Finding the One Decision Here That Removes 100 Decisions
Many of the development activities leading to the filing of an Investigational New Drug Application (IND) are carried out in parallel.
For example, synthesis (small mol)/fermentation and cell culture (biologics), purification, and analytical testing and characterization and formulation are all moving onward at the same time. Sponsors often approach these activities sequentially: run the experiments, develop the process and assays, then prepare and test clinical supplies, saving all writing tasks until last.
But a sequential approach increases the difficulty of preparing an IND and is usually the cause for filing delays, or worse. Based on our familiarity working with smaller emerging biotechs and the FDA, we have found that by adhering to the following principles you can greatly enhance your probability of a timely and successful IND submission.
Construct from the Start
Ideally, even before the research phase, you should study the relevant FDA regulations/guidances and forms for an IND submission, which can be found on the FDA’s web site (and below), and determine how your organization can best meet those requirements. Companies that devote disciplined, systematic attention from day one move far more efficiently toward opening trials than companies who chose to delay.
Be Scientic
The science behind the drug should be rigorous and so should the records of it. It is not unusual for products originating in discovery environments to be missing a detailed, well-documented historical chain of events, and hazy origins will often raise serious issues and not satisfy FDA reviewers.
The failure to design, execute, and generate the right data from the outset can come back to trouble you and cause unwanted delay. To minimize the preparation time required for the chemistry, manufacturing, and controls (CMC) section of the IND especially, writing and document preparation should also be integrated with the other development activities and coordinated by experienced technical writers and editors.
The documentation will be fresh and most important accurate and you will have time to make sure that it is scientically sound, and addresses a requirement.
Ensure Sufficient Documentation
Regulatory agencies raise questions if appropriate content items are not present or are inconsistent throughout the documentation and if insufficient details or data are provided on the manufacturing process, sample testing, or container stability.
Unfortunately, when some companies find themselves before the FDA with inadequate data, they go into survival mode and defend the product, arguing that the agency should approve the IND anyway. Doing this runs the risk of losing credibility with the agency on all counts.
Some sponsors wait until very late in the process to begin creating the IND application. You should write up each of the milestones required on the application as you complete them. If your organization does not have prior experience with writing INDs, hire a professional contractor who understands the types of issues that the FDA often raises.
This will be money well spent, because your IND document will be proficiently prepared according to FDA expectations.
How to FILE the IND Application
The following links are relevant to filling an Investigational New Drug application in the US. Quality
- CGMP for Phase 1 Investigational Drugs
- Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)
- Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)
- Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
- Q5A: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin
- Q5B: Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products
- Child Resistant Packaging Requirements
- Everything Added to Food in the US
- Inactive Ingredient Database Search
Procedural
- FDA’s Page on INDs
- Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs
- Information for Sponsor-Investigators Submitting INDs
Note: this provides excellent instructions if you’ve not led an IND before.
- Exploratory IND Studies (aka microdose studies)
- IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment of Cancer
- IND Forms
Electronic Submissions
- Providing Regulatory Submissions to CBER in Electronic Format – Investigational New Drug Applications
- Emergency IND Applications for Antimicrobial Products
- Charging for Investigational Drugs – August 13, 2009 Final Rule
- Submitting and Reviewing Complete Responses to Clinical Holds
Common Technical Document – CTD
- M4 Organization of the CTD
- M4 The CTD – General Questions and Answers
- Comprehensive Table of Contents Headings and Hierarchy (Maps standard IND sections to the CTD format, starting on page 12)
- M4 The CTD – Quality
- M4 Quality Questions and Answers/Location Issues
- M4 The CTD – Efficacy
- M4 The CTD – Efficacy Questions and Answers
- M4 The CTD – Safety
- M4 The CTD – Safety Appendices
Nonclinical
- S2A Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals
- S2(R1): Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use
- S2B: Genotoxicity: A Standard Battery for Genotoxicity Testing for Pharmaceuticals
- S3A: Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies
- S3B: Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies
- S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals
- S6 Addendum: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals
- S7A: Safety Pharmacology Studies for Human Pharmaceuticals
- S7B : The Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) By Human Pharmaceuticals
- S8 : Immunotoxicity Studies for Human Pharmaceuticals
- S9: Nonclinical Evaluation for Anticancer Pharmaceuticals
- M3: Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
- Nonclinical Safety Evaluation of Drug or Biologic Combinations
Clinical
- Information Sheets for IRBs, Investigators, and Sponsors
- Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection
- E6(R1): Good Clinical Practice: Consolidated Guideline
- E8: General Considerations for Clinical Trials
- E9: Statistical Principles for Clinical Trials
CDER Manual of Policies and Procedures (MaPP)
- MaPP 6030.1 – IND Process and Review Procedures
- MaPP 6030.2 – INDs: Review of Informed Consent Documents
- MaPP 6030.4 – Screening INDs
- MaPP 5100.3 – OCP of Clinical Pharmacology’s Prioritization, Triage, and Review Process for INDs and Pre-INDs
- MaPP 6030.8 – INDs: Exception from Informed Consent Requirements for Emergency Research
- MaPP 6010.7 – Clinical Hold/Refusal-to-File Committee
- MaPP 7400.4 – Tertiary Review of Genetic Toxicology Studies Resulting in a Recommendation for a Clinical Hold or Conduct of Additional Studies
Regulations – 21 CFR
- Part 50 Protection of Human Subjects
- Part 54 Financial Disclosure by Clinical Investigators
- Part 56 Institutional Review Boards
- Part 58 Good Laboratory Practice for Nonclinical Laboratory Studies
- Part 210 Current Good Manufacturing Practice in Manufacturing, Processing, Packing or Holding of Drugs; General
- Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals
- Part 310 New Drugs
- Part 312 Investigational New Drug Application
- Part 1300 Controlled Substances
- Part 1302.03 (f) Clinical Study Exception from Controlled Substance Labeling Requirements
Regulations – 16 CFR
Regulations – 45 CFR
Law
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