Biologics and Biosimilars vs Brand and Generics same yet unique

Drugs vs Biologics:

A drug is produced by synthetic chemical interactions, typically by combining specific chemical ingredients in an ordered process. On the other hand, a biological product is biologically engineered in a living system such as a microorganism, plant or animal cell. Most biologics are very large, complex molecules or mixtures of molecules. Many biologics are produced using a specific technique called “recombinant DNA technology”. Generally, drugs have well-defined chemical structures, and the final product of the drug can usually be analyzed to determine all its various components.

On the other hand, the testing methods that are available in the laboratory make it difficult, if not impossible, to characterize a complex biologic, and some of the components of a finished biologic may be unknown. The cell-based manufacturing process that is utilized in the production of biological therapies therefore significantly defines their biological activity. Thus, manufacturers must ensure product consistency, quality, and purity by ensuring that the manufacturing process remains substantially the same over time. Biologics can be made by living systems that are sensitive to even the tiniest changes in the manufacturing process. Small variations in the manufacturing process can have a significant impact on the final biologic’s nature and, most importantly, its body function.

Thus, Biologics manufacturers must consistently employ hundreds of process controls that guarantee predictable manufacturing outcomes and tightly control the source and nature of starting materials in order to ensure that a manufacturing process remains constant over time.

For each brand-name drug there are generics but for biologics there are biosimilars:

A generic drug is a medication manufactured to be the same as an already promoted brand-name drug in dosage form, safety, efficacy, route of administration, quality, performance characteristics, and Indications. This resemblance helps to explain bioequivalence, which means that a generic medication works in a similar way and affords the same clinical benefit as the original medicine. In other words, generic drugs share the same active ingredient as brand-name medicines, but may include different other characteristics, such as colors and flavorings, that do not affect the performance, safety, or effectiveness of the generic medicine, may be different. Manufacturers of can easily produce an exact copy of the brand molecule because it has a well-defined chemical structure.

Unlike small-molecule drugs, which are one-dimensional and chemically defined molecular entities, biologics are much larger in size and have greater structural complexity, including primary, secondary, tertiary and, possibly, quaternary structures. Therefore, Biosimilars are designed to be highly similar to the reference branded innovator biological drug. Biosimilars are required to have the same amino acid sequence as the brand biological product although it is nearly impossible to be the same in structure as the parent Biologic due to structural complexity. They should demonstrate similar physical, chemical, microbiological property, biological function, clinical efficacy and safety to that of an already licensed biologic reference product. They are not allowed to have minor differences even in clinically inactive components. Some researchers consider Biosimilars as the “generic version” of the branded biological drugs. Conversely, others do not prefer this terminology as not all biosimilars will be the exact copies of the biologics they reference.

Patency:

When a pharmaceutical company develops a new medicine to treat a disease, it first sells it under a brand name for which physicians can prescribe it. The drug is protected by a patent, which means that only the pharmaceutical company that owns the patent can manufacture, market, and ultimately profit from it. The primary goal of patent laws is to ensure that the inventor gets paid back in money and time for creating a new product.

When a patent lapses, the FDA endorses generic drugs based on the confirmation of pharmaceutical equivalence and bioequivalence through analytical analysis and similar bioavailability results; Since small molecule drugs have the same chemical structures, comparing the levels of the brand-name and generic drug in the blood can help ensure that they have the same biological activity. Since any manufacturer can replicate the original product, this allows for price competition and eventually puts an end to the monopolistic practice of patent-holding companies. The same holds true for biosimilars and biologics.

Biosimilars, like generics, are unlikely to be included in the pharmaceutical arsenal unless they result in significant savings for health authorities. Biosimilars, on the other hand, are more difficult to manufacture and more expensive than generic versions of small-molecule drugs. A biosimilar can be brought to market in five to ten years with an investment of $100 million to $250 million, whereas a conventional generic can be developed in two years with an investment of $1 million to $10 million, especially given the complicated patent landscape in the United States.

Selected categories of biologic agent structure:

1. Hormones (growth hormone, parathyroid hormone, insulin): A substance, usually a peptide or steroid, produced by one tissue and conveyed by the bloodstream to another to effect physiological activity, such as growth or metabolism.
2. Interferons: Proteins that are normally produced by cells in response to viral infection and other stimuli.
3. Interleukins: A large group of cytokine proteins. Most are involved in directing other immune cells to divide and differentiate.
4. Growth factor: A substance such as a vitamin B12 or an interleukin that promotes growth, especially cellular growth.
5. Monoclonal antibodies (MAbs): A single species of immunoglobulin molecules produced by culturing a single clone of a hybridoma cell. MAbs recognize only one chemical structure, i.e., they are directed against a single epitope of the antigenic substance used to raise the antibody.
6. Polypeptides: Peptides containing ten or more amino acids. Typically, a peptide consists of fewer than 50 amino acids, while a protein has more than 50 amino acids.
7. Proteins: Naturally occurring and synthetic polypeptides having molecular weights greater than about 10,000 (the limit is not precise).
8. Vaccine: An agent containing antigens produced from killed, attenuated or live pathogenic microorganisms, synthetic peptides, or by recombinant organisms. Used for stimulating the immune system of the recipient to produce specific antibodies providing active immunity and/or passive immunity in the progeny.

Biologic reference products and their approval processes:

Drug manufacturers must first complete a variety of studies, including animal and laboratory testing, repeat-dose toxicity studies that examine the pharmacokinetics (PK), pharmacodynamics (PD), and adverse events of the agent, and then submit an investigational new drug (IND) application to the FDA or a clinical trial application (CTA) to the EMA in order to earn agreement to develop a drug. The biologic’s pharmacologic effects and mechanism of action, as well as information on the product’s absorption, distribution, metabolism, and excretion (ADME), will then be examined by the FDA or EMA. The FDA or EMA will, if necessary, approve the proposed investigational drug for further human testing after reviewing the data.

The FDA and EMA use a three-phase clinical testing procedure. The product’s metabolism, pharmacology, and safety in humans at single or increasing doses are the focus of phase I trials. Proof-of-concept (efficacy), dose determination, and initial safety are all components of Phase II trials. The agent will begin the third phase of clinical trials once the FDA or EMA deems it ready. In Phase III, randomized controlled trials (RCTs) are conducted on a large number of patients with various diseases for which the biologic is anticipated to be effective to determine clinical efficacy, additional outcomes, and adverse events. The process of getting approval to sell a drug is expensive, costing manufacturers around from $1 billion to $1.8 billion.           

Characterization studies are also conducted to describe structural elements responsible for biological activity (such as active sites, receptor and ligand binding sites, and features responsible for signal transduction) in addition to clinical studies. The active ingredient and its excipients are also investigated for any physicochemical interactions. Potential interactions between the product and primary packaging are investigated to minimize any loss of biological activity or potency caused by sorption during storage. The active substances’ stability should be investigated, including how the molecule’s integrity will be affected by the formulation, manufacturing conditions, and storage (such as changes in temperature, pH, salt, pressure, and shear). Under a variety of process conditions, the formulated product or drug substance’s stability must also be investigated.

Biosimilars and their approval process:

A biosimilar must pass stringent trials before it can be approved. Although the reference biologic’s primary structure may be known, the sponsor and regulatory agencies keep the manufacturing process private. The biosimilar’s reverse engineering studies will likely employ newer, more advanced techniques that were unavailable for the reference product’s development. This will likely result in extensive comparative data between the biosimilar and the reference product. For biosimilars, the FDA and EMA have similar approval procedures. When demonstrating bio similarity to a reference product, scientific considerations include: According to the FDA’s 2015 Guidance for Industry, structural and functional assays must be carried out. Toxicology tests, PK and PD tests, and immunogenicity tests can all be done on experimental animals in vivo. Comparative clinical trials are required to demonstrate PK and immunogenicity equivalence after a single dose between the reference product and the biosimilar, with clinical PK similarity needed for three endpoints: 1) the maximum concentration of serum; 2) the area between the first and last measured time points of the time-concentration curve, and 3) the area below the time-concentration curve from the first extrapolated time point to infinity. In order to gather comparable data on safety, pharmacology, immunogenicity, and efficacy, at least one RCT is typically carried out on humans. At least one of the clinical indications for which the reference product has been approved is the subject of these studies. Typically, the designs of these studies are based on previous RCTs that demonstrated the reference product’s efficacy. Biosimilars need to exhibit comparability to the reference item in these examinations and not just non-inferiority. A multiple-switching PK/PD study is required if an interchangeability designation is desired.

While the FDA’s requirements for biosimilar approval are similar to those of the EMA, there are two significant differences: the EMA requires a post-marketing surveillance plan, and individual European nations decide on interchangeability or switching from a reference product to its biosimilar.

List of Biosimilars Approved in the United States

References:

1. Blackstone, E. A., & Joseph, P. F. (2013). The economics of biosimilars. American health & drug benefits, 6(8), 469–478.
2. Chan, J. C. N., & Chan, A. T. C. (2017). Biologics and biosimilars: what, why and how?. ESMO Open, 2(1), e000180. https://doi.org/10.1136/esmoopen-2017-000180.
3. Palak K. Patel, Caleb R. King & Steven R. Feldman (2015) Biologics and biosimilars, Journal of Dermatological Treatment, 26:4, 299-302, DOI: 10.3109/09546634.2015.1054782.
4. van de Vooren, K., Curto, A. & Garattini, L. Biosimilar Versus Generic Drugs: Same But Different?. Appl Health Econ Health Policy 13, 125–127 (2015). https://doi.org/10.1007/s40258-015-0154-9.