A material amendment to the law regulating drugs and medical
devices in Japan has recently been implemented. The amendment
mainly covers (i) establishing a fast-track authorization process
for regenerative medicine products (described below), (ii)
restructuring medical device regulations, and (iii) establishing
reporting obligations for package inserts for drugs and medical
devices. In addition, the name of the law regulating drugs and
medical devices will be changed from the "Pharmaceutical
Affairs Law" (Law No. 145 of August 10, 1960; "PAL")
to "The Law on Ensuring Quality, Efficacy and Safety of
Pharmaceuticals and Medical Devices, etc." (referred to as the
Pharmaceuticals and Medical Devices Law, or
"PMDL").
The Law for Partial Amendment to PAL, etc. (Law No. 84 of November
27, 2013) was enacted on November 20, 2013 and promulgated on
November 27, 2013.1 Its relevant Ministerial Ordinances
and Notification, which provide detailed regulations concerning GxP
quality guidelines for regenerative medicine products, were
published during the period of July to November 2014, and the
partial amendment comes into effect on November 25, 2014.
Fast-Track Authorization Process for Regenerative Medicine products Established
Background
As shown by the work of Nobel Prize winner Professor Shiya
Yamanaka, regenerative medical care using induced pluripotent stem
cells is highly anticipated to be one of the methods for innovative
medical care, and there is high demand for early access to such
regenerative medicine products by patients. There remain, however,
concerns regarding safety due to the characteristics of
regenerative medicine products. Taking into consideration these
issues, the PMDL establishes a new approval process for
regenerative medicine products which enables a company to
manufacture and market regenerative medicine products at an earlier
stage under certain terms and conditions.2
Definition of "Regenerative Medicine
Products"
Regenerative medicine products are newly defined under
the PMDL as follows (Article 2.9 of PMDL):
- A product for medical use in humans and/or animals to reconstruct, restore, or form the structure or function of a human or animal body, which cells of humans and/or animals are cultured or otherwise processed (i.e., regenerative medicine products);
- A product for medical use in humans and/or animals to remedy or prevent the disease, which cells of humans and/or animals are cultured or otherwise processed (i.e., cell therapy products); or
- A product for medical use to remedy the disease of humans and/or animals, which is introduced into the human or animal cells and includes a gene expressed in the body (i.e., gene therapy products).
Authorization Process
The PMDL establishes a new authorization process to
manufacture and market the regenerative medicine products. Under
the PMDL, there are two routes to obtain authorization. The first
route is the same as the standard authorization system for drugs
under the PAL (see chart (a) below) (Article 23-25 of PMDL); thus,
the efficacy and safety of the regenerative medicine product must
be shown in order to obtain authorization, as is the case in the
application for any drug. The concern in following the standard
authorization procedure, however, is that it will take a
significant amount of time to launch a regenerative medicine
product because the quality of regenerative medicine products is
heterogeneous by nature. It is therefore difficult to collect the
data necessary to evaluate and demonstrate the efficacy of a
regenerative medicine product, potentially leading to long delays
in the approval process.
The second route is intended to address this concern. Using this
second route, if the regenerative medicine product is
heterogeneous, the efficacy of the regenerative medicine product is
assumed. Thus, if the safety of the regenerative medicine product
is demonstrated through clinical trials, the Minister of the
Ministry of the Health, Labor, and Wealth ("MHLW") may
authorize the applicant to manufacture and market the regenerative
medicine products with certain conditions for a fixed term after
receiving an expert opinion from the Pharmaceutical Affairs and
Food Sanitation Council (see chart (b) below).
An example of the "conditions" contemplated by the
concept of "with certain conditions for a fixed term" is
to restrict marketing places to medical organizations with
professional doctors and equipment. A "fixed term" would
be a term specified by the Minister of the MHLW upon the
authorization, which does not exceed seven years after the
authorization date (Article 23-26.1 of PMDL). If the applicant
obtains authorization subject to certain conditions with a fixed
term, it must conduct drug-use-results surveys in accordance with
the regulations of good post-marketing surveillance practice and
report the results to the Minister of the MHLW (Article 23-26.3 of
PMDL), in parallel with manufacturing and selling the regenerative
medicine product. Thereafter, by the end of the fixed term
specified by the Minister of the MHLW, the authorization holder
must apply for a nonconditional approval to manufacture and market
the regenerative medicine product with application materials
including drug-use-results surveys that demonstrate the efficacy
and safety of the regenerative medicine product (Article 23-26.5 of
PMDL).
With this amendment, it is expected that companies attracted by
this fast-track authorization process may initiate research and
development of regenerative medicine products and may commence to
market such products earlier than previously
anticipated,3 allowing patients to have earlier access
to regenerative medicine products.
Patent Term Extension on Regenerative Medicine
Products
Under the current Patent Law (Law No. 121 of April 30,
1959) in Japan, the patent term is 20 years after the date of the
patent application (Article 67.1 of Patent Law), and if the patent
cannot be implemented due to safety or other reasons, including
those arising under pharmaceutical regulations, the patent term can
be extended for a maximum of five years upon the request of the
patent holder (Article 67.2 of Patent Law, Article 3.2 of
Enforcement Order of Patent Law). The period when the patent cannot
be implemented is the term from the date of commencement of
clinical trials for the drug or the registered date of the patent,
whichever is later, to the date the patent holder receives the
notice of drug authorization (Patent Examination Guideline on
Patent Term Extension).
Along with the establishment of the fast-track authorization
process for regenerative medicine products, the term extension for
patents covering regenerative medicine products is also established
by the new legislation. Under the amendment of Enforcement Order of
the Patent Law,4 the same patent term extension applies
to regenerative medicine products. The period when the patent
cannot be implemented in this case is the term from the date of
commencement of clinical trials for the drug or the registered date
of the patent, whichever is later, to the date the patent holder
receives the notice of drug authorization with certain conditions
and fixed term (Report by Working Group to Consider Patent Term
Extension of the Regenerative Medicine Products of Patent System
Subcommittee of Intellectual Property Committee of Industrial
Structure Council on February 26, 2014). With this amendment,
regenerative medicine products receive the same protection from a
patent extension as that of standard pharmaceutical products.
Others
Due to the characteristics of regenerative medicine
products, health care professionals are obligated to use
significant efforts to explain the use of regenerative medicine
products in an appropriate manner and obtain the informed consent
of the user of these products (Article 68-4 of PMDL).
As with the regulations of certain medical devices, in order to
prevent expansion of health care risks, the holder of a business
license for the manufacture and marketing of regenerative medicine
products must keep records of, and adequately maintain, the name,
address, and other information concerning the distributor,
hospital, or medical clinic and other related entities (Article
68-7.1 of PMDL). At the same time, the health care professional
must keep records of the name, address, and other information
concerning the users of regenerative medicine products (Article
68-7.3 of PMDL).
Restructuring of Medical Device Regulations
Background
As indicated by its name, the Pharmaceutical Affairs Act
("PAL") was focused on the regulation of drugs rather
than medical devices. Recently, however, medical devices have been
recognized to have the following characteristics that distinguish
them from drugs: (i) medical devices are clinically implemented,
(ii) medical devices are continually undergoing improvement and the
life cycle of any individual medical device is short, (iii) the
efficacy and safety of medical devices depend largely on the
doctor's technique, and (iv) a great number of types, but a
small amount of each type, of medical devices are clinically used.
Further, it takes a significant amount of time for new medical
devices to be authorized and launched in Japan, and Japanese
regulations need to be harmonized with international regulations
for medical devices so that medical devices created in Japan can be
commercialized globally. Taking into consideration these issues,
the PMDL restructures the regulation of medical devices as
follows.
Expansion of the Scope for Certification of the Registered
Certification Body
The PAL incorporates the concept of the classification of
medical devices in accordance with the classifications agreed upon
by the December 2003 Global Harmonization Task Force
("GHTF") and classifies medical devices as follows:
Classificaton |
Classification under PAL |
Regulatory Requirements |
Class I |
General Medical Devices |
Extremely low risk to the human body in case of the failure of the medical devices |
Notification to the Pharmaceuticals and Medical Devices Agency ("PMDA") |
Class II |
Controlled Medical Devices |
Relatively low risk to the human body in case of the failure of the medical devices |
Certification by a registered certification body (some medical products require authorization by the Minister of the MHLW after the PMDA review) |
Class III |
Specially Controlled Medical Devices |
Relatively high risk to the human body in case of the failure of the medical devices |
Authorization of the Minister of the MHLW after the PMDA review |
Class IV |
Specially Controlled Medical Devices |
Highly invasive to the patients and life-threatening in case of the failure of the medical devices. |
Authorization of the Minister of the MHLW after the PMDA review |
Under the PMDL, the regulatory requirement of some medical devices
(e.g., dental implants, contact lenses) that are classified as
Class III changes from authorization by the Minister of the MHLW
after the PMDA review to certification by a registered
certification body. With this change, the PMDA is able to
concentrate its resources on the review of high-risk medical
devices and to speed up its review procedures (Article 23-2-23.1 of
PMDL).
New Regulations on Medical Device Software
Medical device software (e.g., a program for processing,
storage, and display of graphic data photographed by MRI (magnetic
resonance imaging), etc.) by itself was previously not subject to
the PAL, and it was reviewed along with the medical device hardware
into which the medical software was incorporated. Due to the
development of new systems using IT technology and harmonization
with U.S. and EU regulations, however, the PMDL now covers medical
device software as an independent medical device. Accordingly,
software may be authorized as a medical device independent of the
medical device hardware into which it is incorporated.
System Change for Medical Devices Manufacturing
Under the PAL, a company that wishes to manufacture a
medical device must obtain authorization to do so. The PMDL changes
this system so that a company may manufacture a medical device when
the company registers such medical device (Article 23-2-3.1 of
PMDL). With this change, the burden on the company manufacturing
the medical device is mitigated to some extent (e.g., the company
is not subject to an inspection of the manufacturing site's
buildings and facilities).
Streamlined Quality Management Service ("QMS")
Inspection
Under the PAL, a QMS inspection was performed for each
medical device for its authorization and its renewal. Under the
PMDL, this regulation is streamlined, which means that the QMS
inspection is performed for each category of medical products.
Thus, the company that applies for the authorization of a new
medical device or has obtained approval is exempted from a QMS
inspection if the following conditions are met:
- The company has already obtained a QMS regulation conforming certificate on its existing medical device and the existing medical device falls into the same category as the new medical device separately stipulated by a Municipal Order; and
- The new medical device will be manufactured at the manufacturing site in such regulation conforming certificate (Article 23-2-5.7 of PMDL).
For example, if a company has obtained a QMS regulation conforming
certificate on an artificial blood vessel using collagen (Category:
Artificial Blood Vessel) at site A and the company applies for
authorization for an artificial blood vessel using gelatin
(Category: Artificial Blood Vessel) at site A, the company will be
exempted from the QMS inspection on an artificial blood vessel
using gelatin. With this change, the QMS inspection burden on a
company that applies for authorization of a medical device or
requests renewal of an authorization will be mitigated.
Establishment of Notification Obligation for Package Inserts
Background
Under the PAL, the package insert for drug and medical
devices must include certain information on the proper use of such
drug or medical devices (Article 52 and 63-2 of the PAL), but the
holder of a business license for the manufacture and marketing of
drugs and medical devices is not obligated to obtain authorization
for the package insert from, nor even notify, the Japanese
government. In this respect, the "Panel to consider drug
administration to prevent drug-induced hepatitis" pointed out
that it is necessary to reconsider the legal status of package
inserts and to clarify the responsibility of the government in its
first proposal on April 30, 2009. Further, the "Committee to
consider the revision of drugs, etc. regulations" of the
Health Science Council issued its report on the revision of drugs,
etc. regulations on January 24, 2011. According to the report, the
committee discussed how to clarify the Japanese government's
authority regarding package inserts under the PAL. Eventually, the
majority concluded that a company manufacturing and marketing a
drug or medical device must notify the Japanese government
regarding the contents of the package insert in advance of
commencing manufacturing and marketing the drug or medical device
and, if necessary, revise the package insert. Another proposal to
require the government's authorization of the package insert
was not adopted mainly due to the possible chilling effect such
obligation would have on the provision of medical care. It was also
pointed out that it is important to reflect the latest findings
concerning drugs and medical devices, which is not clear under the
PAL.
New Rule
Under the PMDL, when the holder of a business license for
the manufacture and marketing of regenerative medicine products,
drugs,5 or medical devices manufactures and markets
these products, the license holder must notify the Minister of the
MHLW of the contents of the package insert, including any
cautionary statements necessary to use and deal with these products
and the other items, before it manufactures and markets them. The
same rule applies when the license holder changes the package
insert (Article 52-2.1, 63-3.1 and 65-4.1 of PMDL). Immediately
after the license holder provides such notification, the license
holder must publish the contents of the package insert on the
website of the PMDA (Article 52-2.2, 63-3.1 and 65-4.2 of
PMDL).
Footnotes
1 Other than this partial amendment, three partial
amendments to the PAL were enacted and promulgated in 2013: (i) Law
for Partial Amendment to Law to Control Narcotics and Psychotropic
and PAL (Law No. 17 of May 17, 2013); (ii) Law for Partial
Amendment to the Relevant Laws for Reform Promotion to Improve
Local Autonomy and Independence (Law No. 44 of June 14, 2013); and
(iii) Law for Partial Amendment to PAL (Law No. 103 of December 13,
2013). This Commentary does not cover them.
2 Other than this partial amendment, new laws regarding
regenerative medical care were enacted and promulgated in 2013; (i)
Law to Comprehensively Promote the Measures so that Japanese People
may Receive the Regenerative Medical Care Promptly and Safely (Law
No. 23 of May 10, 2013); and (ii) Law for Safety Assurance, etc. of
Regenerative Medical Care, etc. (Law No. 85 of November 27, 2013).
This Commentary does not cover them.
3 According to Nikkei newspaper, JCR Pharma has applied for the
authorization of its cell therapy drug on September 26, 2014
(Nikkei newspaper, September 27, 2014), and if it is authorized, it
may be the first authorized regenerative medicinal product.
4 This amendment was promulgated on October 22, 2014 and came into
effect on November 25, 2014.
5 Certain category of drugs including, but not limited to, in
vitro diagnosis and drugs manufactured by drugstores are
exempted from this rule.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.