La qualità e la sicurezza preclinica quali processi integrati

processi integrati nello sviluppo di un
prodotto biologico/biotecnologico
Raffaella Tinghino
Centro Nazionale per la Ricerca e la Valutazione dei Prodotti
Immunobiologici (CRIVIB)
Annarita Meneguz
Dipartimento del Farmaco
ISTITUTO SUPERIORE DI SANITA’
I contenuti della presentazione
ono attribuibili esclusivamente ag
autori e non riflettono
necessariamente l’opinione
dell’Autorità competente.
Un medicinale biologico e' un prodotto il cui principio
tivo e' una sostanza biologica. Una sostanza
ologica e' una sostanza prodotta, o estratta, da una
nte biologica e che richiede per la sua
aratterizzazione e per la determinazione della sua
ualita‘ una serie di esami fisico-chimico-biologici,
onche le indicazioni sul processo di produzione e il
uo controllo.”
D.lg. 219 attuazione Direttiva 2001/83/C
er materie prime (starting materials) si devono
ntendere tutte le materie dalle quali la sostanza attiva
iene fabbricata o estratta.
ualunque altro materiale impiegato per fabbricare o
strarre la/le sostanza/e attiva/e, ma dalle quali non si
cava direttamente la sostanza attiva, come i reagenti,
rreni di coltura, il siero fetale di vitello, gli additivi, i
mponi utilizzati nella cromatografia, ecc., sono note
ome materiali sussidiari (raw materials).
D.lg. 219 attuazione Direttiva 2001/83/C
ntendono tutte le sostanze di origine biologica,
ali microrganismi, organi e tessuti di origine vegetale o
imali, cellule o liquidi biologici (compreso il sangue o i
asma) di origine umana o animale e costrutti cellulari
otecnologici (substrati cellulari, ricombinanti o meno,
luse le cellule primarie).
D.lg. 219 attuazione Direttiva 2001/83
omplessità del prodotto già a partire dalla materia prim
Prodotti Biologici: necessità di nuove linee guida o di
aggiornamenti di quelle esistenti
ideline on the requirements for quality documentation concerning
logical investigational medicinal products in clinical trials.
MA/CHMP/BWP/534898/2008) Date for coming into effect 15 April 20
eclinical safety evaluation of biotechnology-derived pharmaceuticals
H S6(R1). Parent Guideline dated 16 July 1997, Addendum dated 12
ne 2011, incorporated at the end of June 2011
flection paper on the use of starting materials and intermediates
lected from different sources in the manufacturing of biological
edicinal products (EMA/CHMP/BWP/729106/2011). Deadline for
mments 31 August 2012
Medicinali chimici e biologici
Chimici
Biotecnologici
Aspirina:
peso molecolare 180
Interferone beta: peso molecolare
19.000
Differences between small molecular
weight drugs and biopharmaceuticals
Biopharmaceuticals
Small molecules
ecular size: <1kDa
y be electrophilic
y be metabolised to reactive products
ribution to many organs & tissues
mical synthesis and reactive impurities
sible
mical toxicity unrelated to target
•
•
•
•
•
•
•
Molecular size: >5kDa, 150kDa for m
Typically not electrophilic
Catabolised to peptides and amino a
Distribution limited – blood volume an
interstitial fluid
Fermentation synthesis
Toxicity generally related to
pharmacological mechanism of actio
Often high target selectivity and high
species specificity
Lotti (non GMP/ GMP)
impiegati negli studi di non clinica
comparabilità tra i lotti*
Lotti GMP impiegati negli studi clinici
Lotti ottenuti con un processo produttivo simile
e clinici
ta di produzione della DS e del DP (GMP/no GMP) con
icazione dei numeri di lotto
andezza del lotto (studi clinici di fase I)
zio studi di stabilità, dati degli studi di stabilità e shelf-life
piego di ciascuno lotto in quali studi
dicazioni sul processo produttivo impiegato (eventuali
erenze – giustificazioni)
ti di comparabilità tra lotti se necessari
Richiedono l’applicazione di una metodologia internazionalmente codificata, aderente a
norme e linee guida internazionali.
ficacy studies (non-GLP)
In vitro studies
Animal disease models
Mechanism of action studies
afety studies (GLP)
Safety pharmacology
Pharmacokinetics and metabolism
Local tolerability
General toxicity (single and repeateddose)
Genetic toxicity
Carcinogenicity
Reproductive and developmental
toxicity
a Sicurezza Preclinica nello sviluppo d
un prodotto biologico/biotecnologico
Parent Guideline: Preclinical Safety Evaluation of
Biotechnology-Derived Pharmaceuticals
ICH S6
Approval by the Steering Committee under Step 4 and
recommendation for adoption to the three ICH
regulatory bodies: 16 July 1997
nitial safe dose and subsequent dose escalation schemes in
ans; 2) to identify potential target organs for toxicity and for t
y of whether such toxicity is reversible; and 3) to identify safe
meters for clinical monitoring.
linical safety testing should consider:
election of the relevant animal species;
ge;
hysiological state;
e manner of delivery, including dose, route of administration, and
ment regimen; and
ability of the test material under the conditions of use.
city studies are expected to be performed in compliance with Good
oratory Practice (GLP); however, it is recognised that some studies
loying specialised test systems which are often needed for
harmaceuticals, may not be able to comply fully with GLP.
1935 Elixir Sulfanilamide: 105 morti, 34 bambini (Ann. Intern.Med.
1995) Prima presa di coscienza “pubblica” del fatto che non è
sufficiente che un composto sia efficace per essere un medicinale
(dietilenglicol)
1960-62 Thalidomide > 4000casi di focomelia (JAMA 180, 1106-114,
1962) Presa di coscienza degli addetti ai lavori e dei “regulators” del
fatto che di un medicinale, la sicurezza dovesse essere stabilita prima
della sua immissione sul mercato, oltre all’efficacia
13 marzo 2006: 6 giovani volontari sani trattati con TGN1412 (anticorpo
monoclonale superagonista delle cellule T), dopo circa 60 minuti dall’infusione,
sono colpiti da gravissima patologia associata ad un improvviso e rapido
rilascio di citochine proinfiammatorie. Presa di coscienza degli addetti ai lavori
e dei “regolatori” del fatto che un farmaco biologico non può essere valutato
con gli standard validi per un medicinale chimico
Il caso TGN 1412
a tragica ed inaspettata (?)
gravità
delle reazioni avvers
manifestatesi in tutti e 6 i volontari sani arruolati in un
perimentazione clinica di fase I, trattati con TGN1412, h
videnziato i rischi insiti in una sperimentazione di prim
omministrazione all’uomo (First Time In Man FTIM) con un nuov
nticorpo monoclonale. (editoriale Nature Biotechnology vol.24, n°
May 2006).
TGN 1412
First Time in Man (FTIM)
Fase I , 13 marzo 2006
8 soggetti in una prima corte
Giovani maschi volontari
sani
2 Placebo
6 Attivi
Tutti 8 trattati in rapida
successione
Dose basata sul NOAEL
Rapido instaurarsi
sindrome da liberazione
citochine
angioedema
Monitorati immediatament
Insufficienza multiorgano
Tutti ricoverati in terapia
intensiva
Prolungata
immunosoppressione
1 cancrena
EU
EMEA + 27 SM
USA
FDA
Japan
JMPA
DRAFT AGREED BY CHMP EXPERT GROUP 6 March 200
DATE FOR COMING INTO EFFECT 1 September 2007
mpared to humans. For example, there might be differences in affinity for
lecular targets, tissue distribution of the molecular target, cellular
sequences of target binding, cellular regulatory mechanisms, metabolic pathway
ompensatory responses to an initial physiological perturbation.
armacodynamics
armacodynamic studies should address the mode of action, and provide knowled
he biology of the target. These data will help to characterise the pharmacologica
cts and to identify the most relevant animal models. The primary and secondary
rmacodynamics, should be conducted in in vitro animal and human systems and
o in the animal models. These studies should include target interactions preferab
ed to functional response, e.g. receptor binding and occupancy, duration of effec
dose-response.
hough GLP compliance is not mandatory for pharmacodynamic and
armacokinetic studies, the should be of high quality and consistent with the
nciples of GLP.
armacokinetics
ndard pharmacokinetic and toxicokinetic data should be available in all specie
d for safety studies before going into human (ICH S3, S6, M3).
afety Pharmacology
tandard core battery data should be available before the first
dministration in humans (CHMP/ICH guidelines S7A, S7B, S6, M3).
oxicology
he toxicology programme should be performed in relevant animal
pecies and include toxicokinetics.
should be noted that human specific proteins are likely to be
mmunogenic in animal species. Therefore repeat dosing studies in
nimals may not predict the effects of such substances in humans
.g. presence of neutralising antibodies).
stimation of the first dose in human
he estimation of the first dose in human is an important element to
afeguard the safety of subjects participating in first-in-human studies.
No Observed Adverse Effect Level (NOAEL) ‘
Minimal Anticipated Biological Effect Level (MABEL)
Insegnamenti principali
Rilevanza della specie
NOAEL Verso MABEL
Modelli transgenici e omologhi
Genetically altered rodents, surrogate antibodies and early microdos
studies in humans.
Keliximab, efalizumab (Raptiva; Genentech) and infliximab (Remicad
Centocor) are examples of mAbs for which transgenic mice and
surrogate antibodies have been successfully used in the developmen
biomarkers or for preclinical efficacy and safety assessment.
Insegnamenti principali
Rilevanza della specie
NOAEL Verso MABEL
Perché cominciare con la dose più alta che si è
mostrata sicura (NOEL) e non da quella più bassa c
si è dimostrata attiva (MABEL)
MoAb
Specificità verso un solo epitopo quindi, capacità di legarsi
esclusivamente a certe strutture molecolari.
In questi casi si suggerisce di individuare la minima dose
biologicamente efficace, per il cui calcolo va presa in
onsiderazione anche la prima dose farmacologicamente attiv
elsus 1493 – 1541
ing' sind Gift und nichts ohn' Gift; allein die Dosis macht, das ein Ding kein Gift ist.
hings are poison and nothing is without poison, only the dose makes a thing be poison."
eneral, the No Observed Adverse Effect Level (NOAEL) determined in non
cal safety studies performed in the most sensitive and relevant animal spe
sted with allometric factors or on the basis of pharmacokinetics gives the m
ortant information. The relevant dose is then reduced/adjusted by appropri
ty factors according to the particular aspects of the molecule and the desig
clinical trials.
nvestigational medicinal products .......omissis…have been identified, an
tional approach to dose calculation should be taken.
‘Minimal Anticipated Biological Effect Level’ (MABEL) approach is
mmended. The MABEL is the anticipated dose level leading to a minim
ogical effect level in humans. When using this approach, potential
rences of sensitivity for the mode of action of the investigational medicinal
uct between humans and animals, need to be taken into consideration e.g
ved from in-vitro studies. A safety factor may be applied for the calculation
irst dose in human from MABEL.
BIOTECHNOLOGY-DERIVED PHARMACEUTICALS
S6(R1)
Parent Guideline dated 16 July 1997
Addendum dated 12 June 2011 incorporated at the en
of June 2011
5 topics
- Species Selection
- Study design
- Immunogenicity
- Reproductive/developmental toxicity
- Carcinogenicity
One or two species for safety evaluation
Two species (if relevant) for 1 month, one species for longe
term (e.g. 6 months)
One species with ‘clinical candicate’ sufficient
Studies in a second species with a homologous product (in
addition to a study with a clinical candidate) are not
recommended
ICH S6 R(1)
Update of the Guideline by an Addendum (2008)
5 topics
- Species Selection
- Study design
- Immunogenicity
- Reproductive/developmental toxicity
- Carcinogenicity
Study design (TOPICS)
-Agreed on chronic study duration: 6 months
sufficient
- Guidance on selection of high dose level (HDL)
- Recovery groups
Agreed on chronic study duration:
- 6 months sufficient
- Longer duration are not anticipated to provide
useful information
Selection of HDL:
ationale should be provided for dose selection taking into account the
aracteristics of the dose-response relationship. PK-PD approaches (e.g., simple
posure-response relationships or more complex modeling and simulation
proaches) can assist in high dose selection by identifying 1) a dose which
ovides the maximum intended pharmacological effect in the preclinical species;
d 2) a dose which provides an approximately 10-fold exposure multiple over the
aximum exposure to be achieved in the clinic. The higher of these two doses
ould be chosen for the high dose group in preclinical toxicity studies unless there
a justification for using a lower dose (e.g., maximum feasible dose)......omissis....
Recovery groups:
- Study of recovery only in one study
- Not necessarily in the high dose group
- Not always to full recovery (duration limited)
ICH S6 R(1)
Update of the Guideline by an Addendum (2008)
5 topics
- Species Selection
- Study design
- Immunogenicity
- Reproductive/developmental toxicity
- Carcinogenicity
Immunogenicità/Immunotossicità
munogenicity assessments are conducted to assist in
e interpretation of the study results and design of
bsequent studies. Such analyses in nonclinical
imal studies are not relevant in terms of predicting
tential immunogenicity of human or humanized
oteins in humans.
appropriati, cambi di produzione della materia prima,
luppo e validazione di metodologie immunologiche
mmonoassay”) e fallimenti nella valutazione della
munogenicità/ immunotossicità.
Immunogenicità/Immunotossicità (mAb)
- Và controllata la risposta anticorpale per capire se si
sviluppano anticorpi anti-mAb neutralizzanti o cross reattivi
- I primi pur preoccupando perché spesso riducono efficacia
e alterano la cinetica non sono predittivi della risposta
nell’uomo
- I secondi sono molto pericolosi perché possono interagire
con proteine endogene e causare effetti tossici.
- Questi effetti possono essere predetti saggiando la
proteina omologa nella specie appropriata ( ad esempio
’anticorpo murino saggiato nel topo, la proteina
“cynomolgus” saggiata nella scimmia)
- L’uso di animali transgenici, può essere un’alternativa
accettabile agli studi di sicurezza standard, in particolare
quando è difficile definire la specie rilevante
ICH S6 R(1)
Update of the Guideline by an Addendum (2008)
5 topics
- Species Selection
- Study design
- Immunogenicity
- Reproductive/developmental toxicity
- Carcinogenicity
- Fertility testing in NHPs when the only relevant species
- An appropriate assessment of reproductive toxcity with
the clinical candidate preferred over studies with
homologous product. Sponsor can provide scientific
justification for alternative approaches including use of
homologous products
- one well-designed study in NHPs that includes dosing
from day 20 of gestation to birth can be considered,
rather than separate EFD and/or PPND studies.
ICH M3 rev 2
ICH S6 R(1)
(www.ema.europa.eu )
(reduce/refine/replace) principles
hanced PPND study design involves holistic assessment of all
elopmental toxicity endpoints in a single cohort of gestationally expos
mals
Reduces need for 2 separate studies (EFD and PPND studies)
One treated group and control will reduce numbers further
Timing: provide for registration
n include fertility aspects in chronic tox studies – not separate
ies
e of only one relevant species for chronic toxicity even if 2 relevant
ies
covery groups not required for all treatment groups or all studies
eement on 6 months chronic toxicity duration could reduce number o
ated dose toxicity studies required for non-oncology products: FIHporting and 6 months chronic
e of a surrogate for reprotox with appropriate justification
containing
iotechnology-derived proteins as active substanc
Non-clinical and clinical issues
ore initiating clinical development, non-clinical studies should
ormed. These studies should be comparative in nature and
uld be designed to detect differences in response betwe
similar biological product and the reference medicinal produ
not just the response per se.
EMEA/CHMP/BMWP/42832/20
Qualità
Sicurezza Preclinica
“case by case!”
Circa il 50% di tutti i nuovi farmaci in sviluppo
inano dalle biotecnologie, e la proporzione cresce nei trattam
più innovativi come: ormoni della crescita, fattori
di crescita ricombinanti, vaccini, anticorpi monoclonali per
trattamento di tumori e malattie infiammatorie/infettive, terap
cellulare ecc.
settore delle biotecnologie per la cura della salute cresce og
anno di circa il 15%, più del doppio rispetto alla farmaceutica
tradizionale.
MAB e mercato
he nearly 35 years since the first process for creating mAbs was
oduced, they have remained a centerpiece of the growing biotechnolo
ustry. Thirty therapeutic mAbs have been approved around the world,
uding 23 in the United States.
umber of these drugs have attained blockbuster status, with sales
ching the coveted billion-dollar mark and well beyond. Rituxan,
micade, Avastin, Herceptin, and Humira alone generated sales of ove
on each in 2008, and global sales for this entire sector surpassed $30
on last year.
nical pipeline with over 250 candidates
Biotech Product
Development
Grazie per
l’attenzione