Tatsuo_Kuroyanagi
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Compensation and Insurance for
Participants/ Subjects Harmed in Clinical
Research Studies:
Process of the Inheritance of Good Clinical
Practice (GCP) in Japan and its Present Status
Tatsuo Kuroyanagi
Attorney-at-Law; Legal Advisor
Japan Medical Association
WMA Expert Conference on the Declaration of Helsinki
February28-March1,2013, Tokyo,Japan
Revision of the third sentence of paragraph14
of the DoH at Seoul in 2008
• “The protocol should include…provisions for
treating and/or compensating subjects who are
harmed as a consequence of participation in the
research study.”
• Guaranteeing (free) treatment and compensation
for loss to subjects who are harmed is at the core
of the protection of subjects, and this provision
needs to be strengthened further in the future.
Experience of numerous large lawsuits brought by
victims of drug-induced suffering against
pharmaceutical companies, physicians,
and the national government
• Thalidomide
• Streptomycin (SM) hearing loss and shock death
• SMON (subacute myelo-optic neuropathy) caused by
chinoform (clioquinol)
• Quadriceps and other muscle contracture resulting
from intramuscular injection of chloramphenicol, etc.,
in infants
• Chloroquine retinopathy
Changes in the Pharmaceutical Affairs Act
in Japan, etc.
1960: (New) Pharmaceutical Affairs Act enacted
1961: Universal health insurance coverage launched
1964: WMA DoH adopted
1971: Drug efficacy reevaluation system introduced;
sale of Dihydro SM and Compound SM
suspended
1975: Revisions to WMA DoH adopted in Tokyo
Changes in the Pharmaceutical Affairs Act
in Japan, etc.
1977: Judge Kabe of the Tokyo District Court issued a
settlement proposal in the SMON case.
1979: Major revision of the Pharmaceutical Affairs
Act; Adverse Drug Reaction Sufferings Relief
Fund Law enacted
1989: Good Clinical Practice for Trials on Drugs
(Notification) issued by the Director of
Pharmaceutical Affairs Bureau, Ministry of
Health and Welfare of Japan
1990: Manual of Good Clinical Practice (GCP) for
Trials on Drugs published
Origin of Japanese GCP
In 1989, the Ministry of Health and Welfare of Japan
added the subtitle “GCP” to the Japanese title for the
Good Clinical Practice for Trials on Drugs
(Notification).
That most likely originated with the EC’s (at the time)
Good Clinical Practice for Trials on Medicinal Products
in the European Community (1989).
When the above guidelines were announced, the final
draft of the EC GCP and the text (in English) of France’s
GCP were introduced alongside of the DoH revised at
Venice in 1983, FDA regulations (U.S.A.)
Origin
of
Japanese
GCP
Declara4on
of
Helsinki
France’s
GCP
EC
GCP
(1989)
FDA
regula4ons
1989
Japanese
GCP(No4fica4on)
1996
ICH-‐GCP
1997
Japanese
GCP(Ministerial
Ordinance
)
Changes in the GCP system (1)
—from administrative guidance to a legal system
1983: Work began on preparing the Japanese GCP
Oct. 1989: Good Clinical Practice for Trials on Drugs
(Notification)
Apr. 1990: Manual of Good Clinical Practice (GCP)
for Trials on Drugs published
Apr. 1990: Japan, together with the EU and the US,
participates in the International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human
Use
Changes in the GCP system (2)
—from administrative guidance to a legal system
Jul. 1995: Product Liability Act went into force
May 1996: ICH-GCP Yokohama Accord
Oct. 1996: DoH Somerset West revision
(placebo provisions)
Mar.1997: Japanese Ministerial Ordinance on Good
Clinical Practice for Drugs
May1997: About Application of Good Clinical
Practice for Drugs
Content of Good Clinical Practice (GCP)
for Drugs
1998: Full implementation of new GCP
Inclusion of the GCP system in the Pharmaceutical
Affairs Act and establishment of the compensation
system for health damage
• 1989 GCP standards when conducting clinical
studies (trials) subject to Pharmaceutical Affairs
Act, the sponsor was requested (administrative
guidance) to take steps to provide compensation
and insurance for subjects, and interested parties
followed those requests.
• It became essential to insert in consent forms and
explanatory statements provisions for “treatment
and compensation” in the event a subject’s health
is damaged.
Inclusion of the GCP system in the Pharmaceutical
Affairs Act and establishment of the compensation
system for health damage
• Based on the above provisions, interested parties
promised (free) treatment and compensation and, at the
same time, requested non-life insurance companies to
create indemnity insurance policies that they then took
out.
• The GCP ministerial ordinance of 1997 is based on law
and the compensation system for health damage was
elevated to a legal system. However, it is just a general
framework with no definite details spelled out for the
compensation system.
Typical example of a “treatment and
compensation for health damage” provision
The following is an example of a treatment and compensation
for health damage provision:
“Please consult your primary doctor immediately if you develop
symptoms during this trial that you did not have before. Appropriate
treatment and appropriate measures shall be taken if you suffer an
adverse effect or other health damage during or after participation in
this trial. You may also receive compensation according to the type
and degree of health damage.
However, please be aware that you may not receive compensation if
it is found that you did not follow your primary doctor’s instructions
or that the health damage was due to your own carelessness.”
Present status of the compensation system
Japan has developed a compensation system that covers a victim’s
loss to a certain limit in exchange for not requiring proof of
negligence, with the aim of providing relief for the victim, apart from
tort liability that questions negligence and provides indemnity for
gross damages.
Occupational accidents are one example, which have a compensation
system based on the Industrial Accident Compensation Insurance
Act. As a rule of thumb, this system determines the amount to be paid
(compensation) by removing consolation money from the gross
damages items, dividing the degree of harm (loss of capacity to work
= after effect) into 14 levels (grades), and taking the grade into
consideration, with average wages as the base.
This is the model for many compensation systems (the Automobile
Liability Security Act uses the above occupational accident
compensation system in certification of after effects impediment).
Present Status
of the Compensation System
Even now there is an adverse drug reaction relief
system for marketed drugs.
The problem is that, even though the times have
changed since the system was developed the
system still excludes anticancer and carcinostatic
drugs from coverage and discards victims with
grade 7 or below injuries for occupational
accidents (traffic accidents).
Present status of the compensation system
Two compensation systems
Trials in which healthy individual participate (Phase I):
A system that handles compensation according to the
occupational accident compensation system was
established by the later period of the old GCP age and
has lasted up to the present.
Trials in which patients participate (Phase II and III):
Many pharmaceutical companies proposed to pay in
conformity with the compensation system of the adverse
drug reaction relief method. The reporter is against this.
Present status of compensation insurance（１）
At present, pharmaceutical companies that conduct trials
based on the Pharmaceutical Affairs Act invariably take
out liability insurance covering compensation for loss up
to the highest amounts of compensation provided by the
occupational accident compensation system and the
adverse drug reaction relief system, respectively.
This is because they are required to submit the proposed
subject consent and information sheet and the certificate
of insurance coverage issued by an insurance company to
the institutional review board.
Examples of three types of are shown at the next slide.
Present status of compensation insurance（１）
A. Comprehensive Liability Insurance
Certificate of Insurance Coverage
Period: 1st March, 2013〜1st March, 2014
Covered Perils Comprehensive General Liability
1)〜，2) Products，3) Fire Legal，〜6)
Clinical Testing Liability and Experimental Testing of New
Drugs Endorsement/Compensation in Clinical Trials
Endorsement (The Indemnity provided by this policy shall
apply to legal liability and compensation for bodily injury to
third parties in clinical trials conducted by or on behalf of the
Insured .)
Limit of Liability;〜
Present status of compensation insurance （２）
B. Healthy Subject Compensation Insurance
Certificate of Product Liability Insurance Coverage (Schedule)
Insured: ABC Co., Ltd.
Term: Midnight on 1st April 2013 to Midnight on 31st March 2014
Amount payable: Bodily injury liability per person: 100 million yen; per
accident: 300 million yen(3.2 million USD)*; during the
insurance term: 300 million yen
Deductible: Per accident: 500,000 yen(5,263 USD)
Notes: Clinical Trial Liability Insurance Rider
・ Per accident, during insurance term: 300 million yen (coverage for bodily
Injury liability per accident, payment within the limit during the insurance
term)
・ Coverage limit per victim: as shown on reverse (no exemption from
responsibility)
25th February 2013
○○○ Fire Insurance Company
*US dollar/JPY exchange rate: US$1 ≒95 yen
Present status of compensation insurance（３）
B. Reverse
Coverage limit per subject
Degree of health damage: trial on healthy individuals
Payment limit (per subject)
Death: 30 million yen(0.3 million USD)
After effects impediment grade 1: 90 million yen (0.9 million USD)
After effects impediment grade 2: 90 million yen (0.9 million USD)
After effects impediment grade 3: 70 million yen (0.7 million USD)
After effects impediment grade 4: 65 million yen (0.7 million USD)
After effects impediment grade 5: 55 million yen (0.6 million USD)
After effects impediment grade 6: 50 million yen (0.5 million USD)
After effects impediment grade 7: 40 million yen (0.4 million USD)
After effects impediment grade 8: 32 million yen (0.3 million USD)
After effects impediment grade 9: 25 million yen (0.3 million USD)
After effects impediment grade 10: 20 million yen (0.2 million USD)
After effects impediment grade 11: 15 million yen (0.2 million USD)
After effects impediment grade 12: 10 million yen (0.1 million USD)
After effects impediment grade 13: 7 million yen (0.1 million USD)
After effects impediment grade 14: 4 million yen (42,105 USD)
Lost work time compensation payment: 13,000 yen (137 USD) per subject per day for the period
beginning on the fourth day of no wages due to lost work time
Present status of compensation insurance （４）
C．Patient Subject Compensation Insurance
Certificate of Product Liability Insurance Coverage
Policy Owner: XYZ Co., Ltd.
Insured: XYZ Co., Ltd.
Term: Midnight on 1st January 2013 to Midnight on 31st December 2015
Coverage limit: Bodily injury liability per person: 100 million yen (1.1 million USD) ;
per accident: 500 million yen (5.3 million USD);
during the insurance term: 500 million yen
Deductible: Bodily injury liability per accident: 1 million yen (10,526 USD)
Notes: Investigational drug code: PP-001; investigation drug rider ancillary;
clinical trial compensation
liability insurance ride ancillary
Death: 20 million yen (0.2 million USD)
After effects impediment grade 1: 70 million yen (0.7 million USD)
After effects impediment grade 2: 50 million yen (0.5 million USD)
25th November 2012
ZZZ Marine Insurance Company
Reporter note:
Since after effects impediment grades 1 and 2 are the only ones covered by the insurance, it is clear that only
compensation equivalent to the adverse drug reaction compensation system is being considered.
Compensation for clinical research besides trials
“Ethical Guidelines on Clinical Research” (1)
• ICH-GCP (6) does not distinguish between clinical trial
studies subject to the Pharmaceutical Affairs Act and other
clinical research. The government requires interested parties
to comply with the GCP ministerial ordinance of 1997,
limited to studies subject to the Pharmaceutical Affairs Act,
but it has done nothing to develop standards relating to
clinical research not covered by the Pharmaceutical Affairs
Act.
• On July 30, 2003, the Japanese Ministry of Health and
Welfare established Ethical Guidelines on Clinical
Research, but they are nothing more than administrative
measures. These guidelines went through a major revision
of DOH in 2008 and have come down to the present.
Compensation for clinical research besides trials
“Ethical Guidelines on Clinical Research” (1)
• Statements regarding compensation for subjects
were apparently strengthened during the 2008
revision. The heads, etc., of clinical research
organizations are required to “take out insurance
and take other necessary measures for
compensation for health damage to subjects,” and
to “sufficiently explain beforehand the content of
insurance and other necessary measures for
compensation for health damage and obtain
subjects’ consent.”
Compensation for clinical research besides trials
“Ethical Guidelines on Clinical Research” (2)
• However, with the provision that, “the existence or
non-existence of compensation for health damage to
subjects associated with the conduct of the clinical
research must be indicated in the clinical research
protocol,” if it is indicated that compensation will not
be provided and the subjects’ consent is obtained,
compensation is not needed. Further, by expressing the
view that, “Other necessary measures refers to things
such as the provision of medical care for health damage
or the provision of other services,” it pulls down with
its own hands the foundation of the basic principles
built at the beginning.
Compensation for clinical research besides
trials (present status – 1)
• Research besides clinical research subject to
the Pharmaceutical Affairs Act is mainly
conducted by university hospitals and national,
public, or other large medical institutions. In
recent years, a variety of clinical research has
been conducted jointly by multiple institutions
(and sometimes even with institutions in other
countries).
Compensation for clinical research besides
trials (present status – 1)
• Restricting our conversation to research in Japan,
the biggest financer or aid provider for research
funding for these studies is most likely the
national government. The problem is that aid is
not always sufficient, and researchers are forced
to conduct research with minimal outlays. As a
result, the reality is that even if there is a need,
they cannot take out insurance to cover
compensation.
• This results in a situation where clinical research
—despite being cutting-edge research—continues
unreservedly without compensation.
Compensation for clinical research besides trials
(present status – 2)
The following is an example use by an organization called JCOG.
“There is a possibility of developing unforeseen serious complications
or other health damage during or after completion of participation in
this clinical study. In that case, appropriate responses will be taken, the
same as with treatment for health damage in usual medical care.
However, the medical expenses shall be borne by the patient, since the
treatment will be provided as health-care services provided under health
insurance, the same as usual treatment.
If you feel some kind of health damage that does not occur during
usual treatment, as a result of participation in this clinical study, inform
your doctor without reservation. Also note that no sympathy money,
other type of benefit, or any kind of special financial compensation has
been prepared for health damage sustain in this clinical study.”
Reporter note:
JOCG (Japan Clinical Oncology Group) is a research organization run partially with research funding of an Oncology Grant-
in-Aid from the Ministry of Health, Labour and Welfare and partially with a Health and Labour Sciences Research Grant
called a Grant for the Third-Term Comprehensive 10-Year Strategy for Cancer Control. It consists of 13 specialty study
groups and enjoys the participation of nearly 200 hospitals across Japan.
Compensation and insurance for clinical
research besides trials
• A lot of clinical research not covered by the Pharmaceutical
Affairs Act is conducted in many education-related hospitals
such as university hospitals, and recently regulatory
agencies have started to provide strong direction to take out
compensation insurance.
• As a result, researchers are hoping to take out insurance, but
with little understanding on the part of interested parties, the
reality is that there is not even a form in place, as compared
to trials that have only just gotten underway.
• The legislation of guidelines with solid content needs to
take place as soon as possible, the same as with
pharmaceuticals, in order to realize the principles of the
ICH-GCP, which aimed for substantial championship of
subjects. This is an urgent issue to be resolved that has been
left before us.
Conclusion
• I attempted to put the current status of today’s
issues in Japan into a figure to wrap up today’s
report.
Conclusion
GCP
ministerial
ordinance
Ethical
guidelines
on
clinical
research
Subject
to
Clinical
studies
(trials)
covered
by
the
Pharmaceu:cal
Affairs
Act
Other
clinical
studies
Subjects
Health
individuals
Pa:ents
Health
individuals/
pa:ents
Compensa:on
Yes
Yes
Provision
exists,
but
“without
compensa:on”
accepted
Content/
degree
Similar
to
the
occupa:onal
accident
relief
system
(grade
1
to
grade
14)
Similar
to
the
adverse
drug
reac:on
relief
system
(excludes
grades
8
and
below
from
the
occupa:onal
accident
system
and
an:cancer
drugs)
Actual
condi:on
is
chao:c
Backed
up
by
insurance
Yes
Yes
Insufficient/
undeveloped
Type
of
insurance
•
Treatment
only
•
Treatment
only
•
Combined
with
product
liability
insurance,
etc.
•
Combined
with
product
liability
insurance,
etc.