WORKING WITH PHARMA
SPONSORS IN RESEARCH
Becky Hubbell, PharmD, MBA
Sr Ex Dir, Clinical Research
Operations
Background
• 10 years hospital pharmacy practice
• Assistant Professor KU School of Pharmacy
• 20 years pharmaceutical industry
– 13 years Marion labs -> Aventis
– 6 years Pharmion -> Celgene
• Clinical development
• Outcomes Research
• Therapeutic areas—last 6 years oncology
• KUCC—Clinical Research Operations
Pharmaceutical Industry: Drug Development
• 1999: 1,800 compounds in development
• 2009: 2,900 medicines in development
• 2008: Food and Drug Administration approved 31
drugs and biologics
• 2006: cost to develop a drug $1.3 billion dollars and
takes between 10 and 15 years
Research Relationship with the Pharma
Industry
• Many of the research projects undertaken at
academic medical centers are part of the drug
development process
• The pharmaceutical industry can be a funding source
for innovative ideas through investigator-initiated
trials (IITs)
Objective
• Briefly discuss the process of drug approval from the
pharmaceutical industry perspective
• Discuss how to optimize and improve our working
relationship with our partners in the pharma industry
around clinical research
• Disclaimers:
– Overview for discussion and thought
– Not complete review of regulatory activity/responsibility for
clinical trials
– Not complete review of internal processes
Pharmaceutical Companies
• Wide variations
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Global or local
Therapeutic focus—single area, e.g., oncology or broad
Size—start ups vs. mega corporations
Publically or privately held
Culture
Etc.
Points of contact with Pharma
• Sales and marketing
– On label discussions
– You can request material off label—information usually will
come from medical information department
• Medical science liaison
– Medical departments, provide scientific information
– Contact for IITs
– May or may not be involved in studies
• Clinical development
– CRAs, Scientists, Operations
– Research/study specific
– Contract Research Organizations
• Others as well
New Drug Application (NDA)
• Drug is safe and effective in its proposed use and the
benefits outweigh the risk
• The drug’s proposed labeling (package insert) is
appropriate
• The methods used in manufacturing the drug are
adequate to preserve the drug’s identity, strength,
quality and purity
• Documentation is supposed to tell the drug’s whole
story
• 100,000 pages and more
• Outcome: Approval, Approvable, Not Approved
Drug Development
• International Conference on Harmonization (1990) –
ICH guidelines
– USA, Europe, Japan
• Preclinical -> IND
• Clinical
– Phase I
– Phase II
– Phase III: NDA requires studies
• NDA (Advisory Panel)
– Phase IIIb, IV
Planning Drug Development
• Product development plan
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Shortest path to marketing (NDA, MAA)
Plan should target the labeling
Least number of studies
Each study results in more information
Meetings and guidance from regulatory authorities (FDA,
EMEA, etc)
– Budget
– Time to market is crucial
• Marketing success
– Will additional studies be required to provide additional
information
Labeling: Package Insert
Off Label Marketing: Pfizer Pays $2.3
Billion to Settle Marketing Case
• Published New York Times: September 2, 2009
• WASHINGTON — The pharmaceutical giant Pfizer
agreed to pay $2.3 billion to settle civil and criminal
allegations that it had illegally marketed its painkiller
Bextra, which has been withdrawn. It was the largest
health care fraud settlement and the largest criminal
fine of any kind ever.
Off Label Marketing: Pfizer Pays $2.3
Billion to Settle Marketing Case
• Bextra was approved in 2001 by the Food and Drug
Administration to treat arthritis and menstrual cramps. The
drug was not approved for the treatment of acute pain, nor
was it shown to be any more powerful than ibuprofen. But
Pfizer instructed its sales representatives to tell doctors
that the drug could be used to treat acute and surgical
pain and at doses well above those approved, even
though the drug’s dangers — which included kidney, skin
and heart risks — increased with the dose, the
government charged. The drug was withdrawn in 2005
because of its risks to the heart and skin.
Drug Development—Preclinical
• Drug discovery (5,000–10,000)
• Preclinical (250)
– 3–6 years
• File Investigational New Drug application (IND)
– Includes a protocol
– 30 day wait
Drug Development: Clinical
• Clinical Trials
– Phase 1: Assesses safety and evaluates how the compound
affects the body
• Small number of healthy subjects
• May evaluate dose (dose escalation)
• Role of biomarkers
• Food effects
– Phase II testing of the compound in patients
• Safety
• IIa Dosing
• IIb initial efficacy
Drug Development
• Clinical trials
– Phase III (Pivotal)
• Large scale trials (2 or more)
• Multicenter
• Randomized, double blind, placebo controlled
• Basis of drug approval
• Efficacy
• Safety including more rare events
• Target population (elderly, disease state, etc…)
– Submission of NDA: Indication and PI will be defined by
data from clinical trials, especially pivotal
Pharma Sponsored Trial designs
• FDA input into drug development
– Trial design, especially phase I and phase III, FDA should
have extensive input
– May not be the most scientifically interesting
– Issues encountered
• Comparator agent: approved vs. most current thought
• Treatment plan may be a compromise
• Patient numbers
• Inclusion, exclusion
Increasing Complexity of Studies
Unique Procedures
per trial
Total procedures
per trial
Clinical Staff work
burden (work effort
units)
Length of clinical
trials
1999
2005
Percent Change
24
35
46%
96
158
65%
21
35
67%
460
780
70%
Becoming a Study Site
• Patient Recruitment
– Support for the number of patients who qualify; how many
will enroll, competing studies—be realistic, have data to
support
• Adequate resources to conduct the study
• Study start up
– 1572
– Contract
– IRB
• Study budget
• Pre study or qualification site visit
Study Conduct
• Recruitment
• Quality work
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Data entered in timely fashion, respond to queries
Regulatory compliance
Study deviations
Study endpoints
Adverse event reporting
• Monitoring visits
– Personnel to support including PI availability
– Collaborative working relationship
Study Monitoring
• Ensures the trial is conducted and documented
properly
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Communication
Study drug
Verify protocol adherence
Patient eligibility
Verify source documents
Checking accuracy and completeness of CRF
Adverse events
Maintaining essential documents
Etc.
• Monitoring report
Monitoring—Contract Research Organization
• CRO
– Can perform any of the responsibilities of the sponsor (TOR)
– Quality and integrity of the trial data always rests with
sponsor
– Can facilitate or hinder communications
– Feedback to the sponsor as necessary
Auditing
• Independent of monitoring, to evaluate trial
conduction and compliance with the protocol, SOPs,
Good Clinical Practices (GCPs) and regulatory
compliance
– Audit plan guided by the importance of the trial to the
submission to regulatory authorities, number of subjects in
the trial, level of risk to subjects and identified problems
– Auditing or monitoring that identifies serious and/or
persistent non compliance, sponsor should terminate the trial
and report to regulatory authorities and IRB
Study Closure
• Final patient visits: endpoints, safety data
• Study close out visit
– Final monitoring
– Study drug
– Records retention
• FDA (or other regulatory authority) audits
– Will audit phase III study sites, and other studies as they
deem appropriate
– Generally select high enrolling sites
– Always contact the sponsor for support
Support of IITs
• Pharma motivation:
– Support their product: Might be part of their product
development plan
– Will not lead to product approval, but will be cited as
“supportive” in the NDA
– Hypothesis generating
– Publication, presentations
– Less costly than internally conducted trials
Support of IITs
• You have a great idea for a trial, now what?
– Regulatory responsibility:
• Sponsor
• Filed to IND
• Data integrity
• 1572
– Idea
• Well-thought-out hypothesis
• Reasonable scope
• Patients
• Resources
Pharma Support for IITs
• Identify logical funding source
– Approach about interest and process
• Contact? Probably the medical science liaison, sales
rep may locate the contact
• Format
• Budget
• Is the idea of interest; if not what similar ideas are of
interest?
Pharma Support for IITs
• Budget
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Funding cycle
Level of support
Include all areas of support
Indirect expenses
• Internal process for IITs
– When in place submit the idea and budget to the sponsor
Hybrid
• A pharma-sponsored trial, that is a collaborative effort
with a PI
• Idea must be central to the PDP
• Requires a close working relationship
• Will be conducted as part of the NDA
• You probably will lose some scientific creativity
Questions?