Compliance Considerations in Pharmaceutical

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• Compliance Considerations in Pharmaceutical
• Product Development

John C. (Jack) Garvey, Esq. THE WEINBERG GROUP
INC. PRINCETON, NJ
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Compliance in Drug Development

• The Drug Development Challenge
• A Sampling of Key Compliance Focus Areas
• Structuring Compliance for Sustainability
• Closing Thoughts

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Business Climate
Various sources estimate the current average drug
approval costs between 900 million and 1.7
billion
Estimates are that 1 FDA-approved drug results
from 5-10,000 that enter the discovery phase
PHRMA member companies increased RD spending
53.5 between 2000 and 2005 to 40 billion
Goldman Sachs estimates that pharma RD spending
will increase 7 per year from 2004 to 2009
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Snatched from the Headlines
From CNNMoney.com, 16 August 2007
The pharma industry is suffering a dearth of new
drug approvals thanks to an increasingly
stringent FDA.
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."  . .
This year's approvals include only seven drugs
that can be considered completely new, which is a
10-year low for the industry. .
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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
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The Drug Development Cycle(Simplified)
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Drug Development Compliance Touchpoints
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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

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The Changing Landscape of Development
Compliance
Guidance Establishment and Operation of
Clinical Trial Data Monitoring Committees (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 Adverse Event Reporting
Improving Human Subject Protection (Out for
Comment 4/07)
Guidance Immunotoxicity Studies for Human
Pharmaceuticals (4/06)
Guidance ICH Q8 Pharmaceutical Development
(5/06)
Draft Guidance Supervisory Responsibilities of
Clinical Investigators (Out for Comment 5/07)
Draft Guidance Approaches to Complying with
CGMP During Phase I (12/06)
Draft Guidance ICH Q10 Pharmaceutical Quality
System (7/07)
Guidance Computerized Systems Used in Clinical
Investigations (5/07)
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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

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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

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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

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Clinical Investigator Inspections 2006
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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
• FDAs 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

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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

• What happened
• Trial investigator introduced study to patient
  during routine treatment
• Allegations of mixed signals with warnings due to
  doctor patient relationship
• If a patients doctor is an investigator, there
  should be additional counsel for the patient
  about study participation

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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

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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

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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

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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.
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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

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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 its 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?
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Case Study MDS Pharma
Warning Letter 12/04 A systematic problem of
inadequate analysis and investigation of
anomalous results across multiple studies for
multiple sponsors.
FDA Letter to Sponsors of Approved ANDAs
(1/07) Serious 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..
Warning Letter 8/06 Failure 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.
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Case Study MDS Pharma (Contd.)

• Lesson 1 You dont 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.

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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)

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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

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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

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Dont mess with data integrity
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Data Integrity According to FDA
What they are seeing
What they are doing about it

• 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

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Four Quadrant Compliance Program Framework

• Process Management
• Process definition
• Process characterization
• Process execution

• Governance
• Reporting Management Review
• Metrics
• Executive Linkage

• Compliance Systems
• Policies, Procedures, Work Instructions, etc.
• Personnel and organizational structures
• Audits, QA activities, etc.

• Knowledge Environment
• Organizational Culture
• Regulatory Intelligence
• Training Education

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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

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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

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Applied Regulatory Intelligence
And remember
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Zones of Compliance Certainty
Clearly above legal requirements and enforcement
expectations
Clearly below legal requirements and enforcement
expectations
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Closing Thoughts

• Is compliance a companys 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?

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Thank you.Questions?
For More Information, Contact John C. (Jack)
Garvey, Esq. THE WEINBERG GROUP
INC. john.garvey_at_weinberggroup.com Office
609-919-6373 Mobile [phone]