Clinical Research: NIH and Pharmaceutical industry funding

Adrian S. Dobs, M.D., M.H.S.Professor of Medicine

The Johns Hopkins University School of Medicine

Outline

• Research questions

• Career paths in academic medicine

• Promotions

• Personal reflections of how to have a successful career

Bedside Observation

• HIV-AIDS first recognized 1983

• 1985 cases of hypotension, electrolyte abnormalities

• Autopsies showing destruction of the adrenal gland

Postulating a Research Question

• Question – Could these patients have Addison’s Disease (adrenal Insufficiency)?

• Original description by Addison – Invasions of the gland by TB or auto-immune destruction

• Hypothesis – Men with HIV disease commonly have adrenal insufficiency due to invasion of the adrenal gland by CMV or HIV or granulomatous infection (TB)

Findings from our First Study of Endocrine Disorders in HIV

• Our primary hypothesis was wrong: Adrenal insufficiency was rare

• Our other measures showed significant findings: Low testosterone (hypogonadism) was common

Total Testosterone in AIDS, ARC, and Asymptomatic Patients

900

800

700

600

500

400

300

200

100

0Asymptomatic ARC AIDS

To

tal T

esto

ster

on

e (n

g/d

L)

Dobs AS, et al. Am J Med. 1988;84:611-616.

Outline

• Research questions

• Career paths in academic medicine

• Promotions

• Challenges faced by the clinical investigator

• Personal reflections of how to have a successful career

Information Flow in Health Research

Infectious AgentsCell and Organ Systems

POPULATION SCIENCE

Translational Research

Clinical Trials

Epidemiology

Behavioral Research

Outcomes and Health Services Research

BASIC RESEARCH

Pathways and DrugDiscovery

Groups at Risk

Environmental Hazards

CLINICAL TRIALS

*Adapted from David Nathan; presented at theClinical Research Roundtable meeting, June 12 2002

Realms of Clinical Research

Bedside Observation

Epidemiologic analysis

Patient-oriented Study

Health care services

Examples of Clinical Trial Study Designs

• Phase I clinical trials– First time in humans, safety studies, dose finding,

pharmacokinetics

• Phase II clinical trials– Use in the diseased population, small sample size, intense

study

• Phase III clinical trials– Large scale studies, in diseased population, pre-FDA filing

• Phase IV clinical trials– Post-approval, new indications, new populations

My Path

• Fellowship – Basic science lab– Mentor was not committed to me– Dropped too many test tubes

• Instructor – Didactic training and Pharmaceutical studies– MHS in Epidemiology– Began to learn the basics

• Assistant Professor – NIH collaborations– Epidemiology studies who needed MD input

• Associate Professor – NIH Principal Investigator• Professor – NIH Center grant

Research Spending in the US25

NIH20

15

10

5

Pharmaceutical Industry

$ (

Bill

ion

)

Sources: PhRMA, National Institutes of Health

5,000

10,000

15,000

20,000

25,000

1993 1994 1995 1996 1997 1998 1999 2000 2001

Year

Pharmaceutical Industry

NIH

US Pharmaceutical Industry R&D Expenditure & NCE Approvals, 1963-99

0

10

20

30

40

50

1963 1966 1969 1972 1975 1978 1981 1984 1987 1990 1993 1996 1999

NC

Es

0

4

8

12

16

20

24

28

R&

D (1999 $ b

illion

)

NCEs Inflation-adjusted R&D expenditure (in 1999$)NCE Trend

Source : Tufts CSDD Approved NCE database and PhRMA; Analysis by Joseph DiMasi, Ph.D.

Types of Clinical Research Studies

• Case Reports

• Cross-sectional

• Case-control

• Observational cohort

• Clinical trial

Building a Clinical Research Staff Team

• Staff support– Share resources: Access to someone else’s group– Research coordinator: Smart college grad– Research nurse– Technitian– Data manager– Budget administrator

• Trainees– Post-docs– Fellows– Students

Building a Collaborative Clinical Research Investigator Team

• Content investigator

• Method investigator

• Biostatistician

• Outcome investigator

• Basic science investigator

Logistics for Success

• Funding,– GCRC, R21

• Space– GCRC, 550 Brdwy, clinic area

• Staff support– Coordinator, recruiter, phlebotomist

• Equipment– Centrifuge, freeezers

• Data management

Advantages of Pharmaceutical Studies

• Networking with other national leaders in a clinical field

• Expanded knowledge of the field

• Quality study design and quality assurance

• Unrestricted funds

• Opportunity to hire staff to help with non-funded studies

Budgets in Industry-funded Studies

• Often given a set per-patient reimbursement

• Try to put as much as possible outside the patient, e.g IRB work, advertizing

• External budget – based on procedure done– Visit 1 – screening, PEx– Visit 2 – phlebotomy, specimen preparation

• Internal budget – based on %FTE

Investigator-initiated studies

• A means of support for key opinion leaders

• Sometimes meritorious - sometimes not

• Sometimes at odds with product label

• Can provide novel insights

• Investigators enter into contracts with industry

Career Progression as a Clinical Investigator

• Didactic training – MPH, MHS, GTPCI, short courses

• NIH progression – NRSA, K23, R21, R01, Program projects, U grants

• Know them, collaborate, start as a junior person on someone else’s grant

• Problems: – Multiple pressures to see patients, teach, do research– Difficult to succeed alone

A Balanced Research Portfolio

National Institutes of Health

Pharmaceutical Industry

Co-investigator with others

Other Federal/Foundation Funding

Disadvantages of Industry-funded Studies

• Budget is based on per-patient recruited, i.e. work without reimbursement

• More research is being done in private practices, free-standing research facilities and internationally

• Difficulty in identifying patients

• Major delays in the administration

Common Contract Problems

• Publication rights

• Intellectual property

• Terms of payments

• Conflict of interest

• Low priority for ORA

Problems for Clinical Research

Campbell, JAMA 286, 800-6, 2001

0

10

2030

4050

6070

8090

100

Issue

Pressure to seepatientsInsufficient clinicalrevenuesQuality researchers

External support

Competition fromCROsIRB process

Finding subjects

Challenges to the Institution to Help the Clinical Investigator

• Streamlining of IRB and especially ORA• Consent process – video, instructions• Case Report Form management repository• Consistency in advertising of studies• Regulatory checklists for all studies – RO1• Certification programs which vary by personnel • Standing Data Safety and Monitoring Boards

Health Research Continuum & the Two Translational Blocks

Basic Scientific Research

Clinical Trials

Health Services,

Outcomes, Evaluative,

and Comparative

Research

Goal:Improved

Health

Block 1

Block 2

Translation from basic science to

human studies

Translation ofnew knowledge

into clinical practice

Delivering the Promise

Clinical Research could…

Be a powerful vehicle to deliver the promises of basic science to the public

OR

Emerge as the block limiting the translation of basic science to

benefit the greater public health

How to Identify Industry Sources

• Persaverance

• Asking colleagues

• Searching on web sites

• Local people

Outline

• Research questions

• Career paths in academic medicine

• Promotions

• Personal reflections of how to have a successful career

Change in Ass’t and Associate Professors at Johns Hopkins SOM Based on Gender

Change in Full Professors at Johns Hopkins SOM Based on Gender

Faculty Representation and Attrition at Johns Hopkins

• The proportion of women at the ranks of Assistant and Associate Professor has remained roughly constant over the past six years.

• Women now constitute 15% of full professors, up from 7.5% in 1994.

• Women are less likely than men to be promoted to a higher rank.

• Women take longer to be promoted than men. • The attrition of women faculty is higher than that of

men. • There are currently 3 (out of 30) female department

directors

Salary Discrepancies Between Men and Women at Johns Hopkins

Ambivalence of the Clinical Investigator

No81%

Yes19%

Do you believe that clinical research receives the same support, recognition, and credit for promotion as more basic research?

UCSF - 2000

Outline

• Research questions

• Career paths in academic medicine

• Promotions

• Personal reflections of how to have a successful career

Some Facts Not on My CV

• Married for 27 years to a physician

• Four children

• Had children when chief resident, instructor, fellow, and assistant professor

The Ten Top Things To Remember in Life

• #10 -You Can Do Anything, but Not Everything

• #9 - Everyone Has a Life

• #8 - Have Your Children

• #7 - There Are Lots of Childcare Options

• #6 - Compartmentalize Life

The Ten Top Things To Remember in Life

• #5 - Keep Your Private Life Private

• #4 - Family Rituals

• #3 - Share Your Work With Family

• #2 - Don’t Let Your Spouse Off the Hook

The Ten Top Things To Remember in Life

• #1 - No One at Work Will Remember You When You’re Dead and Gone

Conclusion

• Working in science and medicine is a true privilege

• Academics provide opportunities for helping patients, teaching students and trainees and pursuing scientific questions

• Success is that winding path of finding mentors, sincere desire to help, and a balance with personal growth