The development of biologics represents a major advancement, enabling the treatment of patients with many illnesses for which no other therapeutics were previously available. When developing biologics, sponsors must manage several scientific considerations specific to large-molecule products, including biochemical characterization studies to confirm structural identity, biological activity studies to confirm potency, and mechanism of action maintenance.

As with small molecules, clinical trials of biologics are designed to determine pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy. PK studies are conducted to confirm that dosimetry remains unchanged, and toxicology studies are needed to confirm that the therapeutic ratio and safety profile remain unchanged.

This two-part blog series gives an overview of general clinical pharmacology considerations in biologics development, with Part 1 focusing on the definition and distinct characteristics of biologics. Read Part 2, covering regulatory pathways and pharmacometric analysis for biologics.

Definition of biologic products

Section 351 of the Public Health Service Act defines a biological product as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product . . . applicable to the prevention, treatment, or cure of a disease or condition of human beings.”

Essentially, a biologic is a product that is produced from living organisms or that contains components of living organisms. These products can be derived from humans, animals, or microorganisms using biotechnology. Biologics include a wide range of products, including:

• Vaccines
• Blood and blood components
• Allergenics
• Somatic cells
• Gene and cellular therapies
• Tissues
• Recombinant therapeutic proteins
• Hormones
• Cytokines
• Growth factors
• Fusion proteins
• Insulin
• Interferons
• Monoclonal antibodies

Biologics change the manner of operation of natural biologic intracellular and cellular actions. They may contain proteins that control the action of other proteins and cellular processes, genes that control production of vital proteins, modified human hormones, or cells that produce substances that suppress or activate components of the immune system. Gene-based and cellular biologics, for example, often are at the forefront of biomedical research and may be used to treat a variety of medical conditions for which no other treatments are available.

Biologic products are used for the prevention or treatment of numerous diseases and conditions, including:

• Cancer
• Autoimmune diseases
• Anemia
• Chronic migraine
• Hepatitis B
• Hemophilia
• Respiratory syncytial virus prophylaxis
• HPV
• Rheumatoid arthritis
• Inflammatory bowel disease
• Ulcerative colitis

Characteristics of biologic products

The primary distinctions between biologics and small-molecule drugs are their size, structural complexity, and the way they are produced. The molecular weight of a small-molecule drug is typically less than 1 kilodalton (kDa), or 20–100 atoms, whereas the molecular weights of biologics range from a few kDa to 1000 kDa.

Small molecules have known structures and are primarily chemically synthesized. In contrast, most biologics are complex mixtures that are difficult to completely identify or characterize. They are often heat-sensitive, membrane-impermeable, subject to enzymatic degradation, and susceptible to microbial contamination (a factor that impacts manufacturing steps and quality considerations). The various physiochemical properties of biologics affect their mechanisms of action, PD, and PK, and can impact safety and efficacy.

Nonclinical testing

Biologics often require case-by-case, science-based, flexible approaches to preclinical testing. Many biologics cannot be tested in commonly used animal species, such as rats and dogs, because of their biological activity and certain species- or tissue-specific considerations. In vitro binding assays and functional tests might be required to identify the test material that is pharmacologically active, and a potency assay is required due to the complexity and heterogeneity of biologics.

ADME and dosing regimen

Biologics also have complex characteristics in absorption, distribution, metabolism, and elimination, that lead to significant differences in their development. Due to their larger molecular size, biological products are primarily delivered via intravenous, subcutaneous, or intramuscular injections and absorbed slowly. The molecular size also leads to limited renal excretion, so biologics are eliminated primarily through other means.

Biologics are often dosed based on factors such as body weight or surface area, due to the impact of body size on PK, PD, and clinical response, and certain modeling and simulation approaches can be used to determine dosing regimen and exposure-response relationships. Single- and multiple-dose PK and toxicokinetic studies are designed to assess absorption, disposition, exposure, and clearance and to explore dose-response relationships.

Side effects

Like all drugs, biologic therapies have the potential to cause side effects. Since biologics can suppress the immune system, there is increased risk of upper respiratory infections, urinary-tract infections, skin infections, pneumonia, and other infections. Immunogenicity can also lead to a loss of therapeutic efficacy, the formation of immune complexes, or cross-reactions with endogenous substances. Therefore, immunogenicity testing is often needed in screening and mechanistic studies for biologics.

Premier Consulting can help you to move your biologic product through the development process with our high-science, innovative solutions. Contact us to learn how we can advance your program, and read Part 2 of this blog series, covering regulatory pathways and pharmacometric analysis for biologics.

Co-Authors:

Agnieszka Marcinowicz, PhD
Manager, Pharmacokinetics

Stacey Ayres, PhD
Vice President, Regulatory and Strategy