Offlabel promotion is - the use of medical device for an indication not approved by FDA.
Company Responsibilities
Company has the responsibility for promotion, marketing and labelling of medical device. The FDA many monitor company's practices and enforce regulations when necessary. enforcement may include criminal and civil actions
Labelling
All medical devices distributed by company must contain the required labeling On product ,On packaging and In manuals
Product Nomenclature
The company medical device may fit into a specific product description used by the FDA.
Company personnel should not refer to the medical device by nomenclature other than that used by the FDA.
It is recognized that individuals not employed by the company may refer to the device with nomenclature different than that used by the FDA
Sales Effort
Efforts of sales personnel should focus on market opportunities, potential customers and physicians who will utilize the medical device for indications that are approved for use by the FDA. Sales training and meetings should only address indications that are approved for use by the FDA.
Example of off label promotion cases
Schering-Plough Example of An Off-Label Case
U. S. Department of Justice investigation into sales, marketing and clinical trail practices and programs. The government claimed:
Schering salespeople were trained how to win off-label sales and were paid for doing so.
Tactics included "illegal remuneration" to doctors for "sham advisory boards" and "lavish entertainment“.
Aggregate settlement amount of $435 million:
One count of conspiracy to make false statements to the government. Criminal fine of $180 million.
$225 million to resolve civil aspects of the investigation.
Schering required to sign an addendum to an existing corporate integrity agreement
Tuesday, June 16, 2009
CGMP guidance for Phase I Investigational Drugs
This guidance got approved in July , 2008
This Replaces guidance issued in 1991 “Preparation of Investigational New Drug Products for the manufacture of phase I investigational drugs” . However the 1991 guidance still applies to the manufacture of investigational new drugs(human and animal) used in phase II and phase III clinical trials
This guideline is intended to help in applying current good manufacturing practice (CGMP) required under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) in the manufacture of most investigational new drugs (IND) used in phase I clinical trials.
This guidance describes an approach to
•Implementation of manufacturing controls that are appropriate for phase I clinical trial stage of development
•Product quality differences
−Between investigational drugs and commercial manufacture
–Among the various phases of clinical trials
•FDA's CGMP for the 21 Century initiative
– Where applicable, manufacturers are also expected to implement manufacturing controls that reflect product and manufacturing considerations, evolving process and product knowledge, and manufacturing experience .
Scope
This guidance DOES NOT apply to phase I investigational drugs for human use that are
−Human cell or tissue products regulated solely under § 361 of the Public Health Service Act
−Clinical trials for products subject to the device approval or clearance provisions of the FD&C Act
−Investigational products manufactured for phase II and phase III clinical trials
−Previously approved products that are being used in phase I clinical trials (e.g. for a new indication)
−Positron Emission Topography (PET) drugs that are subject to § 501(a)(2)(C) of the FD&C Act and/or the new PET CGMP in 21 CFR part 212 when finalized
This Replaces guidance issued in 1991 “Preparation of Investigational New Drug Products for the manufacture of phase I investigational drugs” . However the 1991 guidance still applies to the manufacture of investigational new drugs(human and animal) used in phase II and phase III clinical trials
This guideline is intended to help in applying current good manufacturing practice (CGMP) required under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) in the manufacture of most investigational new drugs (IND) used in phase I clinical trials.
This guidance describes an approach to
•Implementation of manufacturing controls that are appropriate for phase I clinical trial stage of development
•Product quality differences
−Between investigational drugs and commercial manufacture
–Among the various phases of clinical trials
•FDA's CGMP for the 21 Century initiative
– Where applicable, manufacturers are also expected to implement manufacturing controls that reflect product and manufacturing considerations, evolving process and product knowledge, and manufacturing experience .
Scope
This guidance applies to phase I investigational drugs for human use that are
•manufactured in small or large-scale environments
•typically designed to assess tolerability, or feasibility, for further development of a specific drug or biological product
•new drug and biological products including finished dosage forms used as placebos
- Investigational drugs used in phase I studies described in 21 C.F.R. § 312.21 of FDA’s IND regulations are EXEMPTED from the Current Good Manufacturing Practice (“CGMP”) requirements in 21 C.F.R. Part 211
- This exemption does not apply to an investigational drug for use in a phase I study once the investigational drug has been made available for use by or for the sponsor in a phase II or phase III study, or the drug has been lawfully marketed
- The exempted phase I drugs are, however, still required to meet statutory (as opposed to regulatory) requirements for CGMP
This guidance DOES NOT apply to phase I investigational drugs for human use that are
−Human cell or tissue products regulated solely under § 361 of the Public Health Service Act
−Clinical trials for products subject to the device approval or clearance provisions of the FD&C Act
−Investigational products manufactured for phase II and phase III clinical trials
−Previously approved products that are being used in phase I clinical trials (e.g. for a new indication)
−Positron Emission Topography (PET) drugs that are subject to § 501(a)(2)(C) of the FD&C Act and/or the new PET CGMP in 21 CFR part 212 when finalized
What is design validation and what are rules applied
Design Validaiton is a requirement of regulators prior to placing a product on the market. It is considered the last step of the Design Control process prior to transfer of the design to manufacturing. However, it is intimately tied to Process Validation a portion of Production Controls. Companies must assure that they are properly conducting Design Validation with products from a validated production process to avoid audit/inspection observations, and the risk of placing a violative product on the market.
Find below the regulations to look out for design validation as stated in http://www.fda.gov/
I. REQUIREMENTS
§ 820.30(g) Design validation.
Each manufacturer shall establish and maintain procedures for validating the device design.
Design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents.
Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions.
Design validation shall include software validation and risk analysis, where appropriate.
The results of the design validation, including identification of the design, method(s), the date, and the individual(s) performing the validation, shall be documented in the Design History File.
Cross-reference to ISO 9001:1994 and ISO/DIS 13485 section 4.4.8 Design validation.
II. DEFINITIONS
§820.3(y) Specification means any requirement with which a product, process, service, or other activity must conform.
§ 820.3(z) Validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled.
Process Validation means establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications.
Design Validation means establishing by objective evidence that device specifications conform with user needs and intended use(s).
§820.3(aa) Verification means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled.
Find below the regulations to look out for design validation as stated in http://www.fda.gov/
I. REQUIREMENTS
§ 820.30(g) Design validation.
Each manufacturer shall establish and maintain procedures for validating the device design.
Design validation shall be performed under defined operating conditions on initial production units, lots, or batches, or their equivalents.
Design validation shall ensure that devices conform to defined user needs and intended uses and shall include testing of production units under actual or simulated use conditions.
Design validation shall include software validation and risk analysis, where appropriate.
The results of the design validation, including identification of the design, method(s), the date, and the individual(s) performing the validation, shall be documented in the Design History File.
Cross-reference to ISO 9001:1994 and ISO/DIS 13485 section 4.4.8 Design validation.
II. DEFINITIONS
§820.3(y) Specification means any requirement with which a product, process, service, or other activity must conform.
§ 820.3(z) Validation means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled.
Process Validation means establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications.
Design Validation means establishing by objective evidence that device specifications conform with user needs and intended use(s).
§820.3(aa) Verification means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled.
Saturday, May 2, 2009
Overview of ISO 14971
It has 9 clauses.
Clause -1 - Scope
It covers all medical devices including IVDs.
It applies to all phases of product life cycle.
It does not
-define acceptable risk
-Apply to clinical decision making
-Does not require quality system
Clause -2 - Definition
- Clause provides definitions of terms
- there are new terms and definitions
- To provide uniformity among standards many definitions are harmonized with other standards and also with Guide 51 which is used by ISO and IEC for common definitions
- Clause also contains updated definitions from ISO 9000:2005
Definition changes
-in vitro diagnostic medical device– “medical device intended by the manufacturer for the examination of specimens derived from the human body to provide information for diagnostic, monitoring, or compatibility purposes”
- life-cycle– “all phases in the life of a medical device, from the initial conception to final decommissioning and disposal”
- Post-production – new term – “part of the life-cycle of the product after the design has been completed and the medical device has been manufactured”
- Use error – “act or omission of an act that results in a different medical device response than intended by the manufacturer or expected by the user” – from IEC 62366
Clause -3 -General Requirements
- Sub-clause 3.2 “Management responsibilities” expands description of requirements and indicates that documentation created in the process and the risk management review can be part of the quality system documentation.
-Sub-clause 3.3 indicates in a Note that risk management activities can be performed by “representative of several functions, each contributing their specialist knowledge”
-Does not require a single individual be assigned the total responsibility for risk management
-Personnel assigned these activities must have proper training, background, education and experience
- Sub-clause 3.4 describes the Risk management plan
- Requirements unchanged
-In response to many comments in ISO 14971 voting process, extensive notes added to provide explanations and references to additional information in Annex D and Annex F
- Sub-clause 3.5 has been revised to include the traceability requirement removed from Clause 8 Risk management report
- Risk management report for complex devices was getting unwieldy
- Note indicates the Risk management file can be in any form or medium (such as electronic files)
Clause -4 - Risk Analysis
- Clause 4 covers Risk Analysis and Risk Estimation
- Sub-clause 4.1 re-titled to “Risk analysis process” from “Risk analysis procedure”
- New Notes point to informative annexes with additional information
- Sub-clause 4.2 Note 1 indicates “misuse is intended to mean incorrect or improper use of the medical device”
- Sub-clause 4.3 title changed to “Identification of hazards”
- Note points to E.2 and H.2.4 for guidance in hazard identification
- Sub-clause 4.4 title changed to “Estimation of the risk(s) for each hazardous situation”
- This is a new emphasis in Second Edition, from idea that harm cannot occur unless a Hazardous Situation leads to an exposure to a hazard
- Extensive notes used to explain this Subclause
Clause -5 - Risk Evaluation
- Evaluation requirement is in reference to “Hazardous situation” instead of “Hazard”
- Evaluation is comparison of Risk to Acceptability Criteria established in Risk Management Plan
Clause -6 - Risk Control
Sub-clause 6.1 removed requirement to reduce residual risk associated with each hazard to acceptable
- Addressed under “Residual Risk”
Sub-clause 6.2 Title changed to “Risk Control Option Analysis”
- Extensive Notes provide information and reference including use of other standards as part of option analysis
- Sub-clause 6.3 Implementation of risk control measure(s)
- Indicates that verification of effectiveness of risk control measures may include validation activities
- Sub-clause 6.4 Residual risk evaluation
- adds Note to Annex J for information on disclosing residual risk
- Sub-clause 6.5 Risk/benefit analysis
-Adds note referring to Annex D.6 for more information on Risk/benefit analysis
- Sub-clause 6.6 title changed to “Risks arising from risk control measures”
- Includes introduction of new hazards or hazardous situations
- Adds requirement that these new risks or increased risks be managed with process in sub-clauses 4.4 to 6.5
- Sub-clause 6.7 Completeness of risk control
- Changes “hazard” to “hazardous situation”
- Changes “The results of this assessment…” to “The results of this activity…”
Clause -7 - Evaluation of overall Residual risk acceptability
Clause 7 title changed to “Evaluation of overall residual risk acceptability”
- Adds requirement for deciding what information to disclose on overall residual risk
- Add reference to Annex D.7 on Overall residual risk
-Adds reference to Annex J on disclosure of residual risk
Clause -8 - Risk Management report
- Clause 8, removed the traceability requirement from the Risk management report to the Risk Management File (see Sub-clause 3.5)
- Adds requirements for responsibility for review and documentation of review that demonstrates
-“the risk management plan has been appropriately implemented;
-the overall residual risk is acceptable;
-appropriate methods are in place to obtain relevant production and post-production information.”
Clause - 9 - Production and post production process
- The Title was changed to “Production and post-production information” to emphasize that there is information available during production which is important to Risk Management
- Adds a requirements for systems collecting and reviewing device information
Clause -1 - Scope
It covers all medical devices including IVDs.
It applies to all phases of product life cycle.
It does not
-define acceptable risk
-Apply to clinical decision making
-Does not require quality system
Clause -2 - Definition
- Clause provides definitions of terms
- there are new terms and definitions
- To provide uniformity among standards many definitions are harmonized with other standards and also with Guide 51 which is used by ISO and IEC for common definitions
- Clause also contains updated definitions from ISO 9000:2005
Definition changes
-in vitro diagnostic medical device– “medical device intended by the manufacturer for the examination of specimens derived from the human body to provide information for diagnostic, monitoring, or compatibility purposes”
- life-cycle– “all phases in the life of a medical device, from the initial conception to final decommissioning and disposal”
- Post-production – new term – “part of the life-cycle of the product after the design has been completed and the medical device has been manufactured”
- Use error – “act or omission of an act that results in a different medical device response than intended by the manufacturer or expected by the user” – from IEC 62366
Clause -3 -General Requirements
- Sub-clause 3.2 “Management responsibilities” expands description of requirements and indicates that documentation created in the process and the risk management review can be part of the quality system documentation.
-Sub-clause 3.3 indicates in a Note that risk management activities can be performed by “representative of several functions, each contributing their specialist knowledge”
-Does not require a single individual be assigned the total responsibility for risk management
-Personnel assigned these activities must have proper training, background, education and experience
- Sub-clause 3.4 describes the Risk management plan
- Requirements unchanged
-In response to many comments in ISO 14971 voting process, extensive notes added to provide explanations and references to additional information in Annex D and Annex F
- Sub-clause 3.5 has been revised to include the traceability requirement removed from Clause 8 Risk management report
- Risk management report for complex devices was getting unwieldy
- Note indicates the Risk management file can be in any form or medium (such as electronic files)
Clause -4 - Risk Analysis
- Clause 4 covers Risk Analysis and Risk Estimation
- Sub-clause 4.1 re-titled to “Risk analysis process” from “Risk analysis procedure”
- New Notes point to informative annexes with additional information
- Sub-clause 4.2 Note 1 indicates “misuse is intended to mean incorrect or improper use of the medical device”
- Sub-clause 4.3 title changed to “Identification of hazards”
- Note points to E.2 and H.2.4 for guidance in hazard identification
- Sub-clause 4.4 title changed to “Estimation of the risk(s) for each hazardous situation”
- This is a new emphasis in Second Edition, from idea that harm cannot occur unless a Hazardous Situation leads to an exposure to a hazard
- Extensive notes used to explain this Subclause
Clause -5 - Risk Evaluation
- Evaluation requirement is in reference to “Hazardous situation” instead of “Hazard”
- Evaluation is comparison of Risk to Acceptability Criteria established in Risk Management Plan
Clause -6 - Risk Control
Sub-clause 6.1 removed requirement to reduce residual risk associated with each hazard to acceptable
- Addressed under “Residual Risk”
Sub-clause 6.2 Title changed to “Risk Control Option Analysis”
- Extensive Notes provide information and reference including use of other standards as part of option analysis
- Sub-clause 6.3 Implementation of risk control measure(s)
- Indicates that verification of effectiveness of risk control measures may include validation activities
- Sub-clause 6.4 Residual risk evaluation
- adds Note to Annex J for information on disclosing residual risk
- Sub-clause 6.5 Risk/benefit analysis
-Adds note referring to Annex D.6 for more information on Risk/benefit analysis
- Sub-clause 6.6 title changed to “Risks arising from risk control measures”
- Includes introduction of new hazards or hazardous situations
- Adds requirement that these new risks or increased risks be managed with process in sub-clauses 4.4 to 6.5
- Sub-clause 6.7 Completeness of risk control
- Changes “hazard” to “hazardous situation”
- Changes “The results of this assessment…” to “The results of this activity…”
Clause -7 - Evaluation of overall Residual risk acceptability
Clause 7 title changed to “Evaluation of overall residual risk acceptability”
- Adds requirement for deciding what information to disclose on overall residual risk
- Add reference to Annex D.7 on Overall residual risk
-Adds reference to Annex J on disclosure of residual risk
Clause -8 - Risk Management report
- Clause 8, removed the traceability requirement from the Risk management report to the Risk Management File (see Sub-clause 3.5)
- Adds requirements for responsibility for review and documentation of review that demonstrates
-“the risk management plan has been appropriately implemented;
-the overall residual risk is acceptable;
-appropriate methods are in place to obtain relevant production and post-production information.”
Clause - 9 - Production and post production process
- The Title was changed to “Production and post-production information” to emphasize that there is information available during production which is important to Risk Management
- Adds a requirements for systems collecting and reviewing device information
FDA/IEC Software Standard 62304
IEC- The International Electrotechnical Commission (IEC) is a worldwide organization for standardization comprising all national electrotechnical committees (IEC National Committees). The object of IEC is to promote international co-operation on all questions concerning standardization in the electrical and electronic fields.
FDA has approved IEC 62304 as recognized software development standard, allowing submissions stipulating conformance to 62304
How FDA plays with it
FDA has approved IEC 62304 as recognized software development standard, allowing submissions stipulating conformance to 62304
How FDA plays with it
- FDA uses QSIT in regard to auditing this area.
- By standardizing to 62304, companies can eliminate confusion during compliance audits, and especially show FDA personnel how the development happens for your S/W
- By adopting the standard, all staff will be on the same development platform, thus easing audits and lessening FDA Form 483’s and Warning Letters or worse.
Basic Assumptions
SOUP=software of unknown provenance (acronym)
SOUP is a SOFTWARE ITEM that is already developed and generally available and that has not been developed for the purpose of being incorporated into the MEDICAL DEVICE (also known as “off-the-shelf software”) or software previously developed for which adequate records of the development PROCESSES are not available
AUDIT TOOLS—REMEMBER FDA TIGHTLY AUDITS THIS UNDER 820.70(i) AND YOUR FIRM MUST CONTROL ALL SOUP VIA DESIGN, CHANGE PURCHASING AND DOCUMENT CONTROLS
Software safety classification
a) The MANUFACTURER shall assign to each SOFTWARE SYSTEM a software safety class (A, B, or C) according to the possible effects on the patient, operator, or other people resulting from a HAZARD to which the SOFTWARE SYSTEM can contribute.
The software safety classes shall initially be assigned based on severity as follows:
Class A: No injury or damage to health is possible
Class B: Non-SERIOUS INJURY is possible
Class C: Death or SERIOUS INJURY is possible
This standard does not specify an organizational structure for the MANUFACTURER or which part of the organization is to perform which PROCESS, ACTIVITY, or TASK. This standard requires only that the PROCESS, ACTIVITY, or TASK be completed to establish compliance with this standard.
This standard does not prescribe the name, format, or explicit content of the documentation to be produced. This standard requires documentation of TASKS, but the decision of how to package this documentation is left to the user of the standard.
This standard does not prescribe a specific life cycle model. The users of this standard are responsible for selecting a life cycle model for the software project and for mapping the PROCESSES, ACTIVITIES, and TASKS in this standard onto that model.
For the purposes of this standard:
· “shall” means that compliance with a requirement is mandatory for compliance with this standard
· “should” means that compliance with a requirement is recommended but is not mandatory for compliance with this standard
· “may” is used to describe a permissible way to achieve compliance with a requirement
·“establish” means to define, document, and implement
·REMEMBER—FDA DEFINES ESTABLISH THE SAME WAY
Compliance
Compliance with this standard is defined as implementing all of the PROCESSES, ACTIVITIES, and TASKS identified in this standard in accordance with the software safety class.
NOTE 1 This assessment could be carried out by internal or external audit{FDA expects this}
NOTE 2 Although the specified PROCESSES, ACTIVITIES, and TASKS are performed, flexibility exists in the methods of implementing these PROCESSES and performing these ACTIVITIES and TASKS.
NOTE 3 Where any requirements contain “as appropriate” and were not performed, documentation for the justification is necessary for this assessment.
NOTE 4 The term “conformance” is used in ISO/IEC 12207 where the term “compliance” is used in this standard.
Ref -
ISO 14971, Medical devices – Application of risk management to medical devices.
FDA expects ISO 14971 style r/m..although they cannot require it. By adopting thus standard, you now must comply to ISO 14971. ISO 13485:2003 also require ISO 14971
Make sure and study all of the definitions in the standard
Software Development plan
The MANUFACTURER shall establish a software development plan (or plans) for conducting the ACTIVITIES of the software development PROCESS appropriate to the scope, magnitude, and software safety classifications of the SOFTW ARE SYSTEM to be developed.
The s/w DEVELOPMENT LIFE CYCLE MODEL shall either be fully defined or be referenced in the plan (or plans).
AUDIT TOOL—INVESTIGATE DHF CONTENT FOR REQUIREMENT TRACES, MATRICES AND INTER-RELATIONSHIPS BETWEEN DEPARTMENTS
The plan shall address the following:
a) the PROCESSES to be used in the development of the SOFTW ARE SYSTEM
b) the DELIVERABLES (includes documentation) of the ACTIVITIES and TASKS;
c) TRACEABILITY between SYSTEM requirements, software requirements,
SOFTWARE SYSTEM test, and RISK CONTROL measures implemented software
AUDIT TOOL—PARSE APART THE DHF, SHOWING ALL PROCESSES IN USE,V/V FOR OTS S/W AND TRACE MATRICES
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