Preclinical Data Standardization Process for regulatory submission to U.S. Food and Drug Administration

Transcription

1 Preclinical Data Standardization Process for regulatory submission to U.S. Food and Drug Administration Gabriele Pesavento, 23 May 2018

2 Aptuit An Evotec company A full service CRO that delivers purpose built solutions for drug discovery and development using proven domain expertise Discovery Development Manufacturing Supporting Analytics Target Validation, Lead Identification & Optimization Chemistry, Pharmacology, DMPK, etc. IND Enabling Studies, Formulation Development, QA/QC, Toxicology, Safety Pharmacology, ADMET, SEND and regulatory support etc. API, Drug Product (Solid Oral Dosage, Inhaled), Chemical Development, Pharmaceutical Development Solid State Characterization, Release Testing, Stability, Bioanalytical, etc. 1

3 Agenda Regulatory aspects SEND Implementation in Aptuit GLP compliance 2

4 Drug Development Process Regulatory aspects Research and Discovery Pre Clinical Development Clinical Development Phase I Phase II Phase III Post Approval Phase Initial IND NDA, ANDA, BLA Investigational New Drug (IND) Application submitted to propose to study an unapproved drug, or an approved product for a new indication New Drug Application (NDA) the formal proposal for the FDA approval of a new pharmaceutical for sale and marketing in the U.S.. Investigational New Drug (IND) become part of the NDA Abbreviated New Drug Application (ANDA) Biologics License Application (BLA) 3

5 Investigational New Drug (IND) Application Regulatory aspects Submitted to obtain permission to study an unapproved drug, or an approved product for a new indication, in clinical trial; must contain data in three broad areas: Animal Pharmacology and Toxicology Studies Manufacturing Information Clinical Protocols and Investigator Information IND documentation includes: General Investigation Plan Investigators Brochure CTD (Common Technical Document) 4

6 Common Technical Document Regulatory aspects Module 1 regional information such as forms, cover letter, labeling, and investigational brochures Module 2 summaries such as quality, clinical and non-clinical summaries Module 3 quality information Module 4 non-clinical information Module 5 clinical information 5

7 Electronic formats Regulatory aspects Electronic Common Technical Document (ectd) Date requirements (FDA) NDAs, ANDAs, BLAs 05 May 2017 INDs 05 May 2018 Electronic study data standard format 6

8 Why a standard format? Regulatory aspects Provides a standardized study data tabulation for interchange between sponsors, CROs and FDA 7

9 Guidance Documents Regulatory aspects FDA Binding Guidance Documents The Food and Drug Administration Safety and Innovation Act (FDASIA),including the fifth authorization of the Prescription Drug User Fee Act (PDUFA V) 9st of July, 2012 Dec 2014: Guidance for Industry Providing Regulatory Submission in Electronic Format - Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act Dec 2014: Guidance for Industry Providing Regulatory Submission in Electronic Format - Standardized Study Data FDA Non-Binding Guidance Document Mar 2018: Study data Technical Conformance Guide v4.1 Apr 2018: Data Standards Catalog v5.0 Mar 2017: CDER/CBER Study Data Standardization Plan Recommendations 8

10 CDISC FDA Clinical Data Interchange Standards Consortium (CDISC) is the nonprofit standards development organization responsible for developing the FDA-mandated electronic standards. Currently supported study data standards: Study Data Tabulation Model (SDTM) for clinical data Analysis Data Model (ADaM) for analysis of clinical data Standard for Exchange of Nonclinical Data (SEND) for nonclinical data Case Report Tabulation Data Definition Specification (Define-XML) for the metadata that accompany SEND, SDTM, and ADaM datasets 9

11 Regulatory aspects SEND Implementation in Aptuit GLP compliance 10

12 What is SEND? Standard for Exchange of Nonclinical Data (SEND) SEND structure: SEND is built around the concept of observations collected about subjects included in a nonclinical study Test results, examinations, and observations are represented in a series of SEND domains through a list of variables A domain is defined as a collection of logically related observations with a common topic 11

13 SEND rules Standard for Exchange of Nonclinical Data (SEND) Most subject-level observations collected during the study should be represented according to one of the three SEND general observation classes: Interventions, Events, or Findings. Each observations are represented in a series of SEND domains through a list of variables. Each variable can be classified according to its Role. A Role determines the type of information conveyed by the variable about each distinct observation and how it can be used. All datasets/domains are structured as flat files with rows representing observations and columns representing variables. 12

14 Controlled Terminology Standard for Exchange of Nonclinical Data (SEND) The National Cancer Institute s Enterprise Vocabulary Services, in collaboration with CDISC, develops, supports and maintains SEND controlled terminology. The terminology is updated 2-3 times every year; it is not essential to use the same version for the entire regulatory package, but it is required to use a single version within a study. 13

15 Regulatory Mandate SEND FDA Study Types Single dose general toxicity Repeat-dose general toxicity Carcinogenicity Safety pharmacology cardiovascular and respiratory Reproductive toxicity Safety pharmacology CNS Genetic toxicity Date Requirement begins 18 Dec 2016 (NDAs, ANDAs and BLAs) 18 Dec 2017 (IND) 8 Jul 2018 (NDAs, ANDAs and BLAs) 8 Jul 2019 (IND) In development guidances for industry 14

16 Regulatory Mandate SEND Rest of the World (Europe and Japan) EMA does not have formal plans to adopt CDISC standardized formats. Jun Reflection paper on expectations for electronic source data and data transcribed to electronic data collection tools in clinical trials Apr Final advice to the European Medicines Agency from the clinical trial advisory group on Clinical trial data formats The Clinical Trial Advisory Group on clinical trial data formats (CTAG2) PMDA (Pharmaceuticals and Medical Devices Agency) will require drug makers to submit electronic data in CDISC standard format beginning 01 October 2016, with a 3.5 year transitional period 15

17 Regulatory aspects SEND Implementation in Aptuit GLP compliance 16

18 SEND Implementation Guide Implementation CDISC SEND IG v3.1 Datasets and Domains Coding and Controlled Terminology Assumptions Observations and Variables Define-XML Metadata 17

19 SEND dataflow Implementation 1. Data Collection 2. Data Handling 3. Data Validation External Systems SAS Clinical Data Integration Pinnacle21 SEND package Aptuit LIMS and other internal software SAS Office Analytics 18

20 SEND Package Delivery SEND Datasets Define.xml Study Data Review Guide SEND Package 19

21 SEND domains for study xxxx Four Week Oral Repeat Dose Toxicity and Toxicokinetics Study in the Beagle Dog with a 4-Week Treatment-free Period Dataset Dataset Label Observation class Dataset Dataset Label Observation class BG Body Weight Gains Findings MI Microscopic Findings Findings BW Body Weights Findings OM Organ Measurements Findings CL Clinical Observations Findings PC Pharmacokinetics Concentrations Findings CO Comments Special-Purpose PP Pharmacokinetics Findings Domain Parameters DD Death Diagnosis and Findings RELREC Related Records Relationship Datasets Details DM Demographics Special-Purpose Domain SE Subject Elements Special-Purpose Domain DS Disposition Findings SUPPMI Supplemental Qualifiers for Microscopic Findings Relationship Datasets EG ECG Findings TA Trial Arms Trial Design EX Exposure Findings TE Trial Elements Trial Design FW Food and Water Findings TS Trial Summary Trial Design Consumption LB Laboratory Findings TX Trial Sets Trial Design MA Macroscopic Findings Findings VS Vital Signs Findings 20

22 TE Trial Elements domain Study Identifier Four Week Oral Repeat Dose Toxicity and Toxicokinetics Study in the Beagle Dog with a 4-Week Treatment-free Period Domain Abbreviation Variable Description of Element Rule for Start of Element Rule for End of Element xxxx TE Screen Start of Pretreatment 2 week after start of Element xxxx TE Vehicle Control First day of dosing with vehicle control 28 days after start of Element xxxx TE 3 mg/kg/day - Drug <Test Item> First day of dosing with 3 mg/kg/day - Drug <Test Item> 28 days after start of Element xxxx TE 10 mg/kg/day - Drug <Test Item> xxxx TE 30 mg/kg/day - Drug <Test Item> First day of dosing with 10 mg/kg/day - Drug <Test Item> First day of dosing with 30 mg/kg/day - Drug <Test Item> 28 days after start of Element 28 days after start of Element xxxx TE 90 mg/kg/day - Drug <Test Item> First day of dosing with 90 mg/kg/day - Drug <Test Item> 28 days after start of Element xxxx TE Recovery 1 day after last dose with drug or vehicle control 28 days after start of Element Observation 21

23 BW Body weights domain Four Week Oral Repeat Dose Toxicity and Toxicokinetics Study in the Beagle Dog with a 4-Week Treatment-free Period Study Identifier Domai n Abbrev iation Unique Subject Identifier Sequence Number Test Short Name Test Name xxxx BW xxxx BW Body Weight Result or Findings as Collected Unit of the Original Result Stand. Result in Character Format Stand. Result in Numeric Format Unit of the Stand. Result Planned Study Day of Collection Date/Time Animal Weighed Study Day Animal Weighed 9.4 kg kg /03/ Test Name Result or Findings as Collected xxxx BW xxxx BW Body Weight Unique Subject Identifier xxxx BW xxxx BW Body Weight xxxx Body Weight xxxx BW xxxx BW Body Weight Unit of the Original Result Stand. Result in Numeric Format Unit of the Stand. Result Planned Study Day of Collection Date/Time Animal Weighed Study Day Animal Weighed 9.2 kg kg -7 16/03/ kg kg 1 23/03/ kg 9.2 kg 10 01/04/ kg 9 9 kg 7 29/03/ xxxx BW xxxx BW Body Weight 9.2 kg kg 10 01/04/ xxxx BW xxxx BW Body Weight 9.5 kg kg 14 05/04/ xxxx BW xxxx BW Body Weight 9.6 kg kg 21 12/04/ xxxx BW xxxx TERMBW Terminal Body Weight 9.2 kg kg 29 20/04/

24 Regulatory aspects SEND Implementation GLP compliance 23

25 Today GLP compliance No GLP compliance expectation Currently the service provided by Aptuit is a non-glp SEND dataset performed in parallel but outside the scope of the study Study Director GLP Protocol Study Data QA Audit Report Non GLP SEND IT / Statistician 24

26 Why claim compliance? GLP compliance Critical Issue: Omitted results from the SEND datasets are not captured by current published validation rules, but it will severely impact the usefulness of the datasets; moreover it would appear untrustworthy to a reviewer. A GLP standardization process comports a de-risking of the regulatory submission. Aptuit s foresight is that in the future claiming GLP compliance of SEND datasets will become a Sponsor (Regulatory Authorities?) expectation. 25

27 How to claim GLP compliance GLP compliance In order to claim GLP compliance: The standardization process must be validated SEND will be included in GLP study protocol SEND process and datasets will be audited by Quality Assurance Study Director will be accountable for the SEND datasets 26

28 Tomorrow GLP compliance Claiming GLP compliance of SEND dataset is the future challenge Study Director GLP Protocol Study Data QA Audit Report Non GLP SEND IT / Statistician 27

29 Barbara Vaccarini Manager, Quality and Compliance Marco Pergher Manager, Biometry Service Your contact: Gabriele Pesavento GLP Quality Specialist