If we consider regulatory developments by the U.S. Food and Drug Administration (FDA) since 2015, one noticeable focus of the FDA is on drug development. Whether it be on early FDA consultations, the use of biomarkers, the co-development of a therapeutic drug and an in vitro companion diagnostic device or the development of orphan drugs, botanical drugs and other disease specific therapeutics, FDA has recommendations for drug and biologic manufacturers as well as other entities involved in drug development such as clinical research organizations (CROs), non-clinical testing facilities and analytical laboratories.

FDA consultations during drug development
When planning early drug development, FDA liaison is often sought, for instance, through pre-investigational new drug (IND) meetings, end-of-phased I (EOP1) and end-of-phased II (EOP2) meetings. However, drug manufacturers should go about their correspondence in a manner acceptable to the FDA. Why? Consider for example the impact of reaching out to the wrong contact within FDA.

Contacting a FDA review panel for an IND submission may interrupt the reviewers’ work on critical public health assignments and may lead to responses not appropriately vetted internally, potentially resulting in inaccurate, non-comprehensive advice. Therefore, without FDA supervisory approval, FDA strongly discourages the biopharma industry from contacting FDA reviewers for an IND. The FDA review division Regulatory Project Manager (RPM) is the preferred contact for complex technical/scientific product queries and status update inquiries.

However, the Center for Drug Evaluation and Research’s (CDER’s) Office of Pharmaceutical Quality regulatory business project managers handle meeting requests, regulatory submissions, and other inquiries solely related to chemistry, manufacturing and controls (CMC), including facility and product quality issues. CDER’s Office of Surveillance and Epidemiology safety regulatory project managers manage sponsor requests for proprietary name review.

Correspondence regarding complex technical/scientific product queries should be done through submissions or formal meetings like face-to-face meetings, teleconferences or written responses only (WRO). An informal communication strategy, such as mode, frequency and contacts for communication, can be considered around the time of the Investigational New Drug (IND) submission and adjusted as needed, for instance, upon receiving FDA feedback on a new protocol. 

Developing a biosimilar? There are five formal meetings that can occur between sponsors or applicants and FDA staff to discuss development of a biosimilar biological product. These include a Biosimilar Initial Advisory Meeting and the Biosimilar Biological Product Development (BPD) Type 1, 2, 3 and 4 meetings and FDA has established good meeting management practices (GMMPs) that can be applied by industry.

Drug development tool qualification
To facilitate drug development, FDA has established a process for recognition of various drug development tools (DDTs) that can be used by the biopharma industry.

DDTs may be biomarkers, animal models and clinical outcome assessments (COA) such as patient-reported outcome (PRO) measures, clinician-reported outcome (ClinRO) measures, observer-reported outcome (ObsRO) measures, and performance outcome (PerfO) measures. FDA has established a qualification process for DDTs. A FDA qualified DDT means that the DDT can be used during drug development in investigational new drug applications (INDs), new drug applications (NDAs), biologic license applications (BLAs) within the qualified context of use (criteria or conditions and boundaries within which the DDT is qualified for use) without further FDA approval.

FDA anticipates the DDT qualification process to benefit public health by increasing the availability of effective drugs, increasing earlier access to medical therapies and enhancing knowledge of the drug under development. Qualification is recommended for a DDT that has the potential to be used in multiple drug development programs. In this instance, qualification may reduce duplication of efforts, allow resource and information sharing, and facilitate regulatory acceptance of the DDT for future applications utilizing the same context of use.

FDA has published several guidance documents for industry in relation to DDT qualification. These include:

• Considerations for Use of Histopathology and Its Associated Methodologies to Support Biomarker Qualification, Guidance, May 2016¹
• Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease, a Patient-Reported Outcome Instrument for the Measurement of Severity of Respiratory Symptoms in Stable Chronic Obstructive Pulmonary Disease: Qualification for Exploratory Use, Draft Guidance, March 2016²
• Qualification of Biomarker – Plasma Fibrinogen in Studies Examining Exacerbations and/or All-Cause Mortality in Patients With Chronic Obstructive Pulmonary Disease, Draft Guidance, July 2015³
• Qualification of Biomarker – Total Kidney Volume in Studies for Treatment of Autosomal Dominant Polycystic Kidney Disease, Draft Guidance, August 20154

FDA consultation, innovative technologies and methodologies
Have a new biomarker, clinical outcome assessment (COA), an innovative conceptual approach to clinical trial design and analysis, an emerging technology or a new use for an existing technology? FDA’s Critical Path Innovation Meetings (CPIM) can be strategically utilized to obtain a gap analysis / general advice on how the methodology or technology of concern might enhance drug development. For instance, a CPIM may be used to help prepare for COA qualification or to understand the strengths and weaknesses of an emerging technology in relation to its potential uses at different drug development stages.

Co-development of therapeutic drug and in vitro companion diagnostic device
An in vitro companion diagnostic device is an in vitro diagnostic device (IVD) essential for the safe and effective use of a corresponding therapeutic drug product. Increasingly, manufacturers consider the co-development of the therapeutic drug and IVD companion diagnostic. FDA has therefore issued guiding principles, regulatory requirements and planning considerations for co-development.

For instance, in co-development programs, the goal is usually to identify a population expected to benefit from the therapeutic product, or a particular dose, or to avoid serious toxicities caused by the therapeutic product. Therefore, sponsors should pay close attention to the range of analytes and establishing the appropriate assay cut-offs to adequately define this population.

When a clinical trial design establishes a therapeutic product’s safety and efficacy in a population based on measurement or detection of a marker, the clinical trial results can also be used to clinically validate the IVD companion diagnostic. The success of a clinical trial design strategy depends on various factors, including a) the characteristics of the marker as applied to the intended target population of the therapeutic product, specifically the mechanistic rationale for selecting the marker, its predictive/prognostic/other utility and its intrinsic properties—e.g., variability and specificity with respect to the disease; b) the disease nature; and c) the characterization of the therapeutic product’s benefit—risk profile.

To achieve contemporaneous marketing authorizations, FDA recommends that therapeutic product and IVD sponsors plan ahead. This may include coordinating regulatory submission review timelines including for drugs under FDA expedited approval programs like the breakthrough, fast track, accelerated approval or priority review, and accessibility to any referenced master files.

Orphan drug development
Orphan drugs are prescription pharmaceuticals and biologics intended to treat or prevent rare diseases i.e. disorders or conditions affecting less than 200,000 people in the U.S. In addition to specific recommendations for non-clinical and clinical studies and chemistry and manufacturing controls (CMC), FDA recommends an understanding of the rare disease including pathophysiology through natural history studies and careful selection of biomarkers be considered early in drug development.

Botanical drug development
Botanical drugs contain botanical drug substances, which include plant materials, algae, macroscopic fungi and combinations thereof. There are various FDA regulatory considerations for both investigational new drug (IND) applications and new drug applications (NDA) of botanical drug products. For instance, prior human experience, for example in books on Ayurveda or traditional Chinese medicine, can be useful in planning a dose for a phase I study. Drug development plans should allow for the adequate characterization of botanical raw material(s), botanical drug substance(s) and the botanical drug product. Pharmacokinetic/toxicological studies should evaluate the pharmacology/toxicology and metabolic fate of chemical constituents in the botanical drug. 

Drug development: Specific therapeutic drugs
As with orphan and botanical drugs, there are specific diseases that have elicited specific FDA recommendations for drug development. Consider the following FDA guidance documents:

• Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment, Draft Guidance, June 2015⁵
• Allergic Rhinitis: Developing Drug Products for Treatment, Draft Guidance, Feb 2016⁶
• Anthrax: Developing Drugs for Prophylaxis of Inhalational Anthrax, Draft Guidance, Feb 2016⁷
• Head Lice Infestation: Developing Drugs for Topical Treatment, Draft Guidance, Dec 2015⁸

As FDA continues to focus on drug developments and FDA recommendations become increasingly specific in relation to the nature of the therapeutic drug, it is imperative that drug and biologic manufacturers, clinical research organizations, non clinical testing and analytical laboratories perform the necessary regulatory due diligence with an intent to stay on top of pertinent regulatory developments by the agency. 

References

1. US Food and Drug Administration. Considerations for Use of Histopathology and Its Associated Methodologies to Support Biomarker Qualification. US Food and Drug Administration; 2016.
2. US Food and Drug Administration. Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease, a Patient-Reported Outcome Instrument for the Measurement of Severity of Respiratory Symptoms in Stable Chronic Obstructive Pulmonary Disease: Qualification for Exploratory Use. US Food and Drug Administration; 2016.
3. US Food and Drug Administration. Qualification of Biomarker – Plasma Fibrinogen in Studies Examining Exacerbations and/or All-Cause Mortality in Patients With Chronic Obstructive Pulmonary Disease. US Food and Drug Administration; 2015.
4. US Food and Drug Administration. Qualification of Biomarker – Total Kidney Volume in Studies for Treatment of Autosomal Dominant Polycystic Kidney Disease. US Food and Drug Administration; 2015.
5. US Food and Drug Administration. Duchenne Muscular Dystrophy and Related Dystrophinopathies: Developing Drugs for Treatment. US Food and Drug Administration; 2015.
6. US Food and Drug Administration. Allergic Rhinitis: Developing Drug Products for Treatment. US Food and Drug Administration; 2016.
7. US Food and Drug Administration. Anthrax: Developing Drugs for Prophylaxis of Inhalational Anthrax. US Food and Drug Administration; 2016.
8. US Food and Drug Administration. Head Lice Infestation: Developing Drugs for Topical Treatment. US Food and Drug Administration; 2015.

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Rachelle D’Souza has licensed various medical and consumer products and facilities for start-ups and multi-national companies. Her expertise also includes clinical trial master file documentation, and the design and maintenance of globally compliant quality, safety/pharmacovigilance and medical information systems. At Regulatory Heights Inc., Rachelle continuously monitors the current regulatory environment and utilizes regulatory intelligence as a strategic business driver for her clientele. Her numerous articles and webinars on the latest international regulatory developments have been published in print and on-line by regulatory professional associations, webinar hosting platforms and industry magazines around the world. Her versatility has enabled Regulatory Heights Inc. to support companies, in particular, start-ups with the licensing of their drugs and medical devices in international markets. Rachelle can be reached at rachelle@regulatoryheights.com.