5: Drug Development for Traditional Drugs and Biologics
- Explain the phases of the drug development process.
- Compare and contrast the drug development process between traditional drugs and biologics.
- Identify the role of the FDA in ensuring that drugs are safe and effective.
- Explain why the FDA may expedite drug approval or encourage the development of certain drugs.
- Describe the role of the health care team in post-marketing surveillance.
5.0 Introduction to the Drug Development Process
In the United States, the drug development process occurs within a structured framework to determine that a candidate drug has proven benefits that outweigh known and potential risks for the intended patient population. This process includes several stakeholders, including the pharmaceutical company (sponsor) developing the candidate drug and the Food and Drug Administration (FDA). The Center for Drug Evaluation and Research (CDER) is the FDA division responsible for regulating the approval and use of drug products as defined by the Federal Food Drug and Cosmetic (FD&C) Act, including prescription and over-the-counter medications, certain biological therapeutics, and generic drugs. 1,2 In addition, CDER considers products such as fluoride toothpaste, antiperspirants, dandruff shampoos, and sunscreens to be drugs and, therefore, is also responsible for regulating their approval and use. 2 The Center for Biologics Evaluation and Research (CBER) is the FDA division responsible for the regulation of biological products under the authority of the Public Health Services (PHS) Act and the FD&C Act. 3-5 Examples of products regulated by CDER and CBER are provided in Table 1.
Table 5.1 CDER and CBER Product Regulatory Responsibility
4
,5
CDER Responsible |
CBER Responsible |
|---|---|
|
Naturally occurring substances from mineral or plant source materials (excluding vaccines or allergenics) |
Vaccines and vaccine-associated products |
|
Products produced from nonhuman animal or human solid tissue sources |
In vivo diagnostic allergenic products |
|
Chemically synthesized molecules, including those that bind to the receptors for biological products and mononucleotide or polynucleotide products (e.g., cytokines, thrombolytics, monoclonal antibodies, immunomodulators) |
Human blood or human blood-derived products, animal-derived procoagulant products, and animal- or cell culture-derived hemoglobin-based products (e.g., red blood cell substitutes) |
|
Antibiotics |
Immunoglobulin products |
|
Hormone products (e.g., insulin, human growth hormone, pituitary hormones) |
Products composed of or intended to contain intact cells or intact microorganisms, including bacteria, fungi, viruses or virus pseudotypes, or viral vectors (e.g., gene therapy products) |
|
Certain substances produced by fungi or bacteria (e.g., disaccharidase inhibitors, HMG-Co-A reductase inhibitors) |
Protein, peptide (40 or fewer amino acids), or carbohydrate products produced by cell culture except antibiotics, hormones, and products previously derived from human or animal tissue and regulated as approved drugs |
|
Animal venoms or constituents of venoms |
|
|
Synthetically-produced allergenic products intended to specifically alter the immune response to a specific antigen or allergen |
|
|
Certain drugs used in conjunction with blood banking and/or transfusion |
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 Discovery, Development, and Preclinical Research
The discovery, development, and preclinical research phases (Figure 5.2) encompass the drug development work that occurs before investigational drugs being tested in humans. This process may take 4 – 7 years to complete, with several steps occurring simultaneously (Figure 5.1). 7
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, i n 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 (LD 50 ) 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 Clinical Research
Once the FDA approves an IND application, a three-step clinical research phase begins, during which the investigational drug is tested in humans. The goal of the clinical research phase is to establish safety, efficacy, and effectiveness of new drugs in humans.
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
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
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
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
5.3 Regulatory Process and Timeline
The FDA and CDER have a clearly defined structure to guide sponsors and regulate the drug development process that includes timelines and deadlines related to formal reviews and approvals. Two critical components of this structure are the IND application and New Drug Application (NDA) or Biologics License Application (BLA), which are described below and incorporated into the timeline depicted in Figure 5.1. While sponsors must follow the IND and NDA/BLA processes, they are encouraged to seek guidance from the FDA throughout the drug development process. In particular, sponsors are encouraged to have a pre-IND meeting with the FDA to review guidance documents, share with the FDA their proposed drug development plan, and solicit FDA feedback on strategies to address specific questions related to the investigational drug’s development.
6,9,11
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
The FDA estimates that approximately 25–30% of drugs entering Phase 3 move on to the next phase: NDA.
11
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
5.4 Phase 4: Post-Marketing Surveillance
Phase 4 of drug development research refers to the post-marketing evaluation of newly approved drugs. These studies are designed to provide additional information related to the safety, increasing pharmacovigilance, and efficacy of the new drug.
1,7,11
References:
1. Gibofsky A. The FDA and the Drug Development Process. In: Lockshin MD, Crow MK, Barbhaiya M, eds. Diagnoses Without Names . Springer International Publishing; 2022:69-74. doi:10.1007/978-3-031-04935-4_7
2. U.S. Food & Drug Administration. Center for Drug Evaluation and Research | CDER. Published August 14, 2023. Accessed September 18, 2023. https://www.fda.gov/about-fda/fda-or...-research-cder
3. Van Norman GA. Drugs, Devices, and the FDA: Part 1. JACC: Basic to Translational Science . 2016;1(3):170-179. doi:10.1016/j.jacbts.2016.03.002
4. BioStock. Drug development: the four phases. Published January 2, 2023. Accessed September 19, 2023. https://www.biostock.se/en/2023/01/d...e-four-phases/
5. U.S. Food & Drug Administration. Step 1: Discovery and development. Published January 4, 2018. Accessed September 18, 2023. https://www.fda.gov/patients/drug-de...nd-development
6. Steinmetz KL, Spack EG. The basics of preclinical drug development for neurodegenerative disease indications. BMC Neurol . 2009;9(Suppl 1):S2. doi:10.1186/1471-2377-9-S1-S2
7. U.S. Food & Drug Administration. Step 2: Preclinical research. Published January 4, 2018. Accessed September 18, 2023. https://www.fda.gov/patients/drug-de...nical-research
8. U.S. Food & Drug Administration. Step 3: Clinical research. Published January 4, 2018. Accessed September 18, 2023. https://www.fda.gov/patients/drug-de...nical-research
9. Thomas D, Chancellor D, Micklus A, et al. Clinical Development Success Rates and Contributing Factors 2011-2020 . Biotechnology Innovation Organization | Informa Pharma Intelligence | QLS Advisors LLC; 2021. https://go.bio.org/rs/490-EHZ-999/im...s2011_2020.pdf
10. U.S. Food & Drug Administration. Investigational new drug (IND) application. Published July 20, 2022. Accessed September 19, 2023. https://www.fda.gov/drugs/types-appl...nd-application
11. U.S. Food & Drug Administration. Step 4: FDA drug review. Published January 4, 2018. Accessed September 18, 2023. https://www.fda.gov/patients/drug-de...da-drug-review
12. Brown DG, Wobst HJ, Kapoor A, Kenna LA, Southall N. Drug development times for innovative drugs. Nat Rev Drug Discov . 21:793-794. doi:10.1038/d41573-021-00190-9
13. U.S. Food & Drug Administration. Accelerated Approval. Published February 24, 2023. Accessed September 18, 2023. https://www.fda.gov/patients/fast-tr...rated-approval
14. U.S. Food & Drug Administration. Fast track. Published January 4, 2018. Accessed September 18, 2023. https://www.fda.gov/patients/fast-tr...iew/fast-track
15. U.S. Food & Drug Administration. Breakthrough therapy. Published January 4, 2018. Accessed September 18, 2023. https://www.fda.gov/patients/fast-tr...hrough-therapy
16. U.S. Food & Drug Administration. Priority review. Published January 4, 2018. Accessed September 18, 2023. https://www.fda.gov/patients/fast-tr...riority-review
This chapter titled Drug Development for Traditional Drugs and Biologics is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Robert J. DiDomenico from Introduction to Pharmacology by Carl Rosow, David Standaert, & Gary Strichartz ( MIT OpenCourseWare ) via source content that was edited to the style and standards of the LibreTexts platform; a detailed edit history is available upon request. Figures by Riley Cutler.