S6-1_Yasuhiro Fujiwara

A New Perspective on the Ethics of
Compassionate Use
Yasuhiro FUJIWARA, MD., Ph.D.
Chief Executive
Pharmaceuticals and Medical Devices Agency
December 1st, 2023 World Medical Association’s Regional Expert Meeting in Pacific on the WMA Declaration of Helsinki
“Idea of global standard”
By participation in the clinical trial
unapproved drugs will be available
However,
patients suffering from a disease
for which no satisfactory authorised alternative therapy exists
or who are not eligible for a clinical trialには、
can be addressed through compassionate use program.
Japan, US, Europe: to provide unapproved drugs outside of a clinical trial
– Expanded registration-directed clinical trial (Japan)
– Expanded Access Program (the United States)
– Compassionate Use (EU)
2
Revision of GCP Ordinance
3
Compassionate Use Program
“Expanded registration-directed clinical trial”
https://www.pmda.go.jp/review-services/trials/0016.html
Compassionate Use Program “Expanded registration-directed clinical trial” ①
3
⚫Drugs
– Operation since January 25, 2016
⚫ Medical devices
⚫ Regenerative medical products
– Operation since July 21, 2016
Scope
Investigational products for treating serious diseases (Same as in Europe and the US)
– significant impact on life
– no existing treatment methods are effective
After completion / completion of enrollment of a clinical trial
– final stage of domestic development
– high probability that benefits will be obtained from an unapproved drug administration (“pivotal trials”).
* Pivotal trials: Registration-directed clinical trial intended to verify efficacy and safety, which are usually conducted after the
indication and dosage and administration have been determined through a series of trials
* To avoid delays in development and approval that would impede the provision of effective new drugs to large numbers of
patients, the premise, as in similar systems in Europe and the US, is that the system must in no way adversely influence the
implementation of pivotal trials (and the commercialization of the drugs)
https://www.pmda.go.jp/files/000209680.pdf 4
Compassionate Use Program “Expanded registration-directed clinical trial” ②
Legal Positioning
 Implemented: within the scope of PMD Act (Registration-directed
clinical trial)
– ensuring safety of subjects (unapproved drugs are used to patients)
Handling
 Conducted : an open-label, single-arm, active drug trial
– focus on safety, based on the pivotal trial protocol
https://www.pmda.go.jp/files/000209680.pdf 5
Compassionate Use Program “Expanded registration-directed clinical trial” ③
Trial Site
The investigational sites of the pivotal trials
✓ Having a history of administering the relevant drug
✓ Sufficient knowledge and experience with adverse drug reactions of the relevant drug, etc.
Study Duration
Terminated at the following time points
✓ Approval or Disapproval
✓ Application is withdrawn or Development is discontinued (efficacy is not observed)
Expenses for Investigational Products
May be asked to the patient
✓ Patient consent : obtained upon providing a thorough explanation and written information
Compensation
Appropriate compensation measures: taken based on the GCP Ordinance
https://www.pmda.go.jp/files/000209680.pdf 6
Compassionate Use Program “Expanded registration-directed clinical trial” ④
EU as a whole also made a “Compassionate use program”
based on the French model.
https://www.ema.europa.eu/en/human-regulatory/research-development/compassionate-use
https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/guideline-compassionate-use-medicinal-products-pursuant-article-83-regulation-ec-no-726/2004_en.pdf
7
8
http://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm 8
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm163982.htm
FDA Single Patient IND
Japan does not have a “Compassionate use
program” which can address individual patients
Like equivalent to single patient IND in US
and nominative ATU in France
9
The regulatory agency is now using data
for regulatory approval from compassionate use
10
Real World Evidence is used for regulatory approval
11
 Since the last revision of the DoH in 2013,
the concept of “clinical research” seems to have been changing.
– Real-world evidence (RWE) and real-world data (RWD), including data
from the CU program obtained in medical care settings, have been
increasingly used for regulatory approval and safety monitoring, as
research data.
– However, the blurring of the boundary between medical research and
clinical practice has not been reflected in the DoH.
– It is mentioned only in Article 37 vaguely.
12
Unproven Interventions in Clinical Practice
37. In the treatment of an individual patient, where proven interventions
do not exist or other known interventions have been ineffective, the
physician, after seeking expert advice, with informed consent from the
patient or a legally authorised representative, may use an unproven
intervention if in the physician’s judgement it offers hope of saving life,
re-establishing health or alleviating suffering. This intervention should
subsequently be made the object of research, designed to evaluate its
safety and efficacy. In all cases, new information must be recorded and,
where appropriate, made publicly available.
However, in the current Declaration of Helsinki
13
 Given this era of digital health, in the next revision of the
DoH and in preparation for the next pandemic or disaster,
– We think that the DoH must address a new type of clinical
research, CU and RWD/RWE, to facilitate development of
drugs, devices, and diagnostics which will promote global
human health.
14
 Article 37 should be amended to state that unproven interventions,
including CU, should be restricted for the duration.
Otherwise, such interventions may cause not only individual
harm but distrust of public health care.
 It should also be noted that conducting clinical trials after CU for
the same condition is very difficult.
The phrase “intervention should subsequently be made the object
of research” now seems to be an empty slogan.
15
Disruption over the “Fabricated” big data of Surgisphere
Open letter of inquiry May 28, 2020
Lancet May 1 2020 epub
Retraction notice June 4, 2020 epub
NEJM May 1 2020 epub
Retraction notice June 4, 2020 epub
16
Following this Surgisphere matter,
Lancet’s editors changed its peer review process.
Lancet 396: 1056, 2020 (Oct 10)
17
Regulatory authorities should try
– to gather individual patient data,
– to summarize results for transparency, and
– to validate data obtained
from CU and RWD/RWE.
18
Thank you for your attention
19