This piece was edited in April 2021 to update the definition of “Synthetic polymer.”
Clinical trial1: A research study that uses human volunteers to help test the safety and/or efficacy of new treatments for diseases and conditions.
Drug class: Molecules that share a common principal chemical scaffold, or specific arrangement of atoms, belong to a common drug class. For example, quinolone antibiotics share a distinctive ring system at their core.
Drug development2: The process of rigorously testing a new drug candidate for safety and efficacy in order to bring it to market. The U.S. Food and Drug Administration (FDA) reviews the results of this testing, as well as manufacturing information, before it will consider approving a drug for use in patients.
Clinical testing in the development of a drug involves multiple phases. Each has standard parameters and specific requirements that must be met before a drug can advance to the next stage. The progression is generally as follows:
- Preclinical or nonclinical testing: Laboratory and animal studies are used to determine a drug’s antibacterial activity under experimental conditions, its efficacy in animal models, and whether the drug candidate may be safe enough to test in people. Before clinical trials can begin, drug developers must file an investigational new drug application with FDA based on preclinical information that supports testing the drug candidate in humans.
- Phase 1: The drug or treatment is tested in a small group of healthy volunteers (20 to 80) to evaluate whether it is sufficiently safe. During this phase, developers examine how the drug is absorbed and metabolized.
- Phase 2: A drug candidate’s effectiveness and safety are evaluated in a group of patients (generally 30 to 300) who have the condition the drug is meant to treat. Developers examine the side effects and potential risks of the drug and the initial evidence of its effectiveness. Phase 2 studies provide information on the drug’s optimal dose and how it should be administered.
- Phase 3: The drug is tested in a large group of patients (>1,000) to gather statistically significant evidence about its safety, effectiveness, benefits, and risks. Test subjects are patients with the condition the drug is meant to treat. Phase 3 studies provide key information that FDA considers in deciding whether to approve a drug for use.
- New drug application (NDA) or biologics license application (BLA): A drug developer’s request to FDA for approval to market a drug or biologic to patients. This application contains the results of all animal and human studies of the drug as well as information on its manufacturing. The agency reviews the application and decides whether the drug can be approved or needs additional testing.
- Complete response letter3: If after review of the new drug application a drug is not approved, FDA issues a complete response letter, which reflects the complete review of data submitted in an original application. In the letter, the agency provides specific descriptions of deficiencies in the application and gives the drug developer an opportunity to address these issues.
- Phase 4 (post-marketing studies): FDA sometimes requires sponsors to monitor the long-term risks and benefits of a drug after it has been approved and to make that information available to the public. In some cases, post-marketing studies focus on a subgroup of the general population that could not be adequately evaluated during clinical testing, such as children or pregnant women.
Drug discovery: Early laboratory research to identify or design promising compounds that could eventually become approved medicines.
Drug target: The bacterial structure that an antibiotic acts upon. For example, macrolide antibiotics bind to a specific part of the bacterial ribosome to impede the essential process of manufacturing proteins.
Gram-negative bacteria4: Bacteria that appear pinkish or red when subjected to a laboratory method known as the Gram stain, which is used to differentiate categories of bacteria based on the presence or absence of an outer membrane. Gram-negative bacteria can readily acquire resistance to multiple drugs and easily spread resistance to other bacteria. They have a double-layered outer membrane and a variety of pumps that expel drugs from the cell, factors that make them particularly difficult to attack with antibiotics. Gram-negative bacteria cause a wide range of serious infections, and some have become increasingly resistant to available antibiotic treatments, including antibiotics of last resort. Examples of important Gram-negative pathogens with known drug resistance are Escherichia coli, Neisseria gonorrhoeae, and Gram-negative ESKAPE bacteria: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.
Indication: The disease or condition for which a drug was approved by FDA. Antibiotics may be approved to treat for several conditions, including urinary tract infections, bacterial pneumonia, skin infections caused by multidrug-resistant bacteria, and a variety of others. Indications are described on the drug’s label and package insert.
Nontraditional products: A wide-ranging category of antibacterial products that differs substantially from existing antibiotics in molecular structure and mechanism of action. Traditional antibiotics are generally small molecules that kill or inhibit the growth of bacteria directly. Nontraditional products affect bacteria through alternative approaches.
- Antibody: A protein that is naturally produced by the immune system to identify and help remove potentially harmful pathogens. Novel therapies may take advantage of the specific targeting capacities of antibodies to bind to bacteria and/or their virulence factors and inactivate them in a variety of ways, as well as augment immune response.
- Bacteriophage: A virus that infects, replicates within, and lyses bacteria. When the bacterial cell lyses, new bacteriophages are released to infect nearby bacteria. Bacteriophages are abundant in nature, and these products often consist of a mixture of bacteriophages (called a cocktail) to target multiple, specific pathogenic strains.
- Live biotherapeutic product (LBP): A live microorganism that helps to maintain and restore populations of beneficial bacteria in the human gut. The administration of broad-spectrum antibiotics often indiscriminately kills gut bacteria, increasing the possibility of side effects and colonization by harmful microorganisms, such as Clostridioides difficile. Administering LBPs alongside antibiotics may help to alleviate these risks.
- Lysin: An enzyme derived from bacteriophages that breaks up the bacterial cell wall architecture, resulting in cell lysis. Like bacteriophages, it is highly specific to particular bacterial strains.
- Peptide immunomodulator: A short chain of amino acids that enhances or dampens the immune response to infection.
- Synthetic antimicrobial peptide: A short chain of amino acids that targets and disrupts the composition of bacterial membranes or cell walls, usually resulting in bacterial cell lysis.
- Synthetic polymer: A macromolecule composed of repeating units that can have varied modes of action, such as inherent antibacterial activity, or increasing potency of an existing antibiotics, or microbiome modulation.
- Virulence inhibitor: A molecule that works by disarming pathogens, preventing and neutralizing their harmful effects (such as bacterial toxins), inhibiting bacteria to attach to or infect individual host cells, or weakening bacterial defenses to help patients’ immune systems overcome infections.
- Vaccine: An agent that stimulates the body’s immune system to recognize and destroy pathogens, such as bacteria, protecting the patient from infection. Vaccines typically contain inactivated disease-causing pathogens or components that resemble them.
Qualified infectious disease product (QIDP): Under the Generating Antibiotic Incentives Now (GAIN) Act signed into law in 2012, drug developers may request that FDA grant a QIDP designation to “an antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections.” Antibiotics designated as QIDPs are eligible for incentives, including faster FDA review and, if they are approved for patients, an additional period during which they are free from generic competition.
- National Institutes of Health, “NIH Clinical Research Trials and You,” accessed Sept. 19, 2016, http://www.nih.gov/health/clinicaltrials/basics.htm.
- U.S. Food and Drug Administration, “FDA Drug Approval Process Infographic,” accessed Sept. 19, 2016, http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm295473.htm; U.S. Food and Drug Administration, “The FDA's Drug Review Process: Ensuring Drugs Are Safe and Effective,” accessed Sept. 19, 2016, http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534.htm; PhRMA, “Biopharmaceutical Research & Development: The Process Behind New Medicines,” accessed Sept. 19, 2016, http://www.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf.
- U.S. Food and Drug Administration, “Applications for FDA Approval to Market a New Drug,” 21 C.F.R. § 314.110, https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.110.
- National Institute of Allergy and Infectious Diseases, “Gram-Negative Bacteria,” accessed Sept. 19, 2016, https://www.niaid.nih.gov/research/gram-negative-bacteria.