OFFICIAL (CLOSED) NON-SENSITIVE
Richard Yeo
Snr Lecturer
School of Applied
Science
A3720C Pharmaceutical Legislation
Lesson 05:
Innovator Drugs and Generic Drugs, Biologicals and
Biosimilars
Copyright © 2020 by Republic Polytechnic, Singapore
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Learning Outcomes:
Copyright © 2020 by Republic Polytechnic, Singapore
1. Describe what a patent is (competent)
• Apply the Patents Act for regulations on drugs (proficient)
• Name the criteria for eligibility of patent (competent)
• Recall how long a patent lasts (competent)
• Identify the process for patent application (competent)
2. Examine the characteristics of innovator drugs (competent)
• Define “innovator drugs” (competent)
• Explain how innovator drugs occur (proficient)
• List down examples of innovator drugs (competent)
• Identify the process of new drug application (NDA) for
innovator drugs (competent)
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Learning Outcomes:
Copyright © 2020 by Republic Polytechnic, Singapore
3. Examine the characteristics of generic drugs (competent)
• Define “generic drugs” (competent)
• Discuss the reasons for the existence of generic drugs
(competent)
• Identify when innovator and generic drugs should and
should not be used interchangeably (proficient)
• List down some examples of generic drugs (competent)
• List the criteria for generic drug application (GDA)
(competent)
• Identify what a Singapore Reference Product is (competent)
• Differentiate between NDA and GDA (proficient)
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Learning Outcomes:
Copyright © 2020 by Republic Polytechnic, Singapore
4. Examine the characteristics of biologicals (competent)
• Define “biologicals” (competent)
• Explain how biologicals occur (proficient)
• Identify the process of new drug application (NDA) for
biologicals (competent)
5. Examine the characteristics of biosimilars (competent)
• Define “biosimilars” (competent)
• Discuss the reasons for the existence of biosimilars
(competent)
• Identify when biologicals and biosimilars should and should
not be used interchangeably (proficient)
• List the criteria for approval of biosimilars (competent)
• Identify what a Singapore Reference Biological Product is
(competent)
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Patents
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Patent
• A patent is a right that is granted to the owner for an
invention that prevents others from making, using,
importing or selling the invention without his permission.
• It can take the form of a new product, process or technical
improvement to existing technology.
Copyright © 2020 by Republic Polytechnic, Singapore
Register
patent for
invention
Exclusive
right over
patent
Economic
opportunities
Unless
permission
given to
others 6
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Eligibility for Patent
Copyright © 2020 by Republic Polytechnic, Singapore
New
• Should not be
publicly known
• Invention must
be kept secret
until patent
application has
been made
Inventive
Step
• Improvement
over any existing
product or
process
• Improvement
must not be
obvious within
the related
industry
Industrial
Application
• Useful
• Practical
application
• Can be made or
used in the
industry
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Term of Patent
Patents Act (Chapter 221)
Copyright © 2020 by Republic Polytechnic, Singapore
Date of
filing
Expiry of
patent
End of
extension
20 years of
exclusive right
???
(extension
on case by
case basis) 8
Patents Act, (Chapter 221), Sections 36 & 36A
Term of patent
36.—(1) A patent granted under this Act shall be treated for the purposes of this
Act as having been granted, and shall take effect, on the date of issue of the
certificate of grant and, subject to subsection (2) and section 36A, shall continue
in force until the end of the period of 20 years beginning with the date of filing
the application for the patent or with such other date as may be prescribed.
(2) A patent shall cease to have effect at the end of the prescribed period for the
payment of any renewal fee if it is not paid within that period.
(3) If during the period of 6 months immediately following the end of the
prescribed period the renewal fee and any prescribed additional fee are paid, the
patent shall be treated for the purposes of this Act as if it had never expired, and
accordingly —
(a) anything done under or in relation to it during that further period shall be
valid;
(b) an act which would constitute an infringement of it if it had not expired shall
constitute such an infringement; and
(c) an act which would constitute the use of the patented invention in
accordance with section 56 if the patent had
not expired shall constitute that use.
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(4) Rules shall include provision requiring the Registrar to notify the registered
proprietor of a patent that a renewal fee has not been received from him in the
Registry before the end of the prescribed period and before the framing of the
notification.
Extension of term of patent
36A.—(1) The proprietor of a patent may apply to the Registrar to extend the
term of the patent on any of the following grounds:
(a) that there was an unreasonable delay by the Registrar in granting the patent;
(b) where the patent was granted on the basis of any prescribed documents
referred to in section 29(1)(d) relating to one corresponding application or related
national phase application, that —
(i) there was an unreasonable delay in the issue of the corresponding patent or
related national phase patent (as the case may be); and
(ii) the patent office that granted the corresponding patent or related national
phase patent (as the case may be) has extended the term of the corresponding
patent or related national phase patent (as the case may be) on the basis of such
delay;
(c) where the subject of the patent includes any substance which is an active
ingredient of any pharmaceutical product, that —
(i) there was an unreasonable curtailment of the opportunity to exploit the patent
caused by the process of obtaining marketing approval for a pharmaceutical
product, being the first pharmaceutical product to obtain marketing approval
which uses the substance as an active ingredient; and
(ii) the term of the patent has not previously been extended on this ground.
(2) A delay by the Registrar in granting a patent shall not be treated as an
unreasonable delay under subsection (1)(a) unless such requirements as may be
prescribed are satisfied.
(3) Where the proprietor of a patent has made an application under subsection
(1)(a) and has satisfied the Registrar that there was in fact a particular type of
unreasonable delay by the Registrar in granting the patent, the Registrar shall
extend the term of the patent by such period as may be prescribed for that type
of unreasonable delay.
(4) Where the proprietor of a patent has made an application under subsection
(1)(b) and has satisfied the Registrar of the matters referred to in sub-paragraphs
(i) and (ii) of subsection (1)(b), the Registrar may, if the Registrar thinks fit, extend
the term of the patent by such period, not exceeding 5 years, as the Registrar may
determine.
(5) A curtailment of the opportunity to exploit a patent, the subject of which
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includes a substance which is an active ingredient of any pharmaceutical product,
caused by the process of obtaining marketing approval for a pharmaceutical
product, being the first pharmaceutical product to obtain marketing approval
which uses the substance as an active ingredient, shall not be treated as an
unreasonable curtailment under subsection (1)(c) unless such requirements as
may be prescribed are satisfied.
(6) Subject to subsections (7), (8) and (9), where the proprietor of a patent has
made an application under subsection (1)(c) and has satisfied the Registrar that
there was in fact an unreasonable curtailment of the opportunity to exploit the
patent under subsection (1)(c), the Registrar shall extend the term of the patent
by such period as may be prescribed.
(7) The Registrar shall not extend the term of the patent under subsection (6)
unless the applicant has procured and submitted to the Registrar a certificate
from the relevant authority stating such matters as may be prescribed.
(8) In determining the period by which to extend the term of the patent under
subsection (6), the Registrar shall rely on, and shall not be concerned to inquire
into the truth of, the statements contained in the certificate from the relevant
authority under subsection (7).
(9) Where the term of a patent has been extended under subsection (6), the
protection conferred by the patent during the
term of the extension shall apply only to the substance referred to in subsection
(1)(c).
(10) Every application to extend the term of a patent shall be —
(a) made by the proprietor of the patent in the prescribed form within the
prescribed period;
(b) filed in the prescribed manner; and
(c) accompanied by the prescribed fee and any prescribed documents, and the
Registrar may reject any application that fails to comply with any requirement
under this subsection.
(11) As soon as practicable after the Registrar has extended the term of a patent,
he shall —
(a) send to the proprietor of the patent a certificate of extension of patent term in
the prescribed form specifying —
(i) the period of the extension; and
(ii) any limitation on the protection conferred by the patent during the term of the
extension; and
(b) publish in the journal a notice of the extension.
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(12) The proprietor of a patent who has made an application under subsection (1)
may withdraw the application by informing the Registrar in writing of the
withdrawal of the application, and any such withdrawal shall not be revocable.
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OFFICIAL (CLOSED) NON-SENSITIVE
Patent Application Process
• Pre-filing checklist
✓ When? First person gets priority!
✓ Where? Consider scope and cost in different countries…
✓ What? Technical and accurate description needed.
✓ Claims not ready? Apply for Provisional Application.
✓ Overseas patent first? Obtain National Security Clearance.
• 2 routes of application
1. National Phase (domestic)
2. Patent Co-Operation Treaty (PCT) National Phase Entry
(international)
Copyright © 2020 by Republic Polytechnic, Singapore
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https://www.ipos.gov.sg/protecting-your-ideas/patent/application-process
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Innovator Drugs
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Innovator Drugs
• Also known as “brand-name drugs”
• Originally discovered and developed by a
pharmaceutical company
• First of its kind to be approved for use
• Efficacy, safety and quality would have been fully
established
Copyright © 2020 by Republic Polytechnic, Singapore
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OFFICIAL (CLOSED) NON-SENSITIVE
Innovator Drugs
• Patented → prevents others from using, copying, or
making the invention without the patent owner’s
consent during the patent period
Patents Act, Chapter 221, Section 36(1)
• Patents last for 20 years. → exclusive sales
• In most situations, patents cannot be extended. Any
requests for extensions are subject to approval.
Copyright © 2020 by Republic Polytechnic, Singapore
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Patents Act, Chapter 221, Section 36(1) and 36A(1)
Term of patent
36.—(1) A patent granted under this Act shall be treated for the purposes of this Act as
having been granted, and shall take effect, on the date of issue of the certificate of grant
and, subject to subsection (2) and section 36A, shall continue in force until the end of
the period of 20 years beginning with the date of filing the application for the patent or
with such other date as may be prescribed.
Extension of term of patent
36A.—(1) The proprietor of a patent may apply to the Registrar to extend the
term of the patent on any of the following grounds:
(a) that there was an unreasonable delay by the Registrar in granting the patent;
(b) where the patent was granted on the basis of any prescribed documents
referred to in section 29(1)(d) relating to one corresponding application or
related national phase application, that —
(i) there was an unreasonable delay in the issue of the corresponding patent or
related national phase patent (as the case may be); and
(ii) the patent office that granted the corresponding patent or related national
phase patent (as the case may be) has extended the term of the corresponding
patent or related national phase patent (as the case may be) on the basis of such
delay;
(c) where the subject of the patent includes any substance which is an active
ingredient of any pharmaceutical product, that —
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(i) there was an unreasonable curtailment of the opportunity to exploit the patent
caused by the process of obtaining marketing approval for a pharmaceutical
product, being the first pharmaceutical product to obtain marketing approval
which uses the substance as an active ingredient; and
(ii) the term of the patent has not previously been extended on this ground.
What is a patent?
A patent is a right granted to the owner of an invention that prevents others from
making, using, importing or selling the invention without his permission.
A patentable invention can be a product or a process that gives a new technical solution
to a problem. It can also be a new method of doing things, the composition of a new
product, or a technical improvement on how certain objects work.
Once it is granted, its term of a patent is 20 years from the Date of Filing, subject to the
payment of annual renewal fees.
The benefits of registering a patent
Once you register a patent, apart from using the patent to prevent others from exploiting
your invention, you can employ it to raise funds for your business, license it to third
parties for commercial returns or sell the patented invention.
For an invention to be patentable, it must, in general, satisfy three key criteria:
1. New – The invention should not be publicly known in any way, anywhere in the world.
Owners of inventions should be careful to keep the invention secret until a patent
application has been successfully made. If the idea has already been talked about,
commercially exploited, advertised or demonstrated, then the novelty of the invention
may be compromised.
If the invention needs to be disclosed to a third party before a patent application has
been made, a non-disclosure agreement should be drawn up.
Once a Date of Filing has been obtained for the patent application, the invention can
claim a “Patent Pending” status and the applicant can proceed to disclose the invention
as indicated in the patent application to interested parties. As part of the application
process, the patent application will be published after 18 months and if the statutory
requirements are met. Once published, details of the invention will be made available for
public inspection.
2. Inventive step – The invention must be something that represents an improvement
over any existing product or process that is already available.
The improvement must not be obvious to someone with technical skills or knowledge in
the invention’s particular field. If an invention is new yet obvious to a person skilled in
the art, the invention would not fulfil the inventive step requirement.
3. Industrial application – The invention must be useful and have some form of practical
application. It should be capable of being made or used in some form of industry.
The following is not a patentable invention:
An invention of a method for the treatment of the human or animal body by surgery or
therapy, or of a diagnosis practised on the human or animal body.
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An invention that could encourage offensive, immoral or anti-social behaviour, even if it
satisfies the key criteria for patents.
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Examples of Innovator Drugs
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OFFICIAL (CLOSED) NON-SENSITIVE
New Drug Application (NDA)
• NDA-1
• First strength of new chemical or biological product
• NDA-2
• New combination
• New dosage form / presentation / formulation
• New route of administration
• New indication / dosage recommendation / patient
population
• Products that do not qualify for NDA-1, NDA-3 or generic
drug application (GDA)
• NDA-3
• Subsequent strength(s) submitted as NDA-1 or NDA-2 (all
other parameters must remain the same, e.g. dosage
form)
Copyright © 2020 by Republic Polytechnic, Singapore
How To Apply
For Registration
In Singapore?
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HSA GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
NDA New Drug Application
NDA-1: For the first strength of a product containing a new3 chemical or biological
entity.
NDA-2: (a) For the first strength of a product
(i) containing a new combination of registered chemical or biological entities;
(ii) containing registered chemical or biological entity(ies) in a new dosage form (e.g.
tablets, capsules, injectables), new presentation (e.g. single-dose vials, multi-dose
vials, pre-filled syringe) or new formulation (e.g. preservative-free);
(iii) containing registered chemical or biological entity(ies) for use by a new route of
administration; or,
(iv) containing registered chemical or biological entity(ies) for new indication(s), dosage
recommendation(s) and/or patient population(s).
(b) For products that do not fall under the requirements for NDA-1, NDA-3 or GDA.
NDA-3: For subsequent strength(s) of a product that has been registered or has been
submitted as an NDA-1 or NDA-2. The product name, dosage form, indication, dosing
regimen and patient population should be the same as that for the NDA-1 or NDA-2.
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OFFICIAL (CLOSED) NON-SENSITIVE
Generic Drugs
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OFFICIAL (CLOSED) NON-SENSITIVE
Generic Drugs
• Copies of innovator drugs with comparable…
• strength,
• intended use,
• effects,
• side effects,
• route of administration,
• risks,
• safety, and
• strength.
• Intended to be interchangeable with the innovator drug, but
manufactured without requiring permission from the innovator
company
Copyright © 2020 by Republic Polytechnic, Singapore
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HSA GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
https://www.hsa.gov.sg/docs/default-source/hprg/therapeutic-products/guidancedocuments/guidance-on-therapeutic-product-registration-in-singapore_jan2019.pdf
A generic drug product is a therapeutic product that contains one or more chemical
entities, and that is essentially the same with a current registered product with respect
to its qualitative and quantitative composition of active ingredients, pharmaceutical
dosage form and clinical indication.
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Are generic drugs patentable?
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OFFICIAL (CLOSED) NON-SENSITIVE
Generic Drugs
• Once patent expires, any other company can
produce generics
• Marketed after the expiry date of the patent or
other exclusive rights
• Allows increased access of drugs to the public
• Public has greater access to healthcare
• More affordable
• More patients have more options
• Help healthcare institutions save costs
• Lead to better therapeutic outcomes
Copyright © 2020 by Republic Polytechnic, Singapore
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OFFICIAL (CLOSED) NON-SENSITIVE
Examples of Generic Drugs
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OFFICIAL (CLOSED) NON-SENSITIVE
Characteristics of Generic Drugs
• Marketed under a non-proprietary name or approved
name
• Original brand name cannot be used → exclusive to patent
owner
• Chemically and biologically equivalent
• No statistical difference in efficacy
• Similar therapeutic index
• May be different in terms of:
• Colour
• Flavour
• Inactive ingredients
• Shape
• Size
Copyright © 2020 by Republic Polytechnic, Singapore
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OFFICIAL (CLOSED) NON-SENSITIVE
Reasons for producing Generic Drugs
Good for patients / consumers too!
Copyright © 2020 by Republic Polytechnic, Singapore
Lower development
cost
Lower selling price
vs profit margin
Creates competition
between drug
companies
Gain market share
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OFFICIAL (CLOSED) NON-SENSITIVE
Interchangeability with
Innovator Drugs
• A generic drug is the same as an innovator
drug in dosage, safety, strength, quality,
the way it works, the way it is taken and
the way it should be used.
• Exceptions are drugs with narrow
therapeutic index
• For example, warfarin and theophylline
Copyright © 2020 by Republic Polytechnic, Singapore
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HSA GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
APPENDIX 10 PRODUCT INTERCHANGEABILITY AND BIOWAIVER REQUEST FOR
CHEMICAL GENERIC DRUG APPLICATIONS
1 PRODUCT INTERCHANGEABILITY
A generic product is considered to be interchangeable with the Singapore reference
product if it demonstrates therapeutic and pharmaceutical equivalency. A BE study is
generally the most appropriate method for demonstrating therapeutic equivalence
between products that are pharmaceutically equivalent.
For generic products containing a different salt, ester, ether, isomer, mixture of isomer,
complex or derivative of the active substance compared to the Singapore reference
product, applicants are required to submit data to demonstrate that the different form
does not differ from the active substance in the Singapore reference product in terms of
the pharmacokinetic, pharmacodynamic, efficacy or toxicity profile.
The applicant is responsible for demonstrating product interchangeability between the
generic product and the Singapore reference product. The outcome of the evaluation
will only be determined based on the documents provided in the application dossier.
HSA reserves the right to request for additional information, including in vivo BE data, if
deemed appropriate to determine product interchangeability.
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OFFICIAL (CLOSED) NON-SENSITIVE
What is Therapeutic Index?
TI: Indicates
relative safety
of drug
Ratio of the
lethal dose to
the
therapeutic
dose
Lower T.I.
ratio → more
toxic
1
Therapeutic effect
(eg pain relief)
Toxic effect
(eg. Seizures)
Lethality
Cumulative Response %
Log
Dose
0
25
50
75
100
99
Therapeutic Index
ED50: dose that produces
desired effect in 50% of
the population
LD50: dose that
produces death in 50%
of the population
FYI. Not tested.
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OFFICIAL (CLOSED) NON-SENSITIVE
Singapore Reference Product
• Currently registered product
• If not, then selected alternate registered comparator must be
adequately justified by applicant and agreed upon by HSA.
• Generic products being compared should be of same
• active substance(s);
• strength(s);
• dosage form.
• If generic products are of different chemical forms (e.g. different
salts or isomers), applicants must submit data to prove that PK,
PD, efficacy and toxicity profiles do not differ from the Singapore
Reference Product.
Copyright © 2020 by Republic Polytechnic, Singapore
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PK = pharmacokinetics = the study of the time course of drug absorption, distribution,
metabolism, and excretion (ADME)
PD = pharmacodynamics = relationship between drug concentration at the site of action
and the resulting effect, including the time course and intensity of therapeutic and
adverse effects
HSA GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
https://www.hsa.gov.sg/docs/default-source/hprg/therapeutic-products/guidancedocuments/guidance-on-therapeutic-product-registration-in-singapore_jan2019.pdf
16.2 Singapore Reference Product
The Singapore reference product must be a currently registered product that has been
granted market authorisation based on the evaluation of the product’s quality, efficacy
and safety – i.e. a dossier with chemical, biological, pharmaceutical, pharmacologicaltoxicological and clinical data. If such a reference product is not registered in Singapore,
then an alternate registered comparator product may be used if adequately justified
(e.g. a registered generic therapeutic product widely used by local hospitals) by the
applicant and agreed upon by HSA.
The generic product should contain the same active substance(s) and strength(s) and be
the same pharmaceutical dosage form as the Singapore reference product.
For generic products containing a different salt, ester, ether, isomer, mixture of isomer,
complex or derivative of the active substance compared to the Singapore reference
product, applicants are required to submit data to demonstrate that the different form
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does not differ from the active substance in the Singapore reference product in terms of
the pharmacokinetic, pharmacodynamic, efficacy or toxicity profile of the active
substance in the reference product.
Applicants are advised to search HSA’s Register of Therapeutic Products to identify the
Singapore reference product. Applicants are encouraged to contact HSA to discuss the
acceptability of a GDA if the generic product does not have a registered Singapore
reference product of the same strength. In these instances, applicants should provide
scientific justification for HSA’s consideration. However, a generic drug application for a
higher strength than the Singapore reference product will not be accepted.
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OFFICIAL (CLOSED) NON-SENSITIVE
Criteria for HSA approval of a
Generic Drug
Copyright © 2020 by Republic Polytechnic, Singapore
Singapore
Reference
Product
Same
pharmaceutical
dosage form
Same route of
administration
(ROA)
Same
conditions
of use Bioequivalent
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HSA GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
https://www.hsa.gov.sg/docs/default-source/hprg/therapeutic-products/guidancedocuments/guidance-on-therapeutic-product-registration-in-singapore_jan2019.pdf
16.1 Generic Product
A generic product must have the same qualitative and quantitative composition in active
substances and be of the same pharmaceutical form as a currently registered product in
Singapore (known as the ‘Singapore reference product’). A generic product must
demonstrate bioequivalence to the Singapore reference product via appropriate
bioequivalence studies.
The generic product must fulfil the following criteria:
(a) the generic product is the same pharmaceutical dosage form as the Singapore
reference product. However, different conventional oral immediate-release dosage
forms (i.e. tablets and capsules) are considered to be the same pharmaceutical
form;
(b) the route of administration of the generic product is the same as the Singapore
reference product;
(c) the conditions of use for the generic product fall within the directions for use
(including indication(s), dosing regimen(s) and patient group(s)) for the Singapore
reference product; and
(d) the generic product is bioequivalent with the Singapore reference product.
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OFFICIAL (CLOSED) NON-SENSITIVE
Bioequivalence Studies
Bioequivalent =
• pharmaceutically equivalent or
pharmaceutical alternatives +
• bioavailabilities (rate and
extent) after administration in
the same dose lie within
acceptable predefined limits
(usually not more than 5%)
Limits are set to ensure
comparable in vivo performance,
i.e. similarity in terms of safety
and efficacy.
Copyright © 2020 by Republic Polytechnic, Singapore
FYI. Not tested.
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Generic Drug Application
• GDA-1: First strength of a generic chemical
product
• GDA-2: Subsequent strength(s) that has been
registered or submitted as GDA-1 (product name
and dosage form should be the same)
Copyright © 2020 by Republic Polytechnic, Singapore
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HSA GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
GDA Generic Drug Application
A generic drug application applies to a therapeutic product that contains one or more
chemical entities, and that is essentially the same with a current registered product with
respect to its qualitative and quantitative composition of active ingredients,
pharmaceutical dosage form and clinical indication. Follow-on biologic products (also
known as biosimilar products) are not eligible for a GDA and are required to be
submitted via a NDA.
GDA-1: For the first strength of a generic chemical product.
GDA-2: For subsequent strength(s) of the generic chemical product that has been
registered or submitted as GDA-1. The product name and dosage form should be the
same as that for the GDA-1.
In cases where multiple strengths of a generic product are submitted together, the
strength of the product used in the BE study is considered as GDA-1. The remaining
strength(s) should be submitted as GDA-2.
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OFFICIAL (CLOSED) NON-SENSITIVE
NDA versus GDA
Copyright © 2020 by Republic Polytechnic, Singapore
Source:
https://www.hsa.gov.sg/docs/default-source/hprg/therapeutic-products/guidancedocuments/guidance-on-therapeutic-product-registration-in-singapore_jan2019.pdf
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NDA = New Drug Application
GDA = Generic Drug Application
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OFFICIAL (CLOSED) NON-SENSITIVE
Activity 1
1. People who are switched to a generic drug are at risk of
treatment failure.
2. According to HSA guidelines, a generic drug needs to have
the same quality and performance as the Singapore
reference product.
3. Generic drugs cost less because they are inferior to innovator
drugs.
4. A patent for Drug X was filed on 1st March 2000. A generic
version of Drug X can only be manufactured after 2nd March
2020.
5. The colouring and flavouring agents contained in the generic
drugs must be the same as the Singapore reference product.
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OFFICIAL (CLOSED) NON-SENSITIVE
Biological Products /
Biologics
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OFFICIAL (CLOSED) NON-SENSITIVE
Biological Products
• Macromolecules extracted from organisms (such as proteins,
nucleic acids, proteoglycans, cytokines and growth factors), OR
• Any substance derived from a biological system, including
(a) whole cell or micro-organism, such as a whole virus or bacterium used as a
vaccine;
(b) a part of a micro-organism, such as a sub-unit vaccine;
(c) a plasma-derived product; or
(d) a biotechnology-derived substance, such as a protein or polypeptide.
• Manufacturing process is highly complex – small changes can
result in significant differences in clinical properties
• May be used to treat a variety of medical conditions for which no
other treatments are available (e.g. gene-based and cellular
biologics)
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https://www.hsa.gov.sg/docs/default-source/hprg/therapeutic-products/guidancedocuments/guidance-on-therapeutic-product-registration-in-singapore_jan2019.pdf
https://www.hsa.gov.sg/docs/default-source/hprg/therapeutic-products/guidancedocuments/appendix-15_guidance-on-registration-of-biosimilar-products.pdf
A biological entity refers to any macromolecule extracted from an organism (such as
proteins, nucleic acids, proteoglycans, cytokines and growth factors), or any substance
derived from a biological system, including any of the following:
(a) a whole cell or micro-organism, such as a whole virus or bacterium used as a
vaccine;
(b) (b) a part of a micro-organism, such as a sub-unit vaccine;
(c) (c) a plasma-derived product; or
(d) (d) a biotechnology-derived substance, such as a protein or polypeptide.
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Biological Products
• Intended to treat diseases and medical conditions,
prevent or diagnose diseases.
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Vaccines Blood &
Blood Products
Allergenic Extracts
Human Cells & Tissues
Gene Therapies
Cellular Therapies
Tests to screen potential blood
donors for infectious agents
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https://www.fda.gov/aboutfda/transparency/basics/ucm194516.htm
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New Biological Application
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Any challenges faced in
manufacturing biologicals?
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The Challenges in Manufacturing Biologics
WE WRITE ESSAYS FOR STUDENTS
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Biosimilar Products
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OFFICIAL (CLOSED) NON-SENSITIVE
Making of Biosimilar biologicals
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Biosimilar Medicines
The Evolution of Biotechnology – The Arrival of
Biosimilars
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Biosimilars
• Also known as “follow-on biologic products”.
• A biological therapeutic product demonstrated to be similar in
physicochemical characteristics, biological activity, safety and
efficacy to an existing registered biological product (“reference
biological product”).
• Only minor differences in clinically inactive components are
allowable in biosimilar products.
• It is generally used at the same dose to treat the same disease.
They are NOT GENERICS, and NOT IDENTICAL, and as
such do not guarantee therapeutic equivalency!!!
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HSA GUIDANCE ON THERAPEUTIC PRODUCT REGISTRATION IN SINGAPORE
https://www.hsa.gov.sg/docs/default-source/hprg/therapeutic-products/guidancedocuments/appendix-15_guidance-on-registration-of-biosimilar-products.pdf
Biological medicines are produced using a living system or organism. They are different
from traditional chemical medicines in many ways. The manufacturing process of a
biological medicine is highly complex and is a determining factor in the development of
a biological medicine. The definition of “process” includes the type or identity of the
source material and the individual process steps in cell fermentation, protein
purification, sterile filling and drug product formulation. Even very small process changes
can result in significant differences in the clinical properties of the biological medicines.
The expiration of the patents on many biological products has prompted the
development of these products as similar biological products, or biosimilar products. A
biosimilar product would have an abbreviated non-clinical and clinical development
programme leveraging on the existing information of the original product and focusing
on demonstration of similarity with the original product. While the launch of such
biosimilar products would provide patients with potentially cheaper alternatives, it is
also prudent to ensure that the quality, safety and efficacy of such products are not
compromised.
A biosimilar product is intended to be similar in terms of quality, safety and efficacy to a
registered biological product (reference biological product) for which there is substantial
evidence of safety and efficacy. The comparability exercise for a biosimilar product is
designed to show that the biosimilar product has highly similar quality attributes when
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compared to the reference biological product. Demonstration of similarity of a biosimilar
product to a reference product in terms of quality is a prerequisite for determining the
non-clinical and clinical data set required for registration. Significant differences between
the biosimilar product and the chosen reference biological product detected during the
comparability exercise would be an indication that the products are not similar and more
extensive non-clinical and clinical data may be required to support the application for
licensing. If relevant differences are found in the quality, non-clinical, or clinical data, the
product is unlikely to qualify as a biosimilar product. Comparability exercises to
demonstrate similarity are more likely to be applied to highly purified products, which
can be thoroughly characterised (such as some biotechnology-derived therapeutic
products). Vaccines, blood or plasma-derived products and their recombinant
alternatives, and other types of biological therapeutic products, such as gene or cell
products used for advanced therapy, and human tissues or cells intended for human
application, are of a complex nature and applications based on biosimilarity for such
products will not be considered at the present moment
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Reasons for producing Biosimilars
• Patent expiration on original biological products
• Shorter periods of non-clinical and clinical
development of biosimilars
• Leverage on existing information of original biological
products
• Focus on demonstrating similarity with original biological
products
• Patients get cheaper alternatives
• However, interchangeability could be an issue…
Copyright © 2020 by Republic Polytechnic, Singapore
38
The expiration of the patents on many biological products has prompted the
development of these products as similar biological products, or biosimilar products. A
biosimilar product would have an abbreviated non-clinical and clinical development
programme leveraging on the existing information of the original product and focusing
on demonstration of similarity with the original product. While the launch of such
biosimilar products would provide patients with potentially cheaper alternatives, it is
also prudent to ensure that the quality, safety and efficacy of such products are not
compromised.
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OFFICIAL (CLOSED) NON-SENSITIVE
Singapore Reference Biological Product
• Should be a biological therapeutic product that is
currently registered in Singapore
• A registered biosimilar product cannot be used as a
reference product
• Biosimilar applicants should search HSA’s Register
of Therapeutic Products to identify the
corresponding Singapore registered biological
product.
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https://www.hsa.gov.sg/docs/default-source/hprg/therapeutic-products/guidancedocuments/appendix-15_guidance-on-registration-of-biosimilar-products.pdf
2.2 Choice of Reference Biological Product
The chosen reference therapeutic biological product must be a therapeutic biological
product registered in Singapore. A biosimilar product cannot be used as a reference
product.
The same chosen reference biological product should be used throughout the
comparability assessment for quality, safety and efficacy studies during the development
of a biosimilar product in order to allow for the generation of coherent data and
conclusions. The active substance of a biosimilar product must be similar, in molecular
and biological terms, to the active substance of the reference therapeutic biological
product. The pharmaceutical form, strength, and the route of administration of the
biosimilar product should be the same as that of the Singapore reference biological
product (SRBP). Any deviations from or differences between the biosimilar product and
the SRBP will have to be justified by appropriate studies.
3 SUBMISSION PROCEDURE
• Prospective applicants are encouraged to discuss the submission and documentary
requirements in a pre-submission consultation prior to the submission of a biosimilar
product application. The request for a consultation should be made in writing, with
the purpose and agenda for the consult stated, via email to
HSA_TP_Enquiry@hsa.gov.sg.
• The application for a biosimilar product is to be submitted as a new drug application
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(NDA) via the abridged evaluation route. The timelines and fees applicable for a NDA
via the abridged evaluation route apply. The administrative requirements are as per
those required for an NDA via the abridged evaluation route.
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OFFICIAL (CLOSED) NON-SENSITIVE
Criteria for HSA approval of a
Biosimilar
• Active substance(s) should be similar in molecular and biological
terms to the Singapore reference biological product.
• Pharmaceutical form, strength and route of administration should
be the same as the Singapore reference biological product.
• Conditions of use must fall within the directions for use (including
indication(s), dosing regimen(s) and patient group(s)) of the
Singapore reference biological product.
• A biological product with no suitable Singapore reference
biological product will not qualify for registration as a biosimilar
product in Singapore.
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https://www.hsa.gov.sg/docs/default-source/hprg/therapeutic-products/guidancedocuments/guidance-on-therapeutic-product-registration-in-singapore_jan2019.pdf
19.1 Biosimilar Product
The standard generic approach of bioequivalence demonstration with reference to a
chemically-derived drug product is scientifically inappropriate for biosimilar product
applications since biological drugs are much more complex in their structure and
inherent properties as compared to chemically-derived drugs. The biosimilar product
approach, based on comparability (demonstration of similarity), should be followed.
The development of a biosimilar product involves stepwise comparability exercises
starting with the comparison of the quality characteristics of the biosimilar product and
the reference biological product. The demonstration of similarity in terms of quality is a
prerequisite for the reduction of the non-clinical and clinical dataset required for
registration. However, if relevant differences are found in the quality, non-clinical and/or
clinical data, the product is unlikely to qualify as a biosimilar product and a more
extensive non-clinical and clinical dataset may be required to support registration.
19.2 Singapore Reference Biological Product
The following are considerations for the choice of a biological reference product:
• The reference product should be a biological therapeutic product that is currently
registered in Singapore (hereinafter known as ‘Singapore reference biological
product’). A registered biosimilar product cannot be used as a reference product.
• The active substance(s) of the biosimilar product and the Singapore reference
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biological product should be similar in molecular and biological terms;
• The pharmaceutical form, strength and route of administration of the biosimilar
product should be the same as the Singapore reference biological product. Any
differences will require additional comparability assessment data and have to be
justified by appropriate studies; and
• The conditions of use for the biosimilar product must fall within the directions for use
(including indication(s), dosing regimen(s) and patient group(s)) of the Singapore
reference biological product. A biological product with no suitable Singapore reference
biological product will not qualify for registration as a biosimilar product in Singapore.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedand
Approved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241
719.htm
What are biosimilar products?
Biosimilars are a type of biological product that is licensed (approved) by the FDA
because they are highly similar to an already FDA-approved biological product, known as
the biological reference product (reference product) and have been shown to have no
clinically meaningful differences from the reference product. Minor differences in
clinically inactive components are allowed. But there must be no clinically meaningful
differences between the biosimilar and the reference product it was compared to in
terms of the safety, purity, and potency of the product
Biological products are made from a variety of natural sources and, like drugs, biological
products are used to either treat or cure diseases and medical conditions, prevent
diseases, or diagnose diseases. Biological products can be made of sugars, proteins,
nucleic acids, complex combinations of these substances, or may be living entities such as
cells and tissues.
What are interchangeable products?
Interchangeable products are both biosimilar to an FDA-approved reference product, and
can be expected to produce the same clinical result as the reference product in any given
patient. An interchangeable product may be substituted for the reference product
without the intervention of the health care provider who prescribed the reference
product.
In addition, for a biological product that is administered more than once to an individual,
the risk in terms of safety or efficacy of alternating or switching between the biological
product and the reference product will not be greater than the risk of using the reference
product without alternating or switching.
Prescribing biosimilars and interchangeables:
Health care professionals can prescribe biosimilar and interchangeable products just as
they would prescribe other medications- by writing the proprietary name or
nonproprietary name on the prescription.
A biosimilar can be approved only for those indications and condition(s) of use previously
approved for the reference product, but a biosimilar can be approved for fewer than all
the indications and condition(s) of use approved for the reference product. Therefore, it
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is important for health care professionals to review the product labeling (prescribing
information) to determine which conditions of use and routes of administration the
biosimilar was approved for.
Because interchangeable products have met additional criteria for approval, they may be
substituted at the pharmacy without the intervention of a healthcare provider.
Currently, there is only one biosimilar approved for use in the U.S. – Zarxio (filgrastimsndz), which is biosimilar to Neupogen (filgrastim).
How are biosimilars and interchangeables approved?
The Patient Protection and Affordable Care Act (Affordable Care Act), signed into law by
President Obama on March 23, 2010, amended the Public Health Service Act (PHS Act) to
create an abbreviated licensure pathway for biological products that are demonstrated to
be “biosimilar” to or “interchangeable” with an FDA-licensed (approved) biological
product. This pathway is provided in the part of the Affordable Care Act known as the
Biologics Price Competition and Innovation Act of 2009 (BPCI Act).
What data does the FDA review to determine biosimilarity and interchangeability?
The manufacturer’s application for a biosimilar or interchangeable biological product
must include, among other things, information demonstrating biosimilarity based upon
data from:
Analytical studies demonstrating that the biological product is “highly similar” to the
reference product notwithstanding minor differences in clinically inactive components;
Animal studies (including the assessment of toxicity); and
A clinical study or studies (including the assessment of immunogenicity and
pharmacokinetics (PK) or pharmacodynamics (PD)) that are sufficient to demonstrate
safety, purity, and potency in 1 or more appropriate conditions of use for which the
reference product is licensed and for which licensure is sought for the biosimilar product.
An application for an interchangeable biological product also must include data or
information to show that the proposed interchangeable biological product is expected to
produce the same clinical result as the reference product in any given patient. In addition,
for a product that will be administered more than once to an individual (as many
biological products are), the application must include information that demonstrates that
the risk in terms of safety or diminished effectiveness of alternating or switching between
use of the proposed interchangeable product and the reference product is not greater
than the risk of using the reference product without alternating or switching.
The goal of this approval pathway is to demonstrate biosimilarity or interchangeability
between the proposed product and a reference product, not to independently establish
safety and effectiveness of the proposed product.
HSA – GUIDANCE ON REGISTRATION OF BIOSIMILAR PRODUCTS
2.2 Choice of Reference Biological Product
The chosen reference therapeutic biological product must be a therapeutic
biological product registered in Singapore. A biosimilar product cannot be used as
a reference product.
The same chosen reference biological product should be used throughout the
comparability assessment for quality, safety and efficacy studies during the
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development of a biosimilar product in order to allow for the generation of
coherent data and conclusions.
The active substance of a biosimilar product must be similar, in molecular and
biological terms, to the active substance of the reference therapeutic biological
product.
The pharmaceutical form, strength, and the route of administration of the
biosimilar product should be the same as that of the Singapore reference
biological product (SRBP). Any deviations from or differences between the
biosimilar product and the SRBP will have to be justified by appropriate studies.
If the comparative studies are performed with a reference biological product
(RBP) from a non-Singapore registered manufacturing source, the manufacturer
needs to demonstrate that the RBP is comparable to the SRBP and hence suitable
to support the application for marketing authorisation of a biosimilar product by
providing an additional bridging study. The type of bridging data needed will
typically include data from analytical studies (e.g. structural and functional data)
that compare all three products (the proposed biosimilar product, the SRBP and
the RBP), and may also include clinical PK and/or PD bridging studies data for all
three products. All comparisons should meet the target acceptance criteria for
analytical and PK/PD similarity which will be determined on a case-bycase/product-type basis. A final determination regarding the adequacy of the
scientific justification and bridging data will be made during the evaluation of the
application.
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Summary of Biological Products
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Biological products
Originator
Biologicals
– Used as “reference
product” for the
development of biosimilar
products
Biosimilar products
– Biologicals that can be
marketed after patent of
the originator biological
products have expired
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Are biosimilars patentable?
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Are biosimilars interchangeable
with the biologics?
• Unlike generic chemical drugs, a biosimilar product does
not usually have an identical structure to the reference
biological product.
• Even though a biosimilar product may be approved to be
similar in terms of quality, safety and efficacy to the
reference biological product, switching between products
may trigger an immune response in the patients.
• A warning statement on the risks associated with the
switching of products during treatment is to be included in
the package insert of the biosimilar product.
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Next Week’s Topic:
Parallel import & Licences –
Manufacturer, importer,
wholesaler
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