Nonclinical Data Assessment and Strategic Planning

TOPRA MSc Module 2: 4-6thFebruary 2015

Nonclinical Data Assessment and Strategic Planning

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSIONENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSIONENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

PlanningA presentation by Lesley Reeve, Associate Director, Global Regulatory Strategy, Covance Inc.

� Nonclinical development ‘standard’ vs. alternative approaches

� Planning (timing of regulatory interactions)

� Nonclinical data in documentation (CTA/IND, PIP/PSP, CADs, MAA/NDA and support for RMP, SmPC and label)

� Regulatory Strategy (timings, regional diffs, additional issues)

In this presentation we will cover:

issues)

� Impact of changes to DS and DP (intended and unintended)

� Duration often > 10 years

� Cost ~ $ 2,558 million (average)1

~ $1,395 million “out-of-pocket” costs

~ $ 1,163 million lost investors’ returns during development

� Post approval R&D ~ $312 million

Cost and Timing

� new indications, new formulations, new dose strengths & dose regimens, PMCs, PhV

� Total cost of product lifecycle: $ 2,870 million!

� Non-clinical contribution: average cost $6.2 million (range $700K to $20 million)2

1Tufts (2014)

2 Stergiopoulos et al., (2013)

Legislative Need (EU)

Directive 2001/83/EC (Community code relating to medicinal products for human use) “as amended”

� [Article 8 (3)] For marketing authorisation, need:

� The results of physico-chemical, biological or microbiological tests, toxicological and pharmacological tests & clinical trials

� Annex 1

� details the “analytical, pharmaceutical & clinical standards and protocols in � details the “analytical, pharmaceutical & clinical standards and protocols in respect of the testing of medicinal products” which should be provided:

� Part 1 - administrative data

� Part 2 - Chemical, pharmaceutical & biological testing of medicinal products

� Part 3 - Toxicological and pharmacological tests

� Part 4 - Clinical documentation

Legislative Need (EU)

� Annex 1, Part 3

� details what toxicological and pharmacological data are needed and comprises:

� pharmacodynamics/pharmacology

� pharmacokinetics

� single dose and repeated dose toxicity

� reproduction toxicity� reproduction toxicity

� mutagenic potential

� carcinogenic potential

� others (eg local tolerance)

Legislative Need (USA)

Numerous Congressional Acts but most relevant for toxicology are:

● Federal Food Drug and Cosmetic Act 1938

● Prescription Drug User Fee Act (PDUFA) 1992

● FDA Modernization Act 1997

● PDUFA (V) – renewed 2012 (needs to be reviewed and authorised ● PDUFA (V) – renewed 2012 (needs to be reviewed and authorised every 5 years)

USA - CODE OF FEDERAL REGULATIONS

21 CFR Part 312 - Investigational New Drug Application (IND)

21 CFR Part 314 - New Drug Application (NDA)

21 CFR Part 601 - Biologics Licence Application (BLA)

21 CFR Part 316 - Orphan Drugs

21 CFR Part 58 - Good Laboratory Practice (GLP) for animal studies

21 CFR Part 50 - Protection of Human Subjects

21 CFR Part 56 - Institutional Review Boards

21 CFR Part 201 - Drug Labelling

Legislative Need (Japan)

� Ordinances

�The highest level administrative documents issued only by the Ministry of Health, Labour and Welfare. e.g. “MHLW Ordinance No. 64 (April 4, 2002)” - Partial revision of the Enforcement Regulations of the Pharmaceutical Affairs Law.64 (April 4, 2002)” - Partial revision of the Enforcement Regulations of the Pharmaceutical Affairs Law.

� Notifications

�The highest level of administrative documents issued by the various Bureaux of the Ministry of Health, Labour and Welfare - such as the Pharmaceutical and Medical Safety Bureau (PMSB), and at ministerial level as well. e.g. PFSB Notification No. 0613007 (GLP)

●Determine and predict undesirable toxic and target organ

effects in animals at relatively large doses

●Demonstrate that the potential drug elicits the required

pharmacological responses in animals that are likely to be

analogous to the desired effects in man

●Attempt to define absorption, distribution, metabolism and

Role of nonclinical development

●Attempt to define absorption, distribution, metabolism and

excretion (ADME)

●Essential in designing early clinical trials, (determination of

HED levels, starting dose and escalations - using NOELs,

NOAELs, MABELs and TK data)*

●Go vs. no-go decisions

* Baldrick (2008a & 2008b)

� Data on attrition rates indicate that the probability of a drug candidate passing from nonclinical stage (i.e. the first GLP toxicology study) to market is 6% or less*

� The most common factors resulting in project failure have been reported as: lack of efficacy (25%), clinical safety concerns (12%) and toxicological findings in nonclinical

Drug Attrition

concerns (12%) and toxicological findings in nonclinical evaluation (20%)*

#Kola and Landis (2004)

Overview of Drug Development

� Pharmacology

� Safety pharmacology (ICH S7A & S7B)

� Pharmacokinetics (ICH S3A; ICH S3B; ICH S3A Q&A)

� Acute toxicity – dose escalation / range-finding studies, MTD (possibly delay to support Phase III) (e.g. OECD 420)

� Repeat dose toxicity studies (e.g. OECD 407)

“Standard” Approach – studies to support Phase I

� Repeat dose toxicity studies (e.g. OECD 407)

� Genotoxicity studies (ICH S2)

� Reproductive toxicity studies (if needed) (ICH S5)

# ICH M3(R2): Nonclinical Safety Studies

� Chronic dose toxicity studies (ICH S4; e.g. OECD 425)

� Carcinogenicity studies (ICH S1 series; OECD 451)

� Reproductive toxicity studies (if WCBP exposed >3 months)

� Appropriate toxicity/genotoxicity studies on metabolites, impurities and/or excipients

� Additional safety pharmacology (if necessary)

“Standard” Approach – to support Phase II, III and marketing

� Additional safety pharmacology (if necessary)

� Additional genotoxicity studies (if necessary)

� Pharmacokinetics (studies on absorption, distribution, metabolism and excretion)

� Other toxicity (phototoxicity [ICH, S10], juvenile toxicity [ICH S11] etc)


Duration of Toxicity Studies to Support Clinical Trials

Minimum duration of toxicity studies

Duration of trial Rodent Non-rodent

Up to 2 weeks 2 weeks* 2 weeks

2 weeks to 6 months Same as clinical trial duration**

Same as clinical trial duration **duration** duration **

> 6 months 6 months 9 months ***

*In US as an alternative to repeat dose studies, single dose toxicity studies with extended examinations may support human trials up to 14 days **Special cases where different include paediatric medicines and serious, life-threatening conditions.

***Data from 6 months in non-rodents is acceptable in EU and in special cases in USA and Japan


Duration of Toxicity Studies to Support Marketing

Minimum duration of toxicity studies

Duration of clinical trial

Rodent Non-Rodent

Up to 2 weeks 1 month 1 month

Up to 1 month 3 months 3 months

Up to 3 months 6 months 6 monthsUp to 3 months 6 months 6 months

> 3 months 6 months* 9 months*, **

*Requirements can differ for special cases e.g. paediatric medicines or those for serious, life-threatening conditions.

** In EU, 6 months non-rodent considered acceptable.


“Microdose”

●Single dose ≤ 100 µg (≤ 100th active dose; ≤ 100th NOAEL)

●Up to 5 doses of ≤ 100 µg (≥ 6 half-lives washout)

“Exploratory”

●Single dose, sub-therapeutic into therapeutic range

“Alternative” Approaches

●Single dose, sub-therapeutic into therapeutic range

●Multiple dose trials


Microdose Trials – supporting nonclinical studies

Single Microdose

●Pharmacology

●Single dose extended study (rodent, top dose 1000-fold clinical dose)

Up to 5 microdoses

●Pharmacology

●7 day study in 1 species (rodent)

●No safety pharmacology●No safety pharmacology

●No genotoxicity

●No safety pharmacology

●No genotoxicity


Exploratory Trials – supporting non-clinical studies

Single dose sub-therapeutic / into therapeutic

●Pharmacology

●Safety pharmacology (core battery)

Up to 14 days into therapeutic range

●Pharmacology

●Safety pharmacology (core battery)

battery)

●Single dose extended studies (2 species)

●Genotoxicity

●Repeat dose tox:

–Rodent 2 weeks

–Non-rodent 2 weeks, OR ≥ 3 days, OR escalating dose

●Genotoxicity


Alternative approaches – product specific

� Biological products*

� Species selection

� Immunogenicity

� Exposure (PK and TK)

� Safety pharmacology (//

� Single dose toxicity

�Repeated dose toxicity

� Immunotoxicity

�Reproductive toxicity� Safety pharmacology (// NCEs)

�Metabolism (not needed)

* ICH S6(R1)

�Reproductive toxicity

�Genotoxicity

�Carcinogenicity

� Local tolerance

� Anti-cancer products (ICH S9)

� Dosing schedules, toxicity assessment (STD10 vs. NOAEL), reprotoxicity and genotoxicity only prior to marketing, no carcinogenicity, no juvenile toxicity

� Vaccines (CPMP/SWP/465/95; WHO, 2005)

� Appropriate species? Generally no developmental toxicity, genetic toxicity or carcinogenicity studies.


or carcinogenicity studies.

� Gene therapy products (e.g.EMEA/CHMP/GTWP/125459/2006; EMA/CAT/GTWP/671639/2008)

� Appropriate species? Xenoreactions, homologous or immune-deficient models

� Diagnostic imaging agents (FDA, 2004)

� Safety pharm, extended single dose then 2- to 4- week repeated dose, genotoxicity, immunotoxicity, reproductive & developmental toxicity (waiver?)

� Medical devices / drug containers or delivery devices (ISO 10993 series; FDA, 1999; FDA, 2013a)


(ISO 10993 series; FDA, 1999; FDA, 2013a)

� Extractables and leachables, interactions with DP

Regulatory Interactions – “standard” milestones

DISCOVERYDISCOVERY DEVELOPMENTDEVELOPMENT COMMERCIALIZATIOCOMMERCIALIZATIONN

PHASE IVRESEARCH PRE-CLINICAL PHASE I PHASE II PHASE III

Non-clinical pharmacology, pharmacokinetics and toxicology

Regulatory Affairs

Pre-IND Meeting

End of Phase II Meeting

Pre-NDA MeetingMeeting

Initial IND Submission

II Meeting Meeting

NDA Submission

1st CTA submission

Scientific advice meetings

Ongoing submissions to IND

Subsequent separate CTAsMAA

Submission

� CTA

� Investigator’s Brochure (IB)

� Investigational Medicinal Product Dossier (IMPD)

� Toxicology study reports not supplied (ICH E6; EC, 2010/C 82/01)

� IND

Nonclinical Content in Key Regulatory Documents

� IND

� Investigator’s Brochure (IB)

�Nonclinical summary

� Toxicology study reports need to be supplied (ICH E6; FDA, 1995; FDA, 2006)

� Briefing books (scientific advice meetings)

� Standalone nonclinical Qs / Multidisciplinary Qs (EMA/691788/2010 Rev.7;

� Background rationale / information FDA, 2009)

� Parallel advice from EMA/FDA (EMEA/24517/2009)

� MAA / NDA

� CTD 2.4 (NCO)

� CTD 2.6 written and tabular summaries

� CTD 4 nonclinical study reports (ICH M4S; ICH M4S Q&A)

� RMP (EU)

� Part II (Safety Specification) SII (nonclinical part of the safety specification)

� include all negative findings (secondary pharmacology, safety pharm,

Nonclinical content in Key Regulatory Documents

� include all negative findings (secondary pharmacology, safety pharm, kinetics and toxicology)

� Special populations (EMA/465926/2013 Rev.1)

� Labelling

� US Package insert (PI) sections 8.1 (pregnancy), 8.3 (nursing mothers), 8.4(pediatric use), 13.1 (carc,. “mutagenesis”, impairment of fertility) and 13.2(tox / pharm) as required

� EU SmPC sections 4.6 (fertility, pregnancy and lactation) and 5.3 (preclinical data) (Baldrick, 2014)

Regulatory Interactions – additional milestones

DISCOVERYDISCOVERY DEVELOPMENTDEVELOPMENT COMMERCIALIZATIONCOMMERCIALIZATION

PHASE IVRESEARCH PRE-CLINICAL PHASE I PHASE II PHASE III

Non-clinical pharmacology, pharmacokinetics and toxicology

Regulatory Affairs

Orphan drug designation application PMCs

PSP submission

PIP submission

SPA to CAC

CAD

� Orphan designation application

� Tabular format of nonclinical data (EU) (ENTR/6283/00 rev. 4)

� Nonclinical pharmacology data (USA) (21CFR 316.20)

� PIP (EU)

� Section D3 – strategy in relation to nonclinical aspects (EC 2008/C 243/01)


� Section D3 – strategy in relation to nonclinical aspects (EC 2008/C 243/01)

� PSP (USA) (FDA, 2013b)

� Section 5 – summary of planned studies (incl. nonclinical)

� Section 7 – brief summary of existing data and rationale for planned studies

� Carcinogenicity Assessment Document (ICH S1 concept paper)

� N/A for drugs following ICHS6(R1)

� Rationale for whether carcinogenicity studies would add value to the nonclinical package (if not, waivers could be granted).

� Data to include:


� Pharmacological targets,

� risk factors for neoplasia,

� evidence of hormonal / growth factor disruption,

� genotoxicity,

� known class effects

� SPA to CAC for carc studies for submission to FDA

� Submit data to CDER’s Carcinogenicity Assessment Committee to allow dose selection / justification for all carc. studies planned for future submission to FDA

� Repeated dose tox studies,

� TK (particularly AUC)

� Metabolism

� Genotoxicity (FDA, 2002)

Regional Considerations

� MAD agreements

� e.g. Issue of nonclinical data generated in China vs. OECD GLP / 21 CFR 58.

Dec 2014: cFDA delegates to MHRA indicated to ABPI that China will pursue membership of the OECD MAD program (GLP)

But still requirement for Single Dose Acute Toxicity Study in China (modified guideline issued May 2014)

Regional Considerations

� Key role

� predicting and addressing potential problems before they become an issue!!

� Sources

� Legislation, guidance and Scientific Advice

� Public Assessment Reports e.g. UKPAR from MHRA, EPAR from EMA

� Approval History (e.g. Pharmacology & Toxicology Reviews) and SBoA from FDA

Regulatory Intelligence

� Approval History (e.g. Pharmacology & Toxicology Reviews) and SBoA from FDA

� Advisory Committee meetings with FDA (“open forum” / public)(Cox & Scott, 2014)

� PMCs can indicate regulatory issues or regulatory creep.

� Published literature

Nonclinical issues contributing to FDA review failures

Examples of MAA Failures

� CMC

� Incomplete information on development of product (eg consistency of manufacturing process, development of formulation, stability data), quality control

� Nonclinical

� Flaws in design of studies, incomplete information, poor interpretation of data

� Clinical

33

� Clinical

� Lack of demonstration of efficacy, flaw in pivotal clinical studies (eg incorrect population for target disease, limitations in study design), irrelevant study end points (eg markers of efficacy), lack of blinded assessment, lack of risk management

� PMCs

�Requested by Regulatory Agency

�Agreed by the Applicant at time of approval

�Voluntarily proposed by the Applicant

� Nonclinical PMCs

Nonclinical PMCs

�At last review, nonclinical PMCs comprised around 10% of total requests*

� Increased with increasing date of approval (despite increased guidance)

� Increased proportion of applications with nonclinical PMCs not an increase in overall applications

*Reeve (2009)

Nonclinical PMCs by endpoint

15

20

25

30

35

0

5

10

Nonclinical aspects during Product Life Cycle

� Changes during product life-cycle

� ‘Unintended’

� Intended

36

� Impact on nonclinical data requirements

�Changes to Drug Substance & Drug Product

�Changes to container / closure system or delivery device

�Changes in dose route / indication / population

� Drug Substance

� E.g. Impurity profile

� Qualification of new/higher level impurities

(ICH Q3A(R2); ICH Q3B(R2); ICH Q3C(R5); ICH Q3D; ICH M7)

� Drug Product

� e.g. ‘new’ vs. ‘essentially new’ excipient

Impact of changes to DS, DP and container

� e.g. ‘new’ vs. ‘essentially new’ excipient

� e.g. higher level of existing / established excipient

(IPEC, 1997; Uchiyama, 1999; FDA, 2005; EMEA, 2007)

� Container/Closure & Delivery Device considerations

� Extractable and leachable materials

(EMEA, 2005; FDA, 1999; ISO 10993 part 17, 2002; FDA 2013a)

� Bridging packages

� Additional nonclinical data to “bridge” to existing data can be limited or extensive

� Considerations

� Exposure – comparative PK (ADME)

� Short-term repeat dose toxicity (if needed)

Impact of changes to dose route

� Short-term repeat dose toxicity (if needed)

� Safety pharmacology (if needed)

� local tolerance

� special studies e.g. Phototoxicity considerations for products topically applied or distributed to skin / eye;

(FDA, 2008)

� Use of regulatory strategy

● To minimise time and cost of nonclinical development

● To provide maximum reassurance of safety

� Use of standard and “alternative” approaches

● Reduced nonclinical packages for microdose / exploratory trials

● Reduced nonclinical packages for specific products / indications

� Non-clinical documentation

In this presentation we covered

� Non-clinical documentation

● Standard – e.g. IND/CTA, NDA/MAA

● Non-standard / regional / voluntary – e.g. SPA to CAC (USA) / CAD

� Regulatory Interactions

● Scientific advice

● Advisory Committees (FDA)

� Regulatory Intelligence

Use of existing information on similar products (EPARs, SBoAs, product labels)

�Understand your product

�Use common sense, guidance and scientific advice

�Tell your story well

�Always tell the truth

Overall . . .

� Baldrick (2008a). Reg Tox Pharm 51: 230-236

� Baldrick (2008b). Reg Tox Pharm 51: 237-243

� Baldrick (2014). Reg Tox Pharmacol 69(3): 546-557

� Cox and Scott (2014). Reg Rapporteur 11(11): 5-8

� EC, 2010/C 82/01. Communication from the European Commission – Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1). O.J. C82/1 30 March 2010.

� EMEA (2005). Guideline on plastic immediate packaging materials. European Medicines Agency, Committee for medicinal products for human use (CHMP) Committee for Medicinal Products for

References

Committee for medicinal products for human use (CHMP) Committee for Medicinal Products for Veterinary Use (CVMP), London 19 May 2005. CPMP/QWP/4359/03 & EMEA/CVMP/205/04.

� EMEA (2007). Guideline on excipients in the dossier for application for marketing authorisation of a medicinal product. EMEA/CHMP/QWP/396951/2006.

� FDA (1995). Guidance for Industry. Content and Format of INDs for Phase I Studies of Drugs, Including Well-Characterised, therapeutic, biotechnology-derived Products. CDER & CBER November 1995.

� FDA (1999). Guidance for Industry, Container closure systems for packaging human drugs and biologics, CDER, CDRH, May 1999.

� FDA (2002). Guidance for Industry. Carcinogenicity Study Protocol Submissions. CDER May 2002.

� FDA (2004). Guidance for Industry, developing Medical Imaging Drug and Biological Products Part 1: Conducting Safety Assessments

� FDA (2005). Guidance for Industry, Nonclinical studies for the safety evaluation of pharmaceutical excipients, CDER May 2005.

� FDA (2006). Guidance for Industry, Investigators and Reviewers. Exploratory IND Studies, CDER January 2006.

� FDA (2008). Guidance for Industry and Review Staff. Nonclinical safety evaluation of reformulated drug products and products intended for administration by an alternate route. CDER. Draft Guidance March 2008.

� FDA (2009). Guidance for Industry. Formal Meetings Between the FDA and Sponsors or Applicants. CDER, May 2009.

References

� FDA (2009). Guidance for Industry. Formal Meetings Between the FDA and Sponsors or Applicants. CDER, May 2009.

� FDA (2013a). Draft Guidance for Industry and FDA staff. Use of International standard ISO-10993, “Biological Evaluation of Medical Devices Part 1: Evaluation and Testing”. April 23, 2013.

� FDA (July 2013b). Guidance for Industry, Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Pediatric Study Plans DRAFT GUIDANCE.

� IPEC (1997). The proposed guidelines for the safety evaluation of new excipients. The International Pharmaceutical Excipients Council, Europe Safety Committee. Eur. Pharm. Rev. 1997.

� ISO 10993-17 (2002). Biological evaluation of medical devices – Part 17: Establishment of allowable limits for leachable substances. ISO Copyright Office, Case Postale 56, CH-1211 Geneva 20, Switzerland.

� Kola and Landis (2004). Nat Rev Drug Dis 3: 711–715

� Reeve (2009) Reg Tox Pharm 55: 181-187

� Sacks et al (2014). Journal of the American Medical Association (JAMA). 2014;311(4):378-384. doi:10.1001/jama.2013.282542

� Stergiopoulos et al., (2013). Contract Pharma June 5, 2013

� Tufts(2014). Tufts Centre for the Study of Drug Development, http://csdd.tufts.edu/news/complete_story/pr_tufts_csdd_2014_cost_study

References

� Uchiyama M (1999). Regulatory status of excipients in Japan. Drug Inform J 33:27.

� WHO (2005). World Health Organisation. WHO Technical report series No. 927. Annex 1, WHO guidelines on nonclinical evaluation of vaccines

QUESTIONS?