compliance considerations in pharmaceutical product development compliance considerations in...
TRANSCRIPT
Compliance Considerations in Pharmaceutical
Product Development
Compliance Considerations in Pharmaceutical
Product Development
John C. (Jack) Garvey, Esq.
THE WEINBERG GROUP INC.PRINCETON, NJ
Compliance in Drug Development
• The Drug Development Challenge
• A Sampling of Key Compliance Focus Areas
• Structuring Compliance for Sustainability
• Closing Thoughts
Business ClimateVarious sources
estimate the current average drug approval costs between
$900 million and $1.7 billion
PHRMA member companies
increased R&D spending 53.5% between 2000
and 2005 to $40 billion
Goldman Sachs estimates that pharma R&D spending will
increase 7% per year from 2004 to
2009
Estimates are that 1 FDA-approved drug results from
5-10,000 that enter the
discovery phase
2007 2008 2009 2010 2011
App
rova
l Cos
t
Snatched from the Headlines…
The pharma industry is suffering a
dearth of new drug approvals
thanks to an increasingly
stringent FDA….
The pharma industry is suffering a
dearth of new drug approvals
thanks to an increasingly
stringent FDA….
From CNNMoney.com, 16 August 2007
The Food and Drug Administration approved 38 new drugs through July of
this year, down 31 percent from 55 approvals during the same period in
2006 ….
The Food and Drug Administration approved 38 new drugs through July of
this year, down 31 percent from 55 approvals during the same period in
2006 ….
FDA spokesperson Susan Cruzan denied that her agency was getting tougher on drug applications. "There have been no systematic changes in how we are approaching the approval standards for new applications," wrote Cruzan in an email to CNNMoney.com, adding that "each application is reviewed on its own merit." . ….
FDA spokesperson Susan Cruzan denied that her agency was getting tougher on drug applications. "There have been no systematic changes in how we are approaching the approval standards for new applications," wrote Cruzan in an email to CNNMoney.com, adding that "each application is reviewed on its own merit." . ….
[T]his year's approvals include only seven drugs
that can be considered
completely new, which is a 10-
year low for the industry. ….
[T]his year's approvals include only seven drugs
that can be considered
completely new, which is a 10-
year low for the industry. ….
The TWO Main Goals of Drug Development
Identifying a chemical entity / compound that has a specific, singular therapeutic impact on a broad population set with minimal adverse
events.
Developing a formulation and
delivery system that consistently delivers the desired biological
availability of the identified compound to the broadest possible
population set.
Then…
The Drug Development Cycle(Simplified)
FDA REVIEW
XFER TO MFG
DISCOVERYPRE-
CLINICAL
CLINICAL
Phase 1
Phase 2
Phase 3
IND Filed NDA Filed
FDA REVIEW
XFER TO MFG
DISCOVERYPRE-
CLINICAL
CLINICAL
Phase 1
Phase 2
Phase 3
IND Filed NDA Filed
Drug Development Compliance Touchpoints
Sampling of Traditional and Evolving
Compliance Considerations • Phase I GMP Guidances • Clinical Trials• Risk Communication• Access for
Investigational Drugs• Early CMS Involvement
in Clinical Requirements• Data Integrity --
Traditional• Data Integrity – Part
11 / CSV Considerations• CMC Issues
• Pre-Approval Inspections• Process Analytical
Technology / Quality by Design
• Pharmacogenomic Data Submission
• Pediatric Studies Requirements
• Safety Reporting Requirements
• Third Party Services• Current “Hot-Button”
Areas• New Guidances
The Changing Landscape of Development Compliance
Guidance: Establishment and Operation of Clinical
Trial Data Monitoring Committees (3/06)
Guidance: Establishment and Operation of Clinical
Trial Data Monitoring Committees (3/06)
Guidance: Using a Centralized IRB
Process in Multicenter Trials (3/06)
Guidance: Using a Centralized IRB
Process in Multicenter Trials (3/06)
Draft Guidance: Exception from Informed Consent Requirements
for Emergency Research (9/06)
Draft Guidance: Exception from Informed Consent Requirements
for Emergency Research (9/06) Draft Guidance: Adverse
Event Reporting – Improving Human Subject
Protection (Out for Comment – 4/07)
Draft Guidance: Adverse Event Reporting –
Improving Human Subject Protection (Out for Comment – 4/07)
Draft Guidance: Approaches to Complying with CGMP During
Phase I (12/06)
Draft Guidance: Approaches to Complying with CGMP During
Phase I (12/06)
Draft Guidance: Supervisory
Responsibilities of Clinical Investigators (Out
for Comment – 5/07)
Draft Guidance: Supervisory
Responsibilities of Clinical Investigators (Out
for Comment – 5/07)
Guidance: Computerized Systems
Used in Clinical Investigations (5/07)
Guidance: Computerized Systems
Used in Clinical Investigations (5/07)
Guidance: ICH Q8 – Pharmaceutical
Development (5/06)
Guidance: ICH Q8 – Pharmaceutical
Development (5/06)
Guidance: Immunotoxicity Studies
for Human Pharmaceuticals (4/06)
Guidance: Immunotoxicity Studies
for Human Pharmaceuticals (4/06)
Draft Guidance: ICH Q10 –
Pharmaceutical Quality System
(7/07)
Draft Guidance: ICH Q10 –
Pharmaceutical Quality System
(7/07)
Phase I GMP Guidance
• Not a new requirement – flows from original GMPs and heritage of 1991 Guidance
• Focus on “Quality Control”– Well controlled procedures– Adequately controlled
equipment– Accurate and consistently
recorded data• Agency Recommendations:
– Evaluate production environment for potential hazards
– Appropriate actions to minimize risks and safeguard quality
– In a phrase: Product Characterization And Risk Mitigation
• Specific Coverage:– Personnel – QC Function– Facility & Equipment– Control of Components
Production & Documentation– Laboratory controls– Container closure and
labeling– Distribution– Recordkeeping
• Other Coverage– Screening Studies/Microdose
Producers– Multi-Product Facilities– Biological and
Biotechnological Products– Sterile Products/Aseptically
Processed Products
US Clinical Trial Regulatory Requirements
• IND – 21 CFR 312• Protection of Human Subjects --- 21 CFR 50• Institutional Review Boards – 21 CFR 56• Financial Disclosure by Clinical
Investigators – 21 CFR 54• FDA Guidance for Data Safety and
Monitoring Boards• NDA Regulations – 21 CFR 314• 21 CFR 11
FDA GCP Concerns
• A strong IRB system• Protection of vulnerable populations• Data Quality and Integrity• Advancing Technology (5/10 FDA guidance)• Personalized Medicine / Pharmacogenomics• International Research• Subject Safety (AE reporting/CI Training)
– Two guidances in draft: AE reporting; Investigator Responsibilities
0%10%20%30%40%50%60%
Protoc
ol
Reco
rdDrug Ac
ct
Cons
ent
A Es
CDER Inspection Deficiencies 2006
0%10%20%30%40%50%60%
Protoc
ol
Reco
rdDrug Ac
ct
Cons
ent
A Es
CDER Inspection Deficiencies 2006
Clinical Investigator Inspections –
2006
Clinical Investigator Inspections 2006 (All Centers)
NAI48%VAI
46%
OAI6%
NAIVAIOAI
Clinical Investigator Inspections 2006 (All Centers)
NAI48%VAI
46%
OAI6%
NAIVAIOAI
Clinical Compliance Issues
• Investigator responsibilities – critical to clinical compliance outcomes– FDA Form 1572 – Provides information
regarding the investigator, protocols, research facilities / labs, responsible IRB, sub-investigator – Commits investigator to responsibilities
– FDA’s focus on Investigators• Personal investigator involvement• Focus on Informed Consent (21 CFR 50) and IRB
responsibilities (21 CFR 56)• Timely, accurate adverse event reporting• Focus on financial disclosure compliance rules
Snatched from the Headlines…From THE WALL STREET JOURNAL, 6 August 2007
Drug: Experimnetal Gene Therapy
Company: Targeted Genetics
Subject: 36 year old woman
Issue: Informed consent process
Outcomes: Patient death; Negative media exposure of company
Drug: Experimnetal Gene Therapy
Company: Targeted Genetics
Subject: 36 year old woman
Issue: Informed consent process
Outcomes: Patient death; Negative media exposure of company
What happened:
• Trial investigator introduced study to patient during routine treatment
• Allegations of mixed signals with warnings due to doctor patient relationship
• If a patient’s doctor is an investigator, there should be additional counsel for the patient about study participation
What happened:
• Trial investigator introduced study to patient during routine treatment
• Allegations of mixed signals with warnings due to doctor patient relationship
• If a patient’s doctor is an investigator, there should be additional counsel for the patient about study participation
Clinical Compliance Issues
• FDA Oversees Clinical Research through– Agency central review – primarily through
safety reports and submissions– Bioresearch Monitoring Program (BIMO)
• Site inspections
• A few FDA Challenges with Clinical Trials– Large, multicenter studies– Data integrity (ALCOA - Attributable, Legible,
Contemporaneous, Organized, and Accurate)– Ex-US studies– Oversight with Limited Resources
Clinical Compliance Issues
• Other Compliance Issues– Documentation practices – appropriateness of
delegations of responsibility, attribution, and accuracy Preparation of Regulatory Binder
– Product Compliance – dispensing, accountability, reconciliation
– ICF accuracy – proper versions– Failure to maintain proper case histories– Investigation not done pursuant to signed
investigation plan or investigator statement– Ensuring accurate AE reporting
Current FDA Hot-Button Areas
• Critical Path Initiative• Risk management• Quality Management• GCP Inspecting
– Updating GCP Compliance Programs (Inspection SOPs)
– Standardized Inspection Reporting (Turbo EIR)
– Site selection criteria– Streamlining Enforcement / Disqualification
Expanded Access for Investigational Drugs
• Abigail Alliance v. von Eschenbach– Issues involve 21 CFR 312.34 – should
terminally ill patients have access to purchase post-phase-I drugs??
– Impacts on the sponsor – liability, cost, etc.• Oral argument on 3/1/07 – Decision
Pending• December 14, 06 – FDA issues proposed
rule on Expanded Access to Investigational Drugs for Treatment Use (71 FR 240, 75147)
UPDATE: August 7th – U.S. Court of Appeals, DC Circuit, reverses
District Court and denies right to expanded access.
UPDATE: August 7th – U.S. Court of Appeals, DC Circuit, reverses
District Court and denies right to expanded access.
CMS Draft Requirements for Clinical
Research• For drugs, biologics or devices that treat
Medicare reimbursable diseases or injuries• Provides what “deemed” studies are and
outlines requirements and criteria– Protocol– Linkage of results in protocol to Medicare
population– Inclusion criteria and consideration of
subpopulations– Study results must be published
Compliance & Use of Third Party Services
• Continually increasing trend towards use of third parties for development activities– CROs / CRAs– AE Reporting– Bioanalytical Services / Testing– Services added all the time
• Some services being moved overseas, particularly those with IT components– Complaint, AE, Pharmacovigilence handling / reporting– Clinical studies– Clinical trials data analysis
When it’s hard enough to keep operations in compliance with domestic oversight, how do we
do this when operations are entrusted with another entity, halfway across the world?
FDA Letter to Sponsors of Approved ANDAs (1/07):
“[S]erious questions remain about the validity of bioequivalence data
generated by MDS in studies during this time period that have not been
inspected by FDA, including the studies you have submitted in
support of your applications. In view of these findings, FDA is informing holders of approved ANDA(s) of
these issues and would like to know what steps are being taken by you to
assure the accuracy of data submitted in these applications and
confirm the validity of MDS's analytical studies that were
conducted from January 2000 through December 2004 and
subsequently submitted to the FDA..”
FDA Letter to Sponsors of Approved ANDAs (1/07):
“[S]erious questions remain about the validity of bioequivalence data
generated by MDS in studies during this time period that have not been
inspected by FDA, including the studies you have submitted in
support of your applications. In view of these findings, FDA is informing holders of approved ANDA(s) of
these issues and would like to know what steps are being taken by you to
assure the accuracy of data submitted in these applications and
confirm the validity of MDS's analytical studies that were
conducted from January 2000 through December 2004 and
subsequently submitted to the FDA..”
Case Study: MDS PharmaWarning Letter:
12/04“A systematic
problem of inadequate analysis and investigation of anomalous results
across multiple studies for multiple
sponsors.”
Warning Letter: 12/04
“A systematic problem of
inadequate analysis and investigation of anomalous results
across multiple studies for multiple
sponsors.”
Warning Letter: 8/06“[F]ailure to
demonstrate the accuracy of your
analytical methods in more than thirty studies for six
different drugs confirm that there are
widespread problems at your facilities….”
Warning Letter: 8/06“[F]ailure to
demonstrate the accuracy of your
analytical methods in more than thirty studies for six
different drugs confirm that there are
widespread problems at your facilities….”
Warning Letter: 12/04
“FDA has concerns about the validity of
other bioequivalence data generated by
MDS, including data submitted in support of currently-approved
applications.”
Warning Letter: 12/04
“FDA has concerns about the validity of
other bioequivalence data generated by
MDS, including data submitted in support of currently-approved
applications.”
Case Study: MDS Pharma (Contd.)
• Lesson 1: You don’t want to have submissions or approved products at risk due to third-party compliance issues.
• Lesson 2: FDA expectations change. Are your service providers keeping up? How do you know?
• Lesson 3: Sponsors maintain responsibility for their products – Responsibility is NOT able to be outsourced!
• Lesson 4: Continual oversight for 3-P services is essential.
Late Stage Development – CMC Issues
• Q7, Q8, Q9 & Q10 are big drivers in late stage development issues
• Risk-based focuses are now the desired “end-state”
• Cannot do enough product and process characterization – essential product requirements– critical to quality attributes– design space (multivariate analysis & modeling)– critical control points (HACCP & like methodologies)– Linearity and linkage from IND product through final
formulation (including clinical impacts)
Preapproval Inspections• Purpose: Insure application, data and
sponsor operational integrity• Joint Center/District activity with Office
of Compliance• Focus on:
– cGMP compliance– Authenticity, integrity of data in the
applications– Adherence to application commitments– Other factors potentially impacting
whether Agency should approve application
Focus on Data Integrity – Examples
• Cutting and pasting of chromatographic data to change OOS results
• Manipulations of sample outcomes to force passing results
• Modifying weights of samples in analytical calculations
• Selective inclusion of raw data into final records
• Disconnect between results obtained and approved methods filed with Agency
Don’t mess with data integrity…
Data Integrity – According to FDA…
• Issues with data integrity and fraud appear to be increasing
• Cuts across regulated product classes, and is occurring in clinical trials and elsewhere in the development process
• FDA is increasing staff focus on data integrity, data manipulation and fraud
• Increasing focus on PAIs and on the data integrity issues
• Focus on following up on tips or information provided regarding data integrity failures or fraud issues
What they are seeing… What they are doing about it…
Four Quadrant Compliance Program FrameworkFour Quadrant Compliance Program Framework
Process Management
• Process definition
• Process characterization
• Process execution
Process Management
• Process definition
• Process characterization
• Process execution
Governance
• Reporting & Management Review
• Metrics• Executive Linkage
Governance
• Reporting & Management Review
• Metrics• Executive Linkage
Compliance Systems
• Policies, Procedures, Work Instructions, etc.
• Personnel and organizational structures
• Audits, QA activities, etc.
Compliance Systems
• Policies, Procedures, Work Instructions, etc.
• Personnel and organizational structures
• Audits, QA activities, etc.
Knowledge & Environment
• Organizational Culture
• Regulatory Intelligence
• Training & Education
Knowledge & Environment
• Organizational Culture
• Regulatory Intelligence
• Training & Education
Application of the 4Q Compliance Model to Pharmaceutical
Development• Look at compliance end to end – should
track to end-to-end quality considerations • Establish an overall Pre-Marketing
Compliance Leadership – Ensures executive involvement
• Focus on ensuring no substantive gaps across the development cycle– Application of substantive requirements to
company business processes / development models
– Linkage from requirements to infrastructure elements
Application of the 4Q Compliance Model to Pharmaceutical
Development (Contd.)
• Break down development cycle or substantive requirements into areas of compliance responsibility– Discovery / pre-clinical– GCP– Data assurance– Late stage / product transfer
• Incorporate compliance metrics into development cycle metrics – Create regular compliance “Management Review”
• Use third party (internal or external) compliance reviews for formal assessments -- “No spin” feedback is essential
Applied Regulatory Intelligence
And remember…
Systems Processes≠
Research & DevelopmentStatutes,
Regulations, Guidances, 483 / WL observations, Agency
Statements, Case Law, etc.
Statutes, Regulations,
Guidances, 483 / WL observations, Agency
Statements, Case Law, etc.
Application Systems Processes&
Clearly below legal requirements and enforcement expectations
Clearly above legal requirements and enforcement expectations
The Rolling the Dice Zone – How much risk do you want to take?
Zones of Compliance Certainty
Closing Thoughts• Is compliance a company’s biggest challenge in
pharmaceutical product development?• Based on all this … will drug development get
less complex? Less Risky? How will you manage this?
• Do you know where in the Zone of Compliance Certainty your organization is? By system? By process?
• Does executive management understand this material?
• Are you proactive or reactive in your approach to compliance? Why?
• What will you do differently when you get back to your company?
Thank you.
Questions?
For More Information, Contact:
John C. (Jack) Garvey, Esq.
THE WEINBERG GROUP INC.
Office: 609-919-6373
Mobile: 732-397-3103
For More Information, Contact:
John C. (Jack) Garvey, Esq.
THE WEINBERG GROUP INC.
Office: 609-919-6373
Mobile: 732-397-3103