TOPRA MSc Module 2: 4-6thFebruary 2015 Nonclinical Data Assessment and Strategic Planning ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION A presentation by Lesley Reeve, Associate Director, Global Regulatory Strategy, Covance Inc.
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Nonclinical Data Assessment and Strategic Planning
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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)
� 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)
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
# ICH M3(R2): Nonclinical Safety Studies
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.
� 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.
� Rationale for whether carcinogenicity studies would add value to the nonclinical package (if not, waivers could be granted).
� Data to include:
Nonclinical content in Key Regulatory Documents
� 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
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� 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
� 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