5: Drug Development for Traditional Drugs and Biologics

Table 5.1 CDER and CBER Product Regulatory Responsibility^4,5

The drug development process includes 5 phases: 1) discovery and development, 2) preclinical research, 3) clinical research, 4) FDA review, and 5) post-marketing safety monitoring. For most drugs, the typical duration from discovery to FDA approval is between 10 and 15 years (Figure 5.1) and may cost in excess of $1 billion.⁶ Each of these phases is described below in more detail.

5.1.1 Discovery and Development

During the discovery phase, scientists identify disease-related mechanisms and processes (e.g., disease pathways, genes, proteins) that may serve as targets for the development of drugs to stop, reverse, or prevent the disease of interest. These discoveries are made in a laboratory setting.

Once a disease-related target has been identified, hundreds to thousands of chemical and/or biological compounds are screened using in silico, or computational, testing to evaluate their ability to interact with the disease-related target and potentially treat or prevent the disease of interest.^7,8 The goal of this process is to identify a small number of compounds—and ultimately a lead compound—that offer the most promise for further development. Promising compounds are further evaluated using in silico and in vitro models to predict physicochemical parameters, pharmacokinetics, and drug metabolism.^8,9

Once a lead compound is identified, the preclinical development includes analytical and bioanalytical methods development and validation, dosage form design, and establishment of good manufacturing processes for the active ingredient (e.g., lead compound) and final investigational drug product to be used in clinical research phases.^8,9 Additionally, in vivo studies are performed on the investigational drug using one or more animal models to evaluate basic pharmacology (e.g., metabolism, pharmacokinetics), perform dose range-finding, and assess experimental toxicology.⁹

5.1.2 Preclinical Research

Before an investigational drug can be tested in humans, definitive, in vivo preclinical studies in one or more animal models are required to assess the safety and toxicology (LD₅₀) of candidate drugs using good laboratory practices (GLP), good manufacturing practice (GMP) in the dosage form and maximally tolerated dose from dose range-finding studies.^9,10 Additional in vitro studies are also performed to assess organ system toxicity (e.g., central nervous, cardiovascular, respiratory, and immune systems) and genetic toxicology (e.g., DNA, cellular genetic processes).⁹ Investigational drugs that exhibit potentially beneficial pharmacological activity to treat the disease of interest and have demonstrated reasonable safety in preclinical research may proceed to the clinical research phase once the sponsor receives approval forf an investigational new drug (IND) application (described further in 5.3.1). Only about 1 in 1,000 potential drugs evaluated in the discovery, development, and preclinical phase proceed to the clinical research phase.⁶

5.2.1 Phase 1

The first step of the clinical research phase is to conduct Phase 1 studies (Figure 5.3). The primary focus of Phase 1 studies is to determine a safe dosage range and administration method and evaluate the investigational drug’s toxicity profile. Part of the determination of a safe dosage range includes evaluations of the drug’s pharmacokinetic properties.

Phase 1 studies are typically conducted in a relatively small number (20 – 80 subjects) of healthy volunteers, although Phase 1 studies evaluating drugs to treat cancer are typically conducted in patients with the targeted type of cancer.^1,7,11 Phase 1 studies may take 1 – 2 years or more to complete (Figure 5.1) and inform the design of Phase 2 studies.^7,11,12

5.2.2 Phase 2

Approximately 40 – 70% of investigational drugs tested in Phase 1 demonstrate a reasonable safety profile and move on to Phase 2 studies (Figure 5.4).^11,12 The purpose of Phase 2 studies is to evaluate the efficacy of the investigational drug to treat the condition of interest while gaining additional safety data. Phase 2 studies often incorporate dose-ranging evaluations to explore the investigational drug’s therapeutic range.^6,7,11

Because Phase 2 studies are designed to evaluate efficacy, they are conducted in patients with the condition of interest. Furthermore, the number of patients studied in Phase 2 studies is larger (100 – 300) compared to Phase 1 studies. Phase 2 studies are generally randomized, controlled studies utilizing a placebo or alternative treatment (e.g., standard of care) and study patients for up to 2 years.¹¹ Efficacy endpoints often relate to symptom relief, pharmacodynamic/physiologic changes expected based on the pharmacology (e.g., blood pressure), and/or biomarker changes indicative of alterations in the disease course. Phase 2 studies serve as a “proof-of-concept” to inform the design of Phase 3 studies.⁷ Overall, it may take 2 – 4 years for Phase 2 studies to be completed (Figure 5.1).^6,11,12

5.2.3 Phase 3

Approximately 30% of investigational drugs tested in Phase 2 demonstrate efficacy and a reasonable safety profile, enabling them to proceed to Phase 3 studies.^11,12 The purpose of Phase 3 studies is to confirm that the investigational drug is both effective and safe in patients with the disease of interest.

To accomplish these goals, Phase 3 studies include much larger (300–3,000 or more) cohorts of patients with the disease of interest and longer durations of follow-up, providing a better assessment of serious, long-term, and/or rare adverse effects.^6,7,11 Like Phase 2 studies, Phase 3 studies compare the investigational drug to a control group, typically a placebo. Efficacy endpoints may also include more robust clinical endpoints such as disease-specific adverse events, including mortality. Phase 3 often takes 1–4 years to complete (Figure 5.1).^6,7,11,12

5.3.1 Investigational New Drug Application

For investigational drugs that show promise in preclinical studies, a critical step in the drug development process is the IND application, the approval of which allows research of the investigational drug in humans to proceed. The IND application is submitted upon completion of the Preclinical Phase. The IND application must include data from preclinical studies (e.g., pharmacology, safety/toxicology); data from previous human experience (if any); chemistry, manufacturing, and control information; protocols for the conduct of each study proposed during the clinical research phase, and information about the investigator(s).^9,11

Once submitted, the FDA will notify the sponsor of the date it was received. The FDA may place the IND application on a Clinical Hold or request additional information before permitting the Clinical Research Phase to proceed.^9,13 If the sponsor does not receive notification of a Clinical Hold or request for more information within 30 days of receiving the application, the IND may go into effect. The IND may go into effect earlier if notified by the FDA that the IND may begin. The manufacturer may ship the investigational new drug to investigators who may administer the drug to human subjects participating in the clinical studies once the IND goes into effect. For more information regarding the components, format, and other details related to the IND application, readers are referred to the Code of Federal Regulations Title 21 Part 312.

5.3.2 New Drug Application & Biologics License Application

For investigational drugs shown to be safe and effective in Phase 3 clinical studies, an NDA (or BLA if the drug is a biologic) must be submitted by the sponsor to the FDA formally requesting approval to market the drug. Before submitting the NDA, the sponsor may meet with the FDA to obtain guidance on the application. The NDA (or BLA) provides the FDA comprehensive information and data regarding the manufacturing process and facilities, quality control, and assurance; complete product description, including the chemical formula/structure, specifications, pharmacodynamics, and pharmacokinetics); data from all preclinical and clinical studies; indications; labeling including directions for use and patient information; safety updates and proposed risk evaluation and mitigation strategies (REMS) that may be applicable; drug abuse information; and institutional review board compliance.^6,14

Once received from the sponsor, the FDA has 60 days to decide to accept it for review.^1,6 Once accepted for review, the FDA aims to complete its comprehensive review and render a decision within 6 – 10 months.^1,6,14 In addition to reviewing the data contained within the NDA (or BLA), the FDA review also includes inspection of production facilities and clinical study sites. Additionally, the FDA review may include review by one or more of the FDA Advisory Committees to get additional, independent advice from experts, including patient representatives.¹⁴ The NDA/BLA review process often takes 1–2 years to complete before the FDA renders a decision (Figure 5.1).^6,12 For more information regarding the details and requirements for submission, readers are referred to the Code of Federal Regulations Title 21 Part 314 for an NDA or Code of Federal Regulations, Title 21 Part 601 for a BLA.

The FDA estimates that approximately 25–30% of drugs entering Phase 3 move on to the next phase: NDA.¹¹ However, a recent analysis of clinical drug development between 2011 – 2020 reported a much higher success rate (57.8%) for investigational drugs moving from Phase 3 to NDA.¹² In this same analysis, the approval rate of NDAs was approximately 90%.

5.3.3 Accelerated Approval & Drug Development Designations

For some candidate drugs, the FDA has several mechanisms in place to expedite drug approval and encourage the development of certain drugs. These mechanisms can abbreviate the typical drug development timeline to as little as ~9 years.¹⁵

• Accelerated Approval: Promising candidate drugs that treat serious or life-threatening conditions and provide greater benefit and/or lower risk over currently available therapies can be granted accelerated approval.^1,16 Drugs granted accelerated approval must demonstrate improvements in surrogate endpoints likely to predict clinical benefit or intermediate clinical endpoints that are less robust that standard endpoints.¹⁶ For drugs granted accelerated approval, the sponsor is required to conduct Phase 4 post-marketing studies to verify and further elucidate the drug’s benefits.^1,16 Approval of a drug granted accelerated approval can be withdrawn if Phase 4 studies fail to verify clinical benefits outweigh the risks associated with the drug.¹⁶
• Fast Track: Candidate drugs that treat serious conditions and fill an unmet medical need, based on preclinical and/or early clinical research, may be designated as fast track to expedite the approval process and make the drug available to patients sooner.¹⁷ The sponsor must request the fast track process.
• Breakthrough Therapy: Similarly, candidate drugs intended to treat serious conditions for which preliminary evidence has demonstrated substantial benefit over currently available therapies may be designated as breakthrough therapy.¹⁸ Like fast track drugs, the sponsor must request breakthrough therapy designation. Drugs designated as breakthrough therapy may also be eligible for fast track designation.
• Priority Review: Drugs that significantly improve the treatment, diagnosis, or prevention of serious illnesses may be designated for priority review, which seeks to reduce the time for the FDA to take action on the NDA from 10 months to 6 months or less.^1,19