Oncology Regulatory Expertise and Early Guidance (OREEG)
Project Catalyst’s Oncology Regulatory Expertise and Early Guidance (OREEG) is an educational initiative of the Oncology Center of Excellence (OCE), providing early-stage oncology companies with product-type advice to inform sound product-specific drug development decisions. This dynamic self-learning platform will be updated and monitored on a continual basis.
This platform consists of three components:
- Bench-to-Bedside chats with regulatory science experts. This series of prerecorded chats highlights concepts in selected guidance documents relevant to early-stage oncology product development. Bench-to-Bedside chats also provide insight into development of drugs and biologics for imminently life-threatening oncology indications.
- Frequently asked oncology drug development questions and answers. Organized by topic, these questions and answers provide helpful advice.
- Opportunities to direct questions to OREEG’s regulatory science experts. Although we welcome questions regarding oncology drug development issues not covered in other OREEG materials, we are limited in scope. Questions should only reference drug development plans not ready for a pre-IND submission to FDA. We ask that you refer to our template and guidelines below before submitting questions.
Bench to Bedside Chats and Early-Stage Oncology Guidance Documents
Small Business and Industry Assistance (SBIA) and Oncology Center of Excellence (OCE): “Oncology Therapy Development Workshop: Pivotal Steps and Avoiding Pitfalls for Start-ups” provide excellent overviews and concepts to consider in your early-stage drug development efforts and are useful summaries of general regulatory expectations for first-in-human (FIH) oncology trials. Individual presentations will be referenced with links in the following discipline-respective sections.
The following points and considerations are for development of well-characterized biologics and small molecule drugs and are not intended to guide 505B2 or biosimilar development plans. These thoughts are based on oncology drug development and are not intended to be used as specific guidance but are provided to help you approach the pre-IND submission process for products regulated by the FDA Office of Oncologic Diseases.
Questions for Contemplation
Do we have the appropriate expertise in house or should we engage consultants?
Effective streamlined drug development is complicated. Consider this carefully when assessing the skills of your company’s team and whether it would be more prudent to invest in a consultant’s broad experience versus on-the-job and on-the-fly learning for members of the company.
Do we have an idea or an actual drug?
Remember, although drug development involves clinical science (an iterative process), and many of the drug products brought forward to FIH trials fail, drug developers generally try to do as much drug development science in the preclinical arena as possible and then bring forward the candidate most likely to succeed. The drug-product manufacturing process may change over the course of the drug-development lifecycle with increasing purity and potency, and the dose and schedule of the drug may change based on pharmacologic data and safety data, but the drug—the chemical or well characterized biologic must remain the same. One role of FDA’s Project Catalyst and the Oncology Center of Excellence is to help you establish that your drug is safe and effective, not your idea or platform.
- Did we start by targeting the biology of the disease pathology for which the drug is indicated? If yes, do we have a means to identify patients with the disease that manifest the specific biology being targeted?
- Do we have a means to measure the effect of the drug product on the targeted biology?
- Do we have a means of making the drug product consistently batch to batch within a specified purity range?
- Do we have a means of measuring potency?
- Do we have expertise in early-phase, FIH clinical trial development, and in particular, the specific disease(s) we are targeting?
- For a well characterized biologic drug product, do we have a relevant toxicological model to study?
The answers to these questions segue into developing a successful pre-IND submission.
Approach the pre-IND process with the mindset that you want to provide the oncology review division with summaries of the studies you have conducted and that you plan to conduct to enable an IND to proceed. All required sections for an IND should be addressed in the pre-IND to utilize FDA resources in the most efficient manner. Study reports or detailed data sets are not appropriate for pre-IND meeting packages. Instead, concise data summaries should be included that reasonably describe the decisions and results of relevant studies. The general idea for the pre-IND submission process, and the approach that oncology attempts to follow as we have limited resources, is a one-time submission per product per sponsor.
Project Catalyst’s Oncology Regulatory Expertise and Early Guidance (OREEG) provides companies with actionable advice on specific limited development questions so that the pre-IND submission process is not utilized for these types of questions when the overall development plan is too premature for a successful comprehensive pre-IND review. Pre-IND questions should not be open-ended questions but phrased in a manner that engenders clear, decisive feedback.
Major goals of the pre-IND process
- Obtaining agreement that FDA does not have any substantive concerns with the already conducted studies and the planned future studies intended to support a successful IND submission.
- Ensuring that the necessary studies are conducted and designed to provide useful information
- Identifying and avoiding unnecessary studies
- That specific proposed strategies are likely to be acceptable depending on the data obtained
- Avoiding a clinical hold
- Obtaining regulatory insight that can inform drug development questions going forward.
- Defining the endpoints and goals of the development program
IND /Pre-IND expectations
The following links to FDA webpages and documents relating to the pre-IND and IND process should be reviewed when developing your pre-IND submission briefing package.
- https://www.fda.gov/drugs/cder-small-business-industry-assistance-sbia/small-business-and-industry-assistance-frequently-asked-questions-pre-investigational-new-drug-ind
- https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application
- https://www.fda.gov/files/drugs/published/Investigational-New-Drug-Applications-Prepared-and-Submitted-by-Sponsor-Investigators.pdf
- https://www.fda.gov/media/72057/download
Additional helpful information
Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics Guidance for Industry https://www.fda.gov/media/115172/download
Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies Guidance for Industry https://www.fda.gov/media/123745/download
Design and Conduct Considerations for First‐in‐Human Trials. Jie Shen et.al. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342261/
Design Considerations for Early-phase Clinical Trials of Immune-oncology Agents. Nolan A. Wages et.al. https://jitc.biomedcentral.com/articles/10.1186/s40425-018-0389-8
Designing Dose-Finding Phase I Clinical Trials: Top 10 Questions That Should Be Discussed With Your Statistician. Shing M. Lee et.al. https://ascopubs.org/doi/full/10.1200/PO.20.00379
Integrated Addendum to ICH E6(R1) Guideline for Good Clinical Practice E6(R2) https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf
(This guideline should be read in conjunction with other ICH guidelines relevant to the conduct of clinical trials (e.g., E2A (clinical safety data management), E3 (clinical study reporting), E8 (general considerations for clinical trials), E9 (statistical principles), and E11 (pediatric populations).
NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template. Although geared towards Phase 2 and 3 clinical trials this is a reasonable template to help in formatting a FIH clinical trial with additional considerations
https://osp.od.nih.gov/wp-content/uploads/Protocol-Template-Version-1.0-040717.docx
- Drs. Paresma Patel and Olen Stephens: Chemistry and Manufacturing Requirements for Early Clinical Development: What’s in there? Prove it.
FDA “Guidance for Industry CGMP for Phase 1 Investigational Drugs”
FDA Guidance on the “Preparation of Investigational New Drug Products (Human and Animal)"
FDA “Guidance for Industry, Investigators, and Reviewers: Exploratory IND Studies.”
FDA “Guidance for Industry: Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients,” Section 19.
FDA “Guidance for Industry Q3A Impurities in New Drug Substances”
ICH HARMONISED GUIDELINE IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS Q3C(R6)
ICH Q3C Maintenance Procedures for the Guidance for Industry Q3C Impurities: Residual Solvents
Q3C “Tables and List Guidance for Industry”
Q3D(R2) – “Guideline for Elemental Impurities DRAFT”
USP <232> ELEMENTAL IMPURITIES-LIMITS
USP <233> ELEMENTAL IMPURITIES
FDA Pharmaceutical Microbiology Manual
Microbial contaminates USP<61> microbial limits ; USP <85> Bacterial endotoxins
Q1A(R2) Stability Testing of New Drug Substances and Products
- Drs. Wendy Weinberg and Kristen Nickens: CMC Considerations for Biotechnology Product Development: A Regulatory Perspective
- ICH Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products
- Points to Consider in the Manufacture and Testing of Monoclonal Antibodies for Human Use
- Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals
- Content and Format of Investigational New Drug Application (INDs) for Phase 1 Studies of Drugs Including Well-Characterized, Therapeutic, Biotechnology-derived Products
- For the Submission of Chemistry, Manufacturing, and Controls Information for a Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody Product for In Vivo Use
- ICH Q5A Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin (Sept. 1998)
- ICH Q5C: Stability Testing of Biotechnology/Biological Products (July 1996)
- ICH Q5D Quality of Biotechnology/Biological Products: Derivation and Characterization of Cell Substrates used for Production of Biotechnology/Biological Products (Sept. 1998)
- ICH Q5E Comparability of Biotechnology/Biological Products Subject to changes in their Manufacturing Process.
- OPQ Emerging Technology Program (ETP)
- Guidance for Industry: Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization (2017)
Oncology Regulatory Expertise and Early Guidance (OREEG) welcomes questions regarding oncology drug development plans that are premature for pre-IND submission,
if those questions are not covered in the materials above. To help ensure an efficient process, please refer to our guidelines (below) and use our email template located in the next tab.
Guidelines
When needed we strongly encourage including an established regulatory consultant(s) and academic clinical trialist(s) on your drug development team in the indication you are pursuing.
Questions should be limited to CDER-regulated oncology products. For biologic products, CBER has developed the CATT Program and the Pre-Pre-IND Interact program to provide early drug-development advice.
Questions regarding drug products which have a pre-IND or IND filed with the FDA should be addressed through the responsible division at FDA by contacting the appropriate Regulatory Project Manager.
Questions should be limited in number (1-3) and each question should be accompanied by one to two pages of concise product or development information that pertains to the specific question.
General product-type advice will be provided, as definitive and product-specific advice requires a more mature development plan.
FDA restrictions prevent us from providing information or advice for the following:
- Suggesting specific models or experiments for activity determinations to de-risk your development plan. The type and extent of activity data to further prosecute development is also at your discretion.
- Confidential information. If we are aware of specific product-type or mechanism-of-action safety concerns that would require additional data, protocol modifications or other interventions/changes, we will inform you of the concerns and possible approaches to address them.
- Recommendations about the indication you are pursuing. We will provide guidance on whether the patient population characteristics, prior therapies, tumor histology, and biomarkers adequately describe the intended indication.
Please copy and paste the information into your email:
- Name of Company/Academic Institution:
- Name of CEO/Developer:
- Name of Contact Representative:
- Address:
- Telephone:
- E-mail:
- Name of Internal Regulatory Manager/External Regulatory Consultant:
- Email Subject Line should include Direct Response Requested and Name of Company/Academic Institution
Attach your 1-2 page data summary and other internal proprietary or publicly available information relevant to your question.
Please send your questions and information to Jeffery Summers at:
OCE[email protected] (Estimated response time is one month)