PREKLINICKÉ  HODNOCENÍ  LÉČIV  

Hradec  Králové,  5.2.2014  

Obecné  požadavky,  role  smluvní  výzkumné  organizace,    MediTox  s.r.o.  

 RNDr.  Ivana  Šurová  

 

General requirements for main cathegories of medicinal products

Preclinical support of clinical trials and

registration

The role of CRO in preclinical development

MediTox s.r.o.

Drug development process

 Understading  of  mechanism    of  regulaXon  

 IdenXficaXon  of  molecular  

target  

 IdenXficaXon  of  structurally  idenXcal  molecules  

Early  preclinical  

Advanced  preclinical  

Clinical  RegistraXon  

Pre-­‐clinical/Toxicological  Phase  First  in  vivo  data  on  bioavailability  and  preliminary    ADME    

non-­‐GLP  exploratory  studies  

First  preliminary  data  related  to  toxicity     non-­‐GLP  exploratory  studies  (MTD,  DRF)    

Safety  (and  environmental  safety)  data  related  to  toxicity,    adverse  effect,  reversibility,    dose-­‐dependency  

non-­‐GLP  and  regulatory  GLP-­‐compliant  studies  

EsXmaXon  of  doses    for  clinical  trials        and  next  step  of  pre-­‐clinical  tesXng  (NOEL,  NOAEL)    

regulatory  GLP-­‐compliant    studies  

IND/CTA,  supporXng  of  all  phases  of  clinical  trials    

regulatory  GLP-­‐compliant  studies  

„Clinical“  data  for  veterinary  use  (TAS)   regulatory  GLP-­‐compliant  studies  

Requirements  –  „chemical“  vs  „drug“  Chemical  preparaXon   Drug  

Regutatory  Authority   ECHA/EPA   EMA/FDA  

Guidelines   OECD/EPA  OPPTS    EMA/ICH/FDA  

Acute  toxicity     LD50,  Acute  Toxic  Class,  GLP-­‐compliant  

MTD,  MFD,  non-­‐GLP  

Immunotoxicity   NO   YES  

Repeated  dose  toxicity   14,  21,  28,  90,  180  days   Corresponding  to  CT  

Route  of  administraXon  

Oral,  dermal,  inhalaXon  i.v.,  i.p.  (EPA)  

Corresponding  to  CT  

Requirements  related  to  specific  cathegories  Small  molecule   Biologic   Medical  Device  

Guidelines   OECD,  EMA/ICH/FDA   EMA/ICH/FDA   ISO  10993,  OECD/FDA  

Genotoxicity   YES   As  usual  NO   YES  

Acute  toxicity   YES  (MTD)   YES  (MTD/MFD)   YES  (MFD)  

Repeated  dose   YES     YES   YES  

TK/PK   YES     YES  (if  feasible)   NO  

Local  effects   YES/NO     YES/NO   YES  

Safety  pharm.   YES   YES   NO  

ReproducXon   YES   NO   YES  

Carcinogenicity   YES   NO   YES  

Immunotoxicity   YES/NO   YES   NO/YES  -­‐  FDA  

RegulaXon  of  drugs  -­‐  EU  (EMA)  vs  US  (FDA)    EMA   FDA  

CTA  (Clinical  Trial  ApplicaXon)  

MAA  (MarkeXng  AuthorizaXon  ApplicaXon  

IND  (InvesXgaXonal  New  Drug  ApplicaXon)  

NDA  (New  Drug  ApplicaXon)    

IMPD  (InvesXgaXonal  Medicinal  Product  Dossier)  

ApplicaXon  Dossier  

CTD-­‐format    (Annex  1  to  DIR  2001/82/EC)  

CTD-­‐format  Title  21  CFR  Part  514.50,  Part  601.2  Guidance  for  Industry  

RegulaXon  of  drugs  -­‐  EU  (EMA)  vs  US  (FDA)    

EMA    CTA  (Clinical  Trial  ApplicaXon)  must  be  submined  to  the  Competent  Authority    of  the  Member  State(s)  where  the  clinical  trial  will  be  conducted.    CTA  is  required  for  all  clinical  studies  including  BEQ        

FDA    IND  (InvesXgaXonal  New  Product  applicaXon)  must  be  submined  to  FDA        IND  is  not  required  for  BEQ  studies  with  the  excepXon  of  cytotoxic  compounds  

1.   AdministraXve  and  prescribing    informaXon  

2.        Overview  and  summary  of                    modules  3  to  5  3.   Quality  (pharmaceuXcal                      documentaXon)  4.   Preclinical  Pharmacology                  and  Toxicology)  5.        Clinical  -­‐  efficacy  (Clinical                    Trials)  

CTD  structure   ICH  M4:  The  Common  Technical  Document  

Clinical  trials  and  preclinical  support  Clinical   Preclinical  Phase  I   IniXal  safety  trial  

Tolerance,  basic  PK  DRF  for  SD  and  RD,  food  effect  

20  –  100  healthy  volunteers  (paCents)  

SD  study,  subacute  (7  –  28  days)  RD  study,  TK/PK  (extended  SD  study  +  TK  for  microdoses)  

Phase  II  a   Pilot  clinical  trial  effecCvity  and  safety,  dosing  range  

≤  200  paXents    Genotox,  safety  pharmacology,  local  tolerance,  subchronic  (90  days)  RD  study,  toxicity  to  reproducXon  

Phase  II  b    

Pivotal  clinical  trial  Proof  of  therapeuCc  effect,  dose-­‐response  

≥  200  paXents,    Design  close  to    phase  III  

Phase  III   Controled  clinical  trial  Comparison  to  placebo/standard  treatment  

Up  to  thousands  paXents  MulCcenter,  randomized,  blinded  study  

Chronic  RD  study,  carcinogenicity  study  

DuraXon  of  repeated  dose  toxicity  studies  supporXng  CTA/IND  Maximum  duraXon  

of  clinical  trial  Recommended  duraXon  of  repeated  dose  studies  

EU   US  

Les  than  2  weeks   2  weeks   Same  as  clinical  trial  

2  weeks   2  weeks    

2  weeks    AlternaXve:  Extended  single  dose  study  

Between  2  weeks  up  to  6  months  

Same  as  clinical  trial   Same  as  clinical  trial    

More  than  6  months   6  months  rodents  &  non-­‐rodents  

6  months  for  rodents  9  –  12  months  for  non-­‐rodents      

The  role  of  CRO  in  preclinical  development  

● Expertise in niche areas

● Flexibility

● Cost and time effective - maintaining cost restraints, keeping quality and timelines ● Understanding the administrative and other demands ● GLP compliance - meeting directives and regulations Outsourcing in pre-clinical development is projected to increase from the current 20-25% to 40-50% of R&D expenditures in the next few years

CRO is between a rock and a hard place

Meeting of regulations

Certification Good Laboratory Practice Certificate OECD GLP [C(97)186 Final] Pharmaceuticals, medical devices and food additives (PHARMA)

Good Laboratory Practice Certificate OECD GLP [C(97)186 Final] Chemicals, agrochemicals (REACH)

Authorization for Using of Experimental Animals The Central Committee for Animal Protection of the Ministry of Agriculture

Authorization for Breeding of Experimental Animals The Central Committee for Animal Protection of the Ministry of Agriculture

Approval for handling with GMO in compliance with Act No. 153/2000 Coll.

Contract-based experimental services (OECD/EMA/FDA/ISO 10993)

Genetic toxicology & cytotoxicity

General toxicology & Non-clinical safety

Safety Pharmacology Local effects Immunogenicity/Immunotoxicity Pre-clinical evaluation of biotech-derived products

Non-clinical implantation studies Biocompatibility & non-clinical local tolerance of medical devices Toxicity to reproduction Carcinogenicity Biodistribution

ANTIFLU: Innovative anti-influenza drugs exluding viral escape (Denmark, France, Germany, Hungary, Israel, United Kingdom, Czech Republic)

OSTEOGROW: Novel bone morphogenetic protein-6 biocompatible carrier device for bone (Austria, Bosnia and Herzegovina, Croatia, Czech Republic, Sweden)

MOTIF: Micorbicide optimization through innovative formulation for vaginal and rectal delivery (Czech Republic, France, Italy, United Kingdom)

HELICOVAXOR: Development of an oral Helicobacter Pylori vaccine (Belgium, Czech Republic, France, Switzerland, United Kingdom)

UNIVERSAL VACCINE: Synthetic self-replicationg RNA vaccines targeted to dendritic cells as „universal“ influenza and future generic vaccines (Czech Republic, France, Germany, Norway, Russia, Switzerland)

MuLeVaClin: Clinical Studies on a Multivalent Vaccine for Human Visceral Leishmaniasis (Czech Republic, Italy, Portugal, Spain, Switzerland)

Selected R&D projects - international

National R&D projects

BIOMEDTEST: Biomedical models of traumatic spinal cord injury and neurodegenerative diseases in miniature pigs for testing of new therapeutic approaches Participants: Institut of Animal Physology & Genetics CAS, MediTox s.r.o.)

Technology Agency of The Czech Republic: ODDC: Original Drug Development Center Participants: Institut of Organic Chemistry and Biochemistry CAS, Institut of Chemical Technology, Institut of Experimental Medicine Cas, Institut of Physiology CAS, MediTox s.r.o., Quinta-Analytica s.r.o., Apigenex s.r.o.)

Contract-based experimental services Animal models of selected human diseases Diabetes model (type II - non-human primates, type I - rats)

Chronic glaucoma model (dogs)

Experimental myocardial infarct (dogs, mini pigs)

Chronic traumatic spinal cord injury model (mini pigs)

Acute contact dermatitis (mini pigs)

Animal models under development: Diabetes in dogs

Obesity model in mice

Pristane-induced arthritis in rats

Experimental model of diabetes – macaque rhesus

* Reference Values, Clinical Chemistry Values, 2013: Unpublished data, MediTox s.r.o. ** K. Hrapkiewicz, L.Medina, Blackwell, 2007: Clinical Laboratory Animal Medicine, Iowa, USA *** S. Wolfe-Coote, 2005: The Laboratory Primate, Elsevier Academic Press, USA

-  The disease is most common in older, obese animals -  Period of obesity-associated insulin resistance that is initially met with compensatory insulin secretion -  Pathological changes in pancreatic islets are also similar to those seen in human diabetics. -  Changes in plasma lipid and lipoprotein concentrations and lipoprotein composition, which may

contribute to progression of atherosclerosis.

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pre-diabetic (males)

pre-diabetic (females)

MediTox Ref. Values (males)*

MediTox Ref. Values (females)*

Clinical Laboratory Animal Medicine **

The Laboratory Primate***

Experimental models of myocardial infarct in beagle dog

Arteria coronaria occlusion Myocardial section (Coomassie blue injected into arteria coronaria):

● Ligation of the left coronary artery producing myocardial ischemia

● Following heart reperfusion

● Morphometric analysis of area at risk and area of infarction

● Determination of the weight of infarct over the weight of area at risk.

Experimental chronic glaucoma in dogs „More than 70 million people worldwide suffer from glaucoma. Glaukoma is leading cause of blindness.“ This experimental glaucoma model has been developped to facilitate the drug develoment. It is easily induceable, stable, showing IOP elevation and revealing chracteristic clinical signs

- corneal opacity - dilated episcleral blood vessels at the corneal edge - reduced or absent pupillary reflex - uveitis.

Client    

CRO    Request    

CDA    

InformaXon    

Targeted    discusion    

Tailored  proposal  

Cost  assessment    

Contract  

Targeted  planning  Ethical  Approval    

Study  Protocol    approval  

Start  of  the  study  

Russia

Australia

India

Israel

Canada

USA

Singapore

Switzerland

Albania

Macedonia

www.meditox.eu  

Thank  you  for  anenXon  !