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Oncology Regulatory Expertise and Early Guidance (OREEG)

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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

Educational Presentations

Early-Stage Oncology Guidance Documents

Small Business and Industry Assistance (SBIA) and OCE “Oncology Therapy Development Workshop: Pivotal Steps and Avoiding Pitfalls for Start-ups” review concepts to consider for early-stage drug development, providing useful summaries of regulatory expectations for first-in-human oncology trials. 

Visit Oncology Center of Excellence Guidance Documents for oncology-specific guidance. 

CBER's Office of Therapeutic Products OTP Learn for industry education.

Project Catalyst strongly recommends reviewing the following regulatory support information offered by Innovator Support Services, Small Business Education and Entrepreneurial Development, NIH Office of Extramural Research:

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.  

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
 

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: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, therapeutic, Biotechnology-Derived Products.”

FDA “Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing-Current Good Manufacturing Practices.”

FDA “Guidance for Industry Q3A Impurities in New Drug Substances”

ICH M7(R1) “Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk"

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

Whitney Helms, PhD: Getting to FIH for Small Molecules and Biologics 

Guidance Documents for Small Molecules Drugs and Well-characterized Biologics with regards to Toxicology

Martha Donoghue, MD: Designing First-in-Human Trials for Small Molecules and Biologics

Guidance Documents on Clinical Development for Small Molecule Drugs and Well-Characterized Biologics 

Donna Roscoe, PhD: Planning for Co-development of Companion Diagnostics  

Guidance Documents for Companion Diagnostics

Investigational Device Exemption (IDE) Guidance Documents 

Additional Resources related to Companion Diagnostics 

  • Payor Communication Task Force. CDRH established the Payor Communication Task Force to facilitate communication between device manufacturers and payors to potentially shorten the time between FDA approval or clearance and coverage decisions. The Parallel Review Program is discussed.
  • Investigational Device Exemption (IDE) Application. Informational website. An investigational device exemption allows the investigational device to be used in a clinical study to collect safety and effectiveness data.  Sponsors of a significant risk device study must submit a complete IDE application to FDA.
  • Medical Device Databases. FDA’s CDRH website that contains multiple data bases for regulatory and medical device information.
  • Device Advice. FDA’s CDRH's web page for comprehensive regulatory education. A text-based resource explains many aspects of medical device laws, regulations, guidances, and policies, encompassing the entire product life cycle.
  • CDRH Learn. The FDA’s Center for Devices and Radiological Health’s web page for multimedia industry education. CDRH Learn is an educational tool, which consists of learning modules describing many aspects of medical device and radiation emitting product regulations, covering both premarket and postmarket topics.

Anthony Fotenos, MD & Donika Plyku, PhD: Clinical Development of Radiopharmaceuticals as Theranostic Pairs and Dosimetry Considerations for Therapeutic Radiopharmaceuticals 

Guidance Documents for Radiopharmaceuticals

Brian Booth, PhD: Getting the Best Dose: The Clinical Pharmacology Studies that Help Achieve this Goal 

Guidance Documents for Clinical Pharmacology 

Kimberly Schultz, PhD: CMC Considerations for CAR T Cell Product Development 
Bo Liang, PhD:  CMC Considerations for Oncolytic Viral Product Development

Guidance Documents for Cellular and Gene Therapy CMC 

Ying Huang, PhD: Preclinical Considerations for Cell and Gene Therapy Products, An FDA Perspective 

Guidance Documents for Cell and Gene Toxicology 

  • Preclinical Assessment of Investigational Cellular and Gene Therapy Products (OCTGT). The guidance provides sponsors and individuals that design and implement preclinical studies with recommendations on the substance and scope of preclinical information needed to support clinical trials for investigational products reviewed by OCTGT. The guidance clarifies current expectations regarding the preclinical information that supports an IND and a BLA for these products.
  • Long Term Follow-Up After Administration of Human Gene Therapy Products. The guidance provides sponsors, who are developing a human gene therapy (GT) product, recommendations regarding the design of long-term follow-up (LTFU) observational studies for the collection of data on delayed adverse events following administration of a GT product. 
  • Good Laboratory Practice FDA 21 CFR Part 58. This part prescribes good laboratory practices for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the Food and Drug Administration, including food and color additives, animal food additives, human and animal drugs, medical devices for human use, biological products, and electronic products.
  • Quality Assurance Unit FDA 21 CFR §58.35. For non-GLP studies conducted in-house, oversight of the conduct of the study and the resulting final study report by an independent QA unit / person.
  • Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products. The guidance document provides recommendations regarding clinical trials in which the primary objectives are the initial assessments of safety, tolerability, or feasibility of administration of investigational products.
  • Formal Meetings Between the FDA and Sponsors or Applicants. This guidance provides recommendations to industry on formal meetings between the Food and Drug Administration (FDA) and sponsors or applicants relating to the development and review of drug or biological drug products (hereafter referred to as products) regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).
  • OTAT Learn: Office of Tissues and Advanced Therapies, the Center for Biologics, Evaluation and Research's (CBER) web page for industry education with online courses. OTAT-regulated products include gene therapy, tumor vaccines, xenotransplantation, stem cells, human tissue for transplantation, combination products, bioengineered tissues and certain medical devices. 
  • CBER Website: The Center for Biologics, Evaluation and Research's (CBER) key web page for industry education. CBER ensures the safety, purity, potency, and effectiveness of biological products, including vaccines and allergenics, blood and blood products, and cells, tissues, and gene therapies for the prevention, diagnosis, and treatment of human diseases, conditions, or injuries.

Peter Bross, MD: FDA’s Clinical Regulatory Perspective: Designing First-In-Human Trial for Cellular and Gene Therapy Products

Guidance Documents on Clinical Development for Cellular and Gene Therapy Products 

  • References for the Regulatory Process for the Office of Tissues and Advanced Therapies (OTAT). CBER’s informational website to address some initial questions and provides a better understanding of the regulatory process in OTAT.
  • OTAT Learn: Office of Tissues and Advanced Therapies, the Center for Biologics, Evaluation and Research's (CBER) web page for industry education with online courses. OTAT-regulated products include gene therapy, tumor vaccines, xenotransplantation, stem cells, human tissue for transplantation, combination products, bioengineered tissues and certain medical devices.
  • Cellular & Gene Therapy Guidances: An FDA CBER website for a wide range of cellular and gene therapy guidances for industry.
  • Expedited Programs for Serious Conditions-Drugs and Biologics. This guidance provides a single resource for information on FDA's policies and procedures related to expedited drug development and review programs. The following programs are intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition (expedited programs): Fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation.
  • Vaccines, Blood & Biologics. Navigate CBER’s website for vaccines, blood & biologics.

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-Catalyst@fda.hhs.gov (Estimated response time is one month)

Additional Information

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