in 2010.
Offshoring clinical trials to emerging markets around the world is receiving increasing attention as a very attractive alternative in the clinical development process.
Its an era of Science Graduates to work on computers,novel system of study in inventing drugs.
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