This document provides an overview of product development from a regulatory perspective. It discusses the steps required to prove a product is safe and effective, including preclinical studies, investigational new drug application, clinical trials in phases 1-3, and the marketing application. The target product profile and good practices for manufacturing, clinical research, and laboratories are also covered. The goal is to help maintain high ethical standards and show favorable risk-benefit analysis for approval.

1. Product Development Overview
(Regulatory Perspective)
Michael Matthews, RAC

2. Product Development Overview
• Prove the product is safe and effective for the proposed indication
• Pharmaceutical products are developed to help treat patients. Always
remember that the patients are people and product development
must maintain a very high ethical standard.
• Risk/benefit
• You also have to remember…
• ~$1 - $5 billion taking into account failed products
• Highly variable
• Drugs for large populations cost more than drugs for rare diseases
• Novelty
• Hurry up and fail

4. Discovery to marketing
http://www.phrma.org/innovation/clinical-trials

5. An API before and after development
10 years,
$1 bil later
An API into preclinical studies API after obtaining marketing approval
Products do not change during the course of development, you
are just learning more about it.

6. Target Product Profile (TPP)
• The TPP is a document describing the goals and objectives of a
product.
• It includes a lot of information that will end up on the final label:
• Indication and usage
• Intended population
• Dosage and administration
• Dosage form/strengths
• Acceptable adverse reactions
• Expected or acceptable efficacy
• Risk/benefit analyses
• It is a living document and expected to be changed as testing
progresses

7. TPP versus product label
• FDA Draft Guidance: Target Product Profile
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory
Information/Guidances/ucm080593.pdf
Keyruda Approved Label
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda
_pi.pdf

8. Example of a TPP
Attribute Minimum Target
Stability 2 years at -30C 4 years at -30C
Storage temperature -30C -30C
Safety No hospitalized adverse events No adverse events
Efficacy Average of 25% reduction in tumor
size within 3 months
Average of 70% reduction in tumor
size within 3 months
Dosage 1-2.75 mL injection every 12 hours 1-2.75 mL injection per day
Duration 6 months 3 months
Administration method IV injection IV injection
Population Diagnostic confirmed glioblastoma
(adults)
Diagnostic confirmed glioblastoma
(adults and children)
Interactions Minimal food effect Minimal cancer drug interactions
FDA Approval NDA approval NDA approval

9. Preclinical IND Phase 1 Phase 2 Phase 3 NDA/BLA
Time
Pre-IND
meeting
End of
Phase 2
meeting
Pre-NDA
meeting
Product Development Process

10. Break

11. Preclinical studies (“IND enabling studies”)
• In vitro assays
• Genotoxicity
• Drug interaction
• In vivo studies
• Pharmacokinetics
• Toxicity (rodent and non-rodent)
• Pharmacology and proof of concept
• Immunogenicity
• Other studies???
• More to come on this later
*Research/discovery are generally not considered preclinical studies*

12. Pre-IND meeting
Meeting with FDA to talk about:
• Proposed indication
• Proposed clinical plan
• Summary information of the product
• Proposed regulatory pathway
• Summary of preclinical studies
• Summary of manufacturing
• Summary of the proposed clinical study(ies)
• Other information
Very strict meeting conduct
Everything stated can and will be used against you.

13. Pre-IND meeting continued
• Notify FDA that an IND is coming soon
• Get agreement with FDA on certain regulatory concerns
• Clinical study design
• Preclinical data
• Manufacturing methods
• Other testing
• Get FDA’s valuable comments

14. Investigational New Drug (IND) Application
• Proposed indication
• Example of the investigational product label
• Summary of the preclinical and manufacturing information and any known
clinical information (focus on clinical risk)
• Complete manufacturing information
• Where and how product is made
• Controls used in the manufacturing process
• Stability plan and known stability data
• Other information
• Complete preclinical reports, including all data
• Full clinical protocol
• Investigator qualifications
• More to come on this later

15. Common
Technical
Document
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/CTD_triangle.pdf

16. IND Amendments
• Required IND amendments
• IND Annual Reports
• Safety Reporting and updated safety information
• Meeting requests/general communications
• Updated manufacturing information (stability data, mfg changes)
• New clinical study protocols
• New nonclinical study reports
• New investigators/sites
• Other IND amendments
• Clinical study reports (CSRs)
• IRB approvals
• Informed consent forms
• Updated investigators brochure or updated foreign market information
• Nonclinical protocols

17. Nonclinical studies
• Animal studies done in parallel with clinical studies
• Pharmacokinetics
• General toxicity
• Chronic toxicity studies
• Carcinogenicity
• Food effect studies
• Reproductive toxicity studies

18. Phase 1 clinical studies
• 20-80 subjects
• Purpose is usually pharmacokinetics or pharmacological effect
• A lot of focus on safety
• Usually open-label, healthy individuals
• Exploratory and can be dose escalation
• Usually a lot of analyses, a lot more visits
• Product may not be completely “GMP”
• GCP compliant

19. Phase 2 Clinical Studies
• 200-400 subjects
• Usually controlled
• Focus on safety
• Dose selection or dose determination
• Can compare two investigational products to each other
• Typically done in target population
• GCP compliant

20. Phase 3 Clinical Studies
• 1000+ subjects
• Expected to be controlled and primary focus on efficacy
• Evaluate risk-benefit analysis
• These studies are to be close to the clinical use of the product
• Usually at least 3 batches of product are used to show manufacturing
consistency
• Need 2 phase 3 studies for marketing approval
• GCP compliant

21. Marketing application (NDA or BLA)
1. A lot of administrative information
• Patenting information, labels and labeling, all of the communications with
FDA
• Postmarketing commitments and/or REMS
2. Summaries of preclinical, clinical, and manufacturing
3. Extensive manufacturing information
4. Complete preclinical and nonclinical study report (complete data)
5. Complete clinical reports (complete data and a lot of other
information)

22. Expedited programs for serious conditions
Fast Track Breakthrough Accelerated Priority
Designation Designation Approval pathway Designation
505(b), FDAMA, FDASIA 506(a), FDASIA CFR314, 601, 506(c) PDUFA
Serious + nonclinical data
Serious + preliminary
Serous + better than
or qualified infectious
clinical evidence + better
available therapy + good
disease product
than available therapy
surrogate endpoint
Serious + significant
improvement in safety or
efficacy or supplement
label change or QIPD or
voucher
Between IND – pre-NDA Between IND – EOP2 Before NDA With NDA or supplement
60 day response 60 day response N/A 60 day response
Expedited review and
Expedited review and
Shorter review clock (6-
rolling review
rolling review
months)
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM358301.pdf

23. Marketing Application Supplements
• Annual Reports
• Phase 4 or post-marketing studies
• Submit reports to FDA on progress of the studies
• Submit final reports once studies are completed
• Most biopharmaceuticals require post-marketing studies
• Safety reporting

24. Post-marketing changes
• A change in indication most often requires clinical studies to prove
efficacy
• A change in manufacturing:
• If extensive change – pre-approval needed
• If moderate change – notify FDA within 30 days
• If minor change – notify FDA in an annual report
• Labeling/promotional changes
• Online ads
• TV commercials

25. Questions???

26. Break time!

27. Regulations and Guidance Documents
• FD&C Act and other applicable laws:
• http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugand
CosmeticActFDCAct/default.htm
• All regulations are publically available – FDA’s interpretation of law
• http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm
• All guidance (FDA +ICH) publically available – FDA’s current thinking
• http://www.fda.gov/Drugs/GuidancecomplianceRegulatoryInformation/Guida
nces/default.htm

28. Applicable Regulations for Development
• 21CFR11 – Electronic Records
• 21CFR50 – Human Subject Protections
• 21CFR54 – Financial Disclosure by Clinical Investigators
• 21CFR56 – Investigational Review Boards
• 21CFR58 – Good Laboratory Practices
• 21CFR211 and other 200s – Good Manufacturing Practices, labeling, ads
• 21CFR312 – Investigational New Drug Regulations
• 21CFR314 – New Drug Application
• 21CFR316 – Orphan Drugs
• 21CFR600s – Biologics

29. Applicable Regulations for Development
• 21CFR25 – Environmental Impact Considerations
• 21CFR200s – Good Manufacturing Practices, labeling, ads
• 21CFR312 – Investigational New Drug Regulations
• 21CFR314 – New Drug Application
• 21CFR316 – Orphan Drugs
• 21CFR600s – Biologics
• 45CFR46 – HHS Policy for Protection of Human Research Subjects

30. GXPs
• Good [anything] practices
• The common ones (these you have to know):
• GLP - Good Laboratory Practices
• GCP - Good Clinical Practices
• GMP - Good Manufacturing Practices
• GDP - Good Documentation Practices (more common in the US)
• Lesser used GXP
• GDP – Good Distribution Practices (more common in Europe)
• GRP - Good Review Practices (used by FDA)
• GCLP – Good Clinical Laboratory Practices
• GPP – Good Programming Practices

31. Good Manufacturing Practices (GMP)
• GMPs are meant primarily for the manufacturing process, testing,
packaging, and labeling of pharmaceutical substances and products.
• GMPs are defined in the regulations under 21 CFR 211 for finished
pharmaceuticals. Ensure products are manufactured as to be safe and
effective.
• Helps prevent products from getting contaminated and helps to
ensure products do what they are supposed to do.

32. Examples of FDA GMP Guidance Documents
• ICH Q7A – Good Manufacturing Practice Guidance for API
• ICH Q1A – Stability Testing of New Drug Substances and Products
• ICH Q2B – Validation of Analytical Procedures: Methodology
• cGMP for Phase 1 Investigational Drugs
• Comparability Protocols – Protein Drug Products and Biological
Products
• Process Validation: General Principles and Practices
• Q&A on cGMP for Drugs
• Quality System Approach to Pharmaceutical cGMP Regulations
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064971.htm

33. Good Clinical Practices (GCP)
• Good Clinical Practices (GCP) are meant primarily for the conduct of
clinical studies using any pharmaceutical products.
• GCP principles are stated in the laws and regulations which govern
clinical studies. All clinical studies must comply with these GCPs.
• An international organization known as ICH published the most
popular and most used GCP guidance (ICH E6)
• Ensures clinical studies are conducted ethically and human subjects
are protected
• Ensures the scientific integrity of the study
http://www.fda.gov/scienceresearch/specialtopics/runningclinicaltrials/default.htm

34. Examples of FDA GCP Guidance Documents
• ICH E6 – Good Clinical Practice
• ICH E3 – Structure and Content of Clinical Study Reports
• ICH E9 – Statistical Principles for Clinical Trials
• Adaptive Design Clinical Trials for Drugs and Biologics
• Alzheimer’s Disease: Developing Drugs for the Treatment of Early
Stage Disease
• Standards for Clinical Trial Imaging Endpoints

35. Good Laboratory Practices (GLP)
• Good Laboratory Practices are mentioned by name in the regulations
(21 CFR 58)
• Meant primarily for animal (in vivo) studies, but may also be
referenced for the isolated cell (in vitro) studies
• Ensures quality study design and the study is conducted in an ethical
and appropriate matter
• Ensure scientific integrity of the data collected

36. Examples of FDA Preclinical Development
Guidance Documents
• Good Laboratory Practices Q&A
• ICH S1A – The Need for Long-term Rodent Carcinogenicity Studies
• ICH S2 – Genotoxicity
• ICH S3 – Toxicokinetics/pharmacokinetics
• ICH S4 – Chronic Toxicity
• Product Development Under the Animal Rule
• Immunogenicity Evaluation of INDs
• Nonclinical Safety Evaluation of Drug or Biologic Combinations
• Safety Testing of Drug Metabolites

37. Good Documentation Practices (GDP)
• GDPs is an industry term used to define how documentation should
be done in a regulated environment
• Applies to all disciplines: manufacturing, preclinical, and clinical
• Ensures all information is captured accurately and all changes are
captured and traced.
• Mostly applies to handwritten documents (batch records,
handwritten medical records, or handwritten results from assays).
• For electronic documentation, a different term is used…Part 11
• ALCOA (attributable, legible, contemporaneous, original and accurate)

38. Other Examples Useful Guidance Documents
• Part 11, Electronic Records; Electronic Signatures – Scope and
Application
• ICH M(series): Electronic Common Technical Document (submission
standards)
• Providing Submissions in Electronic Format – Standardized Study Data
• Format and Content of Proposed Risk Evaluation and Mitigation
Strategy (REMS)
• Formal Meetings Between the FDA and Sponsor
• Pharmacogenomic Data Submissions
• Target Product Profile

39. More Resources
• Manual of Policies and Procedures (MAPP)
• http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtob
acco/cder/manualofpoliciesprocedures/default.htm
• Staff Manual Guides (SMG)
• http://www.fda.gov/AboutFDA/ReportsManualsForms/StaffManualGuides/de
fault.htm
• Data standards
• http://www.fda.gov/ForIndustry/DataStandards/
• Orphan Drug Designations and Approvals
• http://www.accessdata.fda.gov/scripts/opdlisting/oopd/
• Standards Organizations
• USP, CDISC, OECD, HL7, CMS, ICD-9CM(10CM)

40. And More Resources (specific products)
• Warning Letters
• http://www.fda.gov/iceci/enforcementactions/WarningLetters/default.htm
• Clinical Investigator Inspection Search/BIMO
• http://www.accessdata.fda.gov/scripts/cder/cliil/index.cfm
• http://www.accessdata.fda.gov/scripts/cder/bmis/index.cfm
• Drugs@FDA
• http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
• Public Meetings and Advisory Committee Meetings
• http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/default.htm
• ClinicalTrials.gov
• www.clinicaltrials.gov
• Patents
• http://patft.uspto.gov/