Ajay_Kumar

Dr.
 Ajay
 Kumar
 
MBBS,FRCS(Edin.),FIAMS(Uro),FICS(Uro)
 

 President
 :
 Indian
 Medical
 Associa=on
 (2007-­‐2008)
 
 
President
 :
 Urological
 Society
 of
 India
 (2008-­‐2009)
 
Vice
 President
 :
 Commonwealth
 Medical
 Associa=on
 (
 2007-­‐2010)
 
Member
 :Council
 of
 World
 Medical
 Associa=on
 (Since
 2006)
 
Member
 :
 Drug
 Technical
 Advisory
 Comm.,
 DCGI,
 Govt.
 of
 India
 
 (
 2010-­‐2012)
 
Vulnerable
 Groups
 in
 the
 context
 of
 
Clinical
 Studies
 
Bihar,
 India
  Tokyo,
 Japan
 
THE
 EPICENTRE
 OF
 BUDDHISIM
 
 

 Oxford
 dic=onary
 
defines
 vulnerable
 as
 “
 
that
 which
 can
 be
 hurt
 
or
 wounded;
 open
 to
 
hurt
 by
 a^ack
 or
 
cri=cism.”
 
The
 Belmont
 Report
 (1972)
 
Vulnerable
 popula,ons
 are
 
those
 groups
 that
 might
 “bear
 
unequal
 burdens
 in
 research
 
because
 of
 their
 ready
 
availability
 in
 seangs
 where
 
research
 is
 conducted”,
 such
 as
 
prisons,
 hospitals,
 ins,tu,ons
 
and
 camps,
 and
 called
 for
 extra
 
protec,on
 for
 these
 groups.
 
My
 presenta=on
 is
 based
 
on
 Indian
 experience
 
which
 has
 13.5
 %
 world
 
popula=on
 and
 shares
 
the
 problems
 of
 the
 
developing
 world
 which
 
have
 large
 vulnerable
 
popula=on
 
INVESTIGATOR
  SPONSORER
 
REGULATOR
 
VOLUNTERS
 
Vulnerability
 of
 volunteer
 depends
 on
 three
 arms
 of
 
triangle
 and
 his
 own
 handicap.
 
Studies have proved that malpractices are rampant in
clinical trials in India. Recent cases include unethical
testing of contraceptives, fertility drugs, cardiac
treatments and cancer medicines.
Analysts say that as many as two million Indians may
be enrolled in research trials by 2012.
A major problem is that a large proportion of
participants are illiterate and lured into trials by offers
of free health care and financial inducements. They
are often unaware of the benefits and risks of taking
part in a trial, and may not even distinguish between
treatment and research.

 
In
 order
 to
 give
 best
 treatment
 to
 above
 diseases
 research
 
on
 humans
 is
 both
 necessary
 and
 desirable
 
• 
 40
 million
 asthma,c
 pa,ents
 
• 
 34
 million
 diabe,c
 pa,ents
 
 
• 
 8-­‐10
 million
 people
 with
 HIV
 
 
• 
 8
 million
 epilep,c
 pa,ents
 
 
• 
 3
 million
 cancer
 pa,ents
 
 
• 
 
 more
 than
 2
 million
 cardiac-­‐related
 
deaths,
 
 
• 
 1.5
 million
 people
 with
 Alzheimer’s
 
disease;
 
• 
 15%
 of
 the
 popula,on
 is
 hypertensive
 
 
• 
 1%
 suffers
 from
 schizophrenia
 
Large
 no.
 of
 pa=ents
 with
 wide
 range
 of
 disease
 
 
India
 is
 viewed
 as
 a
 favoured
 global
 site
 for
 interna,onal
 clinical
 
trials
 of
 drugs.
 According
 to
 the
 Drugs
 Controller
 General
 of
 
India
 (DCGI),
 India
 will
 be
 a
 preferred
 site
 for
 clinical
 trials
 
because,
 in
 addi,on
 to
 its
 medical
 infrastructure
 and
 trained,
 
english
 speaking
 humanpower,
 it
 has
 a
 “large,
 diverse
 and
 
TREATMENT-­‐NAÏVE
 [UNTREATED]
 POPULATION
 with
 six
 out
 
of
 the
 seven
 gene=c
 varie=es
 of
 the
 human
 race”;
 
A
 recent
 study
 reveals
 that
 
outsourcing
 clinical
 trials
 to
 India
 
may
 be
 ‘rash
 and
 risky’.
 This
 
opinion
 is
 drawn
 on
 the
 basis
 of
 
concerns
 about
 =melines
 for
 
regulatory
 approvals,
 deficiencies
 
in
 the
 func=oning
 of
 the
 ethics
 
commi^ees,
 and
 an
 unethical
 
approach
 to
 the
 recruitment
 of
 
illiterate
 and
 vulnerable
 Indian
 
people
 to
 clinical
 trials.
 
 
•  Treatment
 Naïve
 popula=on
 
•  Women
 
• 
 Children
 
• 
 Mentally
 incapacitated
 
•  Elderly
 
•  Prisoners
 
•  Addicts
 
• 
 Refugees
 
Govt
 Hospital
 not
 able
 to
 provide
 op=mum
 Treatment
 

 Large
 group
 of
 treatment
 naïve
 popula=on
 ideal
 for
 
tes=ng
 new
 drugs
 
• 
 Only
 15
 
 %
 of
 the
 Rs
 1,500
 billion
 spent
 in
 the
 health
 sector
 in
 
India
 comes
 from
 the
 government.
 
 
• 
 4
 
 %
 comes
 from
 social
 insurance
 
 
• 
 1
 %
 
 from
 private
 insurance
 companies.
 
• 
 Remaining
 80
 %
 is
 spent
 by
 individuals
 using
 private
 
 services
 
and
 without
 insurance.
 
• 
 2/3rd
 
 of
 health
 care
 users
 bear
 100
 %
 of
 their
 health
 care
 
expenses.
 
 
• 
 70
 %
 
 of
 these
 health
 care
 users
 are
 poor.
 

 More
 than
 half
 of
 the
 poorest
 20
 
 %
 of
 Indians
 sold
 assets
 or
 
borrowed
 to
 pay
 for
 health
 care
 
 
Originally,
 the
 concept
 of
 
informed
 consent
 was
 
developed
 
 
•  To
 promote
 individual
 autonomy
 
 
•  To
 encourage
 ra,onal
 decision
 
making.
 
•  To
 protect
 pa,ents
 confronted
 
with
 the
 power
 of
 the
 medical
 
profession
 and
 with
 the
 financial
 
domina,on
 of
 the
 drug
 industry.
 
Disclosure
 
 Understanding,
 
 

 
Voluntariness,
 
 

 
Competence
 

 
An
 ethically
 valid
 informed
 consent
 has
 four
 key
 
components:
 
 
This
 creates
 challenges
 for
 researchers
 in
 Paediatrics
 ,
 
Psychiatry,
 emergency
 and
 clinical
 care
 medicine
 
Surrogate
 or
 waived
 consent
 
Makes
 large
 popula=on
 of
 handicapped
 (Physical
 or
 
Mental)
 vulnerable
 
Nov
 1999
 -­‐
 Experimental
 cancer
 drug
 tested
 without
 people’s
 
consent
 
 at
 government-­‐run
 Regional
 Cancer
 Centre
 in
 
Thiruvananthapuram
 
•  25
 Oral
 cancer
 pa,ents
 were
 given
 experimental
 drug
 M4N
 or
 G4N
 
 
when
 there
 was
 established
 treatment
 for
 their
 condi,ons.
 
 
•  Inves,gator
 involve
 was
 not
 qualified
 or
 authorized
 to
 do
 
experiments
 on
 human
 subjects
 .
 
•  Mandatory
 ethical
 IRB
 (Independent
 Review
 board
 permission
 not
 
taken
 
 
 
•  No
 Ethical
 clearance
 from
 John
 Hopkins
 Ins,tute
 but
 released
 fund.
 
•  US
 government
 approval
 for
 export
 of
 chemicals
 not
 taken
 
 
•  Pa,ents
 signed
 the
 informed
 consent
 in
 language
 other
 than
 their
 
na,ve
 language
 
 
•  Research
 not
 approved
 by
 DCGI
 
Not
 informed,
 denied
 established
 treatment
 and
 bypassed
 
 
regulatory
 authori=es
 
2003-­‐
 Drug
 promo/on
 as
 « research“
 ,
 (Sun
 
Pharmaceu=cal
 Industries
 Limited)
 
•  An,cancer
 drug
 Letrozole
 on
 >
 400
 women
 as
 
fer,lity
 drug
 for
 Ovula,on
 induc,on.
 
•  Promo,on
 cum
 Research
 Programme
 
conducted
 by
 Private
 doctors
 
 
No
 consent
 and
 role
 of
 Inves=gator
 doubmul
 
 
2003-­‐2004
 -­‐Research
 in
 emergency
 situa/ons
 
 
(Santa
 Biotech
 )
 
Bioequivalence
 Study
 
Tes=ng
 its
 “
 Clot
 buster
 “
 Streptokinase
 against
 
established
 one
 in
 treatment
 of
 CVA
 
 
2002
 -­‐
 Diabetes
 drug
 tested
 on
 humans
 before
 
toxicology
 studies
 completed
 
 (Novo
 Nordisk)
 
 
• 
 Mul=centre
 trial
 of
 Ragaglitazar
 before
 receiving
 
results
 of
 animal
 study
 
 -­‐
 Bladder
 cancer
 in
 rats
 
 

 
• 
 No.
 of
 Cases
 -­‐
 
 
North
 America-­‐
 650
 
La/n
 America
 –
 200
 
Australia
 /
 New
 Zealand
 –
 100
 
EU-­‐
 800
 
Europe
 (Non
 EU)
 –
 100
 
ASIA
 –
 550
 (India
 –
 130
 at
 eight
 centre)
 
The
 survey’s
 findings
 on
 why
 people
 entered
 a
 clinical
 trial
 were
 
enlightening:
 
• 15
 %
 stated
 that
 they
 entered
 the
 trial
 because
 they
 were
 looking
 
for
 a
 cure.
 
• 13
 
 %
 were
 looking
 for
 “observed
 benefits”.
 
• 15
 
 %
 were
 looking
 for
 a
 be^er
 treatment.
 
• 16
 
 %
 were
 looking
 for
 higher
 quality
 care.
 
• 10
 %
 were
 looking
 for
 free
 medica=on
 and
 medical
 care.
 
• 15
 %
 
 said
 the
 doctor
 advised
 them
 to
 enter
 the
 trial.
 
• 5
 
 %
 said
 they
 entered
 the
 trial
 to
 receive
 money
 for
 par=cipa=on.
 
• 11
 %
 said
 they
 entered
 the
 trial
 to
 help
 advance
 scien=fic
 
knowledge.
 
Presenta/on
 by
 Dan
 Macdonald
 Vice
 President
 ,
 Business
 Development
 ,Excel
 Life
 Sciences
 in
 
mee/ng
 of
 Ins/tute
 of
 Clinical
 Research
 (Indian
 )
 Mumbai
 .
 October
 10-­‐11-­‐2008
 
 
The
 recruitment
 of
 children,
 may
 raise
 concern
 that
 
they
 are
 being
 exploited.
 
•  Children
 are
 considered
 vulnerable
 group
 and
 require
 
addi,onal
 protec,on
 as
 research
 subjects.
 
•  Obtaining
 the
 assent
 of
 a
 child
 and
 the
 permission
 of
 
a
 parent
 or
 guardian
 is
 not
 the
 same
 as
 obtaining
 
informed
 consent
 from
 a
 competent
 adult
 .
 
Although
 it
 seems
 reasonable
 to
 offer
 
payment
 for
 the
 =me
 and
 inconvenience
 of
 
par=cipa=ng
 in
 research,
 children
 and
 their
 
families
 may
 be
 unduly
 influenced
 by
 the
 
offer
 of
 payments
 that
 may
 amount
 to
 
several
 hundred
 dollars
 or
 may
 include
 gir
 
cer=ficates
 to
 toy
 or
 record
 stores.
 
According
 to
 the
 ICMR’s
 guidelines,
 “…
 payments
 should
 not
 be
 
so
 large
 or
 the
 medical
 
 services
 so
 extensive
 as
 to
 make
 
prospec=ve
 par=cipants
 consent
 readily
 to
 enroll
 in
 research
 
against
 their
 be^er
 judgment,
 which
 would
 then
 be
 treated
 as
 
undue
 inducement.”
 
Vulnerable
 Children
 
REGULATOR
 
VOLUNTERS
 
§ 
 Drug
 &
 Cosme=c
 Act
 
 :
 1940
 
§ 
 Medical
 Council
 of
 India
 Act
 1956
 (Amended
 
in
 2002)
 
§ 
 DCGI
 (Drug
 Controller
 General
 of
 India)
 
§ 
 ICMR
 (Indian
 council
 of
 Medical
 Research
 )
 
§  Guidelines
 for
 Exchange
 of
 Biological
 
Material
 (MOH
 order
 1997)
 
§  Right
 
 to
 Informa=on
 act
 (
 RTI
 2005)
 
§  The
 Biomedical
 Research
 on
 Human
 Subjects
 
(
 Regula=on
 ,
 Control
 &
 Safeguard)
 bill
 2005
 
Indian
 Acts
 /
 Orders
 related
 to
 clinical
 trial
 
The phenomenal growth in clinical trial
unfortunately has created a situation
where regulatory mechanism cannot
keep pace. Ethical review is now
mandatory for clinical trial but there is
little review of the functioning of the
ethics committee by the DCGI. There
is little interaction between ethics
committees in different locations,
thereby allowing the practice of
‘Ethics Committee Shopping’, –
sponsors whose trials are rejected by
one ethics committee approach a
different centre for approval.
Loose
 control
 on
 trials
 
REGULATOR
 
VOLUNTERS
 
1. Huge patient base with diversity of
diseases
2. The average cost of drug discovery in US
is estimated at US$ 800 million. Cost of
conducting clinical research in India is
much lower as compared to the developed
countries. Drug companies can save up to
two – third of overall cost of conducting
trials in India compared to the west.
4. English-speaking technical workforce,
good IT infrastructure and low
infrastructure costs can reduce
expenditures for clinical trials by as much
as 60 percent.
 
Why
 
 a^racted
 to
 India
  VOLUNTERS
 
Clinical
 trials
 are
 conducted
 by
 contract
 
research
 organisa=ons
 (CROs)
 which
 
are
 developing
 the
 infrastructure
 for
 
trials
 by
 making
 inroads
 into
 small
 
towns,
 iden=fying
 trial
 sites
 in
 small
 
private
 hospitals
 and
 developing
 
databases
 of
 poten=al
 trial
 
par=cipants.
 Medical
 professionals
 are
 
given
 substan=al
 incen=ves
 to
 recruit
 
their
 own
 pa=ents
 into
 clinical
 trials.
 
 
Creates
 a
 major
 conflict
 of
 interest
 that
 threatens
 the
 
well-­‐being
 of
 pa=ents
 
VOLUNTERS
 
Who
 is
 Inves=gator
 ?
 
•  76%
 of
 pa=ents
 said
 the
 trial’s
 
principal
 inves=gator
 was
 their
 
primary
 physician.
 
 

 
•  21
 %
 of
 pa=ents
 said
 they
 were
 
referred
 by
 their
 primary
 care
 
physician.
 
 

 
CRO
 Excel
 life
 science
 trial
 2008
 

 97
 
 %
 of
 pa=ents
 entered
 the
 trial
 because
 of
 
their
 primary
 care
 physician.
 
VOLUNTERS
 

 Doctor-­‐pa=ent
 rela=onship
 in
 India
 is
 
unequal.
 
 

 
Pa=ents
 may
 not
 ques=on
 their
 
doctors’
 judgement.
 They
 may
 be
 
easily
 influenced
 by
 the
 doctor’s
 
advice.
 
They
 may
 also
 believe
 that
 refusal
 to
 
follow
 the
 doctor’s
 advice
 to
 enter
 a
 
trial
 would
 affect
 their
 access
 to
 care.
 

 
VOLUNTERS
 
PRIVATE
 HOSPITAL
 
•  The
 inves=gator
 is
 paid
 according
 to
 
the
 number
 of
 pa=ents
 recruited
 .
 

 
•  Addi=onal
 benefits
 include
 all-­‐
expenses
 paid
 trips
 abroad
 to
 a^end
 
conferences.
 

 
• 
 Oncology
 trials
 get
 higher
 payments
 
because
 the
 trial
 takes
 a
 
compara=vely
 longer
 =me
 and
 there
 
are
 fewer
 pa=ents
 available
 for
 
recruitment.
 
VOLUNTERS
 
Bye
 

 bye
 
•  Resource-­‐starved
 public
 
hospitals
 see
 trials
 as
 a
 source
 
of
 funds
 for
 much-­‐needed
 
improvements
 in
 
infrastructure.
 
 
•  Many
 trials
 conducted
 in
 
government
 hospitals
 are
 in
 fact
 
the
 last
 resort
 for
 poor
 
pa=ents.
 
• 
 It
 is
 argued
 that
 the
 pa=ents
 
benefit
 since
 they
 get
 free,
 
focused
 and
 more
 frequent
 
medical
 supervision
 for
 the
 
dura=on
 of
 the
 trial.
 
Public
 Hospitals
 
VOLUNTERS
 
•  Failure to obtain informed consent.
•  Falsified data.
•  Ethics unawareness.
•  Inadequate source documentation.
•  Protocol noncompliance.
•  Delinquent or inaccurate data
submission.
•  In the field of rare diseases
sometimes the number of patients
might be the limiting factor for a
clinical trial.
•  Physicians are not as familiar with
the clinical trial process as they are in
the West.
VOLUNTERS
 
Unseen Concern and Challenges
 
a) Regulators needs to generate effective monitoring mechanism for continuous
evaluation of trials throughout the study period ensuring regular and periodic
scientific and ethical review. Strategies should be developed to prevent fudging
the data.
b) Studies should follow strict adherence to ethical guidelines.
c) All persons involved in study should undergo basic training concerning
counselling and preventive strategies.
d) All persons should be recruited in any study after ensuring receipt of proper
informed consent for participation.
e) Adequate care and protection should be provided to vulnerable groups.
f) Community involvement at all stages of the studies.
g) Sharing results with all persons involved in research.
h) Ensure global justice, narrowing gap between developed and developing worlds.
CONCLUSION
 
Contd..
 
l) To favour the promotion of clinical trial in India (Developing
countries), restrictions are necessary to ensure that the health
of the trial subjects is adequately protected in case of any
contingency. Comprehensive health insurance for all the
participant volunteers must be provided by the sponsorer in
the form of a viable bank guarantee ensuring the obligation of
any direct / indirect consequences.
m) If the intervention being tested is not likely to be affordable in
the host country or if the health care infrastructure cannot
support its proper distribution and use, it is unethical to ask
persons in that country to participate in the research, since
they will not enjoy any of its potential benefits.
n) Clinical trials sponsored or regulated by external agencies
should be limited to those that are responsive to the host
country’s health needs
CONCLUSION