Q&A: The IND Journey Phase I – Navigating Success

Advarra experts Sharon Ayd and Leslie Paul answer questions from their webinar, The IND Journey Phase I – Navigating Success.

Q: If an emergency use authorization (EUA) is granted, once there is an approved treatment, does that mean that the EUA is no longer valid?

A: Yes, the EUA is just temporary. If the sponsor wants their drug approved, they need to complete all clinical studies and submit an application.

Q: Please discuss the transfer of investigational new drug (IND) sponsorship from one sponsor to another and that process.

A: This does not usually happen. The sponsor is the pharmaceutical company conducting the trial. I can think of no reason they would transfer this to another sponsor. If you mean using a different contract research organization (CRO) for the different phases of clinical trials – that’s different. There is no problem doing this.

Q: What are the minimum requirements necessary to build a robust quality management system (QMS)?

A: For good manufacturing practice (GMP), you will want to refer to the FDA (Food and Drug Administration) Guidance for Industry CGMP for Phase I Investigational Drugs and address all elements: Personnel, QC Function, Facility and Equipment, Control of Components, and Containers and Closures, Manufacturing Records, Laboratory Controls, Packaging, Labeling and Distribution, and Recordkeeping. For good clinical practice (GCP), refer to ICH E6 (R2) Section 5 and address all quality elements. Of note, you should pay attention to the following elements: Quality Management, Quality Assurance, and Quality Control. Also consider CRO oversight, trial management, data handling and record keeping, as well as allocation of responsibilities.

Your approach to building your QMS will depend on your organization and on what you are doing directly versus what you are outsourcing. An important aspect of your QMS is establishing a robust process for vendor management.

For more information on key components of a fit-for-purpose, phase-by-phase QMS guidance download Advarra’s whitepaper Steps to Implementing a Quality Management System.

Q: What must be done to prove oversight?

A: For all vendors, having documented qualifications prior to use is important. Contracts may include provisions related to oversight, such as the right of the sponsor to audit the vendor. Also consider quality agreements for key vendors, such as contract development and manufacturing organizations (CDMO) and CROs. Quality agreements provide more details regarding how the sponsor and vendor work together. They may include key performance indicators (KPI) and key risk indicators (KRIs) to monitor vendor performance.

Keep any records showing how the sponsor oversees vendor activities. This includes audit records, meeting agenda and minutes, KPIs, KRIs, and records related to quality issues. For GMP vendors, documented reviews of records such as analytical testing and batch records, is also important.

Q: How specifically would a sponsor perform a periodic audit of a vendor?

A: Audits are typically scheduled for one or two days depending on the scope and may be conducted onsite or remotely. Prior to the scheduled audit, the sponsor should send a confirmation letter and agenda. The auditor prepares by reviewing relevant information, such as contracts, as well as select QMS documents and records. During the audit, the auditor conducts interviews and reviews documents and records to assess the vendors’ facilities and equipment, organization and personnel, QMS, and operations. The standard for the audit used depends on the type of vendor and would include the applicable regulations and ICH guidelines.

Q: What is your advice for approaching the regulatory strategy? Do you search for similar products, and use existing IND criteria requirements against the latest manufacturing guidance docs? How does one learn the most appropriate etiquette and terminology when serving as a novice regulatory affairs person without a manager?

A: Working in a pharmaceutical company is the best way to learn this. Each company will have its own processes, but they will all have the same result. While there are courses and even degrees in regulatory affairs, hands-on experience will teach you general topics.

Q: Is the sponsor allowed to record the pre-IND meeting, as opposed to providing copious notes

A: No, this is not allowed.

Q: Can you ship a drug from another country to the U.S. while the IND is in review?

A: No, nothing can happen until the IND is cleared.

Q: Just to confirm, is an IND required if the drug in question is not intended to be shipped across state lines?

A: No, however, then you would be dealing with seeking an IND exemption from the FDA.

Q: Can you explain what are the items included in the briefing document?

A: This is a complex topic and is best outlined in the FDA’s guidance document.

Q: What is the typical time period between the submission of the briefing package and the pre-IND meeting?

A: The FDA’s guidance document indicates the briefing package is submitted four weeks before the meeting

Q: What and when is the best way to communicate with FDA, after the pre-IND meeting, if the clinical study design needs to be modified?

A: The FDA provides guidance for this topic.

Q: What is the major IND filing difference between investigator-initiated trials (IIT) and IND trials?

A: In IITs, an investigator is usually a physician or an academic institution, and the interest is usually in studying a drug in an area of research in which they practice. The sponsor-initiated IND is conducted by a pharma company seeking commercial approval.

Q: When you want to do a study of an FDA-approved drug under an investigational indication, is an IND still required or can you seek an exemption?

A: It depends, but the answer is usually yes. There are only a few very specific exemptions from an IND. Here is the guidance document that will give you more detail.

Guidance for Clinical Investigators, Sponsors, and IRBs, Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Food Safety and Applied Nutrition (CFSAN), September 2013, Clinical/Medical.

NOTE: A stay is in effect for parts of subsection VI.D of this guidance. Additional information about this stay can be found in the Notice of Stay published in the Federal Register, October 30, 2015 (80 FR 66907)

Q: What is the definition of a drug? At what point does the drug substance become a drug product?

A:  The definition of a drug from the Federal Food, Drug, and Cosmetic Act is found in 21 USC 321 Definitions; generally, section (g) (1)  The term “drug” means (A) articles recognized in the official United States Pharmacopoeia,[1] official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C). A food or dietary supplement for which a claim, subject to sections 343(r)(1)(B) and 343(r)(3) of this title or sections 343(r)(1)(B) and 343(r)(5)(D) of this title, is made in accordance with the requirements of section 343(r) of this title is not a drug solely because the label or the labeling contains such a claim. A food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement is made in accordance with section 343(r)(6) of this title is not a drug under clause (C) solely because the label or the labeling contains such a statement.

The term drug substance and drug product are found in the NDA regulations 21 CFR 314.3, and are defined as:

Drug product is a finished dosage form, e.g., tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients.

Drug substance is an active ingredient intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body but does not include intermediates used in the synthesis of such ingredient.

Q: If you would like to conduct an IND study using patients both inside and outside of the U.S., is this acceptable to the FDA? Would they prefer the initial Phase I subjects to be only in the U.S.?

A: Yes and it is common. Phase I (and every subsequent phase) can be in the U.S. or outside. You will need FDA input, so the U.S. population is included in the right places.

Q: Normally, how much “efficacy” versus “safety” data is required to allow a Phase I trial of a new molecular entity? Are there exceptions on a drug-by-drug submission basis?

A: The answer is derived from nonclinical pharm/tox studies in animals. There are numerous studies and determining which studies are the right ones requires an expert toxicologist. This is a discussion you have with the FDA but only after following published guidance. Yes, each drug has its own requirements.

Q: The speaker just stated that the Meeting Package is due 60 days before the meeting date.  My understanding is that the meeting request is due 60 days prior, and the meeting package is due 30 days prior. Could you please confirm?

A: Current guidance can be found here.

Q: When is an IND exemption needed?

A: Here is guidance that should answer your question:

Guidance for Clinical Investigators, Sponsors, and IRBs, Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted without an IND, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Food Safety and Applied Nutrition (CFSAN), September 2013, Clinical/Medical.

NOTE: A stay is in effect for parts of subsection VI.D of this guidance. Additional information about this stay can be found in the Notice of Stay that published in the Federal Register, October 30, 2015 (80 FR 66907)

Q: Ex-U.S. studies – isn’t there a difference between if/how IRBs versus ethics committees (ECs) fulfill commitments noted on the Form FDA 1572?

A: For  FDA 1572 is a Statement of Investigator under US Regulations/Laws. The principal investigator (PI) signs it when they are conducting a study under an IND. The form lists the IRB/EC but does not bind the IRB/EC in how it operates. IRBs are subject to 21 CFR 56 IRBs.

Ex-U.S. ECs must comply with 21 CFR 56 when overseeing a study that is being conducted under an IND, and must also comply with local regulations.

For more information on form FDA 1572 refer to Frequently Asked Questions – Statement of Investigator (Form FDA 1572).

Q: When you are expanding a label, does the IND automatically become a Phase II study?

A: No. To get an approved NDA or Biologics License Application (BLA) you must conduct all phases of clinical studies. Then you can submit an application for approval. If you get approval, then you can conduct clinical trials for other disease indications. If you successfully complete all phases of clinical testing, you can submit a supplemental application for a label expansion.

Q: What is the most advisable pre-IND meeting process?

A: You must follow FDA’s guidance for a pre-IND meeting process.

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