A 2026 QNova LifeSciences Report

Written by:
Jim Sergi

INTRODUCTION

The pathway for transitioning to a successful US FDA IND for a clinical-stage drug company is a crucial step in the development lifecycle of a product, as a favorable safety profile needs to be demonstrated in validated animal models and regulatory approval received before embarking on first-in-human clinical studies. There are numerous analytic, animal safety, CMC and quality considerations prior to obtaining a US FDA IND and initiating the clinical study.

Some of the key considerations to ensure a smooth transition into the clinic are summarized below and include:

• Is my drug development program (i.e., pre-clinical, analytic, design, safety, CMC, quality) in alignment with FDA requirements?
• How does the safety toxicology study design compare to the proposed clinical program?
• Are the CMC and quality requirements scaled for the phase of clinical development or commercial release?
• What areas of the FDA regulation need clarification?
• What clinical expectations need input?
• What data is missing from my testing package for the regulatory submission?
• Do you qualify for special designations (i.e., Orphan, Pediatric, Breakthrough, Fast Track, CNPV, etc.)?

This White Paper will explore these issues.

TARGET PRODUCT PROFILE (TPP)

A starting point for a successful drug development program involves creating a blueprint of the relevant attributes required for a marketed product. The attributes which should be considered essential are usually driven by a TPP. The TPP describes the design criteria for the product and forms the basis for development of the critical quality attributes (CQAs), critical process parameters (CPPs), indications for use (IFU), life-cycle planning, and the competitive landscape.

A TPP helps focus the drug development activities in working towards a clear goal and provides an understanding of the specific attributes that will ensure the quality, safety, and efficacy of a specific product for the patient. Furthermore, during early phases, as the company navigates from pre-clinical into clinical, compilation of these attributes will also enable educated decisions to be made at critical junctures pertaining to investment, candidate selection and progression towards market approval.

The TPP typically includes: 

• Characteristics of the active molecule (i.e., conformation, molecular weight, etc.) and characterization of its impurity profile.
• Physiochemical properties of the active molecule (i.e., pH, melting point, solubility, polymorphism).
• Information on possible mechanism of action and biologic targets.
• Intended use in a clinical setting, including route of administration, dosage form, dose strength, and delivery system.
• Characteristics of the Drug Product (DP) that would facilitate efficacy and safety.
• Therapeutic moiety release or delivery and attributes affecting PK characteristics (e.g., dissolution, aerodynamic performance) appropriate to the DP dosage form under development.
• Competitive clinical study and market landscape.
• Clinical indication for use (IFU) competitive assessment.
• Eligibility for FDA Special Designations.
• Potential barriers to market entry.

While a TPP is not a required FDA regulatory document, some reviewers at the FDA may request your TPP. More importantly, investors and strategic partners will require a TPP to help determine the full potential of the product.

DRUG DEVELOPMENT PLAN

Preparation of a drug development plan that includes the first major milestone, a first-in-human (FIH) clinical study, should take a holistic view of the separate disciplines (i.e., CMC, nonclinical, clinical, and regulatory) to ensure a unified approach to development. A strategic, streamlined, and clearly defined drug development plan ensures reduced costs and faster timelines towards enabling successful approval. Early discussions with key opinion leaders (KOL) in the management of the disease under investigation are critical for establishing the indication for use that will ultimately be licensed.

FDA SPECIAL DESIGNATIONS

The FDA employs various special designations to streamline and incentivize the advancement of drugs addressing medical gaps. While some designations can accelerate FDA timelines for new drug applications (NDAs) and biologics license applications (BLAs), others may abbreviate the duration of clinical trials. This approach grants manufacturers an extended timeframe between drug launches and the eventual loss of exclusivity.

It’s important to note that these special designations do not guarantee automatic FDA approval. The FDA must maintain a delicate balance between promptly approving new drugs to cater to patients in need and demanding sufficient evidence to ensure the safety and effectiveness of these drugs. It is also worth noting that drugs can, and often do, earn multiple special FDA designations.

Priority Review

After the FDA accepts an NDA or BLA, a Prescription Drug User Fee Act (PDUFA) date is assigned. This is the FDA’s target decision date for granting approval or denial. In cases following the standard review timeline, the PDUFA date is scheduled 10 months after the NDA/BLA submission is accepted. However, the Priority Review streamlines this period to six months. Not all NDA/BLA submissions are eligible for Priority Review; those qualifying must demonstrate a “significant improvement in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions.” Determining which drugs meet this criterion falls under the FDA’s interpretation.

Accelerated Approval

Typically, drug approval relies on clinical trial endpoints like overall survival (OS) or progression-free survival (PFS) to demonstrate efficacy. While effective, these endpoints often take time to yield results. The Accelerated Approval Program addresses this delay by employing “surrogate endpoints” such as lab values, imaging, physical signs, and other accepted measures to predict clinical benefit. Accelerated Approval expedites treatment availability, particularly for severe diseases with limited options. However, the FDA requires post-market studies to confirm surrogate results. Approval can be revoked if these studies fail to show efficacy or present safety concerns. Although certain manufacturers who go this route have sometimes delayed or not completed required post-marketing studies, recent trends reflect a push for stricter enforcement of these obligations. In the last several months, multiple products previously receiving Accelerated Approval have been removed from the market because confirmatory study results were not favorable. Oncology products have often received Accelerated Approvals, but the designation may be an option for other severe disease states with slow-developing clinical trial endpoints.

Fast Track

Typically, the FDA mandates that all segments of an NDA or BLA be submitted before a review begins. The Fast Track Program allows manufacturers to submit segments as they’re ready, facilitating an expedited review by the FDA. This approach enhances the efficiency of NDA/BLA submission and review, streamlines the regulatory process, and encourages collaboration between manufacturers and the FDA. To qualify for Fast Track, a drug needs to treat a serious condition and fill an unmet medical need. The FDA uses its best judgment on which products meet this criterion. This covers a wide scope of diseases. Drugs treating cancer, AIDS, Alzheimer’s disease, and heart failure are a few examples of disease states where drugs have earned Fast Track designation.

Breakthrough Therapy

The Breakthrough designation primarily applies to drugs targeting severe or life-threatening conditions. Qualified products must exhibit clinical evidence suggesting substantial improvement over currently available therapies. A notable advantage of the Breakthrough status is the potential for NDA/BLA submission based on Phase 1 or 2 trial results, bypassing the Phase 3 requirement. It is likely that post-marketing trials will be conducted if approval is granted based on early-phase trial results. This expedited approach can significantly shorten the drug’s clinical trial duration before market entry. For example, phase 3 clinical trials often take approximately 3-4 years to complete, depending on the trial design. Furthermore, Breakthrough designation incorporates all benefits from the Fast Track program and offers additional FDA guidance on approval requirements. Earning a Breakthrough designation is somewhat of a higher bar than Fast Track. Breakthrough products often have a novel mechanism of action compared to currently available therapies for a particular disease state.

Regenerative Medicine Advanced Therapy (RMAT)

The RMAT is a close relative to the Breakthrough designation, differing primarily in its exclusive application to certain biologics subject to review by the FDA’s Center for Biologics Evaluation and Research (CBER). A distinctive advantage is that RMAT can include eligibility for Accelerated Approval, a feature not found in the Breakthrough designation. Candidates for RMAT encompass innovative approaches like cell and gene therapies and therapeutic human tissue-engineered products. Like Breakthrough, RMAT is reserved for drugs treating severe or life-threatening conditions with supporting evidence that they have an advantage in safety or efficacy over the currently approved treatment landscape.

Orphan Drug

Because of their limited commercial potential, orphan drugs were once considered a neglected subset of drugs. To address this, the Orphan Designation emerged in 1983, encouraging development for conditions that affected <200,000 U.S. patients. Perks included manufacturer tax credits, fee exemptions, and extended market exclusivity. This program has proven successful, with 54% of novel new drugs approved by CDER in 2022 having an Orphan Drug designation. With around 7,000 identified rare diseases impacting 30 million Americans, the need for treatment persists. Orphan designation is awarded based on the patient population of the disease state treated. There are no requirements related to the severity of the condition or mechanism of action. Also, drugs with an Orphan designation may earn additional FDA approvals covering other disease states with larger patient populations.

FDA Commissioner’s National Priority Voucher (CNPV)

The CNPV pilot program is being explored as a pathway to dramatically reduce review times for drug and biological product applications and manufacturing or efficacy supplements. This innovative program uses a collaborative tumor board-style review process to accelerate review and approval of products that align with one of five critical U.S. national health priorities:

• Public health crisis response – Products addressing urgent/emerging threats or significant population impact.
• Innovative breakthrough therapies – Transformative treatments with novel mechanisms that fundamentally change disease management.
• Large unmet medical needs – Therapies for conditions where existing treatments inadequately address patient outcomes.
• Onshoring and supply chain resilience – Onshoring drug development/manufacturing to strengthen U.S. domestic capacity, reduce foreign dependencies, and improve national security.
• Affordability – Approaches that improve overall value through reduced costs to the healthcare system or that enhance access to important products.

Vouchers may be granted by the FDA for review of a company’s specific drug/biological product application. Benefits of a voucher include enhanced communications and rolling review to help facilitate a shortened review time.

Priority Review Voucher

Expanding on Priority Review’s principles and further incentivizing drug development in underserved rare diseases, the Priority Review Voucher (PRV) program was created. Recently, the PRV program was reauthorized by the US Congress for rare pediatric diseases. However, Congress has not yet reauthorized the PRV program for material threat medical countermeasures. Currently, manufacturers who earn FDA approval for a qualifying drug treating a rare pediatric disease or tropical disease earn the opportunity to have the FDA perform a review on a priority timeline (six months) for another NDA/BLA that would otherwise only qualify for a standard review (10-month timeline). This voucher can be applied to another drug from the manufacturer who earned it or sold to another manufacturer to use on one of their drugs.

A PRV often sells for > $170 million, these vouchers might appear peculiar to some due to their sale. However, it’s logical given that smaller manufacturers, often cash-strapped after drug development expenses, find selling more pragmatic than using these vouchers, especially when no other drug is near FDA submission in their pipeline.

Qualified Infectious Disease Product (QIDP)

With escalating concerns about drug-resistant bacteria and fungal infections, the FDA introduced the QIDP designation due to the limited development of new antibacterial and antifungal products. Like the Orphan designation’s intent, this program encourages manufacturers to address unmet clinical needs. The FDA maintains a list of qualifying pathogens eligible for drug developers to earn a QIDP designation for their product. The drug must target a life-threatening bacterial or fungal infection or a resistant pathogen to qualify. QIDP products also enjoy Fast Track program benefits, and upon approval, the manufacturer gains five more years of market exclusivity beyond what is earned from other sources.

Real-Time Oncology Review (RTOR)

The main impact of drugs reviewed under the RTOR program is that they will likely receive approval from the FDA before the official PDUFA date. Limited to straightforward oncology products with clear endpoints, manufacturers submit supporting materials for FDA review before the official filing. Although the FDA has made early decisions before, the speed of approval for RTOR-designated products can still be remarkable. Products earning RTOR often have a mechanism of action familiar to the FDA. RTOR is less likely to be used by “cutting edge” technology such as cell and gene therapies.

Understanding the FDA’s array of special designations and programs can help manufacturers determine the suitability of their products and allow them to receive their benefits. The advantages these designations and programs offer regarding expedited review timelines, enhanced communication, and incentivized development cannot be overlooked. More importantly, the designations increase companies’ valuation.

While deciding to pursue these designations requires careful consideration, understanding the regulatory landscape can help you decipher the nuances of each designation, strategically apply them to the appropriate drug modalities, and guide your process from development to market entry. As evident from the increasing prevalence of special designations among novel new drug approvals and expanded indications, you should look to maximize the opportunities presented by these specialized pathways.

CHEMISTRY MANUFACTURING AND CONTROLS (CMC)

In any early drug development program for a novel therapeutic entity, companies are required to provide adequate assurance that the product will be safe for use in human subjects. In the context of development of chemical entities, in comparison to complex products containing biological active substance, the purity of the drug substance (DS), and active pharmaceutical ingredient (API) is a key consideration. The impurity profiles of early-stage drug candidates attract particular interest by regulatory authorities when considering the approval of clinical trial applications (CTAs) and investigational new drug (IND) applications. The relevant ICH guidelines must be considered when determining the purity and impurity profile of a candidate.

In addition to the considerations given to the purity/impurity profiles of a drug candidate, regulatory authorities such as the FDA, mandate in legislation that investigational drugs are manufactured in accordance with current Good Manufacturing Practices (cGMP). This ensures the quality of the product and adulteration. Furthermore, establishment of a suitable manufacturing process and quality controls that are development stage specific. The manufacture of non-GMP and GMP material for use in the pivotal nonclinical studies and clinical studies, respectively, are also essential, including the quality and supply agreements.

NON-CLINICAL STUDIES

To support the initiation of a FIH clinical trial, the non-clinical studies required to be completed prior to that need to be identified and executed. These include pharmacology, safety pharmacology and toxicology studies, either in vitro or in vivo. Pharmacology studies are particularly necessary to obtain insight in the mode of action of the drug candidate and at what levels of exposure the intended activity is achieved, to inform the levels needed in humans. Careful selection of relevant in vitro and animal models is therefore essential, though not always possible (e.g., if the drug target does not exist in animals).

SAFETY TOXICOLOGY STUDIES

Safety pharmacology studies, coupled with the toxicology studies are required to assess whether potential safety issues are associated with the drug candidate. Dose and exposure at which these toxicities occur determine the maximum recommended starting dose (MRSD) for the FIH study. These studies also consider, safety margins, experience with drugs in the same class and manageability of the identified potential adverse reactions. The critical FDA drug safety considerations also include:

• The safety studies can be conducted in accordance with GLP and is required for extrapolation to humans.
• Species selection and the animal model must be based on in vitro metabolism and PK data and justified.
• The requirement for two animal species may be waived by the FDA, based on scientific data (i.e., no pharmacology in rodent species for biologics).
• Rodent (i.e., mice, rats, etc) or small animal (e.g., minor species) may be used.
• Non-Rodent (i.e., dogs, nonhuman primates, Göttingen mini-pigs, rabbits, etc.) animal model selection must closely mimic the intended clinical route and dose of administration.
• The major drug metabolites must be expressed in the animal species used for the toxicity studies.

The pivotal GLP non-clinical studies, should be conducted using the intended clinical route of administration for the IFU. The batches of drug product used in the GLP toxicology studies should be representative of the material that will be used in the clinical trial and supported by the quality system. In the US and EU, safety pharmacology and pivotal toxicity studies (including toxicokinetic studies) should be compliant with the Organization for Economic Cooperation and Development (OECD) Principles on GLP. Selecting a CMO that is in an OECD country or regularly inspected by an OECD country is an important consideration.

CLINICAL STUDIES

Development of a FIH clinical study outline and synopsis is one of the early activities required, as it will determine for a large part the nonclinical study design. Route of administration, dosing frequency and duration all affect the CMC and non-clinical strategy. The FDA requires a detailed study synopsis when submitting a Pre-IND meeting request and a complete clinical study protocol with statistical and monitoring plans and an Informed Consent Form when submitting and IND.

The FDA will require the Investigator’s Brochure (IB) to compile a summary of all data available for the drug candidate and needs to be updated at least annually to inform regulatory authorities, ethics committees and investigators conducting clinical trials. The IB also forms the basis for reporting of drug safety information during development and contains a start of what later becomes the Prescribing Information/Summary of Product Characteristics in the US and Europe, respectively.

Whether healthy volunteers or patients with the disease of interest will be enrolled in the FIH is determined by the drug candidate. For example, oncology drugs, may only be tested in cancer patients. The non-clinical toxicology results will also determine whether initially only a single administration of increasing dose can be tested (i.e., SAD), or multiple administrations are allowed (i.e., MAD). Alternatively, this could be done after evaluation of the safety with the single dose administration study. To get the most out of the first study in humans, the study should look for pharmacological or biological effects.

REGULATORY

Planning regulatory actions is of extreme importance. Checking the plans for CMC, non-clinical and clinical with authorities is usually very helpful. Following the advice is recommended as well, with higher chances of development success. These interactions can be at local level (individual European countries, including UK MHRA), European Medicines Agency (EMA) and FDA level. An experienced regulatory affairs person will be able to devise a strategy for interactions like pre-IND meetings, Scientific Advice/Protocol Assistance, and others. Programs to help small to medium enterprises (SMEs) exist. Programs such as orphan drug designation, Innovative Licensing and Access Pathway (ILAP), Priority Medicines scheme (PRIME), INitial Targeted Engagement for Regulatory Advice (INTERACT) are some of the programs helping with the interactions and providing incentives. The choice of the country to conduct the FIH also has strategic aspects to be considered such as cost, speed of approval and e.g., patent restoration time in the US from the moment an IND is open. An early, strategic regulatory plan is therefore critical.

Although the technical aspects of drug development are directly tied to the clinical and regulatory strategy and enable the progression of a drug candidate into the clinic, there are also non-technical aspects that need to be considered and indirectly enable a startup transitioning into a clinical-stage company.

CLINICAL DEVELOPMENT PHASE APPROPRIATENESS

The importance of the clinical phase appropriateness is critical. Oftentimes, clinical-stage companies get ahead of themselves by making unreasonable projections for commercialization without clinical data to substantiate considerably large investments. Inspection readiness, launch planning including commercial CMO selection and tech transfer, and adoption of validated computer systems, are a few of the “too-much, too-soon practices” encountered when working with early-stage pharmaceuticals.

Although it is understood drug development requires long-term planning, the statistics are hard to beat:

• Globally, more than 85% of clinical trials fail to enroll on time resulting in considerable delays and the need to add new study sites.
• The overall success rate of drugs entering clinical development is estimated at approximately 10%.
• The major reasons for clinical failure include a lack of clinical efficacy, toxicity, poor drug-like properties, a lack of commercial viability and poor planning.
• For every 5,000 to 10,000 compounds that enter the R&D pipeline, ultimately only one receives approval for commercialization.
• Often the drug does not fail, but the founders fail to plan appropriately.

Therefore, it is imperative for companies to place their focus on what matters most: ensuring the clinical study design and conduct will yield data that is conducive to advancing the drug candidate through the clinical phases, ultimately resulting in a successful NDA or BLA submission and approval.

An experienced regulatory development and project management team that are knowledgeable, collaborative, and transparent can ensure a successful transition to becoming a clinical-stage company.

PLAN AHEAD

To initiate clinical trials in the US, both the DS and the DP need to be manufactured under the applicable GMP. One of the key considerations in selecting a suitable contract manufacturing organization is to ensure it has the right expertise in the range of services required for the clinical trial material. When moving from the non-GMP to GMP manufacture, the resulting clinical product needs to be of equivalent or better quality to the batches used in non-GMP toxicology studies.

Furthermore, it is important to consider scalability in selection of the contract facilities to allow for the increase in material or resource requirements as development progresses. Testing and further optimization or refinement of transferred synthesis at the selected contract facility may be needed to provide a scalable process for manufacture within their facility. Unless there have been profound manufacturing changes, a formal comparability study is unnecessary.

PROJECT MANAGEMENT & COMMUNICATION

To facilitate effective decision making and collaboration, it is important to establish a project team and establish clear project expectations.  Routine communications are essential to ensure the team is informed and aligned to meet the same key performance indicators (KPI) and any issues are openly discussed, and risks mitigated as a team. A well thought out project plan serves as an effective tool for communicating and tracking important milestones and ensures clear visibility across the entire team.

When developing project timelines and forecasts it is paramount to allow for additional buffer time for unexpected issues (e.g., shipment failures, deviations) and endeavor to define actual costs (including costs of raw material that are often high yet excluded from cost estimates). This will allow for realistic planning.

Contact us at: info@qnovals.com or contact Jim Sergi at 800-229-5764 to learn more.