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
 

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

• 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)
  • https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q-5-d-derivation-characterisation-cell-substrates-used-production-biotechnological/biological-products-step-5_en.pdf
• 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)

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

• ICH S9: Nonclinical Evaluation for Anticancer Pharmaceuticals. This guidance explains basic expectations for anticancer drugs. It aims to facilitate and accelerate the development of anticancer pharmaceuticals and to protect patients from unnecessary adverse effects, while avoiding unnecessary use of animals, in accordance with the 3R principles (reduce/refine/replace), and other resources.
• ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals Questions and Answers. This guidance, in question-and-answer format, facilitates the implementation of ICH S9, as well as to continue progress in the 3Rs of Reduction, Refinement, and Replacement in the use of animals.
• ICH S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. This guidance recommends a basic framework for the preclinical safety evaluation of biotechnology-derived pharmaceuticals. It applies to products derived from characterized cells using a variety of expression systems including bacteria, yeast, insect, plant, and mammalian cells.   
• S6 Addendum to Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. This addendum should be read in close conjunction with the ICH S6 guidance (ICH S6). The addendum complements, provides clarification, and updates the following topics discussed in ICH S6: species selection, study design, immunogenicity, reproductive and developmental toxicity, and assessment of carcinogenic potential. Scientific advances and experience gained since publication of ICH S6 call for this addendum. 
• Estimating the Maximum Safe Starting Dose in Initial Clinical Trial for Therapeutics in Adult Healthy Volunteers. This guidance provides a description and a process to select a maximum recommended starting dose (MRSD) for a first-in-human clinical trial of a therapeutic in adult healthy volunteers.
• CFSAN Redbook 2000. FDA’s Center for Food Safety and Applied Nutrition guidance provides Toxicological Principles for the Safety Assessment of Food Ingredients and includes detailed descriptions of toxicological endpoints.
• 21 CFR Part 58: Good Laboratory Practice for Nonclinical Laboratory Studies. Part 58 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 FDA, including food and color additives, animal food additives, human and animal drugs, medical devices for human use, biological products, and electronic products. 

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 

• Investigational New Drug (IND) Application. Information for pharmaceutical companies, government agencies, academic institutions, private organizations, or other organizations interested in bringing a new drug to market. 
• 21 C.F.R. Part 50: Protection of Human Subjects. Part 58 describes requirements for the protection of humans in clinical investigations. 
• 21 C.F.R. Subchapter D: Drugs for Human Use. Subchapter D contains procedures and requirements governing the use of investigational new drugs, including procedures and requirements for the submission to, and review by, the FDA for investigational new drug applications (IND’s).
• CDER Manual of Policies & Procedures | MAPP.  CDER's Manual of Policies and Procedures (MAPPs) are federal directives and documentation of internal policies and procedures. MAPPs are required by law and made available to the public to make CDER a more transparent organization. 
• Good Review Practice: OND Review Management of INDs and Marketing Applications for Nonprescription Drug Products| MAPP. This MAPP establishes Office of New Drugs (OND) policies and procedures for the regulatory management and review of investigational new drug applications (INDs) and marketing applications (e.g., new drug applications (NDAs) and supplemental applications (sNDAs)) for nonprescription drug products.
• INDs: Review of Informed Consent Documents | MAPP.  This MAPP describes: 1) when an informed consent document (ICD) submitted under an investigational new drug application (IND) should be reviewed; 2) when the Center for Drug Evaluation and Research should request that an ICD be submitted to an IND; and 3) procedures for reviewing an ICD.
• Oncology Center of Excellence Guidance Documents. FDA’s OCE Website for guidance documents regarding oncology and hematologic malignancies. 
• Evaluating Cancer Drugs in Patients with Central Nervous System Metastases. This guidance describes FDA’s recommendations for clinical trial designs of cancer drugs or biological products regulated by CDER and CBER that are intended to support product labeling describing the antitumor activity in patients with central nervous system (CNS) metastases from solid tumors originating outside the CNS. 
• Inclusion of Older Adults in Cancer Clinical Trials Guidance Document. This guidance provides recommendations regarding the inclusion of older adult patients (aged 65 years and older) in clinical trials of drugs for the treatment of cancer. 
• Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination Guidance. This guidance describes an optional streamlined submission process for determining whether use of an investigational in vitro diagnostic (IVD) in a clinical trial for an oncology therapeutic is considered significant risk (SR), nonsignificant risk (NSR), or exempt from investigational device exemption (IDE) requirements.
• Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics Guidance. This guidance provides advice to sponsors regarding the design and conduct of first-in-human (FIH) clinical trials intended to efficiently expedite the clinical development of oncology drugs, including biological products, through multiple expansion cohort trial designs. These trial designs employ multiple, concurrently accruing subject cohorts, where individual cohorts assess different aspects of the safety, pharmacokinetics, and antitumor activity of the drug product. 
• Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials Guidance Document. This guidance provides the pharmaceutical industry, clinical investigators, and institutional review boards with information to facilitate the inclusion of adolescent patients (defined as ages 12 to 17) in adult oncology clinical trials. The guidance focuses on appropriate patient selection criteria for the inclusion of adolescent patients in adult oncology clinical trials at various stages of drug development, considerations for dosing and pharmacokinetic evaluations, safety monitoring, and ethical considerations.
• Cancer Clinical Trial Eligibility Criteria: Minimum Age Considerations for Inclusion of Pediatric Patients. This guidance provides recommendations for eligibility criteria for clinical trials of drugs or biological products regulated by CDER and CBER for the treatment of cancer. It includes recommendations for the inclusion of pediatric patients (i.e., children and adolescents) when appropriate. This guidance is intended to assist stakeholders, including sponsors and institutional review boards (IRBs), responsible for the development and oversight of clinical trials.

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

Guidance Documents for Companion Diagnostics

• Breakthrough Devices Program. Guidance Document. The Breakthrough Devices Program is a voluntary program for certain medical devices and device-led combination products that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions is a voluntary program for certain medical devices and device-led combination products that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. 
• List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools - A searchable table that lists all active indications. 
• Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product Guidance Document. This CDRH’s guidance is a practical guide to assist therapeutic product sponsors and IVD sponsors in developing a therapeutic product and an accompanying IVD companion diagnostic, a process referred to as codevelopment. 
• Statistical Guidance on Reporting Results from Studies Evaluating Diagnostic Tests Guidance. This CDRH’s guidance describes some statistically appropriate practices for reporting results from different studies evaluating diagnostic tests and identifies some common inappropriate practices.
• Publication: “Statistical consideration and challenges in bridging study of personalized medicine”. J Biopharm Stat. 2015; 25(3): 397- 409.

Investigational Device Exemption (IDE) Guidance Documents 

• FDA Decisions for Investigational Device Exemption Clinical Investigations. This guidance facilitates the initiation of clinical investigations to evaluate medical devices under FDA’s Investigational Device Exemptions (IDE) regulations, Title 21 Code of Federal Regulations, Part 812.
• Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program Guidance Document. This guidance provides an overview of the mechanisms available to submitters to request feedback from or a meeting with FDA regarding potential or planned medical device Investigational Device Exemption (IDE) applications, Premarket Approval (PMA) applications, Humanitarian Device Exemption (HDE) applications, Evaluation of Automatic Class III Designations (De Novo requests), Premarket Notification (510(k)) Submissions, Clinical Laboratory Improvement Amendments (CLIA) Waiver by Applications (CW), Dual 510(k) and CLIA Waiver by Application Submissions (Duals), Accessory Classification Requests, and certain Investigational New Drug Applications (INDs) and Biologics License Applications (BLAs) submitted to the Center for Biologics Evaluation and Research (CBER)) (specifically, INDs and BLAs for devices that are regulated as biological products under section 351 of the Public Health Service (PHS) Act.
• Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination Guidance Document. This guidance describes an optional streamlined submission process for determining whether use of an investigational in vitro diagnostic (IVD) in a clinical trial for an oncology therapeutic is considered significant risk (SR), nonsignificant risk (NSR), or exempt from investigational device exemption (IDE) requirements.
• In Vitro Diagnostic (IVD) Device Studies - Frequently Asked Questions. This guidance, in question-and-answer format, assists (the manufacturer, sponsor, applicant, investigator and the IVD device industry in general) in the development of IVD studies, particularly those exempt from most of the requirements of the IDE regulation and provides a broad view of the regulatory framework for the development phase of an IVD device.
• IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites and the Determination of Whether an IND/IDE is Needed. This guidance clarifies IRBs' responsibilities for reviewing the qualifications of investigators, determining the adequacy of research sites, and determining whether an investigational new drug application (IND) or investigational device exemption (IDE) is needed.
• Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable Guidance Document. This guidance inform sponsors, institutional review boards (IRBs), clinical investigators, and agency staff that the FDA intends to exercise enforcement discretion, under certain circumstances, with respect to its current regulations governing the requirement for informed consent when human specimens are used for FDA-regulated in vitro diagnostic (IVD) device investigations.    

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

• Diagnostic Radiopharmaceuticals FDA 21 CFR Part 315. The regulations in Part 315 apply to radiopharmaceuticals intended for in vivo administration for diagnostic and monitoring use. They do not apply to radiopharmaceuticals intended for therapeutic purposes.
• Publication: “Efficacy considerations for U.S. Food and Drug Administration approval of diagnostic radiopharmaceuticals”. J Nucl Med 2013; 54:1479-1484
• Publication: “Recent advances in clinical trial design considerations in Thera“nostics”. Contemporary Clinical Trials 2020; 96:106100
• FDA-SNMMI-NIH Workshop 2019 Theranostics: Regulatory Considerations for Product Development.  A short clip of workshop session on YouTube Video. Workshop’s session PowerPoint presentation.
• FDA-NRC 2020 Workshop. “Enhancing Development of Novel Technologies: Radiopharmaceuticals and Radiological Devices. The FDA workshop’s webpage featuring recorded the webcast and presentations.

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

Guidance Documents for Clinical Pharmacology 

• Bioanalytical Method Validation. This guidance helps sponsors of investigational new drug applications (INDs) or applicants of new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologic license applications (BLAs), and supplements validate bioanalytical methods used in human clinical pharmacology, bioavailability (BA), and bioequivalence (BE) studies that require pharmacokinetic, toxicokinetic, or biomarker concentration evaluation.
• Exposure-Response Relationships – Study Design, Data Analysis, and Regulatory Applications. This guidance provides recommendations for sponsors of investigational new drugs (INDs) and applicants submitting new drug applications (NDAs) or biologics license applications (BLAs) on the use of exposure-response information in the development of drugs, including therapeutic biologics. It can be considered along with the International Conference on Harmonization (ICH) E4 guidance on Dose-Response Information to Support Drug Registration and other pertinent guidances.
• Population Pharmacokinetics. This guidance makes recommendations on the use of population pharmacokinetics in the drug development process to help identify differences in drug safety and efficacy among population subgroups.
• In Vitro Drug Interaction Studies – Cytochrome P450 Enzyme and Transporter- Mediated Drug-Drug Interactions. This guidance helps drug developers plan and evaluate studies to determine the drug-drug interaction (DDI) potential of an investigational drug product. The guidance focuses on in vitro approaches to evaluate the interaction potential between investigational drugs with cytochrome P450 enzymes (CYPs) and transporters, and how in vitro results can inform future clinical DDI studies.
• Clinical Drug Interaction Studies - Cytochrome P450 Enzyme and Transporter- Mediated Drug-Drug Interactions. This guidance helps sponsors of investigational new drug applications and applicants of new drug applications evaluate drug-drug interactions (DDIs) during drug development and determine essential information to communicate in labeling and specifically provides considerations for evaluating pharmacokinetic cytochrome P450 (CYP) enzyme- or transporter-mediated interactions.
• Pharmacokinetics in Patients with Impaired Renal Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. This guidance assists sponsors planning to conduct studies to assess the influence of renal impairment on the pharmacokinetics of an investigational drug. It provides recommendations on when studies should be conducted to assess the influence of renal impairment on the pharmacokinetics of an investigational drug, the design of such studies, and how such studies should be carried out. 
• Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. This guidance provides recommendations to sponsors and applicants who plan to conduct studies to assess the influence of hepatic impairment on the pharmacokinetics (PK) and, where appropriate, the pharmacodynamics (PD) of a drug, including therapeutic biological products. 
• E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. This guidance provides recommendations to sponsors concerning the design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization.
• Food-Effect Bioavailability and Fed Bioequivalence Studies. This guidance provides recommendations to sponsors and/or applicants planning to conduct food-effect bioavailability (BA) and fed bioequivalence (BE) studies for orally administered drug products as part of investigational new drug applications (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplements to these applications. This guidance applies to both immediate-release and modified-release drug products. 
• Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations. This guidance provides recommendations to sponsors planning to conduct food-effect (FE) studies for orally administered drug products under investigational new drug applications (INDs) to support new drug applications (NDAs) and supplements to these applications for drugs being developed under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355).
• Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs —General Considerations. The draft guidance provides recommendations to sponsors and/or applicants planning to include bioavailability (BA) and bioequivalence (BE) information for drug products in investigational new drug applications (INDs), new drug applications (NDAs), and NDA supplements.
• Liposome Drug Products: Chemistry, Manufacturing, and Controls; Human Pharmacokinetics and Bioavailability; and Labeling Documentation. This guidance discusses what types of information the applicant should submit in a new drug application (NDA) or abbreviated new drug application (ANDA) for a liposome drug product reviewed by the Center for Drug Evaluation and Research (CDER).

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 

• Cellular & Gene Therapy Guidances: FDA CBER website for information on a wide range of cellular and gene therapy guidances for industry. 
• Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). This guidance informs sponsors how to provide sufficient CMC information required to assure product safety, identity, quality, purity, and strength (including potency) of the investigational product (21 Code of Federal Regulations (CFR) 312.23(a)(7)(i)). This guidance applies to human gene therapy products and to combination products that contain a human gene therapy in combination with a drug or device.
• Formal Meetings Between the FDA and Sponsors or Applicants. This guidance provides recommendations to industry on formal meetings between the FDA and sponsors or applicants for the development and review of drug or biological drug products regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).
• M4Q: The CTD – Quality. One in a series of guidances that provide recommendations for applicants preparing the Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) for submission to the U.S. Food and Drug Administration (FDA). This guidance presents the agreed upon common format for the preparation of a well-structured Quality section of the CTD for applications that will be submitted to regulatory authorities.
• Current Good Manufacturing Practice for Phase 1 Investigational Drugs. This guidance assists in applying current good manufacturing practice (CGMP) required under section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) in the manufacture of most investigational new drugs (IND) used in phase 1 clinical trials.
• Potency Tests for Cellular and Gene Therapy Products. This guidance provides manufacturers of cellular and gene therapy products with recommendations for developing tests to measure potency. These recommendations are intended to clarify the potency information that could support an Investigational New Drug Application or a Biologics License Application.
• Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus during Product Manufacture and Patient Follow-up. This guidance provides recommendations regarding the testing for replication competent 
• retrovirus (RCR) during the manufacture of retroviral vector-based gene therapy products, and during follow-up monitoring of patients who have received retroviral vector-based gene therapy products.
• Analytical Procedures and Methods Validation for Drugs and Biologics. This guidance discusses how to submit analytical procedures and methods validation data to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products.
• Drug Master Files Guidance for Industry. This guidance provides FDA’s current thinking on drug master files (DMFs), which are submissions to FDA that may be used to provide confidential, detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of human drug products.
• Characterization and Qualification of Cell Substrates and Other Biological Materials Used in the Production of Viral Vaccines for Infectious Disease Indications. This guidance provides recommendations to manufacturers of viral vaccines for the characterization and qualification of cell substrates, viral seeds, and other biological materials used to produce viral vaccines for human use. 
• Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products. CBER’s guidance provides sponsors of VBGT and oncolytic products with recommendations on how to conduct shedding studies during preclinical and clinical development. VBGT and oncolytic products are derived from infectious viruses or bacteria.
• Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products. This CBER guidance provides IND sponsors and applicants for a BLA or a BLA supplement, with recommendations on considerations when assessing whether to submit an EA for GTVVs. The guidance also contains recommendations as to what information should be included in an EA and what you can expect once an EA is filed.
• ICH Considerations: Oncolytic Viruses. This European Medicines Agency’s document identifies general principles for the clinical development of oncolytic viruses.
• ICH Considerations: General Principles to Address Virus and Vector Shedding. This European Medicines Agency’s document provide recommendations for designing non-clinical and clinical shedding studies when appropriate. Emphasis is on the analytical assays used for detection, and considerations for the sampling profiles and schedules in both non-clinical and clinical studies.
• Publication. “Clinical landscape of oncolytic virus research in 2020”. J Immunother Cancer 2020;8:e001486. 
• Sterility FDA 21 CFR § 610.12
• Identity FDA 21 CFR § 610.14
• Purity FDA 21 CFR § 610.13
• Potency FDA 21 CFR § 610.10
• 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.
• Vaccines, Blood & Biologics. A website to navigate the vaccines, blood and biologics section in CBER.

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)