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Marketing authorization applications
for TRYPACLEAR® and MANIACLEAR®

Work presented as part of Regulatory Affairs training (2017 – 2018) by:

Dalila BENAMMAR
Ahlem BOUAZIZ
Anaïs FAUCHE
Emilie PEREZ

Abbreviations and acronyms ................................................................................................................... 6
I. Background ........................................................................................................................................... 8
1. Our (hypothetical) company ........................................................................................................... 8
2. The trypanosomatids: a global concern .......................................................................................... 9
2.1. Human health ........................................................................................................................... 9
2.2. Animal health ......................................................................................................................... 11
3. GNF6702: a selective inhibitor of the trypanosomatids proteasome ........................................... 12
3.1. Trypanosomatids proteasome ............................................................................................... 12
3.2. GNF6702 ................................................................................................................................. 13
II. Regulatory Affairs approaches .......................................................................................................... 14
1. Human indications......................................................................................................................... 14
1.1. HAT current drugs overview ................................................................................................... 14
1.2. Chagas disease current drugs overview ................................................................................. 15
1.3. Marketing Authorization Procedures ..................................................................................... 17
1.3.1. FDA procedure................................................................................................................. 17
1.3.1.1. The Tropical Disease Priority Review Voucher ......................................................... 17
1.3.1.2. Investigational New Drug (IND) Application............................................................. 17
1.3.1.2.1. Contents ............................................................................................................ 17
1.3.1.2.2. Submission......................................................................................................... 18
1.3.1.2.3. Review time ....................................................................................................... 18
1.3.1.2.4. Consultation ...................................................................................................... 18
1.3.1.3. Chemistry, Manufacturing, and Controls (CMC) ...................................................... 19
1.3.1.3.1. List of guidances ................................................................................................ 19
1.3.1.3.2. Drug Master File (DMF) ..................................................................................... 19
1.3.1.3.3. Drug substance .................................................................................................. 19
1.3.1.3.4. Drug product ..................................................................................................... 20
1.3.1.4. Non-clinical studies .................................................................................................. 20
1.3.1.4.1. List of guidances ................................................................................................ 20
1.3.1.4.2. Pharmacology and pharmacokinetics studies ................................................... 21
1.3.1.4.3. Toxicology studies ............................................................................................. 21
1.3.1.5. Clinical Trials ............................................................................................................. 22
1.3.1.5.1. List of guidances ................................................................................................ 23
1.3.1.5.2. Phase I clinical trials........................................................................................... 23
2

1.3.1.5.3. Phases II and III clinical trials ............................................................................. 24
1.3.1.6. New Drug Application (NDA) .................................................................................... 25
1.3.1.6.1. Contents ............................................................................................................ 25
1.3.1.6.2. Submission......................................................................................................... 25
1.3.1.6.3. Review time ....................................................................................................... 25
1.3.1.6.4. Fees.................................................................................................................... 26
1.3.1.7. Common Technical Document (CTD) ....................................................................... 26
1.3.1.7.1. List of guidances ................................................................................................ 26
1.3.1.7.2. Module 1 (US) – Administrative information .................................................... 26
1.3.1.7.3. Module 2 – Summaries and overviews ............................................................. 27
1.3.1.7.4. Module 3 – Quality ............................................................................................ 27
1.3.1.7.5. Module 4 – Safety.............................................................................................. 27
1.3.1.7.6. Module 5 – Efficacy ........................................................................................... 27
1.3.1.8. Paediatric Investigational Plan (PIP) and initial Paediatric Study Plan (iPSP) ........... 27
1.3.1.8.1. List of guidances ................................................................................................ 28
1.3.1.8.2. PIP and iPSP contents ........................................................................................ 28
1.3.1.8.3. PIP and iPSP procedures .................................................................................... 29
1.3.1.9. Pharmacovigilance (US and EU) ............................................................................... 30
1.3.1.9.1. List of guidances ................................................................................................ 30
1.3.1.9.2. Pharmacovigilance System Master File (PSMF) ................................................ 31
1.3.1.9.3. Summary of applicant PV system ...................................................................... 31
1.3.1.9.4. Periodic Safety Update Reports (PSURs) ........................................................... 31
1.3.1.9.5. Risk Management Plan (RMP) ........................................................................... 32
1.3.1.9.6. Literature monitoring ........................................................................................ 32
1.3.1.9.7. Post-Authorization Safety Study (PASS) ............................................................ 32
1.3.1.10. Risk Management Plan (RMP) ................................................................................ 33
1.3.1.10.1. Guideline ......................................................................................................... 33
1.3.1.10.2. RMP structure.................................................................................................. 33
1.3.2. European procedures ...................................................................................................... 36
1.3.2.1. SME qualification process ........................................................................................ 36
1.3.2.2. National procedure (France) .................................................................................... 37
1.3.2.2.1. Overview and guidelines ................................................................................... 37
1.3.2.2.2. CTD Module 1 (EU) ............................................................................................ 37
1.3.2.3. Article 58 procedure (EMA) for use outside Europe ................................................ 38
3

1.3.2.3.1. Guideline ........................................................................................................... 39
1.3.2.3.2. Article 58 eligibility ............................................................................................ 39
1.3.2.3.3. Pre-submission meeting .................................................................................... 39
1.3.2.3.4. Submission application ...................................................................................... 39
2. Veterinary indications ................................................................................................................... 40
2.1. Current drugs overview .......................................................................................................... 40
2.2. Summary of the regulatory strategies.................................................................................... 40
2.3. Clinical Trials ........................................................................................................................... 41
2.4. Maximum Residue Limits (MRL) ............................................................................................. 42
2.4.1. Contents of the dossier ................................................................................................... 42
2.5. Marketing Authorization Procedures ..................................................................................... 45
2.5.1. Decentralised Procedure (DP) ......................................................................................... 45
2.5.1.1. Introduction.............................................................................................................. 45
2.5.1.2. Composition of the Marketing Authorization Dossier ............................................. 46
2.5.1.2.1. Contents of eAF ................................................................................................. 47
2.5.1.3. Additional requirements for the labelling depend on countries ............................. 52
2.5.1.4. Fees........................................................................................................................... 53
2.5.2. Certificate of origin .......................................................................................................... 53
2.5.2.1. Procedures................................................................................................................ 53
2.5.2.2. Composition of the dossier ...................................................................................... 54
2.5.3. Marketing Authorization procedures in Africa ................................................................ 54
2.5.3.1. Tunisia ...................................................................................................................... 54
2.5.3.1.1. Introduction ....................................................................................................... 54
2.5.3.1.2. Registration procedure ...................................................................................... 55
2.5.3.1.2.1. Appointment booking ................................................................................ 56
2.5.3.1.2.2. Submission files .......................................................................................... 56
2.5.3.1.2.3. Clinical and preclinical data assessment .................................................... 56
2.5.3.1.2.4. Data quality assessment of medicinal products ......................................... 56
2.5.3.1.2.5. Assessment of the Marketing Authorization application by the CTSP ....... 56
2.5.3.1.2.6. Marketing Authorization grant................................................................... 57
2.5.3.1.3. Composition of the registration dossier............................................................ 57
2.5.3.1.4. Fees.................................................................................................................... 58
2.5.3.1.5. Veterinary drug control from the boarder ........................................................ 58
2.5.3.2. UEMOA ..................................................................................................................... 59
4

2.5.3.2.1. Introduction ....................................................................................................... 59
2.5.3.2.2. Marketing Authorization procedure ................................................................. 59
2.5.3.2.3. Composition of the Marketing Authorization Dossier ...................................... 60
2.5.3.2.4. Fees.................................................................................................................... 60
2.5.3.3. Cameroon ................................................................................................................. 60
2.5.3.3.1. Regulatory framework....................................................................................... 60
2.5.3.3.2. Applicable legislation......................................................................................... 60
2.5.3.3.3. Marketing Authorization procedure ................................................................. 61
2.5.3.3.4. Requirements for registration ........................................................................... 61
2.5.3.3.5. Composition of the Marketing Authorization Dossier ...................................... 61
2.5.3.3.6. Samples ............................................................................................................. 63
2.5.3.3.7. Fees.................................................................................................................... 63
2.5.3.4. Democratic Republic of the Congo (DRC)................................................................. 63
2.5.3.4.1. Regulatory Framework ...................................................................................... 63
2.5.3.4.2. Southern African Development Community (SADC) Project framework .......... 64
2.5.3.5. Ethiopia..................................................................................................................... 65
2.5.3.6. CHAD......................................................................................................................... 65
2.5.4. Pharmacovigilance System (PVS) .................................................................................... 66
3. Summary........................................................................................................................................ 69
III. Annexes ............................................................................................................................................ 70
IV. Bibliography ..................................................................................................................................... 88

5

Abbreviations and acronyms
AAT
AE
ANSM
CA
CDC
CFR
cGMP
CHMP
CMC
CNS
CRPV
CTA
CTD
CVMP
DEC
DMF
DP
EC
eCTD
EEA
EMA
EPAR
EU
EUA
EV
EVVet
ESG
FDA
FD&C
DNDi
GCP
GLP
GMP
GVP
HAT
ICH
iPSP
IND
MA
MAA
MAD
MAH

Animal African Trypanosomiasis
Adverse Events
Agence Nationale de Sécurité du Médicament et des produits de santé
Competent Authority
Centers for Disease Control and Prevention
Code of Federal Regulations
current Good Manufacturing Practice
Committee for Medicinal Products for Human Use
Chemistry, Manufacturing, and Controls
Central Nervous System
regional pharmacovigilance centers
Clinical Trials Application
Common Technical Document
Committee for Medicinal Products for Veterinary Use
Disease Endemic Country
Drug Master File
Decentralised Procedure
European Commission
electronic Common Technical Document
European Economic Area
European Medicines Agency
European Public Assessment Report
European Union
Emergency Use Authorization
EudraVigilance
EudraVigilance Veterinary
Electronic Submission Gateway
U.S. Food and Drug Administration
Federal Food, Drug & Cosmetics
Drugs for Neglected Diseases initiative
Good Clinical Practice
Good Laboratory Practice
Good Manufacturing Practice
Good Pharmacovigilance Practice
Human African Trypanosomiasis
International Conference for Harmonisation
initial Paediatric Study Plan
Investigation New Drug
Marketing Authorization
Makteting Authorization Application
Multiple Ascending Doses
Marketing Authorization Holder
6

MS
NCA
NDA
NECT
NTD
OIE

Member State
National Competent Authority
New Drug Application
Nifurtimox-eflornithine combination therapy
Neglected Tropical Disease(s)
Organisation Mondiale de la Santé Animale/World Organisation for Animal
Health
PAHO
Pan American Health Organization
PASS
Post-Authorization Safety Studies
PAES
Post-Authorization Efficacy Studies
PDCO
Paediatric Committee
PIP
Paediatric Investigation Plan
PRAC
Pharmacovigilance Risk Assessment Committee
PSMF
Pharmacovigilance System Master File
PSUR
Periodic Safety Update Reports
PV
Pharmacovigilance
PVS
Pharmacovigilance System
QPPV
Qualified Person for Pharmacovigilance
RMP
Risk Management Plan
RMS
Reference Member State
SA
Scientific Advice
SAD
Single Ascending Doses
SAWP
Scientific Advice Working Party
SBIA
Small Business & Industry Assistance
SME
Small and Medium-sized Entreprise
SmPC
Summary of Product Characteristics
spp.
Species pluralis
subsp.
Subspecies
UPI
Unique Product Identifier
US
United States
USC
United States Code
VICH
Veterinary International Conference for Harmonisation
VMPs/VMP Veterinary Medicinal Products/Veterinary Medicinal Product
WHO
World Health Organization

7

I. Background
1. Our (hypothetical) company
EAhD is a medium-sized pharmaceutical company with headquarters in Paris, France. In France, EAhD
also has Research and Development department (GLP certified) with 40 employees, Control Quality
laboratories (cGMP certified) with 20 employees and a drugs manufacturing plant (cGMP certified)
with 80 employees in Parisian region. The company hold another drugs manufacturing plant (cGMP
certified) with 80 employees in Boston, US (Figure 1). EAhD has €32 million in annual turnover.
Specialized in drugs for Neglected Tropical Diseases (NTD), EAhD has produced generics based on old
drugs designed to treat mainly Human African Trypanosomiasis (HAT or sleeping sickness) and
Chagas disease. For ten years, the company has joined the Drugs for Neglected Diseases initiative
(DNDi 1) to develop a new treatment for HAT and Chagas disease. DNDi provided regulatory
supports2 and help to find international founding supports to realize clinical trials in South America.
EAhD also benefited from the support of the European Medicines Agency (EMA) because of its SME
statute (see “User guide for micro, small and medium-sized enterprises” established by EMA based
on regulation (EC) N° 726/2004 provisions and revised in July 20163) and from the support of the U.S.
Food and Drug Administration (FDA) because of its NTD new drug development (see part II.
Regulatory Affairs approaches) and its SME statute (Small Business & Industry Assistance (SBIA)).
Now, after years of preclinical and clinical analyses, EAhD is ready to introduce on the market a new
chemical drug discovered from a phenotypic approach: GNF6702.

Figure 1: EAhD’s organizational chart

1

https://www.dndi.org/
DNDi is the primary sponsor for 33% of Clinical Trials Application for HAT and Chagas disease according to
WHO International Clinical Trials Registry Platflorm (WHO ICTRP, Annexes 1 and 2)
3
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/
WC500004134.pdfhttp://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_gu
ideline/2009/10/WC500004134.pdf
2

8

2. The trypanosomatids: a global concern
The trypanosomatids are human and animals parasites which cause lethal and disabling diseases. In
human, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense are responsible for
HAT in Africa (Figure 2), Trypanosoma cruzi for the Chagas disease in South America (Figure 3) and
Leishmania spp. for leishmaniasis in Asia, Middle-East and South America [1]. In animals, Leishmania
infantum is responsible for canine leishmaniasis in the southern European countries (mainly in South
of France, parts of Spain and Italy) [2], Trypanosoma brucei brucei, Trypanosoma congolense and
Trypanosoma vivax for cattle trypanosomiasis (also called Nagana disease or Animal African
Trypanosomiasis (AAT)) in sub-Saharan Africa [3] and Trypanosoma evansi for the camel
trypanosomiasis (or Surra disease) in Middle-East and Northern Africa [4] (Figure 4).

Figure 2: Distribution of Human African Trypanosomiasis (a. Trypanosoma brucei gambiense, b. Trypanosoma
brucei rhodesiense), worldwide, 2016 (adapted from WHO)

2.1. Human health
The trypanosomatids infections affect 20 million people worldwide and lead to more than 50 000
deaths annually, mainly in poor communities in South America, Africa and Asia [1,5] (Figure 3). The
Chagas disease is imported in the USA and Europe due to immigration from South America [6,7] and
HAT can affect travellers to sub-Saharan Africa [8,9] as well as migrants from Disease Endemic
Countries (DECs) [10,11]. However, these diseases are rare in European non-DECs. Between 2000 and
2010, 94 HAT cases were reported in 19 non-DECs [10] and, in 2009, 4 290 Chagas disease cases were
diagnosed in nine European non-DECs [12]. In non-DECs, the real problem for HAT is to make the
good diagnosis. Most of the time, the patient is suspected to have malaria and is treated for this
disease before the good diagnosis is made (after a microscopy analysis of the patient blood) [8–10].
However, HAT specific treatments (melarsoprol, eflornithine, suramin and nifurtimox) are available
for these patients through the process of anti-trypanosome drugs request to WHO which ensure the
delivery between 24 and 48 hours [10]. In the same way, Chagas disease treatments (nifurtimox and
benznidazole) are available for the North American residents through a drug request to the Centers
for Disease Control and Prevention Drug Service (CDC Drug Service) [13].

9

Figure 3: Distribution of Chagas disease, worldwide, 2006-2009 (WHO)

In 2016, WHO received reports of only 2 184 new cases of HAT in DECs (mainly in Democratic
Republic of the Congo which reported over 75 % of the cases in the last ten years). It represents the
lowest number of HAT cases ever recorded and demonstrates that the elimination of this disease as a
public health problem by 2020 (fewer than 2 000 reported cases by year) is on track (according to the
WHO website).
Contrariwise, Chagas disease, which is present mainly in 21 Latin American countries, kills over
10 000 people every year from its clinical manifestations. An estimated 8 million people are infected
worldwide and more than 25 million people risk acquiring this disease (according to the WHO
website). In 2005, the Pan American Health Organization (PAHO) estimated the prevalence of the
disease in Latin American-born persons living in the US at 300 167 persons. According to this
estimation and based on probability to present clinical manifestations, the researchers calculated
that 30 000 to 45 000 individuals likely to have undiagnosed Chagas cardiomyopathy [14]. Thus
Chagas disease stays one of the major parasitic diseases of the American continent.
Each disease presents two stages. For HAT, they are called stage 1 (haemolymphatic stage) and stage
2 (meningoencephalitic stage) which occurs when the parasites enter into the Central Nervous
System (CNS) [15]. For Chagas disease, they are called acute phase (early infection, when the host
immune system responds) and chronic phase (multi-year, sometimes lifelong) when cardiac and
digestive pathologies can be developed by the host [5].

10

2.2. Animal health
The trypanosomiases in animals (Surra and Nagana diseases, respectively caused by Trypanosoma
evansi and Trypanosoma brucei brucei, Trypanosoma congolense or Trypanosoma vivax) are
economics burden in Africa. These diseases can decimate and disable (causing anemia, lethargy,
immunodepression, weakness and emaciation) cattle and camel in countries where these animals
represent commercial interests and alimentation source [16,17].

Figure 4: Geographical distribution of Trypanosoma evansi in the world, 2013 (from Desquesnes et al. 2013
[4]).

For instance, in the desert areas, Ethiopians mainly depend on camels which are a vital animal to
their daily life as a source of food, means of transportation and their milk is used as a medicine [18].
In Somalia (or Somaliland) studies have shown that the total population could potentially lose
US$223 164 per year [19]. Available information on the prevalence of Surra caused by Trypanosoma
evansi in many countries of the world as reported, are: Mauritania 25% [20], Niger 29% [21], Kenya
28% [22], Ethiopia 21% [23], Sudan 37% [24], Egypt 67% [25], Algeria 14% [26], Morocco between 1418% [27], Tunisia 10% [28], Somalia 38,2% [19] and first outbreaks have been reported in Spain [29]
and France [30].
In the same way, Nagana disease causes serious economic crisis for agriculture sector in Africa, due
to losses in livestock from anemia, and they were estimated to be more than US$4,74 milliard per
year [31]. In the west Democratic Republic of the Congo, Nagana disease was considered in 2013 as
being the main cause of death in cattle, the prevalence rate was 13 % in the largest ranch called the
Mushie ranch [32]. The prevalence of Nagana in others countries is: Benin 6,7 % (in cattle) and 3,8 %
(in sheep) [33], Ethiopia 15 % [34] and Cameroon 40,7 % [35].
In Europe and Northern Africa, Leishmania infantum causes canine leishamniosis in the
Mediterranean basin [2]. Currently it is estimated that at least 2,5 million dogs are infected in southwestern Europe alone [36] and recent publications have reported a northward spread of the endemic
area [37]. Given that canine leishmaniasis is a potentially severe and fatal disease, it represents a
source of suffering for affected dogs and many dog owners are highly concerned about how best

11

they can protect their animals. Moreover, the dog is the principle reservoir for human infection, thus
a high prevalence of this canine disease also represents a zoonotic risk [38].

3. GNF6702: a selective inhibitor of the trypanosomatids proteasome
The parasitic trypanosomatids possess several different hosts and are transmitted to humans and
animals mainly by insect vectors. Leishmania spp. are transmitted by sandflies, Trypanosoma brucei
subsp. by the tsetse fly and Trypanosoma cruzi by triatomine bugs. The life cycle of these parasites is
complex and specific for each species, but two forms can be discriminated: mammalian form
(trypomastigote and amastigote) and insect form (epimastigote), commonly referred to as
bloodstream form and procyclic form, respectively (Figure 5). Trypanosoma evansi is an exception
since it is not able to undergo its life cycle in tsetse fly (due to a loss of mitochondrial/kinetoplastic
genetic material). It is “trapped” in its bloodstream form. Its transmission is mechanic and depends
always on biting insects but also by blood contact and carnivory behaviour. Nevertheless, the
trypanosomatids show a high level of genetic and biologic conservation which could be a key to cure
the diseases which they are responsible for, according to the researchers [4,17,39,40].

Figure 5: Trypanosoma brucei life cycle. a. bloodstream form, b. procyclic form (scale bar is 1 µm), and
c. schematic life cycle. (Adapted from parasite.org.au/ and De Souza et al. 2010 [41])

3.1. Trypanosomatids proteasome
Proteasomes are large multi-subunit, energy-dependent and proteolytic protein complexes that play
an essential role in various intracellular processes including normal proteins turnover and
degradation of misfolded proteins. Proteins destined to be degraded, are conjugated with one or
more ubiquitin chains (ubiquitinylated proteins) in order to be recognised and unfolded by regulatory
proteins that flank the proteolytic core of the proteasome. This proteolytic core of the complex,
called 20S proteasome, contains two stacked rings of seven β subunits between two rings of seven α
subunits (Figure 6). Each subunit is encoded by a separate gene, by consequent there are seven α12

type and seven β-type subunits. In this complex, only β1, β2 and β5 subunits have hydrolytic activity.
The β1 activity is commonly referred to as “caspase-like” activity, the β2 activity as “trypsin-like” and
the β5 as “chymotrypsin-like” [42]. The Trypanosoma proteasome is the most intensively studied of
the parasite proteasomes and the one of Trypanosoma brucei was the first to be purified and
characterized [43]. The Trypanosoma proteasome is essential for cell-cycle progression and cells
differentiation [44].

Figure 6: Scheme of the eukaryotic 20S proteasome (adapted from Bibo-Verdugo et al. 2016 [42]).

3.2. GNF6702
Our products TRYPACLEAR® and MANIACLEAR® are drug products containing our active substance (or
drug substance) GNF6702, a drug candidate for a selective inhibition of the trypanosomatids
proteasome, respectively designed to cure Chagas disease in human, and leishmaniasis, Nagana and
Surra diseases in animals. The compound GNF6702 was identified as a hit in a high-throughput
phenotypic study performed at the Genomics Institute of the Novartis Research Foundation (GNF)
(Figure 7) and the trypanosomatids proteasome was identified as its molecular target [40]. This
target has been validated based on several biological, biochemical and molecular analyses: (i) the
accumulation of ubiquitinylated proteins following the incubation of Trypanosoma cruzi with
GNF6702, (ii) mutations in the β4 gene are sufficient to confer resistance to biochemical proteasome
inhibition and cellular Trypanosoma cruzi growth inhibition, (iii) GNF6702 inhibits parasites
proteasome activity and does not inhibit the human proteasome. GNF6702 inhibits the
“chymotrypsin-like” activity in an unusual non-competitive manner, binding the β4 subunit (and not
β5 subunit) at a site near the β4-β5 interface. Finally, in a mouse model of Chagas disease, 20 days of
oral treatment with GNF6702 was sufficient to reduce Trypanosoma cruzi levels in blood, heart and
colon to undetectable levels [40,42].

Figure 7: Chemical evolution of GNF6702 from the phenotypic hit GNF5343 (Khare et al. 2016 [40]).

13

II. Regulatory Affairs approaches
1. Human indications
1.1. HAT current drugs overview
Five drugs are available in HAT treatment: pentamidine and suramin to treat first-stage, and
melarsoprol, eflornithine and nifurtimox to treat second-stage of the disease (Table 1).
Pentamidine is given intramuscularly once a day for 7 days or in intravenous infusion in saline over
2 hours as a first-line treatment for first-stage gambiense HAT (good efficacy) and an alternative for
rhodesiense HAT (limited efficacy). It is generally well tolerated but causes some adverse events as
hypoglycaemia, hypotension, abdominal pain and gastrointestinal problems [45]. Commercialised as
Pentacarinat® since 1988 in France, Sanofi is the current Marketing Authorization Holder (MAH) in
Europe (since 2008) and Armour Pharm in the USA.
Suramin is given slowly intravenously as a first-line treatment for first-stage gambiense and
rhodesiense HAT. Because of its complicate administration (recommended schedules are complex
and last up to one month), it is used mainly in rhodesiense HAT. A test dose has to be applied before
treatment due to the risk of hypersensitivity reactions. It causes frequent adverse events as pyrexia,
nephrotoxicity, peripheral neuropathy, agranulocytosis and thrombocytopenia [45]. Suramin is
commercialised as Germanin® by Bayer since 1916, and there is a lot of generics on the market.
Nifurtimox-eflornithine combination therapy (NECT) is the first-line treatment for the second-stage
gambiense HAT. It is a combination of oral nifurtimox and intravenous eflornithine, four times a day
for 4 days. NECT is well tolerated, especially in children. Its main adverse events are abdominal pain,
vomiting and headache. As nifurtimox is not authorised for HAT (only for Chagas disease), WHO
supplies DECs a full NECT kit (containing all drugs and material needed for its administration) free of
charge and with express authorization of the national authorities to treat HAT patients off-label [45].
When nifurtimox is unavailable or contraindicated, eflornithine is given as monotherapy, four times a
day for 14 days to treat second-stage gambiense HAT. This schedule imposes specific care to avoid
catheter-related infections and increases the risk of adverse events manifestations, as fever,
hypertension, nausea, vomiting, abdominal pain, headaches, septicaemia and, more rarely,
seizures [39,45]. Eflornithine is commercialised as Ornidyl® by Sanofi since 1990.
Melarsoprol is given intravenously during 10 days. It is restricted to treatment of second-stage
rhodesiense HAT because of its frequent, severe and life-threatening adverse drug reactions as
encephalopathic syndrome and cardiac failure (in addition to the other adverse events observed with
the other drugs) [39,45]. Sanofi is the MAH of Arsobal® which is authorised only for hospital use since
1997 in France. It is not available in the USA except through a “drug request” to Parasitic Disease
Drug Service.
Trypanosoma brucei gambiense has been becoming resistant to the drugs currently on the market.
Resistance to melarsoprol and pentamidine due to mutations in its genome has been documented.
Persistent use for decades of the same compounds without new ones coming onto market induces
resistance as an inevitable outcome [5,45].

14

The 31th January 2018, in a press release (Annex 3), Sanofi and DNDi have announced that Sanofi has
asked the EMA to review fexinidazole, a 10-day oral treatment for all stages of HAT. EMA has
accepted the application under the “article 58” procedure.
Fexinidazole is a perfect candidate to treat HAT: (i) it is a new drug (derived from phenotypic
approaches), (ii) its administration is easy (it is an oral treatment) and, (iii) it is presenting low levels
of toxicity [39,46].

1.2. Chagas disease current drugs overview
Currently, only two drugs are registered to treat Chagas disease: nifurtimox commercialised by Bayer
since 1960’s under the name of Lampit® and benznidazole commercialised by Roche since 1970’s
under the name of Radanil® (Table 1).
These two drugs are effective (up to 80%) during the acute phase (and in newborns with 99% cure)
but, during the chronic phase, the major limitation is the unsatisfactory ways to assess the cure (a
negative result does not indicate the absence of the parasite and the serology can remain positive in
patients for years after treatment). Furthermore, nifurtimox and benznidazole require long term
treatment (60 days) and both induce adverse events as gastrointestinal and neurological effects
(nausea, vomiting, anorexia, irritability, insomnia but also polyneuropathy and peripheral neuritis)
for nifurtimox, and dermatological and neurological effects (rashes, dermatitis, fever, peripheral
neuropathy etc) for benznidazole. For both, tolerance is better in children than in adults [5,13,39].
Like Trypanosoma brucei gambiense, Trypanosoma cruzi has been becoming resistant due to the use
of nifurtimox and benznidazol for decades [5].
A potential new drug is currently in clinical trials in Bolivia thanks to the partnership of Eisai Co. (a
Japanese pharmaceutical company) and DNDi: E1224 (or fosravuconazole) a prodrug of ravuconazole
(antifungal drug) [5]4.
According to these observations, (i) the Chagas disease prevalence which is higher than the HAT
prevalence, (ii) the soon release on the market of a new drug to treat HAT by Sanofi, and (iii) the lack
of safe and effective drugs to treat the Chagas disease, EAhD decided to introduce TRYPACLEAR®
with the unique indication of the Chagas disease to the FDA in the US and the ANSM (Agence
Nationale de la Sécurité des Médicaments et produits de santé) in France.
We will also present the alternative EMA procedure called “article 58” for use outside Europe.

4

Clinical Trials ID: NCT01489228 and NCT03378661 (Annex 2)

15

Table 1: Current drugs that are used to treat HAT and Chagas disease (from Field et al. 2017 [39]).

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1.3. Marketing Authorization Procedures

1.3.1. FDA procedure
The FDA is really concerned by Neglected Tropical Diseases and issued in 2014 guidance to industry
called “Neglected Tropical Diseases of the Developing World: Developing Drugs for Treatment or
Prevention”5 (referred as “FDA NTD guidance 1” below). This guidance gave us an overview of the
procedures needed to introduce a new drug for treat NTD in the US.

1.3.1.1. The Tropical Disease Priority Review Voucher
In 2016, the FDA issued guidance to industry: “Tropical Disease Priority Review Vouchers”6.
According to section 524(a)(3) of the FD&C Act (21 USC 360n(a)(3)7) and the FDA order published in
the Federal Register (80 FR 50559) (adding Chagas disease to the list of tropical diseases)8,
TRYPACLEAR® can benefit from the Tropical Disease Priority Review Voucher.
The priority review voucher is issued by the Secretary of Health and Human Services to the sponsor
of a tropical disease product application and entitles its holder to priority review of a single human
drug application after the date of approval of the tropical disease product application. This “priority
review” means review and action by the Secretary on the human drug application not later than 6
months after receipt by the Secretary.
The priority review voucher can be transferred (given or sold). For example, in 2017, Ultragenyx
obtained a priority review voucher and sold it for US$130 million to Novartis9.

1.3.1.2. Investigational New Drug (IND) Application

1.3.1.2.1. Contents
According to 21 CFR 312.23(a)10, the IND application contains:







Cover-sheet: Form FDA-1571 (Annex 4)
Table of contents
Introductory statement and general investigational plan
Investigator’s brochure
Protocols
Chemistry, manufacturing, and controls information

5

https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm269221.pdf
6
https://www.fda.gov/downloads/Drugs/Guidances/UCM080599.pdf
7
http://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title21-section360n&num=0&edition=prelim
8
https://www.gpo.gov/fdsys/pkg/FR-2015-08-20/pdf/FR-2015-08-20.pdf
9
http://ir.ultragenyx.com/static-files/ac8b6bae-230c-4917-84fc-2b2ce922ea33
10
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Pharmacology and toxicology information
Previous human experience with the investigational drug
Additional information
Relevant information

1.3.1.2.2. Submission
The initial IND submission must be submitted in triplicate to:
Food and Drug Administration
Center for Drug Evaluation and Research
Central Document Room
5901-B Ammendale Rd.
Beltsville, Md. 20705-1266
To submit any documents to the FDA electronically, we have to create an account on the Electronic
Submission Gateway (ESG) website:
https://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/default.htm

1.3.1.2.3. Review time
The review time for initial IND application is 30 days from the date FDA receives the IND.

1.3.1.2.4. Consultation
According to 21 CFR 312.8211, we can request to meet with FDA-reviewing officials early in the drug
development process to review and reach agreement on the design of necessary preclinical and
clinical studies during Pre-IND consultation with the Office of Antimicrobial Products.
Contacts:

Division of Anti-Infective Products
Carmen DeBellas 301-796-1203
Maureen Dillon-Parker 301-796-0706
FAX 301-796-9881

Moreover, according to 21 CFR 312.4712, meetings can be organized between the sponsor and the
agency during the course of clinical investigation. The end-of-phase 2 meeting can be useful to obtain
the FDA help to plan later studies and the Pre-NDA (New Drug Application) meeting can reduce
delays associated to the initial review of the marketing authorization.

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1.3.1.3. Chemistry, Manufacturing, and Controls (CMC)
During new drug application review, the FDA assesses the quality of the drug manufacturing process,
including inspection of manufacturing facilities within and outside the US. We have to provide
sufficient CMC information for the new investigational drug in our IND submission (information
reported in CTD Module 3 with the variations induced by phase I, phase II and phase III clinical trials
results).
1.3.1.3.1. List of guidances
According to FDA NTD guidance 1:



ICH guidance for industry Q7A “Good Manufacturing Practice Guidance for Active
Pharmaceutical Ingredients”
FDA guidance for industry “INDs for Phase 2 and Phase 3 Studies — Chemistry,
Manufacturing, and Controls Information”

We added:




ICH guidance for industry Q6A “Specifications : Test Procedures and Acceptance Criteria for
New Drug Substances and New Drug Products: Chemical Substances”
ICH guidance for industry Q1A(R2) “Stability Testing of New Drug Substances and Products”
FDA guidance for industry “cGMP for Phase 1 Investigational Drugs”

1.3.1.3.2. Drug Master File (DMF)
A DMF can be used to provide confidential detailed information about facilities, processes, or articles
used in the manufacturing, processing, packaging, and storing of one or more human drugs. This
information can be used to support an IND. The FDA issued guidelines about DMF, available on their
website13.

1.3.1.3.3. Drug substance
According to 21 CFR 312.23(a)(7)(a), the description of the drug substance contains:

13



Name: GNF6702



Structure:

https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122886.htm

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Manufacturer: EAhD – Paris, France
General method of preparation
Acceptable limits and analytical methods (to assure identify, strength, quality and purity)
Sufficient information to support stability

1.3.1.3.4. Drug product
According to 21 CFR 312.23(a)(7)(b), the description of the drug product contains:






List of all components: GNF6702, 0,5% methylcellulose (Sigma-Aldrich), 0,5% Tween 80
(Sigma-Aldrich), distilled water
Manufacturer: EAhD – Boston, US
Manufacturing and packaging procedure
Acceptable limits and analytical methods (to assure identify, strength, quality and purity)
Sufficient information to support stability

1.3.1.4. Non-clinical studies
To submit a new investigational drug, we have to perform non-clinical studies (results reported in
CTD Module 4) to ensure safety of our molecule GNF6702 (see 21 CFR 312.23(a)(8)).

1.3.1.4.1. List of guidances
According to FDA NTD guidance 1:





ICH guidance for industry M3(R2) “Nonclinical Safety Studies for the Conduct of Human
Clinical Trials and Marketing Authorization for Pharmaceuticals”
ICH guidance for industry S6(R1) “Preclinical Safety Evaluation of Biotechnology-Derived
Pharmaceuticals”
FDA draft guidance for industry “Microbiological Data for Systemic Antibacterial Drug
Products — Development, Analysis, and Presentation”
FDA guidance for industry “Content and Format of Investigational New Drug Applications
(INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic,
Biotechnology-derived Products”

We added:
 ICH guidance for industry S7A “Safety Pharmacology Studies for Human Pharmaceuticals”
 ICH guidance for industry S7B “The Non-Clinical Evaluation of the Potential for Delayed
Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals”
 ICH guidance for industry S3A “Note for Guidance on Toxicokinetics: The Assessment of
Systemic Exposure in Toxicity Studies”
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 ICH guidance for industry S3B “Pharmacokinetics: Guidance for Repeated Dose Tissue
Distribution Studies”
 ICH guidance for industry S5(R2) “Detection of Toxicity to Reproduction for Medicinal Products
& Toxicity to Male Fertility”
 ICH guidance for industry S2(R1) “Guidance on Genotoxicity Testing and Data Interpretation
for Pharmaceuticals Intended for Human Use”
 ICH guidance for industry M7(R1) “Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk”

1.3.1.4.2. Pharmacology and pharmacokinetics studies
The pharmacology studies are designed to determine drug effect(s) on the body and
pharmacokinetics studies to determine body effect(s) on the drug. They include complete
Absorption-Distribution-Metabolism-Excretion (ADME) studies and safety profiling.
We decided to perform:










Plasma and brain pharmacokinetic analytical assessment (using blood samples from mouse,
rat and dog)
In vitro hepatocyte metabolism (using hepatocytes from mouse, rat, dog, monkey and
human donor samples)
In vitro CYP-450 metabolism (using human recombinant CYP enzyme isotypes)
In vitro transcellular permeability (using Caco-2 or MDR1-MDCK cells)
In vivo metabolism and distribution (using rats)
In vitro cardiac safety (using Human Embryonic Kidney 293 cells)
In vivo cardiovascular safety assessment (using dogs)
In vivo neurobehavioural safety profiling (using rats)
In vivo respiratory safety profiling (using rats)

1.3.1.4.3. Toxicology studies
The toxicology studies are designed to determine toxicity of our product on specific organs, cells or
cellular materials and potential carcinogenicity or mutagenicity.
We decided to perform:






Repeat-dose studies (in rats and dogs, once a day, 28 consecutive days, 50, 200 or 800
mg/kg/day)
Developmental and reproductive toxicology (in rats, once a day, from day 6 to day 17 of
gestation or from day 6 of gestation to day 7 of lactation, 50, 200 or 800 mg/kg/day; and
rabbits, once a day, from day 6 to day 20 of gestation, 20, 40 or 80 mg/kg/day)
In vitro Ames test (using strains of Salmonella typhimurium recommended by the relevant
ICH regulatory guideline, namely TA1535, TA1537, TA98, TA100, and TA102)
In vitro micronucleus test on human lymphocytes
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In vivo mouse bone marrow micronucleus test (in mouse, two oral doses of 0, 500, 1000, or
2000 mg/kg given 24 h apart, bone marrows were harvested 24 h after the second dose)
Ex vivo unscheduled DNA synthesis (UDS) (in rats, 500, 1000 or 2000 mg/kg (two groups per
dose), and the livers were sampled either 2–4 h or 12–14 h after test compound
administration)
Redox potential measurement

1.3.1.5. Clinical Trials
First at all, we decided to perform phase I clinical trials in France and in the US. But, as Chagas
disease concerns mainly Latin American countries, our phases II and III clinical trials have been
conducted outside the US (in Bolivia and Argentina). It is not a problem to submit a New Drug
Application to the FDA, even if the main part of the clinical trials is conducted outside, according to
21 CFR 314.10614. Data collected during clinical trials are reported in CTD Module 5.
We can introduce two kind of clinical trials application: to the European authorities or to the US
authorities, so we can use the two web platforms below.
EudraCT: https://eudract.ema.europa.eu/index.html
U.S. National Library of Medicine ClinicalTrials.gov: https://clinicaltrials.gov/
To submit clinical trials to the European authorities, we have to submit a clinical trials application
(CTA) pretty similar to the IND application according to Directive 2001/20/EC (soon replaced by
Regulation 536/2014). The CTA contains:













Covering letter
EudraCT number allocation
EudraCT form
Protocol
Investigator’s brochure
Investigational Medicinal Product Dossier
List of the European authorities concerned
List of clinical trials with the same Investigational Medicinal Product
Copy of scientific advices
GMP certificates
Manufacturer authorization
Labels

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1.3.1.5.1. List of guidances
According to FDA NTD guidance 1:






ICH guidance for industry E9 “Statistical Principles for Clinical Trials”
ICH guidance for industry E10 “Choice of Control Group and Related Issues in Clinical Trials”
FDA draft guidance for industry “Non-Inferiority Clinical Trials”
FDA guidance for industry “Formal Meetings Between the FDA and Sponsors or Applicants”
FDA guidance for industry “Providing Clinical Evidence of Effectiveness for Human Drug and
Biological Products”

We added:





Declaration of Helsinki (revised by the 64th World Medical Association General Assembly in
Fortaleza, Brazil, October 2013 [47])
ICH guidance for industry E5(R1) “Ethnic Factors in the Acceptability of Foreign Clinical Data”
ICH guidance for industry E6(R2) “Good Clinical Practice (GCP)”
ICH guidance for industry E17 “General principles for planning and design of Multi-Regional
Clinical Trials”

1.3.1.5.2. Phase I clinical trials
Prior to the start of each study, the study protocols were approved by an independent ethics
committee (CPP Ile de France III, Paris, France), by the French health authorities (ANSM) and the
Institutional Review Board (IRB), FDA and written informed consent was obtained from all
participants.
Eligible subjects were healthy male volunteers, US residents of Latin American origin and French
residents of Spanish origin and a body mass index of 18-28 kg/m² at the time of the screening. We
excluded from the studies any subject with evidence of clinically significant acute or chronic disease
(including known or suspected HIV, hepatitis B or C virus infection) or who had a positive drug
screening test.
We conducted three different phase I studies: (i) a three-part study under fasting conditions,
sequential first-in-human study designed to obtain safety, tolerability and pharmacokinetic data after
Single Ascending Doses (SAD) and Multiple Ascending Doses (MAD) oral administration of ascending
doses of GNF6702; (ii) a study to assess the impact of different types of food on the relative
bioavailability; and (iii) a double-blind placebo-controlled study under fed conditions to select one of
the two optimised multiple dosing schedules to be used in subsequent clinical trials in patients based
on modelling of pharmacokinetic data.

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1.3.1.5.3. Phases II and III clinical trials
Phases II and III clinical studies were conducted to determine the efficacy of our product. These
studies were designed according to 21 CFR 314.126(b)(2)(iv)15 as active treatment concurrent control
studies to show superiority (or non-inferiority) of GNF6702 compared to benznidazole. The study
protocols were approved by an independent ethics committee (CPP Ile de France III, Paris, France),
by the ANSM, IBR, FDA and Bolivian and Argentinean competent authorities and written informed
consent was obtained from all participants.










Phase II: 220 participants, randomized, multicenter, safety and efficacy trials to evaluate
different oral GNF6702 regimens and benznidazole for the treatment of adult patients with
chronic Chagas disease
Phase III: 3 500 participants, randomized, multicenter, double-blinded, pivotal, safety and
efficacy, non-inferiority trials to compare safety and efficacy of GNF6702 and benznidazole
for the treatment of adult patients with chronic Chagas disease
Screening criteria: 18 years < age < 50 years, 40 kg < weight < 80 kg, diagnosis of
Trypanosoma cruzi, no signs and/or symptoms of the chronic cardiac and/or digestive form
of Chagas disease, no acute or chronic health conditions that may interfere with the efficacy
and/or safety evaluation of the study drug (including known or suspected HIV, hepatitis B or
C virus infection), no formal contraindication to benznidazole and GNF6702, no known
history of hypersensitivity, allergic, or serious adverse reactions to the study drugs and no
history of Chagas disease treatment with benznidazole or GNF6702 at any time in the past.
Inclusion criteria: confirmed diagnosis of Trypanosoma cruzi infection by serial quantitative
PCR AND conventional serology, women in reproductive age must have a negative serum
pregnancy test at screening, must not be breastfeeding and must use a double barrier
method of contraception to avoid pregnancy throughout the clinical trials and 3 months after
completion of the trial, and normal electrocardiogram at screening.
Exclusion criteria: non compliance with screening criteria, abnormal laboratory test values at
screening for some parameters (total white blood cells count, platelet count, alanine
transaminase assays, aspartate transaminase assays, total bilirubin or creatinine or gammaglutamyl transferase), history of alcohol abuse or any other drug addiction, history of allergy,
any concomitant use of antimicrobial or antiparasitic agents and any planned surgery.

Note: Our hypothetical pre-clinical and clinical studies are based on published materials and
methods used in fexinidazole studies [46,48–51] or current clinical trials conducted on E1224.

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1.3.1.6. New Drug Application (NDA)

1.3.1.6.1. Contents
According to 21 CFR 314.5016, the NDA application contains:













Application form - Form FDA-0356h (Annex 5)
Index
Summary
Technical sections
Samples and labelling (Annex 6)
Case report forms and tabulations
Other
Patent information
Patent certification
Claimed exclusivity
Financial certification or disclosure statement
Format of an original NDA

1.3.1.6.2. Submission
The initial NDA submission (as the initial IND) must be submitted in triplicate to:
Food and Drug Administration
Center for Drug Evaluation and Research
Central Document Room
5901-B Ammendale Rd.
Beltsville, Md. 20705-1266

1.3.1.6.3. Review time
Within 180 days of receipt of an application for a new drug, FDA will review it and send the applicant
either an approval letter under 21 CFR 314.10517 or a complete response letter under 21 CFR
314.11018. This 180-day period is called the “initial review cycle”.

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1.3.1.6.4. Fees
According to the Prescription Drug User Fee Act (PDUFA), in 2018, the user fee rates for a NDA (with
clinical data required) are: US$2 421 495
Nevertheless, as SME submitting our first human drug application for review to the Secretary, we can
benefit from a waiver according to 21 USC 379h(d)(1)(C)19. We have to submit our waiver request to:
CDERCollections@fda.hhs.gov

1.3.1.7. Common Technical Document (CTD)

The FDA guidance “The Comprehensive Table of Contents Headings and Hierarchy”20 describes the
CTD content according to legislation 21 CFR (see Appendix I of the guidance).

1.3.1.7.1. List of guidances





ICH guidance M4 “The Common Technical Document”
FDA guidance “The Comprehensive Table of Contents Headings and Hierarchy”
FDA draft guidance for industry “Submitting Marketing Applications According to the ICHCTD Format — General Considerations”

1.3.1.7.2. Module 1 (US) – Administrative information
Module 1 is the transcription of the NDA in CTD format. It contains all administrative documents
(e.g., application forms, claims of categorical exclusion and certifications), and labelling, including the
documents described below, as needed. This module should be organized in the order listed below:













19
20

Forms (Annexes 4 and 5)
Cover letters
Administrative information (including Tropical disease priority review voucher)
References
Applications status
Meetings
Fast track
Special protocol assessment request
Paediatric administrative information
Dispute resolution
Information amendment
Other correspondence

http://uscode.house.gov/view.xhtml?req=granuleid:USC-prelim-title21-section379h&num=0&edition=prelim
https://www.fda.gov/downloads/drugs/ucm163175.pdf

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Annual report
Labelling (Annex 6)
Promotional material
Risk management plan
Post marketing studies
Proprietary names
Pre EUA and EUA
General investigational plan for initial IND

1.3.1.7.3. Module 2 – Summaries and overviews
Module 2 contains the quality overall summary, non-clinical and clinical summaries which are
objective descriptions of the quality, safety and efficacy data, and the non-clinical and clinical
overviews which are critical analyses of the safety and efficacy data by experts.

1.3.1.7.4. Module 3 – Quality
Module 3 organizes quality information about drug substance (active substance) and drug product
(active substance with excipients).
Our information for this module is summarized above in: 1.3.1.3. Chemistry, Manufacturing, and
Controls (CMC).

1.3.1.7.5. Module 4 – Safety
Module 4 presents the results from the non-clinical studies realised before any clinical trials.
Our information about non-clinical studies is reported above in: 1.3.1.4. Non-clinical studies.

1.3.1.7.6. Module 5 – Efficacy
Finally, module 5 presents the results from the phases I, II and III clinical studies.
Our information about clinical studies is reported above in: 1.3.1.5. Clinical Trials.

1.3.1.8. Paediatric Investigational Plan (PIP) and initial Paediatric Study Plan (iPSP)
Children are as much affected than adults by Chagas disease and newborns have risk of congenital
Trypanosoma cruzi infection [13,14]. Furthermore, in the younger population, the acute phase has a
high rate of mortality, when adult frequently present non-specific symptoms [39]. Current available
drugs are particularly well-tolerated and possess a high level of efficacy in children [13].

27

In the US, the marketing authorization applicant has to submit an iPSP according to 21 CFR 314.5521.
He can ask for a deferred submission and waiver(s) like in the EU procedure.
In the EU, a new legislation, Regulation (EC) No 1901/200622 amended by Regulation (EC) No
1902/2006, was introduced aimed at safeguarding the health of children. According to this
legislation, it is mandatory to submit PIP to EMA when the MA concerns a new medicine, unless the
medicinal product requests a rational exemption.
Our medicinal product cannot benefit any waivers but, given that current available drugs are
effective in children, we decided to request for deferral. We are thinking that conduct studies in
adults prior is safer than using paediatric population in parallel. As soon as we obtained first
pharmacovigilance reports, we will conduct studies in paediatric population.

1.3.1.8.1. List of guidances










ICH guidance for industry E11 “Clinical Investigation of Medicinal Products in the Pediatric
Population”
ICH guidance for industry E11(R1) “Addendum: Clinical Investigation of Medicinal Products in
the Paediatric Population”
ICH guidance for industry E11A “Paediatric Extrapolation”
EMA guideline CHMP/QWP/805880/2012 Rev. 2 “Pharmaceutical development of medicines
for paediatric use”
EMA guideline CHMP/SWP/169215/05 “Need for non-clinical testing in juvenile animals on
human pharmaceuticals for paediatric indications”
EMA guideline CHMP/EWP/147013/2004 “Role of pharmacokinetics in the development of
medicinal products in the paediatric population”
FDA draft guidance for industry “Paediatric Study Plans: Content of and Process for
Submitting Initial Paediatric Study Plans and Amended Initial Paediatric Study Plans”
FDA guidance for industry “Paediatric development of the drug or biological product”

1.3.1.8.2. PIP and iPSP contents

According to the EMA guidelines, PIP contains:






Part A: Administrative and product information
Part B: Overall development of the product
Scientific Part C: Applications for waivers
Part D: Overall strategy for development in children
Part E: Applications for deferrals

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Part F: Annexes (References)

According to the FDA guidances, the iPSP contains:











Overview of planned extrapolation of effectiveness to specific paediatric populations (1-3
pages)
Planned request for drug-specific waiver(s) (1-3 pages)
Plan to request deferral of paediatric studies (1-3 pages)
Tabular summary of planned non-clinical and clinical studies
Age-appropriate formulation development (1-3 pages)
Non-clinical studies (1-3 pages)
Clinical data to support design and/or initiation of studies in paediatric patients (1-5 pages)
Planned paediatric clinical studies
Timeline of the paediatric development plan (1 page)
Agreements for paediatric studies with other regulatory authorities (1-3 pages)

1.3.1.8.3. PIP and iPSP procedures
PIP must be submitted to the EMA’s Paediatric Committee (PDCO). In addition, the applicant can
request any scientific advices from EMA while the preparation of a PIP: this procedure is free of
charge.
As per article 16 of the Paediatric Regulation, applications should be submitted, unless duly justified,
“not later than upon completion of the human pharmacokinetic (PK) studies”, as specified in section
5.2.3 of Part 1 of Annex 1 of Directive 2001/83/EC23. As explained on the EMA website: “The timing
of submission should not be later than the end of healthy subject or patient PK, which can coincide
with the initial tolerability studies, or the initiation of the adult phase-II studies (proof-of-concept
studies); it cannot be after initiation of pivotal trials or confirmatory (phase-III) trials.”
The applicant must notify the Agency of the intent to submit an application for a PIP by using the
template form for the letter of intent. This letter is expected at least two months before the planned
submission of the PIP. It shall be sent to paediatrics@ema.europa.eu (using EudraLink). After
submitting the letter of intent, the MA applicant will receive a Unique Product Identifier (UPI) for the
medicinal product. Then he can electronically apply to EMA and the PDCO at the same time via
Eurdralink, in compliance with templates forms and deadlines.
iPSP has to be submitted to the FDA not later than 60 calendar days after the date of the end-ofphase 2 meeting (21 USC 355c(e)(2)(A)24). After the submission, the FDA has 90 days to review the
iPSP and provide comments to the sponsor. A second 90-day period begins when the sponsor receive
the FDA comments, then the FDA has 30 days to review and issue correspondence confirming
agreement or stating that the FDA does not agree. The total length for review of an iPSP is 210 days.
The form and contents of the iPSP are described in FDA guidances.
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1.3.1.9. Pharmacovigilance (US and EU)
Pharmacovigilance (PV) is the collection of the relevant information to the monitoring of medicinal
products, including information on suspected adverse reactions, when using a drug in accordance
with the terms of its marketing authorization but also in any other use: overdose, misuse, drug
abuse, medication errors. It must be done in all lifecycle the product, from research and
development to the marketing authorization and post-authorization.
Pharmacovigilance is managed in France at the national level by the ANSM, assisted by its network of
31 regional pharmacovigilance centers (CRPV), by the EMA at the European level (PRAC:
Pharmacovigilance Risk Assessment Committee) and by FDA in the US. In France, it is based on a
national and European regulatory basis: laws, decrees, directives, Good Pharmacovigilance Practice
(GVP) published by decree. The GVP describes the roles and responsibilities of each actors involved
as healthcare professionals, patients and drug companies which are the key players in the
pharmacovigilance system.

1.3.1.9.1. List of guidances

















ICH guidance for industry E2A “Clinical Safety Data Management: Definitions and Standards
for Expedited Reporting”
ICH guidance for industry E2B(R3) “Clinical Safety Data Management: Data Elements for
Transmission of Individual Case Safety Reports”
ICH guidance for industry E2B(R3) “IWG Implementation: Electronic Transmission of
Individual Case Safety Reports”
ICH guidance for industry E2C(R2) “Periodic Benefit-Risk Evaluation Report”
ICH guidance for industry E2D “Post-Approval Safety Data Management: Definitions and
Standards for Expedited Reporting”
ICH guidance for industry E2E “Pharmacovigilance Planning”
ICH guidance for industry E2F “Development Safety Update Report”
EMA guideline EMA/816573/2011 “Module II – Pharmacovigilance System Master File”
EMA guideline EMA/541760/2011 “Module I – pharmacovigilance system and their quality
system”
EMA guideline EMA/816292/2011 “Module VII – PSURs”
EMA guideline EMA/838713/2011 “Module V – Risk management systems”
EMA guideline EMA/873138/2011 “Module VI – Management and reporting of adverse
reactions to medicinal products”
EMA guideline EMA/813938/2011 “Module VIII – Post-authorization safety studies”
EMA & FDA guidance “Guiding principles for the international pharmacovigilance cluster”
FDA guidance for industry “E2E Pharmacovigilance Planning”

The FDA bases its pharmacovigilance plan mainly on ICH international guidelines and EMApartnership. According to this, we decided to focus on the European pharmacovigilance regulatory

30

framework. The applicable requirements in the implementation of a pharmacovigilance system are
listed below.

1.3.1.9.2. Pharmacovigilance System Master File (PSMF)
The PSMF is a detailed description of the pharmacovigilance system put in place in the company for
one or more authorized medicinal products and its compliance with the requirements laid down in
the legislation. According to the guideline on good pharmacovigilance practices “Module II
Pharmacovigilance System Master File”, the information included in the PSMF is:








Contact details of QPPV (Qualified Person for Pharmacovigilance)
Organizational structure of the MAH
Data safety sources
Computerised system and databases
Pharmacovigilance process
Quality system
Quality agreements

1.3.1.9.3. Summary of applicant PV system
According to Article 8(3)(ia) of Directive 2001/83/EC, the applicant for marketing authorization is
required to provide a summary of their Pharmacovigilance System, once the authorization is granted.
The summary of the PV system should be provided in Module 1.8.1 of the application for marketing
authorization and includes the following elements:






proof that the applicant has a qualified person responsible for pharmacovigilance,
the Member States in which the qualified person resides and carries out his/her tasks,
the contact details of the qualified person,
a statement signed by the applicant to the effect that the applicant has the necessary means
to fulfill the tasks and responsibilities listed in Title IX of Directive 2001/83/EC,
a reference to the location where the PSMF for the medicinal product is kept.

1.3.1.9.4. Periodic Safety Update Reports (PSURs)
Periodic Safety Update Reports are pharmacovigilance documents intended to provide a safety
update resulting in an evaluation of the impact of the reports on the risk-benefit balance of a
medicinal product. They shall be submitted by marketing authorization holder at defined time points
during the post-authorization phase.
Benefit-risk evaluation should be carried out throughout the lifecycle of the medicinal product to
promote and protect public health and to enhance patient safety through effective risk minimization.
The legal requirements for submission of PSURs are established in the Regulation (EC) No 726/2004 25
25

http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02004R072620130605&qid=1518690910981&from=EN

31

and the Directive 2001/83/EC and the format of PSURs shall follow the structure described in the
European Commission implementing Regulation (EU) No 520/201226.

1.3.1.9.5. Risk Management Plan (RMP)
The marketing authorization holder ensures the submission to the national competent authorities
(ANSM and FDA) of the RMP including a draft risk reduction measures for validation. The RMP
describes the management system set in place for the medicinal product concerned, according to the
modalities described in module V of the GVP.
The risk management plan is submitted according to the format described in Annex I to
Implementing Regulation (EU) No 520/2012 and module V of the GVP.
See below: 1.3.1.10. Risk Management Plan

1.3.1.9.6. Literature monitoring
Scientific and medical literature is an important source of information to identify suspected adverse
reactions with medicines authorized therefore any individual cases report of suspected adverse
reactions will be reported.

1.3.1.9.7. Post-Authorization Safety Study (PASS)
A PASS is a study that is carried out after a medicine has been authorized to obtain further
information on a medicine's safety, or to measure the effectiveness of risk-management measures.
Post-Authorization Safety Studies are conducted in accordance with the provisions of the article
R.5121-178 of the Public Health French Code27, the module VI and module VII of the Good Vigilance
Practice (GVP).
The safety profile of the medicinal product is established in identifying, characterising or quantifying
a safety hazard including also in a specific patient population which safety information is limited or
missing (e.g. pregnant women, specific age groups etc).
The format and content of study protocols and final study reports for non-interventional studies are
described in Module VII of the Good Vigilance Practice (GVP).
Different type study designs can be considered:




26
27

Active surveillance: consists of the collection of adverse events in a given population through
a follow up patients treated with TRYPACLEAR®, a brief survey is completed and with their
permission will be contacted at a later stage.
Observational studies: a cohort study will be performed and patient registers are used to
collect specified outcomes of a population exposed to TRYPACLEAR®.

http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32012R0520&rid=1

https://www.legifrance.gouv.fr/affichCode.do;jsessionid=E94923B8C217422BB05FD1FFF67C0FFF.tplgfr31s_3?i
dSectionTA=LEGISCTA000026596785&cidTexte=LEGITEXT000006072665&dateTexte=20180215

32

A study report was written and submitted to the Agency's Pharmacovigilance Risk Assessment
Committee (PRAC) for evaluation. Based on these outcomes, PRAC evaluate the safety and benefitrisk profile of a medicine and support regulatory decision-making. PRAC makes recommendations to
the marketing holder for the maintenance in term of the marketing authorization.
Time table for the submission: 12 months of the end of data collection.

1.3.1.10. Risk Management Plan (RMP)
According to our pharmacovigilance procedure, we present the RMP designed to be in compliance
with the European and French regulatory frameworks. The RMP is submitted according to the format
described in Annex I to Implementing Regulation (EU) No 520/2012.
The RMP is a document which highlighted knowledge about the safety of medicinal product. It
focuses on the important identified risks that are likely to have an impact on the risk-benefit balance
of the product and therefore provide information about measures and activities required to prevent
or to minimize risks. To enhance the benefit-risk balance the RMP hinges on risks reduction
approaches, on the detection, assessment, understanding and prevention of adverse effects or any
other medicine-related problem during the lifecycle of the drug. The key elements of RMP include
any studies which will allow to assess and to show the efficacy of the drug and the potential risk
associated.

1.3.1.10.1. Guideline


EMA guideline EMA/838713/2011 “Module V – Risk management systems”

1.3.1.10.2. RMP structure
Part I. Product overview
TRYPACLEAR® was developed in order to treat patients infected by Trypanosoma cruzi. It contains
the GNF6702 broad-spectrum antitrypanosomal drug as an active substance.
Refer to the package leaflet of the drug for more information.
Part II. Safety specification
The RMP is established on base of the pre-clinical and clinical outcomes during the research and
development of the drug including all the (un)known information about the drug. This is a summary
of the important potential risks identified, and missing information relative to the product. Data
collection has been collected according the directives in force.

33

--- SI: Epidemiology of the indication(s) and target population
Based on the WHO and PAHO estimations, an estimated 8 million people are infected by
Trypanosoma cruzi worldwide and more than 25 million people risk acquiring this disease. In 2005,
the PAHO estimated the prevalence of the disease in Latin American-born persons living in the US at
300 167 persons. According to this estimation and based on probability to present clinical
manifestations, the researchers calculated that 30 000 to 45 000 individuals likely to have
undiagnosed Chagas cardiomyopathy [14]. In 2009, 4 290 Chagas disease cases were diagnosed in
nine European non-DECs but 100 000 cases are estimated [12,52] and, in 2015, Chagas disease
prevalence is estimated to 18-20% of the Bolivian population (approximately 1 200 000 people) and
1,3% of the Brazilian population (approximately 3-5 million people) [52].
According to these observations, our target population is the Latin American people (and Latin
American origin people in the US and the EU).
--- SII: Non-clinical part of the safety specification
This step gives us an idea to the potential side effects of the drug. If a non-clinical finding relative to
the safety drug is estimated as being an important risk for the target population, it will be considered
as a safety risk in de module VIII of the RMP.
Our product presents a high level of specificity, targeting the trypanosomatid proteasome without
any inhibition of the human proteasome [40].
--- SIII: Clinical trial exposure
This part provides background on safety and efficacy. It is important to have an idea on safety and
the efficacy of the drug. This data collection will be present by categories such as the age, sex,
therapeutic indication, the dosage, the ethnicity.
--- SIV: Populations not studied in clinical trial
An evaluation and a discussion regarding the population not studied will be considered during the
pre-authorization phase including the clinical exclusion criteria’s which won’t be proposed as
constrain indication of the product.
For our product, we exclude only pregnant or breastfeeding women and patients suffering from
other serious and/or chronic illness. The paediatric population will be studied in a second time (after
the safety and efficacy will be ensured by clinical trials in adult population).
--- SV: Post authorization experiences
No applicable.
--- SVI: Additional EU requirements for the safety specification
The elements listed below will be assessed. If one of them presents a potential risk, an evaluation of
the risk minimization activities will be established, and included in the RMP.






Potential harm from overdose
Potential transmission for infectious agent
Potential medication errors
Potential for off-label use
Potential misuses for illegal purposes
34



Paediatric issues in PIP and off label use

--- SVII: Identified and potential risks
Will be considered in this section:




The adverse reactions (identified, important and potential)
Interactions (important and potential)
Adverse event due to pharmacological class of the drug

--- SVIII: Summary of the safety concerns
The safety specification provides us information regarding:




Important Risk identified
Potential Risk identified
Important missing information: use of TRYPACLEAR® off-label to treat HAT in African
population or leishmaniasis in African or Asian populations; use of TRYPACLEAR® in pregnant
women (or breastfeeding) population.

Part III: Pharmacovigilance plan (including PASS)
The PV plan will be established based on the potential and important risk identified detailed in the
part II section SVIII “summary of the safety concerns” (see above). The purpose of the PV plan is to
present an overview and discuss on the way to characterize (severity, frequency, risk factor) and
assess the safety concerns. The risk minimization measures (including evaluation of the effectiveness
of risk minimization activities) will be detailed in the part V “Risk minimization measures (including
evaluation of the effectiveness of risk minimization activities)” of this RMP.
The PV plan is subdivided in “Routine pharmacovigilance activities” and “Additional
pharmacovigilance activities”. “Routine pharmacovigilance activities” will be established in case
where no significant or potential risk has been identified. If an important or potential risk is identified
or important information is missing, additional activities will be carried out: either (non-)clinical trials
or non-interventional trial will be conduct.
For any safety concern an action plan will be proposed and justified.
If studies include children, the PV guidelines for medicinal products used in paediatric population
apply.
All these studies should be designed and conducted according to the recommendations in the GVP
Module VIII.
For our PV plan see above: 1.3.1.9. Pharmacovigilance (US and EU)
Part IV: Plans for Post-Authorization Efficacy Studies (PAES)
When marketing authorization is granted (or at the time of granting the initial MA), the product
efficacy is only based on the limited clinical data (short-term, non-representative population). The
product efficacy can vary over time. In some cases additional efficacy studies will be planned (e.g. no
35

sufficient data provided). Most of the time the MAH pursuant to an obligation from the national
competent authorities or the EMA but they can voluntarily be carried out by the MAH.
Part V: Risk minimization measures (including evaluation of the effectiveness of risk minimization
activities)
For any safety concern the need of the risk minimization measures will be assessed. The risk
minimization plan will be established and will provide the activities detailed in order to decrease the
risk associated.
Will be considered the routine risk minimization activities:
The labelling and the package leaflet provide sufficient information for the prevention.
Note: We fulfilled the RMP with the few pieces of information that we have [40].

1.3.2. European procedures

1.3.2.1. SME qualification process
Before requesting financial or administrative assistance from the EMA, EAhD should apply for SME
statute. As a medium-sized company with 220 employers and € 32 million in annual turnover, it fulfils
the SME criteria set out in the European Commission recommendation 2003/361/EC28. To apply for
SME statute, EAhD should complete the form declaration on the qualification of an enterprise as a
micro-small or medium sized enterprise that available on the EMA website. This form should be
submitted to SME office together with the most recent annual accounts information on ownership
and proof of establishment in the EEA. Once the SME statute has been assigned, the applicant will
receive an EMA-SME number. To maintain its SME statute, the company should submit a complete
declaration annually based on its latest approved accounts.
EAhD benefits thus from a number of incentives including:



28

Direct assistance, briefing meeting on regulatory aspects of pharmaceutical legislation,
advice on regulatory strategy for a product development or authorization.
Fee exemptions and reductions for Pre- and Post-authorization regulatory procedures
including:
o Scientific advice
o Fee reduction for inspection (Post-authorization)
o 100 % reduction for administrative services
o Fee reduction for scientific services (article 58)
o Conditional fee exemption where EMA scientific advice is followed and MAA is not
successful
o 90 % fee reduction for establishment of maximum residue limits
o 40 % fee reduction for pharmacovigilance
o Fee deferral until the outcome of MAA

http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32003H0361&rid=4

36

o
o

Assistance with translation of product information documents submitted in the MAA
Inclusion in an online SME register

1.3.2.2. National procedure (France)

1.3.2.2.1. Overview and guidelines
As Chagas disease is found mainly in endemic areas of 21 Latin American countries including French
Guyana, we decided to submit another marketing authorization application to the French competent
authorities, the ANSM.
TRYPACLEAR® will be submitted to the ANSM and not to the EMA because the fees of the national
procedure (34 000 €) are lower than the centralized procedure (282 100 €).
The ANSM is responsible for granting marketing authorization for TRYPACLEAR®. In order to obtain
this MA, the MA applicant should submit the dossier in the CTD format via Common European
Submission Platform (CESP) http://cesp.hma.eu or directly to ANSM. The agency has 210 days to
review the application and provide comments to the applicant.
Guidelines:



European Commission Notice to applicants “A GUIDELINE ON SUMMARY OF PRODUCT
CHARACTERISTICS (SmPC)” September 2009
European Commission ENTR/F/2/SF/jr (2009)D/869 “Readability of the package leaflet and
labelling of medicinal products for human use”

1.3.2.2.2. CTD Module 1 (EU)
This module describes the administrative information and prescribing information: the application
form and the product information (SmPC, labelling and package leaflet).
Articles 8(3)(j) and 11 of Directive 2001/83/EC and article 6(1) of Regulation (EC) 726/2004 require, in
order to obtain a marketing authorization, a Summary of Product Characteristics (SmPC). The
Marketing Authorisation Holder shall be informed by the competent authorities of the Member
States concerned when the SmPC is approved.
The SmPC is a legal document approved for each medicine which contains information for healthcare
professional about the use of the medicinal product. The SmPC is updated throughout the life-cycle
of the product as new data emerge. Information in the SmPC is presented according to a predefined
structure (Figure 8) detailed in the European Commission guideline “Summary of Product
Characteristics”.
According to articles 54, 55 and 59 of Directive 2001/83/EC, each medicinal product must be
accompanied by outer and/or immediate packaging information (labelling) and a package
leaflet (Annex 6). For preparation of package leaflets, we have followed the European Commission
37

guideline “Readability of the package leaflet and labelling of medicinal products for human use”. The
package leaflet was well designed and worded. However, the elders, children and adolescents and
those with poor literacy skills can use this leaflet.

Figure 8: SmPC structure

1.3.2.3. Article 58 procedure (EMA) for use outside Europe
As an alternative of the procedures presented above, we propose the EMA’s article 58 procedure.
The EMA has placed the article 58 procedure in 2004 to help to increase access to medicines by lowand middle-income countries and improve public health. If we consider that TRYPACLEAR® is
intended exclusively for markets outside the Community (only in DEC) and should be intended to
prevent or treat diseases of major public interest, our product is eligible for evaluation under the
article 58 of Regulation 726/2004. This article is intended exclusively for markets outside the
European area.

38

1.3.2.3.1. Guideline



EMA guideline “Guideline on procedural aspects regarding a CHMP scientific opinion in the
context of cooperation with the World Health Organization (WHO) for the evaluation of
medicinal products intended exclusively for markets outside the community”

1.3.2.3.2. Article 58 eligibility
The applicant needs to request eligibility for evaluation under article 58 for a medicinal product
before submitting an application. This request will be evaluated by the EMA’s Committee for
Medicinal Products for Human Use (CHMP), in collaboration with the WHO.
The eligibility request is made using the pre-submission request form, sent to the following address:
article58@ema.europa.eu and CPEligibility@ema.europa.eu
EMA send the valid eligibility request to WHO for consultation and the CHMP will confirm eligibility
taking into account the WHO’s position.
This request is free and includes the following information:





Epidemiological data on the disease and the summary of available efficacy or safety data (our
information to fulfil this part is in: part I, 2.1. Human health).
This medicine is intended to market in Latin American.
A statement that the applicant does not intend to market the medicinal product in the
European Economic Area.
A draft of SmPC

Once eligibility has been confirmed, the applicant can request a pre-submission meeting in
order to obtain guidance on the procedure.

1.3.2.3.3. Pre-submission meeting
Pre-submission meeting for marketing authorization application usually take place 6-7 months before
submission. The pre-submission request form for article 58 scientific opinions is available on the EMA
website and should be sent at least 6 weeks before the proposed meeting date. The aim of this
meeting is to provide an overview of the most relevant topics (quality, non-clinical and clinical
development, regulatory and procedural issues…) in order to facilitate subsequent validation and
assessment of the application.

1.3.2.3.4. Submission application
The marketing authorization applicant sends the application directly to the EMA. The dossier should
be submitted in the European CTD format. Note that the application form for a marketing
authorization for article 58 is not the same that the other procedures (CP, DCP, MRP). The
administrative information application form for a scientific opinion according to article 58 is available

39

on the EMA website29. The CHMP carries out a scientific assessment of applications submitted under
article 58, and, after consultation with the WHO, adopts a scientific opinion. The maximum term for a
CHMP assessment is 210 days (excluding clock stops). In case of a positive CHMP scientific opinion,
the EMA forwards this opinion to the applicant, WHO and the commission. Finally, the preparation of
the European Public Assessment Report in cooperation with WHO (EPAR) will be carried out.

2. Veterinary indications
2.1. Current drugs overview

Concerning the canine leishmaniasis, the antileishmania drugs improve clinical signs after treatment,
but parasitological cure is not attained [53]. The first canine leishmaniasis vaccine commercialised in
Europe (LiESP/QA-21, CaniLeish® by Virbac) reduces the risk of disease development four folds [38].
For AAT (Nagana disease), no vaccine is available at the moment and the treatment used currently
are not efficient due to the genomic mutation inducing resistance of trypanosoma to the
trypanocidal drugs (for instance homidium, lisometamidium and diminazene) [54]. A tsetse fly
eradication program has been conducted in Africa in order to control this disease, to eliminate the
main vector responsible in several countries as Burkina Faso, Ghana, Mali etc [55].
To treat the Surra disease, trypanocidal drugs, suramine and quinapyramine, have been used since
the 1920s and 1950s [19,56], and only in 1985 the melarsenoxide cysteamine (Cymelarsan®)30 is used
for the treatment and prophylaxis of Trypanosoma evansi in camels [56,57]. So far, the drug is only
registered for use in camels (OIE’s report31). However, camels show resistance and toxicity to the use
of trypanocides from overuse [57].
Thus, MANIACLEAR® is the perfect candidate to treat these diseases because its administration form
(oral solution) is easy and it presents very low toxic reactions in the target animal species.

2.2. Summary of the regulatory strategies
Since the therapeutic indications of our Veterinary Medicinal Product (VMP) concern African
diseases, our main objective is basically to have MA in the African countries concerned. Most African
countries have official national competent authority but their organization set-up and functionality
are variables: from well-organized authorities such as countries belonging to UEMOA, to very weak
legislation and insufficient regulatory capacity (Ethiopia or Chad). In addition, most of African
legislation is not available online which leads our regulatory monitoring very challenging.
When acts are available (Maghreb, UEMOA or some countries), it is specified that no company is
allowed to locally manufacture or import a veterinary medicinal without being granted a MA of origin
country (and sometimes accompanied with a certificate of origin) by the National Competent
29
30

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2009/10/WC500004804.doc

http://www.mci-santeanimale.com/media/produit/pdf/fr/prd477714-fr-cymelarsan-pdf.pdf
31
http://www.oie.int/fileadmin/Home/eng/Animal_Health_in_the_World/docs/pdf/Disease_cards/TRYPANO_EVANSI.pdf

40

Authority (NCA). However, only canine leishmaniasis is present in Europe and especially in France,
Spain and Italia. Only the marketing authorization for this unique indication can be submitted to
these European Member States.
Our veterinary product does not fall in mandatory scope of the centralized procedure as specified in
article 3 (1) and Annex 1 of Regulation (EC) No 726/2004. It could be eligible for optional ones since
containing new active substance (article 3 (3) of Regulation (EC) No 726/2004), i.e. one that has not
yet been authorized in the Community. Nevertheless, costs and duration are less for the
decentralized procedure and more relevant for dog indication (i.e. canine leishmaniasis).
So we prefer the decentralised procedure with France as Reference Member State to get European
MAs and a French certificate of origin for exportation. The Maximum Residue Limit (MRL) procedure
is not mandatory since dogs are not intended for food-production. However, the best regulatory
strategy consists to establish a MRL (by following the European Union Regulation) so as to be
evaluated by the African Regulatory Authorities. Indeed, MRL and therefore the withdrawal period
must be assessed before or at the same time of MA application in Maghreb and Sub-Saharan Africa.
Subsequently we apply to both National Authorities and the centralized procedure of UEMOA.
Insofar UEMOA has a well-organized authority, we only need the UEMOA approval for two
indications (Surra and Naga diseases – Canine leishmaniasis is not present on their territory) while
Tunisia and Sub-Saharan countries require a MA of the country of origin. Accordingly, we submit first
a MA application to the Tunisian Authority (with the MRL procedure) specifying that our first
medicinal product is already authorized for canine leishmaniasis in France, Spain and Italia.
Accordingly, the Tunisian CA only needs to assess the safety and efficacy of Surra and Nagana
indications (considering that quality is already assessed by the RMS). Finally, we apply to the
concerned countries (Cameroon, Chad, Ethiopia, DRC) mentioning that the Tunisian CA already
granted the MA.
We wish we could have broader ambitions by submitting our MA dossier to other countries in SubSaharan Africa (Nigeria, Somalia, etc), nonetheless it is impossible to access to legal documents
(unless we go to embassies): we have to assume that requirements and procedures are similar.
Finally, insofar the Pharmacovigilance System is a national competence, we should elaborate it for
each country where the veterinary medicinal product is authorized. However, in this present report,
we develop the Pharmacovigilance System of the veterinary medicinal product authorized in France.

2.3. Clinical Trials
MANIACLEAR® is a medicinal product intended to treat canine leishmaniasis in Southern European
countries, Nagana disease for cattle in sub-Saharan Africa and camel trypanosomiasis in Northern
Africa, it is why clinical trials were carried out in different countries.
For canine leishmaniasis: the clinical trials were conducted in France. According to the article R51418 of CSP, the applicant should complete the statement of establishment of clinical trial available from
the French Agency for veterinary Medicinal products (ANMV)32. This form should be submitted to email:enreg@anses.fr. Once the applicant receives a favorable opinion, he can start his clinical trials.

32

https://www.anses.fr/fr/system/files/essai%20clinique_Septembre%202013.pdf

41

For camel trypanosomiasis: the clinical trials were conducted in Tunisia. Before conducting a clinical
trial, the applicant should apply for clinical trial to Pharmacy and Drug Directorate. In addition, the
outcomes of clinical trial were assessment by Tunisian committee of experts.
For Nagana disease: the clinical trials were conducted in Cameroon.

2.4. Maximum Residue Limits (MRL)
In order to protect the health of the consumer of food stuffs of animal origin obtained from animal
treated with veterinary medicinal product, it is necessary for a new pharmacologically active
substance to determine the Maximum Residue Limits (MRL) and withdrawal periods. The Applicant
should submit the MRL application before the marketing authorization application notifying the
name of the substance, the intended use and target species.
In this case, for granting the marketing authorization to French CA, we don’t need to submit this
procedure to EMA because this medicine intended to canine leishmaniasis. For registration of this
medicine for treated Surra or camel trypanosomiasis in the north of Africa (Tunisia), we must submit
this application with a copy of marketing authorization to the DPM-Ministry of health.
The contents of the dossier is described in Volume 8 of Eudralex “Maximum residue limits” which
contains guidance on the application of Council Regulation (EEC) No 2377/90 and provide the legal
framework for the establishment of maximum residue limits (MRLs) for medicinal products for
veterinary use.

2.4.1. Contents of the dossier
A. Safety file
A.0. Expert Report:
The Expert Report on the safety file should comprise a critical evaluation of the studies undertaken
to investigate the pharmacological, toxicological and other properties of the substance, and should
conclude with a discussion of all the results observed and a proposal for an acceptable daily intake
(ADI).
A.1.Precise identification of the substance concerned by the application
Each batch used in the tests was well identified and meet to specifications
A.2. Pharmacology
This section presents the summary of the results of the various pharmacological studies
(pharmacodynamics, pharmacokinetics) with particular emphasis on results which may be relevant to
the evaluation of the safety of residues of the substance.
A.3. Toxicological studies
This section contains a full set of toxicological data will usually be required for substances which have
not previously been used in veterinary medicine and additional information outlining the safety
testing of residues of veterinary drugs in food is given in guideline VICH topic GL33
(EMEA/CVMP/VICH/486/02-Rev.2).


Single dose toxicity: Single dose studies to assess acute toxicity are not necessary in the
identification of ADIs for veterinary medicinal substances and are not included in the current
VICH guidelines.
42













Repeated dose (90-days) toxicity testing: this test was conducted in a rodent and a nonrodent species and was conducted in accordance with OECD Guidelines 408 (rodent) and 409
(non-rodent) in order to identify target organs and toxicological endpoints, provide
information that will help the setting of dose levels to be used in repeat-dose (chronic)
toxicity testing.
A NOAEL was identified from the results of each repeat-dose (90-day) toxicity test. This
information is given in VICH Guideline 31: Safety Studies for Veterinary Drug Residues in
Human Food: Repeat Dose (90-days) Toxicity Testing (CVMP/VICH/484/2002).
Repeated Dose (Chronic) Toxicity Testing: this test was conducted in accordance with OECD
guideline 452 (Chronic Toxicity Studies). Chronic toxicity testing was performed to define
toxic effects based on long-term exposures to the compound and/or its metabolites,
identify target organs and toxicological endpoints in relation to dose and/or duration
of exposure, determine dosages associated with toxic and biological responses, and
establish a NOAEL. This information is given in VICH guideline 37: Safety: Repeated Dose
(Chronic) Toxicity Testing. (CVMP/VICH/468/2003).
Study of the effects on reproduction: this study was carried out for detect toxic effects on
fertility in males and females and on other reproductive functions in accordance OECD
guideline 416. Also it was conducted of two generation and the drug was administered to
males and females for an appropriate time prior to mating. This information is given in VICH
22: Safety Studies for veterinary Drug Residues in Human Food: Reproduction Studies
(CVMP/VICH/525/2000)
Study of developmental toxicity including teratogenicity: this test was conducted in
accordance with OECD guideline 414 “Prenatal Developmental Toxicity Study” in order to
detect any adverse effects on the pregnant female and development of the embryo and
foetus consequent to exposure of the female from implantation through the entire period of
gestation to the day before caesarean section. This information is given in VICH 32:
developmental toxicity testing (CVMP/VICH/485/2002).
Mutagenicity: a battery test was conducted in order to evaluate the genotoxicity and
mutagenicity of veterinary drug residues. The battery test consists of three following test:
bacterial reverse mutation test was conducted in accordance with OECD guideline 471, a
chromosomal aberration test was carried out in accordance with OECD guideline 473 and a
mammalian erythrocyte micronucleus test in accordance with OECD guideline 474 using
bone marrow (rat or mouse) or peripheral blood (mouse only). This information is given in
VICH 23: Genotoxicity testing (CVMP/VICH/526/2000).
Carcinogenicity: this test was carried out in accordance with OECD guideline 451 in order to
evaluate the carcinogenic potential of veterinary drug residues in human food. This
information is given in VICH 23: carcinogenicity testing (CVMP/VICH/645/2001).

A.4. Studies of other effects
These tests are required to address safety concerns. Some examples of these studies:


Immunotoxicity: if toxicological manifestations in experimental animals during repeated
dose studies include specific changes in lymphoid organ weights and/or histology and
changes in cellularity of lymphoid tissues, bone marrow or peripheral leukocytes. This test
may be required.
43



Observations in humans: our drug product is used for human and veterinary use. So, in this
section, we should be supply the pharmacological, toxicological and clinical data obtained
for human use.

A5 Safety evaluation of residues
The ADI is an estimate of the amount of a substance, expressed on a body weight basis that can be
ingested daily over a lifetime without appreciable health risk. The formula used to determine the ADI
is as follows: ADI = NOEL (mg/kg bw/day)/Uncertainty Factor (mg/kg bw). The uncertainly factor can
be varied between 10 and 1000.
B. Residue File
B.0. Expert report
The Expert Report on the residue file should comprise a critical evaluation of the studies
undertaken to investigate presence and persistence of residues of the substance under investigation
and should conclude with a discussion of all the results observed, and proposals for MRLs for the
substance concerned in all relevant food commodities.
B.1. Precise identification of the substance concerned by the application
Each batch used for this study should be identified in accordance with point A.1.
B.2. Residue studies






Pharmacokinetics: the pharmacokinetic studies were conducted to evaluate the absorption,
distribution, metabolism and excretion of the drug product in the healthy camel and cattle
target. All studies were conducted and reported in conformity with the principles of GLP.
Depletion of residues: the depletion of the relevant residues was established in all standard
edible tissues (muscle, fat, liver, kidney, milk).
Elaboration of MRLs: The proposed MRLs must meet the requirements laid down in
Regulation (EEC) No 2377/90.
Withdrawal periods: withdrawal periods for cattle and camel as well as their edible tissues
were evaluated with refer to the relevant CVMP guidelines and software
(EMEA/CVMP/036/95 – Note for Guidance: Approach towards Harmonisation of Withdrawal
Periods for meat, EMEA/CVMP/563/02 – Updated Application Software relating to Note for
Guidance on Approach towards Harmonisation of Withdrawal Periods for Meat,
EMEA/CVMP/473/98 – Note for Guidance for the Determination of Withdrawal Periods for
Milk, EMEA/CVMP/231/00 Rev. 1– Updated Application Software relating to Note for
Guidance for the Determination of Withdrawal Periods for Milk).

B.3. Analytical method for the detection of residues
The analytical method used for the detection of residues was validated in accordance with the
guideline VICH GL2 (Validation methods).

44

2.5. Marketing Authorization Procedures

2.5.1. Decentralised Procedure (DP)

2.5.1.1. Introduction
As per articles 28 to 29 of the Directive 2001/83/CE (amended by the Directive 2004/27/CE), the
decentralised procedure is provided so as to enable the marketing authorization holder to market a
medicine in more than one Member State of the European Union, except for medicinal products for
human use falling within the mandatory scope of Regulation (EC) No 726/2006.
Since France is chosen to be the Referent Member State (RMS), the MA applicant must send a
common request form33 to slot.france@ansm.sante.fr six months before the planned submission
date in order to ask France to be the RMS in a decentralised procedure. A response on the
acceptability of the requisition is provided within 14 days after the receipt of the request form. The
RMS will inform the company when the MAA could be submitted and the MA applicant will receive a
procedure number to this application. The RMS also creates the procedure in the Communication
and Tracking System (CTS) data which allows the Concerned Member States (CMSs) and RMS to
exchange information and different views, as explained in the Doc. Ref: CMDh/078/2005/Rev.734.
After this pre-procedural step, the MA applicant can apply to the NCA of Spain, Italia and France, and
notifies the RMS as soon as he dispatches the dossiers.
The MAA will be identical in all of MSs (and RMS) concerned, by using the same template for the
cover letter (CMD website) and the same format. Text proposals for SmPC, Package Leaflet (PL) and
labelling in English only are acceptable with the submission of the dossier and sample mock-ups in an
official language of the EU should be submitted for the application to be valid (Annex 7).
For submission to national competent authorities, the Common European Submission Platform
(CESP) can be used in decentralised procedure. Then, the MA applicant can send at the same time to
all CMSs (and RMS) the same e-submission35.
The assessment step I corresponds to the 120-day period for preparing Draft Assessment Report
(DAR) and comments on draft SmPC, draft PL and draft labelling. Then the RMS relay the Preliminary
Assessment Report (PrAR) (including comments on SmPC, PL and labelling) on the dossier to the
CMSs and the MA applicant.
The assessment step II is a European evaluation phase in 90 days, involving MSs. CMSs should
communicate their comments to the RMS through CTS. If consensus is reached about the approvable
of the MAA, the RMS write the Final Assessment Report (FAR) including agreed SmPC, PL and
labelling. Finally, the RMS may close the procedure, and the procedure continues with the national
step.
33

Common Request Form:
http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/Templates/MA_Application/CMDh_226_2007_Rev05_
2018_01.doc
34
Decentralised procedure member states’ standard operating procedure:
http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/Application_for_MA/DCP/CMDh
_078_2005_Rev07_2016_04_clean.pdf
35
Note that Italian Directorate General for Animal Health and Veterinary Medicinal Products (DGSAF) has recently joined
the CESP System (04.09.17).

45

A 30-day phase after the RMS closes the procedure, allows the National Competent Authority of each
involved MS to adopt a national decision. In case the procedure ended with a favorable decision, the
MAH will submit high quality national translation of the final text proposals for SmPC, PL, labelling
and consolidated annexes of the MA dossier36. The translation procedures are described by CMDh («
Best Practice Guide on the submission of high quality national translations »37) and by EMA38. The
‘blue box concept’ for adequate national information on the label and PL are allowed and are
described below.
Since the translation (into Italian and Spanish) must be realized by a person who has professional
knowledge of the field and whose mother tongue should preferably be the target language (avoiding
the use of machine translations, we decided to work with a professional company such as Language
Connect.
In France, the MAH must submit theses previous documents in French within 7 calendar days after
finalization of the European Procedure, to ueurop@ansm.sante.fr. Information about translations
procedures is available in the recommendations document of the ANSM39.
In Spain, there is a recommendation about translation written by the Spanish Authority40 but
recommendations from Italian Authority were not found.

2.5.1.2. Composition of the Marketing Authorization Dossier
A submission shall contain:
 a cover letter «Formatted table template » (from EMA)41
 eAF (MAA-Vet Form v1.22)42
 the Dossier: A veterinary medicinal product submission is possible with an electronic
submission but must be in compliance with the VNeeS standards as outlined in the
« “Guideline on the specifications for provision of an electronic submission (e-submission) for
a veterinary medicinal product”43. Moreover, Guidelines about how to use PDF format for a
VNees-compliant submission are described in VICH guidelines 53. The folder structure for an
electronic application for a veterinary pharmaceutical product is presented below.

36

Templates for SmPC and Annexes can be found on EMA website:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000134.jsp&mid=
WC0b01ac0580022c59#
37

http://www.hma.eu/fileadmin/dateien/Human_Medicines/CMD_h_/procedural_guidance/01_General_Info/CMDh_255_2
012_Rev0_2012_05.pdf
38
http://www.hma.eu/uploads/media/POS003_Ed-01_Pack_Conclusions_Recommendations_ED-01_Final_-_EMEA-CMDv123457-2008_01.pdf
39
« Recommandations de l’ANSM pour la soumission de traduction de bonne qualité dans le cadre d’une AMM ou de
renouvellement à l’issue d’une procédure de reconnaissance mutuelle ou décentralisée » :
http://ansm.sante.fr/var/ansm_site/storage/original/application/3e1c5c98a7ec41904db1ab12fe2d1e8a.pdf
40
Recomendaciones para la correcta traducción de textos y elaboración de maquetas de medicamentos veterinarios:
https://www.aemps.gob.es/industria/regMedicamentos/docs/guia_maqueta.pdf
41
Formatted table Template:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000427.jsp&mid=
WC0b01ac0580b4bd61
42
http://esubmission.ema.europa.eu/eaf/eaf_1.22.0.0/maa_veterinary_v1.22.0.0.pdf
43
http://esubmission.ema.europa.eu/tiges/docs/E-submission-GL-Ver2.5-Dec2016-tracked-changes.pdf

46

The « News Checker » should be used to check the technical conformity of the file.
With regard to applications for Marketing Authorization where France is a reference Member State
in the decentralised procedure and for chemical drugs only, a sample of the finished product as
intended for sale (only 1 sample is sufficient for a the same lot) must be provided.

2.5.1.2.1. Contents of eAF
PART 1. Administrative documentation
-

Part 1 A consists of the administrative data, packaging, samples or mock-ups
Part 1 B consists of the proposed Summary Product Characteristics (SPC), labelling and package
leaflet
- Part 1 B1 Summary of Product Characteristics (SPC)
- Part 1 B2 Proposals for Packaging, Labelling & Package Leaflet
Part 1 C consists of the Detailed and Critical Summaries and their tabular formats.

-

PART 2. Chemical, pharmaceutical and biological documentation
Our medicinal product is intended for human and veterinary use. According to the Notice to
Applicant vol6 B “guidance to applicants for marketing authorization for veterinary medicinal
products on the presentation of the data requirements and summaries of the dossier”, if the active
substance has been included in a medicinal product for human use authorised in accordance with the
requirements of Annex I to Directive 2001/83/EC the chemical, pharmaceutical and
biological/microbiological information provided for in Module 3 may replace the documentation
related to the active substance or the finished product.
PART 3. Safety and residues documentation
3.A SAFETY TESTS


VICH GL33 (Safety: General Approach): “Studies to evaluate the safety of residues of veterinary
drugs in human food: General Approach to Testing”

3.A.1 Precise identification of the product and of its active substance
Information to provide (Notice to Applicant 6B, p.122):
- International non-proprietary name (INN)
- International Union of Pure and Applied Chemistry Name (IUPAC)
- Chemical Abstract Service (CAS) number, therapeutic, pharmacological and chemical
classification
- synonyms and abbreviations,
- structural formula,
- molecular formula
- molecular weight
- degree of impurity
- qualitative and quantitative composition of impurities
47

-

description of physical properties
melting point
boiling point
vapour pressure
solubility in water and organic solvents expressed in g/l, with indication of temperature
density
spectra of refraction, rotation, etc
formulation of the product.

3.A.2 Pharmacology
3.A.2.1 Pharmacodynamics
In accordance with the provisions of the European Convention for the Protection of Vertebrate
Animals Used for Experimental and Other Scientific Purposes and Directive 2010/63/EU on
protection of animals used for scientific purposes, the 3R principles (replacement, reduction and
refinement) should be applied.
3.A.2.2 Pharmacokinetics in laboratory animals


EMEA/CVMP/133/99: “Guideline for the conduct of pharmacokinetic studies in target animal
species”

3.A.3 Toxicology


EMA/CHMP/CVMP/JEG-3Rs/450091/2012 : “Regulatory acceptance of 3R (replacement,
reduction, refinement) testing approaches”

3.A.3.1 Single dose toxicity
Single-dose toxicity studies may be used to predict:
- the possible effects of acute overdosage in the target species
- the possible effects of accidental administration to humans,
- the doses which may usefully be employed in the repeat dose studies.
3.A.3.2 Repeated dose toxicity
Notice to Applicant (6B): In the case of substances or veterinary medicinal products intended for use
in foodproducing animals, repeat-dose (90 day) toxicity testing shall be performed in a rodent and a
non-rodent species in order to identify target organs and toxicological endpoints and identify the
appropriate species and the dose levels to be used in chronic toxicity testing, if appropriate.


VICH GL31 (Safety: Repeat-dose Toxicity): “Studies to evaluate the safety of residues of
veterinary drugs in human food: Repeat-dose (90 days) Toxicity Testing”

48



VICH GL37 (Safety: Repeat-dose chronic toxicity): “Studies to evaluate the safety of residues of
veterinary drugs in human food: Repeat-dose (chronic) toxicity testing”

3.A.3.3 Tolerance in the target species of animal


VICH GL43 (TAS Pharmaceuticals) : “Target Animal Safety for Pharmaceuticals”

3.A.3.4 Reproductive toxicity including teratogenicity



VICH GL22 (Safety: Reproduction): “Studies to evaluate the safety of residues of veterinary
drugs in human food: Reproduction Testing”
VICH GL32 (Safety: Developmental Toxicity) “Studies to evaluate the safety of residues of
veterinary drugs in human food: Developmental Toxicity Testing”

3.A.3.5 Genotoxicity


VICH GL23 (Safety: Genotoxicity): “Studies to evaluate the safety of residues of veterinary drugs
in human food: Genotoxity Testing”

3.A.3.6 Carcinogenicity


VICH GL28 (Safety: Carcinogenicity): “Studies to evaluate the safety of residues of veterinary
drug in human food: carcinogenicity testing (Revision at Step 9)”

3.A.3.7 ADI (Acceptable Daily Intake)


CVMP/SWP/355689/2006: “Approach to establish a pharmacological acceptable daily intake
(ADI)”

3.A.4 Other requirements/special studies
3.A.4.1 Observations in humans
As explained in Notice to applicant (6B):
Information shall be provided showing whether the pharmacologically active substances of the
veterinary medicinal product are used as medicinal products in human therapy; if this is so, a
compilation shall be made of all the effects observed (including adverse reactions) in humans and of
their cause, to the extent that they may be important for the assessment of the safety of the
veterinary medicinal product, where appropriate including results from published studies; where
constituents of the veterinary medicinal products are themselves not used or are no longer used as
medicinal products in human therapy, the reasons shall be stated.

49


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