Our previous blog posts covered how the Food and Drug Administration (FDA) came to approve therapeutics under the passage of various laws by Congress. We have covered the Federal Food, Drug, and Cosmetic Act (FDCA) of 1938, the Public Health Service Act (PHSA) in 1944, the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Amendments, and the Biologics Price Competition and Innovation Act of 2009 (BPCIA). We also covered new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biological license agreements (BLAs) and the various approval pathways (505(b)(1), 505(b)(2), 505(j), 351(a), and 351(k)) under these laws. Below is a diagram that summarizes the relationship between these laws, modalities, type of applications, and approval pathways.

The Orange Book

Therapeutics approved under the FDCA and Hatch Waxman amendments are listed in the Orange Book. Therapeutics that have not been approved by the FDA, such as therapeutics in clinical trials, are not listed in the Orange Book. It is called the “Orange Book” because early publications were in a book form and the front cover was orange. However, its formal name is “Approved Drug Products with Therapeutic Equivalence Evaluations,” and it is now an online resource found here. It is a compilation of therapeutics approved by the FDA under the FDCA. 

The Orange Book contains important information, including whether a drug is approved under an NDA or an ANDA. For example, consider the drug or active ingredient plerixafor. A search of the Orange Book for this active ingredient yields the following search results:

Under the column “Appl. No.”, the approved NDAs (denoted with an “N” application number) and the approved ANDAs (denoted with an “A” application number) are listed. For each of these applications, the applicant holder is also provided. For this drug or active ingredient, there is an NDA holder (Genzyme Corp.) and several ANDA holders.

For comparison, consider a search in the Orange Book for the active ingredient pirtobrutinib:

For pirtobrutinib, there is only one approved NDA, which covers two different strengths of tablets (50 mg and 100 mg). There are no approved ANDAs for this active ingredient. Also notice how the active ingredient name differs from the proprietary name. The active ingredient name is the name of the actual molecule that provides the pharmacological activity or effects the treatment or prevention of the disease. “Active ingredient” means the particular molecule that causes an effect in humans. The proprietary name, also known as the brand name or trade name, is the name that will be used in the marketplace for the particular drug product. For example, “aspirin” is the name of a specific molecule or active ingredient. “Bayer” is the proprietary name or brand name of the drug product marketed and distributed in the marketplace.

As we discussed in our previous blog post Therapeutics at the FDA: paths to approval, the FDA will not require an applicant to repeat all the pre-clinical and clinical studies of a drug that has been previously approved by the FDA. These generic drugs are approved under 505(j) via an ANDA. In the Orange Book, the FDA will indicate the active ingredient that can serve as a reference drug for an ANDA. These active ingredients are noted as the RLD (Reference Listed Drug). The RLD is the reference standard by which any ANDA applicant must use in its testing to establish the generic product’s bioequivalence or “sameness.” The Orange Book also indicates the Reference Standard (RS). The reference standard is the drug product selected by FDA that an applicant seeking approval of an ANDA must use in conducting an in vivo bioequivalence study required for approval of an ANDA. If there are different strengths of a dosage form, the FDA usually selects the highest strength as the RS. Notice that in both of our examples, plerixafor and pirtobrutinib, one NDA serves as the RLD. In the pirtobrutinib example, the highest strength dosage form is designated as the RS.

The Purple Book

Therapeutics approved under the PHSA and the BPCIA are listed in the Purple Book. The official name is “Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations,” and it made its debut on the FDA’s website on September 9, 2014.  It was given the informal name the “Purple Book” to be similar to the informal name of the “Orange Book.” Thus, we have the Orange Book and the Purple Book in the United States to list approved therapeutics.

The Purple Book contains information about all FDA-licensed biological products, including licensed biosimilar and interchangeable products, and their reference products, in addition to FDA-licensed allergenic, cellular and gene therapy, hematologic, and vaccine products. Similar to the Orange Book, only approved therapeutics are listed. Therapeutics in the clinic or not yet approved by the FDA are not listed in the Purple Book.

As an example, consider a search in the Purple Book for “aflibercept” that yields the following results:

In the right column, the Purple Book provides the regulatory pathway (351(a) or 351(k)) for the drug product. For 351(k) approvals, it also specifies whether the product is a biosimilar or interchangeable. 

In the left column, the proprietary name and the proper name for each product is provided. The proper name, or active ingredient name, is shown in parenthesis. For biologics, a random, four-letter suffix is added to the proper name. This additional naming convention is to facilitate accurate identification of biological products by health care practitioners and patients. It also helps minimize inadvertent substitution of products that have not been designated as interchangeable.

For aflibercept, there are approved reference products (approved under 351(a)), along with biosimilar and interchangeable products (approved under 351(k)).

In contrast, a search of the Purple Book for epcoritamab yields the following results:

For this active ingredient (epcoritamab-bysp), there is only one approved product, marketed under the brand name Epkinly.

The Purple Book and Orange Book serve as valuable resources for professionals in the life sciences or biotech industries. However, each of these online resources are limited to approved therapeutics. Therapeutics currently in the clinic are not listed in either online resource.

For a comprehensive guide to the different therapeutics and modalities, Science for Bankers’ Executive Course: Therapeutics & Modalities provides another valuable resource to professionals in life sciences and biotech. This video-based course provides the necessary scientific background needed for professionals working in life sciences or biotech.

FDCA or PHSA

Certain therapeutics are approved under the FDCA by the submission of a New Drug Application (NDA). Other therapeutics are approved under the PHSA by the submission of a Biological License Application (BLA). Whether a therapeutic is approved under an NDA or a BLA depends on the composition of the therapeutic and how it is manufactured. Our previous blog post “2023 Year in Review: approved NDAs” covered the therapeutics approved in 2023 under an NDA, which included small molecules, peptides, and oligonucleotides. Our blog post “2023 Year in Review: approved BLAs” covered the therapeutics approved in 2023 under a BLA which included antibodies, BiTEs, fusion proteins, small proteins, source plasma, cell therapy, vaccines, gene therapy and microbiome.

Thus, FDA approval for therapeutics such as small molecules, peptides and oligonucleotides fall under the FDCA and are approved under an NDA. Other therapeutics such as biological therapeutics (antibodies, BiTEs, fusion proteins, small proteins, source plasma, cell therapy, vaccines, gene therapy and microbiome) are approved under a BLA under the PHSA. Below is a diagram summarizing this information:

FDCA/Hatch-Waxman

The Federal Food, Drug, and Cosmetic Act (FDCA) of 1938 was amended by the “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the Hatch-Waxman Amendments to increase generic drug entry. Under the FDCA, therapeutics are approved under section 505(b)(1) and applicants have to submit full NDAs. The Hatch-Waxman Amendments formalized two abbreviated pathways for therapeutic approvals by adding sections 505(b)(2) and 505(j). Thus, for therapeutics approved under the FDCA/Hatch-Waxman amendments, there are three approval pathways: 505(b)(1), 505(b)(2), and 505(j).

For any therapeutic to be approved under the FDCA via an NDA, the therapeutic must be:

• safe; and
• effective for the proposed use and the benefits outweigh the risks

Additionally, the manufacturing methods of the therapeutic must preserve the therapeutic’s identity, strength, quality, and purity. 

To prove that the therapeutic is safe, effective, and that the benefits outweigh the risks, an applicant submits data to the FDA. This data package includes pre-clinical data, clinical data, and manufacturing data. The regulatory pathway for a therapeutic depends on the type of data available for that therapeutic.

505(b)(1)

Applications for therapeutics approved under 505(b)(1) are considered full-blown applications. Usually, the data submitted in an application under 505(b)(1) is obtained by the applicant by conducing pre-clinical and clinical studies. Meaning, the applicant designs, oversees and pays for the pre-clinical experiments and the clinical trials to get the data needed to prove to the FDA that the therapeutic is safe and effective. Sometimes, the applicant has not performed the experiments themselves, but has obtained a right of reference. With a right reference, the applicant has the right to use data that is owned by another entity. This may occur when an applicant has licensed a therapeutic from another company and as part of the license agreement has obtain the right to the data.

Thus, under 505(b)(1), the applicant obtains all the data, either by owning the data or by having a right of reference, that is needed to support the application to show that the therapeutic is safe and effective.

505(b)(2)

Applications for therapeutics approved under 505(b)(2) are not exactly full-blown applications, but are abbreviated applications. For example, in this situation there may exist data from previous studies where the applicant does not have a right of reference. Or there could be information in the scientific literature that the applicant relies upon to show to the FDA that the therapeutic is safe and effective. Instead of having to repeat these experiments, the applicant is able to rely upon previous work done by others to show to the FDA that the therapeutic is safe and effective.

Thus, under 505(b)(2), the applicant partially relies upon the data produced by others to prove to the FDA that the therapeutic is safe and effective.

505(j)

In certain situations, an applicant seeks approval from the FDA to market and commercialize a therapeutic that has already been approved by the FDA. Therapeutics that are copies of an already approved drug are considered a generic drug or generic therapeutic. The first or original approved therapeutic is often referred to as the innovator or brand therapeutic. It is also called the reference listed drug (RLD) by the FDA. To avoid an applicant having to repeat pre-clinical and clinical studies wth the RLD, the applicant can submit an application under 505(j). This is considered an abbreviated new drug application or ANDA.  An “ANDA” or “505(j) application” copies the safety and efficacy data from an already approved therapeutic, called the reference drug, or RLD.

PHSA and BPCIA

Certain therapeutics that are considered biologicals are approved under a Biological License Application (BLA) under the PHSA. The PHSA was amended through the passage of the Biologics Price Competition and Innovation Act of 2009 (BPCIA). This legislation created the statutory authority for the FDA to approve generic versions of biological therapeutics, called biosimilars and interchangeables. Thus, with the PHSA and BPCIA, there are two pathways to approval for a biological therapeutic: 351(a) and 351(k).  

For a biological therapeutic to be approved under a BLA, it must be shown to be:

• safe
• potent
• pure

As extensively covered in our Therapeutics and Modalities course, biological therapeutics are manufactured from cells. Because biological therapeutics are made from living systems there are tighter controls over their manufacturing processes to ensure that the product is pure, or does not contain impurities. To show that a biological therapeutic is safe, potent, and pure, an applicant submits pre-clinical and clinical data to the FDA. The pathway selected for a biological therapeutic is dependent on the type of data available.

351(a)

Applications for biological therapeutics submitted under 351(a) are full-blown applications. An application submitted under 351(a) contains all the information and data necessary to show that the biological therapeutic is safe, pure and potent. An applicant submits pre-clinical, clinical and manufacturing data to meet these requirements. A biological therapeutic approved under 351(a) is often referred to as an innovator drug, a brand drug, a reference drug or a reference product.

351(k)

In contrast, an application submitted under 351(k) needs to demonstrate that the biological therapeutic is a biosimilar to, or interchangeable with, a reference drug or a reference product (a biological therapeutic already approved under 351(a)). For a biological therapeutic to be a biosimilar to a reference product, it must be:

• highly similar to the reference product notwithstanding minor differences in clinically inactive components; and
• have no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency

For a biological therapeutic to be interchangeable with a reference product means that the biological therapeutic may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. To be considered an interchangeable, it must be:

• a biosimilar to the reference product;
• expected to produce the same clinical result as the reference product in any given patient; and
• for a product that is administered more than once, the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and the reference product is not greater than the risk of using the reference product

Only if the biological therapeutic meets these additional requirements can it be considered an interchangeable.

Thus, there are five approval pathways for therapeutics in the United States. The pathway selected depends on the type of therapeutic (small molecule, peptides, oligonucleotides, antibodies, BiTEs, fusion proteins, small proteins, source plasma, cell therapy, vaccines, gene therapy and microbiome) and the source of the data that will be used to support the NDA or BLA.

Additional resources

Understanding regulatory pathways is important for any professional working in the life science or biotech industry. Additionally, an understanding of the various modalities common in life sciences is also required no matter your particular role. Science for Bankers offers an Executive Course on Therapeutics and Modalities that covers each modality in depth. The course covers the five main classes of therapeutics, and much more. It is made up of about 45 videos; each under 30 minutes. Watch whenever and wherever. Essentially, a masterclass of therapeutics and modalities, or the science in life sciences.

In the United States, certain modalities are approved by the Food and Drug Administration (FDA) under a biologic license application (BLA). Other modalities are approved under a new drug application (NDA). In our blog post 2023 Year in Review: approved NDAs, we reviewed the types of modalities approved under NDAs in 2023. Here, we review the modalities approved under BLAs in 2023, whether approved by CDER (Center for Drug Evaluation and Research) or CBER (Center for Biologics and Evaluation and Research).

It is important to understand that there is confusion when referencing a therapeutic as a “CDER drug” or a “CBER drug.” Some in the life science industry will try to classify a modality or therapeutic based on whether it is reviewed by CDER or CBER. But classification based on the center at the FDA reviewing the modality is not accurate. Six centers at the FDA are responsible for approving and regulating consumer products such as medical devices, cosmetics, dietary supplements, electronic radiation emitting products, tobacco products, and therapeutics (such as drugs and other therapies). Two centers at the FDA are responsible for approving therapeutics or modalities, under either a BLA or an NDA: CDER and CBER.

In regards to BLAs, some BLAs are approved by CDER and some BLAs are approved by CBER. So, both CDER and CBER review and approved BLAs. CDER approves the majority of NDAs, but CBER could also approve an NDA. So, both CDER and CBER can review and approve BLAs and NDAs. Thus, classifying a therapeutic as a “CDER drug” does not accurately describe the therapeutic, because it could be approved under an NDA or a BLA. Further, various modalities are approved under an NDA and various modalities are approved under a BLA. Thus, referring to a therapeutic as a “CDER drug” tells you nothing about the therapeutic.

Both CDER and CBER review and approved BLAs for therapeutics and modalities. CDER approves BLAs for protein-based therapeutics, such as antibodies, bispecifics, fusion proteins, and therapeutic proteins. CBER approves BLAs for blood products (such as source plasma), vaccines, tissues, and cell-based therapies.

In 2023, 46 BLAs were approved by the FDA. CDER approved 22 BLAs and CBER approved 24 BLAs.

It is important to note that not all approved BLAs are for products that contain novel or new active ingredients. Some BLA approvals are for products that contain active ingredients that were previously approved. For example, compare Epkinly (BLA 761324) and Eylea HD (BLA 761355). Both BLAs were approved in 2023. However, the active ingredient in Epkinly had never been approved before. The active ingredient in Eylea HD, aflibercept, was previously approved in 2011.

CDER approved BLAs in 2023

In 2023 CDER approved 22 BLAs. Of these 22 BLAs, 11 were antibody products, 4 were BiTE products, 3 were fusion protein products, and 4 were small protein products.

CDER is responsible for approving protein-based therapeutics such as antibodies, fusion proteins, and small proteins under a BLA. CDER also approves peptides, small molecules, and some oligonucleotide-based drugs, but they are typically approved under an NDA, not a BLA.

CDER approved antibody products in 2023

CDER approved 11 antibody products in 2023. Some products contained antibodies that were new and novel, while others had been previously approved. The 11 approved antibody products (Leqembi, Zynyz, Rystiggo, Beyfortus, Veopoz, Entyvio, Cosentyx, Bimzelx, Zymfentra, Omvoh, and Loqtorzi) have different indications, mechanisms of actions, dose, dosage, etc. For example, Leqembi (generic name lecanemab-irmb) is a product containing a novel antibody that is approved for the treatment of Alzheimer’s disease. Its mechanism of action is that it binds to aggregated soluble and insoluble forms of amyloid beta to reduce amyloid beta plaques. Zymfentra (generic name infliximab-dyyb) was approved in 2023 for the treatment of ulcerative colitis and Crohn’s disease. The active ingredient in Zymfentra was previously approved in 1998.

CDER approved BiTE products in 2023

CDER also approved 4 BiTEs or bispecific T cell engagers products in 2023. The 4 BiTE products (Epkinly, Columvi, Talvey, and Elrexfio) differ in their targets, approved indications, dose, dosages, etc. For example, both Epkinly and Columvi target CD20 and CD3 and both are approved for relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Note that Columvi is also approved for large B-cell lymphoma (LBCL). Talvey targets GPRC5D (G protein-coupled receptor class C group 5 member D) and CD3 and is approved for relapsed or refractory multiple myeloma. Elrexfio targets BMCA (B-cell maturation antigen) and CD3, and is approved for relapsed or refractory multiple myeloma.

CDER approved fusion protein products in 2023

CDER approved 3 products containing fusion proteins in 2023 by CDER: Ngenla, Eylea HD, and Ryzneuta. Ngenla was approved for use in pediatric patients who have growth failure. Eylea HD was approved for neovascular (wet) age-related macular degeneration, diabetic macular edema, and diabetic retinopathy. Ryzneuta was approved to decrease the incidence of infection, as manifested by febrile neutropenia.

CDER approved small protein products in 2023

CDER approved 4 products containing small proteins in 2023. Three of these products were for enzyme replacement therapy: Lamzede, Elfabrio, and Pombiliti. Lamzede was approved for the treatment of non-central nervous system manifestations of alpha-mannosidosis. Elfabrio was approved for Fabry disease and Pombiliti was approved for Pompe disease. Vyvgart hytrulo, which is a combination of two small proteins, was approved for treatment of generalized myasthenia gravis (gMG).

CBER approved BLAs in 2023

CBER is responsible for approving BLAs for blood products (such as source plasma), vaccines, tissues, and cell-based therapies. In 2023, CBER approved 24 BLAs. Of these 24 BLAs, 6 were for source plasma, 4 were for cell therapy products, 6 were for vaccines, 3 were for gene therapy products, 2 were for protein-based products, 2 were for assays, and 1 was for a microbiome therapy.

CBER approved 6 source plasma products in 2023, including Alygo. Source plasma has many medical and therapeutic uses, including for use in patients with primary immunodeficiency (PI).  

CBER approved 4 cell therapy products in 2023:  Lantidra, Omisirge, Casgevy, and Lyfgenia.

CBER approved 6 vaccines in 2023: Ixchiq, Penbraya, Abrysvo, Balfaxar, Cyfendus, Arexvy,

CBER approved 3 gene therapy products in 2023: Roctavian, Elevidys, Vyjuvek,

CBER approved 2 protein-based products in 2023: Adzynma and AltuvIIIO

CBER approved 2 assays in 2023: Elecsys HTLV and Elecys HIV Duo

CBER approved 1 microbiome therapy product in 2023: Vowst

Understanding whether a therapeutic will be approved under an NDA or a BLA, and whether the therapeutic would be approved by CDER or CBER requires a scientific investigation into the composition of matter, mechanism of action, and manufacturing process of that particular therapeutic. Science for Bankers’ Executive Course: Therapeutics and Modalities covers the scientific background of the common modalities (ASOs, siRNAs, small molecules, bispecifics, fusion proteins, vaccines, etc.). The Executive Course: Therapeutics and Modalities is recommended for any professional working in life sciences or biotech.

About Science for Bankers’ Executive Course: Therapeutics and Modalities

• Over 13 hours of content
• About 45 videos
• Each video is under 30 minutes
• Videos include slides, illustrations, animations, and captions
• A study guide is provided
• Covers the 5 main categories of therapeutics: protein-based therapeutics (or large molecules), small molecules, gene therapy, cell therapy, and RNA therapy.
• Covers additional topics such as PK, PD, pre-clinical experiments, clinical trials, recombinant DNA technology, etc.

Before a therapeutic or drug can be marketed or commercialized in the U.S., the therapeutic must first be approved by the Food and Drug Administration (FDA) under either a new drug application (NDA) or biologic license agreement (BLA). As discussed in our blog post Approval and Regulation of Therapeutics and Modalities at the FDA, NDAs and some BLAs are approved by the Center for Drug Evaluation and Research (CDER) at the FDA. The Center for Biologics and Evaluation and Research (CBER) also approves BLAs. So CDER and CBER both approve BLAs. But, CDER approves nearly all of NDAs at the FDA.

CDER approved approximately 100 NDAs and 21 BLAs in 2023. Note that CDER also approves abbreviated new drug applications or ANDAs, and our blog post Therapeutic FDA approvals: the rise of the ANDA discusses the need for an abbreviated new drug application for some therapeutics. Thus, the 100 NDA approvals in 2023 are separate from the ANDA approvals in 2023.

A common misconception is that NDAs are all small molecules. Other modalities are also approved under NDAs such as peptides and oligonucleotides. Of the approximately 100 NDAs approved in 2023 by CDER, at least 88 were small molecules, 7 were peptides, and 4 were oligonucleotides.

Small molecules

Small molecules are manufactured by chemical synthesis and are usually under 1 kilodalton. Small molecules have simple, well-defined compositions, and they are made by chemical synthesis. Understanding the difference between small molecules and larger, protein-based therapeutics like antibodies and fusion proteins is fundamental in the life sciences or biotech industry. Science for Bankers offers an executive course for mastering these concepts and more.

There is variety among small molecules that are approved under an NDA. They can vary in their use and in their mechanisms of actions. For example, Jaypirca (generic name pirtobrutinib) was approved in 2023 and is a typical small molecule drug. It is a kinase inhibitor approved for chronic lymphocytic leukemia/small lymphatic lymphoma. It is formulated into tablets and administered to patients orally. In contrast, Posluma (generic name flotufolastat F-18 gallium) is a small molecule approved under an NDA, but it is not a therapeutic drug. It is a radioactive diagnostic agent. The small molecule is administered intravenously and includes a chelating complex to hold gallium. This small molecule binds to prostrate-specific membrane antigen (PSMA) which is expressed on cells, including prostate cancer cells. Once administered to a patient, positron emission tomography (PET) is used to image PSMA lesions in men with prostate cancer.

Another example is Airsupra, which is a drug product that is actually a combination of two small molecule drugs: albuterol sulfate and budesonide.  Albuterol sulfate is a short-acting beta-adrenergic agonist and budesonide is a corticosteroid. This combination drug product is administered via inhalation and is used as-needed to treat or prevent bronchoconstriction or asthma.

Each of these examples is a small molecule that is administered to patients. However, one is a therapeutic drug, one is a diagnostic agent and one is a combination of previously approved drugs. Thus, approved small molecules can vary in their use and compositions.

Peptides

CDER also approves peptides under NDAs and in 2023 seven peptides were approved. Examples include Rezzayo (generic name rezafungin acetate) which is a cyclic peptide that is approved as an antifungal, Aphexda (generic name motixafortide acetate) which is a cyclic peptide that is approved as a hematopoietic stem cell mobilizer, Zepbound (generic name tirzepatide) which is a peptide approved for the treatment of chronic weight management, and Zibrysq (generic name zilucoplan sodium) which is a macrocyclic peptide approved for the treatment of generalized myasthenia gravis (gMG).

Although peptides are composed of amino acids, like antibodies, they are approved under an NDA and not a BLA.

Oligonucleotides

Oligonucleotides are also approved under an NDA and in 2023 CDER approved 4 oligonucleotide based therapeutics. Oligonucleotide therapeutics vary vastly based on their compositions and mechanisms of action. For example, Qalsody (generic name Tofersen) and Wainau (generic name eplontersen sodium) are both antisense oligonucleotides, or ASOs. Rivfloza (generic name nedosiran sodium) is also an oligonucleotide approved in 2023, but Rivfloza is a small interfering RNA (siRNA) which has a different mechanism of action from an ASO. Izervay (generic name avacincaptad pegol sodium) was also approved in 2023 and although it is an oligonucleotide, it has a different mechanism of action from ASOs and siRNAs.  

Thus, the different types of oligonucleotides (ASOs, siRNAs, and aptamers) have different mechanisms of actions and compositions. Understanding the differences between small molecules, peptides, and oligonucleotides is fundamental when working in the life science, biotech, or pharmaceutical industries.

Science for Bankers’ Executive Course: Therapeutics and Modalities is a course that covers the different modalities (small molecules, large molecules, protein-based therapeutics, oligonucleotides, etc.) and how they are leveraged in therapeutic strategies. The course is designed for professionals with little to no science background, and is offered asynchronously. Watch whenever, wherever. Learn the “science” of life sciences.

FDCA and PHSA

Under the FDCA, a therapeutic is approved under an NDA, or new drug application. Under the PHSA, a therapeutic is approved under a BLA. Generally, the FDCA (via an NDA) regulates non-biologic drugs (small molecules, oligonucleotides, etc.) and the PHSA (via a BLA) regulates biologic drugs (antibodies, fusion proteins, etc.). However, because the term “drug” is defined so broadly in the FDCA, some biologic drugs have been approved under an NDA.

Hatch-Waxman Amendments

In our blog post Therapeutic approvals: the rise of the ANDA we reviewed how in the 1960s the FDA created two approval pathways for generics, the ANDA and the paper NDA. Then, the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Amendments, codified these abbreviated approval pathways into statute. After the Hatch-Waxman Amendments, drugs could be approved under an NDA (via 505(b)(1) of the FDCA), a hybrid NDA (via 505(b)(2) of the FDCA), or an ANDA (via section 505(j) of the FDCA).

But biologic drugs were approved under the PHSA and not the Federal Food, Drug, and Cosmetic Act (FDCA). How could a generic biologic drug enter the market?

Harmonizing NDA and BLA approvals

Beginning in the 1990s, efforts were made to harmonize how both classes of drugs, biologics and non-biologics, were approved and regulated by the FDA. For example, interpretation of section 351 of the PHSA required biologic drugs to have an establishment license application (ELA) and an approved product license application (PLA). In 1997 the dual licensure requirement was eliminated and the government created a single biologics license application (BLA) requirement.

In our blog post Approval and Regulation of Therapeutics and Modalities at the FDA, we reviewed the various centers at the FDA. Two centers, CDER (Center for Drug Evaluation and Research) and CBER (Center for Biologics and Evaluation and Research Center for Biologics and Evaluation and Research) are responsible for regulating and approving biologic and non-biologic drugs. In the 1990s, BLAs were reviewed by CBER and NDAs were usually reviewed by CDER. In 2003, the FDA harmonized how NDAs and BLAs were reviewed by consolidating the review of BLAs for therapeutic proteins within the same center that approved NDAs: CDER. Since 2003, CDER has reviewed not only NDAs, but also BLAs for antibodies, fusion proteins, peptides, small proteins, etc.

Pathway for generic BLA

In the 1990s there was debate about whether the FDA could approve a generic of a therapeutic protein under either the FDCA or PHSA. Some legislators argued that the FDA already had authority – via an ANDA or a 505(b)(2) pathway. However, there was controversy. Mainly due to the difference between how NDAs and BLAs are reviewed. This is because at the core of the BLA is the scrutiny on the manufacturing processes, which is not as heavily scrutinized in an NDA. Some argued that the FDA should create a “paper BLA” like the “paper NDA.” Others argued that the FDA had no authority under either statute to create an abbreviated BLA and the FDA would need to wait for Congress to pass legislation. 

Biologics Price Competition and Innovation Act of 2009

Years of debate, hearings, and legislative work culminated in the passing of the Biologics Price Competition and Innovation Act of 2009 (BPCIA). This legislation created the statutory authority for the FDA to approve generic versions of therapeutic proteins, called biosimilars.

There were several key scientific issues that had to be resolved regarding generics of biologic drugs. For example, could another manufacturer duplicate a biologic drug by copying and using the same manufacturing process? Could another manufacturer duplicate a biologic drug by using a different manufacturing process? Are there sufficient analytical techniques to measure protein structure and activity so that the FDA could conclude that a biosimilar is a copy of a therapeutic protein, or a reference product? In regards to safety and efficacy, is it possible to determine that two proteins (i.e., a biosimilar and a reference product) are interchangeable? Ultimately, these scientific questions were resolved and the BPCIA was passed. Under this legislation, an approval pathway for generic biologic drugs was codified in statute. There are many aspects to this law related to patents and regulatory exclusivities, but ultimately, this law gave the FDA the authority to approve biosimilars or generics to biologic drugs.

Five classes of therapeutics and modalities

There are five main classes of therapeutics or modalities: small molecules, protein-based therapeutics, gene therapy, cell therapy, and RNA therapy. Each therapeutic needs to be approved by the FDA, under either an NDA or BLA, before the therapeutic can be marketed and commercialized in the U.S. Because it is so critical for any professional working in life sciences, biotechnology, or pharmaceuticals to understand the five main classes of therapeutics, Science for Bankers created an Executive Course on Therapeutics and Modalities. The course is designed for professional with little to no science background. In approximately 45 videos, each under 30 minutes, a professional can learn the “science” in life sciences.

The Federal Food, Drug, and Cosmetic Act (FDCA) and the Pure Food and Drug Act

The Federal Food, Drug, and Cosmetic Act (FDCA) of 1938 was enacted to strengthen the Pure Food and Drug Act of 1906 after approximately 100 patients in the U.S., mostly children, died due to a toxic formulation of sulfanilamide. Under the FDCA of 1938, drug manufacturers had to submit evidence to the FDA showing that a new drug (not an existing drug) was safe before it could be sold in the U.S. This requirement in section 505 of the FDCA created what we refer to today as the NDA, or new drug application. After enactment of the FDCA in 1938 many manufacturers concluded that their drugs were not new drugs or they determined that their drugs were generally recognized as safe and distributed their drugs without NDAs. Thus, after the enactment of the FDCA in 1938 many drugs were sold in the U.S. without NDAs.

Amendments to the FDCA   

Since the FDCA was enacted in 1938 it has been amended several times. In 1962 the FDCA was amended to require, among other things, that new drugs must be shown to be not only safe, but also effective. Also, each NDA submitted to the FDA had to receive approval. This replaced the old system where an NDA would become effective if the government didn’t object within sixty days. Under the 1962 amendments a drug marketer had to wait to receive approval for the NDA before the drug could be sold.

In response to the 1962 Amendment, the FDA created a program called DESI (Drug Efficacy Study Implementation) to review data and ensure that drugs submitted under an NDA were reviewed for safety and efficacy.

The rise of the ANDA

In the late 1960s, the FDA recognized that certain drugs did not need a full NDA. For example, a drug that was a generic version of a drug previously reviewed and approved under the DESI program. For these types of drugs, the FDA created an abbreviated NDA, or ANDA in 1969. The logic was that if a drug was deemed to be safe and effective under the DESI program, then it would also be safe and effective if manufactured by another as long as it was properly manufactured and used under the same conditions. This type of application did not need to contain the safety and effectiveness information; it just needed to show bioavailability and bioequivalence data. Thus, the ANDA was born. It is important to note that there was no statutory authority for this ANDA approval process.

The “paper” NDA

The ANDA was created by the FDA to reduce the burden on certain applicants where the drug was already deemed safe and effective under the DESI program. However, if a previous drug had only been shown to be safe and not effective, or was not previously approved by the FDA, an ANDA was not available. Generic manufacturers for these types of drugs had to use the NDA pathway. To reduce this burden, the FDA created the “paper NDA” which allowed applicants to make generic drugs if there was sufficient evidence of safety and effectiveness in the public domain. For example, by submitted data that had been published in literature or publications.

Thus, by the late 1960s, the FDA had created two pathways for generics to enter the market in the U.S.: the ANDA and the paper NDA.

Drug Price Competition and Patent Term Restoration Act of 1984

Even though the FDA had created two pathways for getting a generic drug on the market (the ANDA and the paper NDA), in the 1980s very few generics were entering the market. To encourage generic drug development the government passed the “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the Hatch-Waxman Amendments. The Hatch-Waxman Amendments were negotiated and designed to increase generic drug entry and thereby lower drug costs in the U.S.

The Hatch-Waxman Amendments, among other things, formalized the ANDA and paper NDA pathways. Previously, these were pathways created by the FDA and were not codified in statute. Section 505 of the FDCA in 1938 had created the NDA, or the new drug application. The Hatch-Waxman Amendments added section 505(b)(2) (previously known as the “paper NDA”) and section 505(j) (known as the ANDA).

In life sciences, biotech, and pharmaceuticals, it is common to refer to a “505(b)(1) drug,” which just means a drug that will require a full NDA or new drug application. Previous safety and efficacy data is not available, so a full NDA is required by the FDA. A “505(b)(2) drug,” is a drug where safety and efficacy data is available, but the applicant needs to reference data in papers, journal articles, or previous clinical studies. An “ANDA” or “505(j) drug” copies the safety and efficacy data from an already approved drug.

In the end, whether a drug is approved under 505(b)(1), 505(b)(2), or 505(j) in compliance with the FDCA, the drug will have been shown to be safe and effective. 

Typically, small molecule drugs are approved under NDAs, but other modalities are as well. It is essential for professionals in life sciences, biotechnology, and pharmaceutics to understand the five main classes of therapeutics and how each is approved under either an NDA or BLA. Science for Bankers offers an executive course that is online, available 24/7, and organized to build your knowledge of the “science in life sciences.” The course is about 45 videos, each under 30 minutes. There is even a study guide that accompanies the course. Science for Banker’s Executive Course on Therapeutics and Modalities is a masterclass in therapeutics and modalities.

NDAs, BLAs, CDER, and CBER

Therapeutics in the U.S. are approved under either an NDA (New Drug Application) or a BLA (Biologics License Application). See our blog post Approval and Regulation of Therapeutics and Modalities at the FDA, which explains the different centers at the FDA. There are two centers at the FDA responsible for reviewing and approving NDAs and BLAs: the Center for Biologics and Evaluation and Research (CBER) or the Center for Drug Evaluation and Research (CDER). Whether a therapeutic is approved under an NDA or BLA, or by CDER or CBER, depends on the composition of the therapeutic.

The Pure Food and Drug Act of 1906

Historically, regulation of drugs and food in the U.S. began with the Pure Food and Drug Act of 1906. Although meant to safeguard public health, this law did not require government review or approval for new drugs. So, drugs could be sold and marketed without first proving that the drug was safe or effective in humans. Shockingly, under the Pure Food and Drug Act selling toxic drugs was not illegal in the U.S.

The Biologics Act of 1902

At this same time vaccines, serums, and other biologicals were also not regulated by the government. Vaccines and other biological products had been around since the 1700s and the manufacturing methods created a danger of contamination. For example, the diphtheria anti-toxin was produced in horses by injecting them with a small amount of diphtheria to generate the anti-toxins. The serum from these immunized horses was extracted and injected into children. However, the extracted serum was contaminated with tetanus and resulted in the death of children. This caused the government to pass the Biologics Act of 1902. The Biologics Act required biologics to be manufactured in establishments holding a license issued by the federal government, where the government could inspect these facilities. The reasoning behind the requirement of a license was that regulation of the manufacturing process would ensure the safety of the resulting biological product.

Thus, drugs and biological products were treated differently under these two statutes.

The Federal Food, Drug, and Cosmetic Act (FDCA) of 1938 replaces the Pure Food and Drug Act

By the 1930s there was dissatisfaction with the strength of the Pure Food and Drug Act in ensuring that drugs sold in the U.S. were safe and effective. However, it was the sulfanilamide tragedy that caused the government to act quickly and pass new legislation. Sulfanilamide was a drug used to treat certain infections and it was sold and distributed in tablet and powder form. Demand rose for a liquid formulation of the drug and the company selling sulfanilamide tablets began experimenting with a new liquid formulation.  Chemists discovered that sulfanilamide would dissolve in diethylene glycol and started manufacturing and distributing this new liquid formulation in 1937. Under the Pure Food and Drug Act of 1906, safety or toxicity studies were not required before a drug was sold and distributed to U.S. patients. Although diethylene glycol dissolved sulfanilamide, it was a deadly poison. Doctors reported patient deaths and FDA inspectors and chemists set out to recover the batches of the formulation distributed to the public. In total, only approximately 234 gallons of the liquid formulation was recovered from the 240 gallons distributed. The remainder was consumed and caused the deaths of patients, many of them children.

The Sulfanilamide tragedy hastened the enactment of the 1938 Federal Food, Drug, and Cosmetic Act (FDCA), which created a new system to regulate and approve drugs to be sold in the U.S. The FDCA had to address how to deal with the drugs already being sold in the U.S. Under section 505 of the FDCA, manufacturers had to submit to the FDA evidence that a “new drug” was safe before it could be sold in the U.S., essentially creating the new drug application, or NDA.  A “new drug” was defined as a drug that was not GRAS: generally recognized as safe. Once submitted to the FDA, an NDA would become effective if the government didn’t reject the application within sixty days. There was no requirement to wait for an approval. 

Many marketers at this time determined that their drugs were not new, or they were GRAS, or generally recognized as safe. As a result, many drugs were sold in the U.S. without an NDA.

The Public Health Service Act (PHSA) of 1944 incorporates the Biologics Act of 1902

Six years after enacting the FDCA, the U.S. passed the Public Health Service Act (PHSA) in 1944.  Within this law, the Biologics Act of 1902 was revised and recodified in section 351 of the PHSA. Section 351 of the PHSA provided that an establishment license could only be issued upon a showing that the establishment and the biological product met standards to ensure the safety, purity, and potency of the product. This new language was interpreted to mean that an establishment license application (ELA) and an approved product license application (PLA) was required for a biological product. The dual licensure requirement was eliminated in 1997 and the government created a single biologics license application (BLA) requirement.

Overlap between the FDCA and the PHSA

Overlap and conflict between the FDCA and the PHSA has been an issue since enactment of the Food and Drugs Act in 1906. This is because the definition of a “drug” under the FDCA is very broad and includes biological products that needed a license under the Biologics Act of 1902. However, the FDA has historically stated that a new drug would not be subject to the FDCA if it was licensed under the Biologics Act of 1902. When the PHSA was enacted, it included a provision stating that nothing in the statue should be construed to modify or supersede the FDCA of 1938. Thus, in the U.S., two different statutes and two different applications regulate the approval of therapeutics: the NDA and the BLA.

This overlap between the FDCA and PHSA has manifested in biological products being approved and regulated under NDAs. Shortly after enactment of the FDCA in 1938, insulin products were approved under NDAs. Human growth hormones derived from the pituitary gland of cadavers was approved in the 1970s under an NDA. Various other hormones or small protein therapeutics were approved under NDAs and not BLAs.

Since the early 1900s the U.S. federal government has treated drugs that are manufactured as tablets and powders (or by chemical synthesis) different from products that are manufactured from animals or cells. This dichotomy still exists today with the NDA and the BLA. The NDA, or New Drug Application came out of FDCA enacted in 1938 and the BLA, or Biologics License Application came out of the PHSA enacted in 1944 (which revised and incorporated the Biologics Act of 1902). 

To determine whether a certain modality would be approved under an NDA or BLA, an understanding of the composition of the modality and how the modality is manufactured is required. Science for Bankers offers an Executive Course on Therapeutics and Modalities that covers how each modality is manufactured, along with its composition of matter and its mechanism of action. The course covers the five main classes of therapeutics, and much more. The course is made up of about 45 videos; all under 30 minutes. Watch whenever and wherever. Essentially, a masterclass of therapeutics and modalities, or the science in life sciences.

Therapeutics and modalities are drugs, such as small molecules, antibodies, bispecifics, or oligonucleotides. They are administered to patients to treat diseases, disorders, or certain symptoms of diseases and disorders. The different types of therapeutics and modalities usually fall within one of five classes: small molecules, large molecules, gene therapy, RNA therapy, and cell therapy. Each therapeutic needs to be approved by the FDA before it can be administered to patients in the U.S.

The FDA is the regulatory agency in the U.S. that protects public health by ensuring the safety, efficacy and security of human and veterinary drugs, vaccines, and biological products. The FDA also regulates medical devices, cosmetics, dietary supplements, electronic radiation emitting products, and tobacco products. There are various offices and centers at the FDA, but six centers are responsible for approving and regulating consumer products. The six centers at the FDA responsible for regulating and approving consumer products are:

Center for Biologics Evaluation and Research

The Center for Biologics and Evaluation and Research (CBER) regulates and approves certain biological and related products. Biological products such as blood products, vaccines, allergenics, tissues, cell-based therapies, and gene therapies.

Center for Devices and Radiological Health

The Center for Devices and Radiological Health (CDRH) regulates medical devices and radiation-emitting products. Examples include surgical lasers, blood warmers, catheters, and stents.

Center for Drug Evaluation and Research

The Center for Drug Evaluation and Research (CDER) regulates and approves over-the-counter and prescription drugs. Examples include small molecule drugs, antibodies, shampoos, sunscreens, and certain oligonucleotide-based therapeutics.

Center for Food Safety and Applied Nutrition

The Center for Food Safety and Applied Nutrition (CFSAN) regulates food, cosmetics, and dietary supplement products.   

Center for Tobacco Products

The Center for Tobacco Products (CTP) regulates tobacco-containing products.

Center for Veterinary Medicine

The Center for Veterinary Medicine (CVM) regulates drugs, food, and devices for use by animals.

Which centers at the FDA approve therapeutics?

Of these six centers at the FDA, two are responsible for ensuring the safety, efficacy, and security of human drugs, vaccines, and biological products: CDER and CBER. CDER and CBER are responsible for approving and regulating all the therapeutics that fall within the five classes of therapeutics and modalities. So, if a therapeutic is administered to a patient in the U.S., it must first be regulated or approved by either CDER or CBER.

Therapeutics or modalities may be approved at the FDA when an applicant submits a New Drug Application (NDA) or a Biologics License Application (BLA). Each therapeutic, whether a small molecule, large molecule, gene therapy, RNA therapy, or cell therapy, is approved under either an NDA or BLA. A drug might be referred to as an NDA drug or a BLA drug, which is meant to specify which type of application it may be approved under.

Which center at the FDA approves NDAs and BLAs?

Each NDA or BLA for a therapeutic is approved by either CDER and CBER. CDER and CBER can approve both types of applications. So, if a drug is referred to as a CDER drug, it just means that it is being reviewed and approved by CDER; it does not indicate whether it is an NDA or BLA. This is because CDER approves both types of applications. The majority of NDAs are approved by CDER, but CBER can also approve NDAs.

What type of application is a therapeutic approved under?

Determining whether a therapeutic should be approved under an NDA or BLA requires an understanding as to the drug’s composition and manufacturing process. Usually, professionals in life sciences, biotechnology, and pharmaceuticals understand the differences between each type of therapeutic. For example, professionals understand the difference between an antisense oligonucleotide and an siRNA molecule. There is an executive-level course on therapeutics and modalities that was created and developed for professionals in the life sciences, biotech, and pharmaceutical industries. It is a course that covers the different classes of therapeutics, designed for professionals with a limited background in science or no science background at all.

Understanding whether a drug is approved under an NDA or BLA has certain implications for the overall value or investment potential of the therapeutic. Professionals in the life sciences, biotech, and pharmaceutical industries should know how to determine if a drug would be approved under an NDA or BLA. Also, any professional in these industries should also know how to determine whether a drug is approved by CDER or CBER.

What is the difference between CDER and CBER?

As stated above, CBER and CDER approved both NDAs and BLAs. So it is not the type of application that determines whether a drug is regulated and approved by CDER or CBER. Instead, it has to do with the actual therapeutic – its composition and how it is manufactured or produced for use in humans.

CDER is responsible for approving a wide variety of therapeutics. This would include therapeutics such as small molecules, antibodies, peptides, and oligonucleotide-based therapeutics. For example, Epkinly (a bispecific antibody) was approved by CDER in 2023. Most small molecules are regulated and approved by CDER.

CBER is responsible for approving products within the gene therapy and cell therapy space. For example, Casgevy (a cell and gene-based therapeutic) was approved by CBER in 2023. If the therapeutic is based on cell therapy or gene therapy, it would be regulated and approved by CBER. 

Understanding the regulatory pathway of a therapeutic, whether it is approved under an NDA or BLA, and whether it would be approved by CDER or CBER, starts with a comprehensive understanding of the various therapeutics common in life sciences, biotech, and pharma. A professional in life sciences, biotech, or pharma looking to get up to speed on therapeutics should enroll in the Executive Course: Therapeutics and Modalities. This course provides comprehensive education on five classes of therapeutics: small molecules, large molecules, gene therapy, RNA therapy, and cell-based therapeutics.

New products and services from scientific problem solving can emerge in just about every industry. The life science industry is rich in scientific advancements that result in new products and services, which are popular investments. However, the life science industry overlaps and blends with biotech and pharmaceuticals.

The life science industry

Companies within the life science industry dedicate their efforts to improving the lives of organisms. This is a really broad category because it includes not just humans but animals as well. A company developing a drug to treat cancer would be considered a life science company. A company using AI to improve speech therapy for people with disabilities is also a life science company. A company dedicated to producing meatless food products from mushrooms would also be considered a life science company. A company focusing on improving technologies for diagnosing animal health problems is also a life science company. Thus, the life science industry includes a diverse collection of companies.

The biotechnology industry

Biotechnology focuses on leveraging an understanding of the natural sciences to create solutions for improving human health. This can include understanding and leveraging concepts in genetics, microbiology, animal cell cultures, molecular biology, embryology, and cell biology. A company developing genetically modified mice for use in drug discovery would be an example of a biotech company. A company developing methodologies for treating infertility could be considered a biotech company. There are a lot of similarities between life science and biotech companies. In fact, biotech and life sciences are terms that can be used interchangeably, and biotech can be viewed as an industry within life sciences.

The pharmaceutical industry

Traditionally, pharmaceutical companies were companies that developed small molecule drugs for the treatment of diseases and disorders. Over the last few decades, therapeutic drugs have expanded beyond small molecules. Antibodies, fusion proteins, and oligonucleotides have emerged as therapeutics for treating diseases and disorders. Many pharmaceutical companies have more than small molecules in their pipelines and as marketed products. Pharmaceutical companies have also expanded by developing biotech tools to aid in drug discovery, blurring the distinction between pharmaceutical companies, biotech companies, and life science companies.   

Although life sciences, biotechnology, and pharmaceuticals have different names, there is a lot of overlap and blurred boundaries between these industries. As science advances and progresses, these industries have blurred. Thus, the terms life sciences, biotech, and pharmaceuticals can be used interchangeably.

Within these industries, life sciences, biotechnology, and pharmaceuticals, there are numerous niches. Medical devices are a niche within life sciences, biotech, and pharmaceuticals. Diagnostic assays are also a niche. Therapeutics and modalities are also a niche. At the root of each of these niches are very specific sciences. Understanding any niche and how investment in a niche can possibly yield income or profit requires an investigation and education into the root sciences.

Therapeutics and modalities are a niche with high investment interest. Companies developing and commercializing a therapeutic could be viewed as a life science company, a biotech company, a pharmaceutical company, or all three. If the product being developed or commercialized is a therapeutic, then the company falls within the blurred boundaries of these industries. These therapeutic companies are attractive to investors, investment banks, and other companies to possibly acquire. For example, AbbVie’s Humira antibody product made $22 billion in 2022. A small therapeutics company, RayzeBio, which develops radiopharmaceuticals, was acquired by Bristol Myers Squibb for $4.1 billion in December 2023.

At the root of the therapeutics and modalities niche lies a complicated science based on biology, chemistry, cell biology, genetics, biochemistry, anatomy, etc. It would take several semesters of college-level courses to understand the necessary science. Even then, a complete understanding would be lacking, as college-level courses rarely cover cutting-edge science. Luckily, there is a course designed for investors, lawyers, consultants, executives, and other professionals working in the life sciences, biotech, or pharmaceutical industries. The Executive Course on Therapeutics and Modalities provides an understanding of the science found at the root of this niche, covering the basics of large molecules, small molecules, gene therapy, cell therapy, and RNA therapy. The course can be leveraged by the solo learner, or it could be used to train teams at investment firms, venture capital groups, law firms, etc.

Broadly, a therapeutic or a modality is something that is administered to a patient to treat a disease or disorder, or the symptoms of a disease or disorder. In short, it is something that is administered to a patient to treat the patient.

For example, for a patient suffering from a heart-related condition, treatments may include surgery, a change in diet (reduction in salt and alcohol), a change in behavior (exercising and ceasing smoking), or taking a medication, such as a statin. There are many treatment options. But a therapeutic or modality is something that is administered to the patient to treat the patient. Administered means something swallowed, inhaled, injected, applied topically, etc. Surgery is not administered to a patient. While a medication, like a statin, is administered to the patient. 

That something that is administered to the patient to treat a disease or disorder can be a wide variety of things. It can be a vaccine, pill, injection, solution, infusion, powder, etc. The therapeutic is not the pill, capsule, gel, powder, or solution. The therapeutic is in that pill, injection, solution, powder, etc. It is the specific thing, like a molecule, that causes the biological effect that treats the disease, disorder, or symptom. It can be a small molecule, an antibody, a collection of cells, or an oligonucleotide.  

And that something, that therapeutic or modality, generally falls within one of five main classes of therapeutics: small molecules, large molecules, gene therapy, cell therapy, and RNA therapy.

Large molecules

Large molecules are also called big molecules or protein-based therapeutics. They are made up of proteins, or specifically, amino acids. The types of therapeutics in this class include antibodies, bispecifics, peptides, fusion proteins, small proteins, etc.

Small molecules

Large molecules and small molecules are distinguished based on their size. But there are other key differences between small molecules and large molecules. Such as how they are manufactured, how they are administered, and their mechanisms of action. Small molecules can include inhibitors, agonists, degraders, and molecular glues.

Gene therapy

The goal of gene therapy is to alter the expression of a gene. Either to cause or increase expression of a gene or to prevent or reduce expression of a gene. This can be accomplished by gene addition or gene editing. An important aspect of gene therapy is the delivery of the genetic material to cells, which can be accomplished by viral and non-viral delivery vehicles.

Cell therapy

Cell therapy involves administering cells (stem cells and non-stem cells) to a patient. The cells may, or may not, be genetically altered. Cell therapy includes the administration of stem cells, iPS cells, CAR T cells, NK cells, and NK CAR T cells.

RNA therapy

RNA therapy involves strategies to either introduce RNA into cells to be translated or to prevent the translation of RNA. Generally, RNA therapy includes RNA addition or RNA silencing (also called RNA interference).  RNA therapy includes therapeutics such as ASOs, mRNA, siRNA, and miRNAs.

These five main classes of therapeutics differ vastly in their structures or compositions, mechanisms of action, routes of administration, and targets in the body. Any professional in life sciences, biotechnology, or pharmaceuticals needs to understand these five main classes of therapeutics. It is essential to not only understand how they differ but also how the technologies in each of these five main classes can be mixed or combined to form new classes of therapeutics. For example, CAR T cell therapy leverages antibody technology and T cells. ADCs leverage small molecules and large molecules.

It should be noted that these classes of therapeutics have overlapping technologies. For example, oligonucleotides are used in both gene therapy and RNA therapy. However, they have different compositions based on whether they are leveraged in gene or RNA therapy. There is also overlap when it comes to antibody technology. Antibody technology is leveraged in large molecule therapeutics and in cell therapies. In essence, it is important to not only understand one class of therapeutics but all five.

An understanding of the five main classes of therapeutics and modalities is essential to understanding how these different types of therapeutics can be leveraged to treat specific diseases and disorders. For example, various companies in the cardiovascular field may be developing different therapeutics. One company may be developing a small molecule, one may be developing a gene therapy, and one may be developing an siRNA. Each company is developing a different therapeutic, but they may be competing for the same patient population.

The Executive Course on Therapeutics and Modalities is an introduction to the five main therapeutic classes. The course consists of approximately 45 videos, all under 30 minutes. The videos explain the five classes of therapeutics, covering their compositions, mechanisms of action, routes of administration, and how the various technologies can be mixed and matched to form new classes of therapeutics. Best of all, the course is designed for someone with no (or limited) scientific background. There are plans for the solo learner or for corporate teams. Want to train your team in therapeutics and modalities? The course platform can accommodate teams of various sizes.

Knowledge and mastery of the five main classes of therapeutics can be leveraged into various other fields and careers – investing, law, consulting, business development, mergers and acquisitions, and many other fields as well. In life sciences, biotech, or pharmaceuticals, knowing the five main classes of therapeutics is essential.