Original drugs, generic drugs,
biosimilars, drugs for modern
therapy, orphans
Fundamental Terms
The Czech Act on Pharmaceuticals (AP) defines
the following terms:
• Substance
• Medicinal Product
What is a substance?
Any matter irrespective of origin, which may be
• human (e.g. human blood or its constituents);
• animal (e.g. microorganisms, toxins, parts of
organs, animal secretions, extracts);
• vegetable;
• chemical.
What is considered a substance?
• Active substances (form part of MPs; initiate
the MP’s effect; this effect is usually
pharmacological, immunological or modifies
the metabolism)
• Excipients (form a part of MPs; have no
therapeutic effect in the quantities applied
and are vital for the manufacture, preparation,
storage or application of MPs)
What is a medicinal product?
• a substance or combination of substances
presented as having therapeutic or preventive
properties or as having influence over
physiological functions, or administered to set
the medical diagnosis.
The PA fails to define “pharmaceuticals” and
“drugs”
…nevertheless, the terms
“pharmaceutical” and “active substance”
“drug” and “medicinal product”
can be considered equivalents.
Names of drugs/MPs
• systemic names, chemical names
• code names
• generic names
• national and international non-proprietary
names (INN)
• Pharmacopoeia names
• Trade names, manufacturer names
Code Names
• working names of medicinal products during
research
• often alphanumeric combinations
• used until an INN-compliant name is allocated
• Example: GSK-184072 (manufacturer: GSK),
originally SRT-501 (manufacturer: Sirtris)
• Example: RU-486
Generic Names
• Internationally used name first used by the
inventor or manufacturer to designate the
substance, adjusted to local language
standards
• Working designation of potential medicinal
products
• Must not be confused with “generics”!
INN – National and International Non-Proprietary Names
• Easy, short and unique names recognised globally as public
domain
• Established in 1950, in use since 1953
• Used only to designate accurately defined substances that can
be clearly characterised with a chemical name or formula
• Not allocated to combinations, herbal drugs or homeopathic
preparations
• INN names incorporate a system prefixes, infixes and suffices
• Example: simvastatin, metoprolol, trastuzumab, sunitinib
Trade/Manufacturer Names
• Protected names used by the manufacturer
Code name Generic name INN name Trade name
VUFB 10615 dosulepin dosulepin PROTHIADEN
GSK-184072 resveratrol resveratrol Stage III KH
T-20, DP 178 pentafusid enfuvirtid FUZEON
LY640315 Not known prasugrel EFFIENT
Ibuprofen…
• The history of this drug starts with Dr. Stewart Adams,
the scientific research manager of Boots Pure Drug
Company in the 1950s. It was patented in 1961
(BRUFEN)
• Analgesic, antipyretic, anti-inflammatory agent
• Generic name: ibuprofen
• INN: ibuprofen
• Systemic name: (RS)-2-(4-(2methylpropyl)phenyl)propanoic
acid
• Trade name: more than twenty…
Ibuprofen…
Generics vs. Original MPs
• Original MPs – originally conceived MPs
• Generic MPs – equivalents to original MPs that
may enter the market:
• once the patent protection of the original MPs expires
• once the principle of fundamental similarity with the
original MP is met
• the price of generic MPs is usually lower than the
price of original MPs
Generics vs. Original MPs
• Medicinal products that have equivalent qualitative
and quantitative composition in terms of active
substances and the same pharmaceutical form with
the reference medicinal product, and that have been
proved to be bioequivalent to the reference medicinal
product by relevant bioavailability studies;
• Various salts, esters, ethers, isomers, isomer
combinations, complexes or derivatives of active
substances are deemed the same active substance,
unless they have substantial different features in
terms of safety or effect;
Types of Bioequivalence Studies
A/ Pharmacokinetic Studies
• Pharmacokinetic studies are carried out when the
pharmaceutical creates measurable concentrations in
various biological liquids (e.g. plasma).
• The approach is based on the fact that the
pharmaceutical’s concentration in the place of its effect
cannot be generally measures and that there is a
relation between the safety, effectiveness and
concentration of a pharmaceutical or active metabolite
in systemic circulation.
Types of Bioequivalence Studies
A/ Pharmacokinetic Studies
• Cross-sectional structure, healthy volunteers
• Basic parameter = pharmacokinetic parameters (AUC, Cmax and
tmax, t1/2); generics must achieve 80-125% of the original MP’s
values so that both products may be declared bioequivalent.
Example of a cross-sectional study
Stage I Washout period Stage II
Group I Tested Reference
Product Product
Group II Reference Tested
Product product
aplikace ukončení aplikace ukončení
odběru odběru
DURATION OF BIOEQUIVALENCE STUDY
Types of Bioequivalence Studies
A/ Pharmacokinetic Studies
• WHO recommends n = 18 to 24 subjects
• Drugs are bioequivalent if their pharmacokinetic parameters are
essentially similar
• …90% reliability interval for the given FK parameters to be found
between 80 and 125% of the corresponding FK parameters of the
compared product (original MP)
• “Bioequivalence” does not necessarily mean “therapeutic
equivalence”
• Antiepileptic drugs? Antibiotics?
Proving Bioequivalence
B/ Pharmacodynamic Studies
• when FK studies are not suitable (products
where systemic absorption is not assumed)
• suitable for topical or inhalation
pharmaceutical forms
Proving Bioequivalence
• In vivo bioequivalence studies are always
required in the Czech Republic if the submitted
application for a generic drug registration
includes reference to the original product.
• In vitro bioequivalence studies (dissolution tests)
can be used solely in the registration of multiple
dosages of the same product or in certain
changes after the approval of both the original
and generic products, and in other cases.
• The position of the regulator (EMA, SUKL) is the
decisive factor.
Biosimilars
• …”generic approach” is not fitting
and justifiable by science in this
case…
Definition of “biosimilars”
“copies” of biotechnological pharmaceuticals
• after the patent protection of the original biotechnological
pharmaceutical expires
• Called Follow-on-Biologics, or FOBs for short, overseas.
• Another similar term, sometimes used e.g. in the terminology of
oncology, is biological treatment (affecting angiogenesis,
differentiation etc.)
In general terms, biological pharmaceuticals are pharmaceuticals
based on the products of micro- or macro-organisms (toxins,
treatment serums, blood products etc.)
“Biotechnological pharmaceuticals”
• manufacture is based on the use of recombinant DNA, produced via
prokaryotic or eukaryotic cells in artificial cultures.
• Very complex structure and molecular weight by two and more
orders higher than common synthetic pharmaceuticals.
• Effect and safety is based not only on the primary but also
secondary, tertiary and possibly quarterly structure.
• This extreme complexity means that these substances, or rather
their safety profile and effect, are very susceptible to change with
even the slightest variation in the manufacturing process – they are
DE FACTO ORIGINALS
“Biosimilars”
• protein nature
• immunogenicity
• sensitivity to chemical, physical and biological
agents
• inability to freely exchange equivalent
medicinal products with their content.
“Biologic Treatment” – Historical overview
• 1972: recombinant deoxyribonucleic acid (rDNA) acquired
• 1975: the first monoclonal antibody (MAb)
• First biotechnological pharmaceutical companies founded in the
follow-up, incl. Genentech in the USA and Biotech in Europe.
• 1982: recombinant insulin becomes the very first biotechnological
product (Genentech, marketed by Eli Lilly)
• 1986: products with significantly more complex structure enter the
market: monoclonal OKT3 antibody (OrthoClode®) or recombinant
interferon
European Regulation…
• EMEA/CHMP/437/2004 - Guideline on Similar Biological Medicinal
Products - overarching guideline – Being revised
• EMEA/CHMP/BWP/49348/2005 - Quality Issues
• EMEA/CHMP/3097/2002 - Guidance on Comparability - Non-clinical and
clinical issues
• EMEA/CHMP/89249/2004 - Clinical Investigation on the Pharmacokinetics
of Therapeutic Proteins
• EMEA/CHMP/BMWP/42832/2005 - Non-clinical and Clinical Issues - Being
revised
• EMEA/CHMP/BMWP/101695/2006 - Non/clinical and Clinical Issues After
a Change in the Manufacturing Process
• EMEA/CHMP/BMWP/14327/2006 - Immunogenicity assessment
Definition and Regulation in the PA
Biological medicinal product similar to the reference biological product.
• Safety and effect is assessed against a benchmark, i.e. the original
product.
• Safety and affect can be assessed solely for a single indication and the
results for others can be extrapolated if the effect in the given
indications is based on the same mechanism
• Data on the product’s immunogenicity must be submitted.
• A pharmacovigilance plan must be compiled and submitted for
approval, with emphasis on:
• expressions of immunigenicity;
• rare adverse effects.
Biosimilars in development…
Biosimilars registered in the Czech Republic
• 12 products at the moment
• substances:
Epoetin alfa – EPREX original MP (generics ABSEAMED, BINOCRIT,
EPOETIN ALFA HEXAL)
Epoetin zeta (RETACRIT, SILAPO)
Filgrastim – NEUPOGEN (BIOGRASTIM, FILGRASTIM HEXAL,
RATIOGRASTIM, ZARZIO)
Somatotropin (GENOTROPIN, HUMATROPE, ZOMACTON)
But in the outlook…
• Patents for more than
30 original MPs to
expire between 2012
and 2015
• This represents about
USD 64 bn by 2015
Monoclonal antibodies
belimumab
ipilimumab
brentuximab vedontin
denosumab
Belimumab
The first inhibitor targeted at a protein
stimulating B-lymphocytes (BLyS), which
reduces the number of abnormal B
lymphocytes causing the
Systemic Lupus Erythmatosis (SLE)
Ipilimumab
Inhibitor of CTLA-4 T lymphocytes receptor
By blocking this receptor, the T lymphocyte remains active against cancerous
cells as melanoma
Stage III clinical trial for treatment of non-small cell lung carcinoma (NSCLC),
small cell lung cancer (SCLC), and stage II trial for treatment of the
metastatic hormone-refractory prostate cancer.
Brentuximab vedontin
An antibody-drug conjugate (ADC) targeted at
CD-30
Used to treat the Hodgkin lymphoma after the
autologous stem cell transplant (ASCT) fails or
after the failure of two prior multi-agent
chemotherapy in patients who are not suitable
candidates for the ASCT
Denosumab
Receptor activator of nuclear factor kappa-B ligand
(RANK ligand, RANKL), which is the key mediator
of the function, formation and survival of
osteoclasts
Prevention of bone loss in patients with bone
metastases from solid tumours.
Fusion Proteins
Aflibercept
Belatacept
Contain molecules of
cytokine receptors or
adhesive molecules and a
part of the Fc fragment of
immunoglobulins that
increases molecular
stability
Aflibercept
• Recombinant fusion protein
• Dimetric glycoprotein contains a vascular
endothelial growth factor VEGFR-1 receptor.
•
• Neovascular (wet) age-related macular
degeneration (AMD).
Belatacept
• Fusion protein composed of the Fc fragment of a human
IgG1 immunoglobin linked to the extracellular domain of
CTLA-4
• Selective blocks co-stimulation of T-lymphocytes
indicated for prophylaxis of organ rejection in adults
after liver transplants
• Approved in combination with immunosuppresive
agents basiliximab, mycophenolate mofetil,
corticosteroids
Kinase Inhibitors
Vemurafenib
Vemurafenib
• Competitive small molecule of serinethreonine
(B-RAF) kinase
• Selective ATP inhibitor of the B-RAF kinase
pathway
• BRAF gene mutations in half of melanoma,
known as V600E
Advanced-Therapy Medicinal Products
Advanced-therapy medicinal products (ATMPs)
Medicinal products of
biological/biotechnological origin that include
• MPs for gene therapy, as defined in Section IV
of Annex I to Directive 2001/83/EC
• MPs for somatic cell therapy, as defined in
Section IV of Annex I to Directive 2001/83/EC
• MPs for tissue engineering, as defined under
letter (b) of Regulation EC 1394/2007
Committee for Advanced Therapies
• CAT (Committee for Advanced Therapies),
established by the EMA
• Prepares draft statement on the quality, safety
and effect of each advanced-therapy
medicinal product for final approval by the
CHMP (Committee for Human Medicinal
Products)
• Established under EC Regulation 1394/2007
National Legislation
• Section 2(a) and (q) of Act No. 378/2007 Coll.
(“Act on Pharmaceuticals”) that define
medicinal products for gene therapy and
medicinal products for somatic cell therapy
• Decree No. 228/2008 Coll., on MP Registration
(Annex 1, Section IV directly provides for
ATMPs)
National Legislation
Legislation that further provides for donations,
acquisition, examination and release of tissues
and cells for use in the manufacture of MPs:
• Act No. 296/2008 Coll. (“Act on Human
Tissues and Cells”)
• Decree No. 422/2008 Coll., on Detailed
Requirements to Ensure Quality and Safety of
Human Tissues and Cells for Human Use
European Legislation
• Directive 2001/83/EX on the community code
relating to medicinal products for human use
• Regulation No. 1394/2007 on advanced therapy
medicinal products (effective from 30 December
2008)
• Directive of the Commission No. 2009/120/EC
amending Directive 2001/83/EC on the
community code relating to medicinal products
for human use as regards advanced therapy
medicinal products
Gene Therapy
• Includes any procedure aimed to treat a
disease through genetic modification of the
patient’s cells.
• Genes, parts of genes, or oligonucleotides are
transferred into cells.
Gene Therapy
• The objective is to transfer genes or parts of
genes to suitable target cells to achieve the
optimum expression of the transferred genes
with the aim to:
• 1. ensure production of a missing substance
• 2. activate immunity system cells so that the
organism may initiate its own immunity response
Gene Therapies
• If the excision of a “bad” allele and its
replacement with a “correct” one was successful,
the doors for “genetic surgery” would open
• Gene therapy: effective treatment would change
the very genetic essence of the disease, not only
its symptoms
• Fears of “genetic doping” already present at the
Turin Winter Olympics
• Questions of “plastic genetics”
Genetic Transfer
In vivo
Transfer directly into the patient’s tissue using lyposomes or
viral vectors (adenoviruses or retroviruses)
Ex vivo
Transfer of cloned genes into cells in a culture
(transplantation of autologous genetically modified cells)
In vivo and Ex vivo gene therapy
Gene Therapies
• Somatic-cell gene therapy (= changes of
genetic information in somatic cells only)
• Germ-line gene therapy (also in stem cell
lines)
Gene Therapy
• of somatic cells
• applicable to single patients
• of stem cells
• applicable to multiple patients
• Germ-line therapy will always be unethical on principle,
since informed consent will always be missing.
• The subsequent generations will be formed by unwanted
results of our experiments.
• We will never be able to foresee all the consequences of
our experiments in the next generations.
Non-Therapeutic Genetic Modifications
- Ethical Problems
• Can the same approach be applied to the genetic
modification of human features that are not
directly related to disease?
• Certain human features have a genetic
component
• height
• colour of skin
• intelligence
Gene Therapy
First successful gene therapy performed on 24
September 1990 in NIH, Maryland, USA
ADA (adenosindeaminosis) deficiency
A four-year old girl suffers from ADA deficiency
Congenital primary combined immunodeficiency
caused by ADA deficiency due to a point gene
mutation for this enzyme (20q13-ter).
Accumulation of adenosine and deoxyadenosine
in tissues has a direct and indirect toxic effect on
T and B cells.
ADA
• In the treatment, the girl’s own
immunity system cells (primarily Tlymphocytes),
modified by having a
normal ADA gene copy inserted ex
vivo, were injected in her
• Several weeks into the gene therapy,
the immunity system’s performance
improved, and after several months,
the patient began to live a
“relatively normal life”
• The 1990 case received a lot of publicity
• The therapy was repeated with other patients
(10 to 12 treatments per patient)
• The gene therapy witnessed its first clear and
undisputed success by treating a related
disease, namely X-linked SCID
First Clear Success of the Gene Therapy: X-SCID
X-SCID (X-linked severe combined
immunodeficiency) – tied to the X-chromosome,
AR
Patients are boys who lack T-cells and NK,
number of B-cells is standard but unable to
produce Ab
• Mutation on the gene for IL-2 (in 2/3 of patients)
First Clear Success of the Gene Therapy: X-SCID
• the treatment was again ex vivo treatment
• a retrovirus containing the IL2R gene that codes the yc
cytokine receptor was used
• marrow bone stem cells exprimating CD34 (=only done
by haematopoietic marrow bone cells) were incubated
for three days in the presence of a retroviral vector
• in that time, the cells divided five to eight times
• these cells were later returned to the patients
• 9 of 11 patients experienced dramatic improvements
with the ability to lead normal lives
First Clear Success of the Gene Therapy: X-SCID
• however, two of the treated boys later
suffered from leukaemia, almost certainly due
to the activation of the LMO2 oncogene
• this oncogene was activated by the insertion
of the retrovirus in its vicinity
• this fact has lead to the suspension of
retroviral lymphocytes transduction studies in
some countries
• http://blisty.cz/art/11770.html
Jesse Gelsinger
• born 18/06/1981
• first symptoms at 2 years and eight months of age
• erratic behaviour; the condition deteriorates dramatically and the patient
enters coma after a protein-rich diet
• diagnosed with OTC (ornithine transcarbamylase
deficiency syndrome), a rare metabolic disease –
50% of children with this disease die within 1
month of birth
• however, JG’s disease is mild and treatable by medication and correct diet
• if the nutrition contains more proteins, more ammoniac is found in the
blood
OTC Syndrome
• the patient does not create the OTC protein
whose task is to remove excessive nitrogen within
the urea cycle
• the nitrogen from proteins accumulates in the
blood and brain as urea
• this may lead to permanent brain damage
• treatment: low-protein diet and, for instance,
phenylbiturate (conjugation with AMK and
exclusion of nitrogen in other form than urea)
• half of the patients die before reaching five years
of age
Jesse Gelsigner
• waits for his 18th birthday to give an informed consent to treatment
• receives genetic therapy on 13 September 1999; gets sick in the evening,
enters a coma the next afternoon
• dies on 17 September
• Within hours after doctors shot the normal OTC gene attached to a therapeutic
virus into his liver, Jesse developed a high fever. His immune system began raging
out of control, his blood began clotting, ammonia levels climbed, his liver
haemorrhaged and a flood of white blood cells shut down his lungs.
• the therapy is the evident and clear cause of the death
• the case causes horror in the scientific community and makes the media
headlines
• the case has lead to many questions concerning the quality of informed
consent
• much of the important information was subject to various business
secrets. Paul Gelsinger (the father) now blames the hospital of
concealing important information and of intentionally putting his son’s
life in jeopardy
The entire memoir of JG, written by his father, is available at http://www.jesse-
gelsinger.com
Possible candidates for gene therapy
• diseases caused by defects in a single gene:
ADA deficiency, cystic fibrosis, haemophilia,
familial hypercholesterolemy, alpha-1
antitrypsin deficiency
• diseases caused by defective interaction of
several genes: diabetes, hypertension
A. Gene Therapy Medicinal Products
• contain or consists of recombinant nucleus acid
used in humans or administered to humans to
regulate, repair, exchange, add or remove genetic
sequences ;
• their therapeutic, prophylactic or diagnostic
effect applies directly to the sequence of the
contained recombinant nucleus acid, or to the
product of the sequence’s genetic expression.
A1. Medicinal Products Containing GMOs
• GMO – Genetically modified organism
• Organisms (not human) capable of
reproduction whose hereditary material was
changed by genetic modification carried out
by a technical procedure set out by the law.
• Gene therapy ATMPs may contains GMOs
(e.g. viral vectors)
GMOs – Legislation
• Regulated by the Ministry of Environment in the
Czech Republic
• GMOs and genetic products may be handled
solely under a license issued under the applicable
legislation
• All the decisions of the Ministry issued under Act
No. 78/2004 Coll., on Handling Genetically
Modified Organisms and Genetic Products, are
published in the Approved GMOs Registry and
the GMO Users Registry
B. Medicinal Products for Somatic Cell Therapy
• contain or consist of cells or tissues that were
subjected to substantial manipulation or cells or
tissues that are not designed for use for the
same fundamental function in the recipient and
donor;
• are used for treatment, prevention or
diagnostics of diseases based on the
pharmacologic, immunologic or metabolic effect
of their cells or tissues, or are used in or
administered to humans for this purpose
Non-substantial Manipulations
• listed in Annex I to Regulation (EC) No.
1394/2007
• cutting, grinding, shaping, centrifugation,
soaking in antibiotic or antimicrobial
solutions, sterilisation, irradiation, cell
separation, concentration or purification,
filtering, lyophilisation, freezing,
cryopreservation, vitrification.
Somatic Cell Therapy Medicinal Products
Example:
• Provenge – prepared by in vitro cultivation of
Dendritic cells and with prostatic acid
phosphatase to treat prostate cancer resisted
to hormonal therapy. Registered in the USA.
• Substantial manipulation (cultivation) +
immunologic mechanism-based effect
Provenge
C. Tissue Engineered Medicinal Products
• serve to recover, repair or replace human
tissue, or is used in or administered to
humans for this purpose
• cells or tissues were subjected to substantial
manipulation or cells or tissues that are not
designed for use for the same fundamental
function(s) in the recipient equivalent to the
fundamental function(s) in the donor
Tissue Engineered Medicinal Products
Example:
• Chondreocelect – viable autologous cartilage
cells that are expanded ex vivo, exprimate
specific protein markers to treat cartilage
lesions. Registered in the EU.
• Substantial manipulation (cultivation) +
designed for tissue reparation
Chondrocelect
Source: http://www.tigenix.com
“Orphan Drugs”
Rare Disease
• Rare disease: prevalence of < 5:10000 [Orphan Drug
Regulation 141/2000] = 27 – 36 million in the EU
• 5,000 to 8,000 diagnoses with this definition are
estimated
• Corresponds to about 5% of population (Germany: 4
million; Czech Republic: 0,5 million)
• Predominantly chronic, progressive, degenerative, lifethreatening
diseases or diseases deteriorating the
quality of life
• 50% is found in children, and 80% is of genetic origin
Rare Disease Medicinal Products (Orphans)
• 2000: EC Regulation No. 847/2000
• Diseases with prevalence ≤ 5/10,000;
diagnosis/prevention/treatment of lifethreatening
or chronically incapacitating
diseases
• Incentives for research and manufacturers
COMP (Committee for Orphan Medicinal
Products) of EMA
Incentives for Research, Development
and Marketing
• Assistance in the administrative registration process
• significant for small and medium enterprises
• Access to centralised procedure
• registration in the entire EU
• Waiver of or discount from the registration fees
• Exclusive right on the market
• 10 years
• Access to other EU incentives
• framework programs of support to public health research
COMP regulation – EU
Designation of “Orphan Drugs” in the EU
Orphan drug designation
Evaluation of medicinal credibility
Application for orphan drug designation
Yes No
No Yes
No prevalence less than 5/10,000 Yes
Do MPs or therapies exist?
Does new drug bring significant improvement?
No Yes Overall
evaluation
Rejected No Yes
review
US Orphan Drug Act – 1983 (FDA)
• 1983-2008:
• - 1,892 designations
• - 326 registrations
• - 200 diagnoses
• - predominantly oncology
Orphans Regulation in the Czech Republic –
Reimbursement of Highly Innovative MPs (VILP)
• Section 39d: temporary reimbursement from health insurance
• 1. product has no alternatives;
• 2. product may be used to treat diseases that so far could not be
treated by existing therapy with sufficient success, and the existing
data indicate clinically significant improvement of effect;
• 3. the products signal an entirely new concept of treatment
compared to the existing therapy when the existing therapy is not
sufficiently suitable for a significant group of patients, and there
clinically significant improvement of effect and safety is reasonably
assumed.
• The S symbol (expensive treatment in centres)
Register of designated Orphan
Medicinal Products (alphabetical)
• http://ec.europa.eu/health/documents/comm
unity-register/html/alforphreg.htm