What are biologics?
Biologic drugs or biologics are produced from living organisms or comprise components of any living organisms. These are genetically engineered proteins targeting specific parts of the immune system to treat the medical indication.
Biologics or biological products have significantly improved the treatment of diseases such as anemia, inflammatory bowel disease (IBD), psoriasis, rheumatoid arthritis (RA), leukopenia, and several forms of cancer. The first biological drug was human insulin and was marketed in 1982.
Biologics include a comprehensive variety of therapeutic formulations derived from human, animal, or microorganisms by using biotechnology or other cutting-edge technologies. Some examples of biologics include blood & blood components, vaccines, tissues, cells, genes, allergens, and recombinant proteins.
Biological drugs are genetically engineered proteins targeting particular parts of the immune system to stimulate inflammation. Biologics work by interfering with the immune system signals involved in any tissue damage.
How are biologics different from a pharmaceutical drug?
Biologics are manufactured in a living system, for example, microorganism, or animal or plant cells. Many of the biologics are large and complex molecules. Most biologics are manufactured via recombinant DNA technology. However, a drug is usually manufactured through a chemical process, which implies that it is made by mixing specific chemical ingredients in an ordered process.
Biologics, including those prepared by biotechnology, are heat sensitive as well as susceptible to microbial contamination. In distinction, this is not the case for pharmaceutical drugs.
How are Biologics approved?
Like pharmaceutical drugs, for approval of biologics, the application needs to be submitted to the regulatory authorities of the specific countries.
Approval in the United States
The Food and Drug Administration (FDA) regulates the approval of biological drugs in the United States. Under the US FDA, some biologics are regulated by the Center for Biologics Evaluation and Research (CBER), while others are regulated by the Center for Drug Evaluation and Research (CDER).
A Biologics License Application (BLA) is generally submitted after an Investigational New Drug (IND) or an Investigational Device Exemption (IDE). Relevant studies must be performed before a BLA is submitted. A BLA is a request for permission for distribution of a biological drug across different states.
According to the FDA, a BLA generally applies to vaccines and other allergenic drug products, cellular & genetic therapies, and blood products.
The Biologics License Application is regulated under 21 CFR 600-680. This application is submitted by any legal entity or person who is a manufacturer or an applicant for a license holding responsibility for compliance with product & establishment standards.
Form 356th specifies the requirements for a biologics license application, and this includes-
A biologics license application asserts that the biological product is safe, pure, & potent. Also, the manufacturing facilities for a biological drug are inspectable, and each package of the drug holds the license number.
As pharmaceutical drugs require an approved NDA (new drug application), all biologics require an approved BLA for marketing in the US.
Approval in the European Union (EU)-
In the European Union, the European Medicines Agency (EMA) regulates biological drugs. Biological drugs are approved through the centralised marketing authorization process, for instance, products manufactured using biotechnology or advanced therapy medicinal products.
To take benefit of the best available expertise for the evaluation as well as the assessment of biological medicinal products, the agency involves its scientific committees and working parties, including experts from all over Europe. The committees and working parties provide coordination, scientific & administrative support.
Approval in Australia-
The Therapeutic Goods Administration (TGA) is accountable for regulating biologics, medicines, as well as medical devices across Australia.
Before biological drugs can be legally manufactured, imported, exported, or supplied in Australia, they must be included on the Australian Register of Therapeutic Goods (ARTG).
The ACB (Advisory Committee on Biologicals) directs and makes recommendations to the Health Minister or the Secretary of the health department on-
The Therapeutic Goods Administration has classified biologics into four classes:
What are the Risks related to Biologics?
As with many pharmaceutical drugs, biological drugs come with the risk of adverse effect or side effects. The most severe possible side effect of a biological drug is an enhanced susceptibility to infections. Moreover, many biologics have the potential to trigger allergic hypersensitivity reactions.
For patients having disorders that are not life-threatening, the threat of probably serious infection may not be worth the risk. After all, it is not as if adverse events are a rare occurrence.
As biological drugs impair the immune system; hence, for all the patients who are on biologics have a heightened risk of infection. Though, it is of particular concern for patients who take biological drugs for debilitating immune disorders. Biologics are a popular & effective treatment, and many patients might consider the increased risk of infection definitely worth the improvement to their overall quality of life.
However, the side effects of biologics depend on the specific biologic drug and its method of administration into the human body.
What is the FDA? The Food and Drug Administration (FDA) is the oldest and most comprehensive consumer protection agency in the United States federal government. The FDA is responsible for the protection of public health by guaranteeing the safety, efficacy, as well as security of human and veterinary drugs, biological products, medical devices, food supply, cosmetics, along with the products that emit radiation. Moreover, the agency also provides precise, science-based health information to the public. FDA approval is relevant for investors, specifically those who are interested in healthcare companies (Pharmaceuticals and biotech players). Also, the approval process is essential primarily for those healthcare companies that are involved in the drug development process. Without an FDA approval, regulated products under the purview of FDA would not be issued for sale in the United States. A look at the History of FDA The FDA is the oldest consumer protection organization in the United States federal government. Since 1848 the US federal government has used chemical analysis for monitoring safety of agricultural products a responsibility inherited by the Agriculture Department in 1862 and later by the FDA. The regulatory functions of the FDA began with the 1906 clearance of the Pure Food and Drug Act. Since then, the FDA has changed together with social, political, economic as well as legal modifications in the US. Examination of the history of these modifications explains the evolving role that the regulatory agency has played in encouraging public health. What are the responsibilities of the FDA? FDA has the responsibility of ensuring public health safety. The agency helps to protect public health by assuring food safety & quality, from electronic product radiation to regulating tobacco products. The responsibilities of FDA extend to 50 Unites States including Puerto Rico, the Virgin Islands, the District of Columbia, Guam, American Samoa, and other territories & possessions in the United States. A glance at the responsibilities of FDA- FDA maintains public health safety by assuring the safety of food poultry and some egg products. To make sure safety & effectiveness of human and veterinary drugs, vaccines & other biological products, and medical devices that are intended for human use. Protection of the public from electronic product radiations. Ensuring the cosmetics, as well as dietary supplements, are safe and labeled appropriately. Advancing public health by helping to fast-track product innovations. What does FDA regulate? FDA is accountable for upgrading human health & safety by boosting innovations that make medical products more effective, safer, as well as affordable. The FDA is renowned for its work in regulating the development of innovative treatments. The FDA has established some rules concerning the clinical trials that must be completed on every new drug. Healthcare players must perform clinical trials before marketing of new drug into individuals. To know more about clinical trials, click here. Generally, FDA regulates foods, drugs, medical devices, biologics, electronic products that give off radiation, cosmetics, veterinary products, and tobacco products. How Can FDA Approvals transform the fate of Healthcare companies? Approval or rejection from the FDA for a new drug or sale of an existing drug in the United States can have a financial impact on any healthcare company. If the FDA approved any drug, it could drive an increase in the revenue of the company. The FDA also performs inspection animal testing facilities and clinical trials sites. For small-cap companies that are developing a new drug, their fate depends on receiving approval from the regulatory authorities. Also, the market value of healthcare shares depends on the FDA approval process. The decision of the FDA might affect the stock market and give investors an idea about how the company is going to operate in the upcoming period. To understand the impact of an FDA approval in a specific stock, click here. How does the FDA drug approval process work? Drug development and animal testing- After manufacturing a new drug, the manufacturer or sponsor seek authorization by the FDA for commercialization in the US. The new drug must be assessed by the sponsor for toxicity in animals. Investigational New Drug (IND) Application and Review- After animal testing, the sponsor submits an investigational new drug application to the FDA based on the results from the initial testing. The initial experiments include the drug’s composition and manufacturing process. Based on these experiments, the sponsor develops a plan for testing the drug in clinical trials. FDA Approval to conduct clinical trials- Once the FDA approves the drug after reviewing its IND, the clinical trials of the drug are performed. Review meeting- The FDA meets with the drug manufacturer or sponsor before submission of a New Drug Application (NDA). NDA Application- The drug sponsor formally seeks advice from the FDA to approve the drug for marketing in the US by submitting an NDA. An NDA includes all animal and human information related to how the drug works in the body. It also comprises information about the manufacturing process of the drug. Review of Application- After receiving an NDA, the FDA has two months to decide whether to file it to review or not. Once the FDA files an NDA, a review team is assigned for evaluating the research on the safety and efficacy of the drug. Drug Labeling- Once the application is reviewed, the FDA also reviews the professional labeling & makes sure that appropriate information is communicated to the healthcare professionals. Facility Inspection- FDA examines the manufacturing facilities where the tested drug will be manufactured. FDA Drug Approval- After the entire review and inspection process, the FDA reviewers will approve the application of sponsor or provide a response letter, also known as a Complete Response Letter.
What is an Orphan Drug? Orphan drugs are medicinal products that are meant for the prevention, diagnosis, or treatment of rare diseases or orphan diseases. Due to their limited market, very few pharmaceutical companies engage in the research and development for such drugs. Pharmaceutical companies are generally not interested in developing orphan drugs under normal market conditions. This is because the costs related to the drug development process and marketing costs cannot be retrieved by the anticipated sales of medicines without providing incentives. What is an Orphan or Rare Disease? A rare or orphan disease is a condition that affects a relatively small number of people and has different definitions for different regions. In the United States, an orphan disease is a condition that affects not more than 200,000 persons. In the European Union (EU), an indication that affects 1 in 2,000, or a maximum of 250,000 individuals, is termed as an orphan indication. For Japan, an indication is designated as an orphan disease if it affects less than 50,000 people. Symptoms of some orphan diseases might be observed at birth or during childhood. Some of the rare diseases include spinal muscular atrophy, patent ductus arteriosus (PDA), lysosomal storage disorders, cystic fibrosis, and familial adenomatous polyposis (FAP). Over half of orphan diseases occur during adulthood, for example, glioma, renal-cell carcinoma, and acute myeloid leukemia (AML). In the US, the FDA (Food and Drug Administration) is responsible for the authorization of orphan drugs. In Europe, the European Medicines Agency (EMA) performs a central role in assisting the development and authorization of medicines for rare diseases. Almost 30 million citizens in the European Union (EU) suffer from an orphan or rare disease. In Japan, the Ministry of Health, Labour and Welfare (MHLW) manages the designation of orphan drugs/diseases. As rare diseases are a global concern, the agencies work closely together on the designation as well as the assessment of orphan medicines. What is an Orphan Drug Designation? The Orphan Drug Act (ODA) provides a special status or designation to a drug or biological product for treating a rare or orphan disease at the application of a sponsor. This status is known as orphan drug designation or orphan drug status. In the United States, the orphan drug status is also applicable for medical devices and dietary products. Orphan drug status gives pharmaceutical companies exploring cures for orphan diseases the exclusive right for manufacturing drug or treatment for a specific condition. Orphan drug designation can be granted for new drugs, and drugs that are already approved and in the market. However, in the case when the drug is already approved, the sponsor must submit a reasonable assumption on how the drug is clinically superior to former drugs or undeveloped drugs. Orphan Drug Designation in the United States Granting orphan drug status may enable the sponsor to obtain the following advantages for the development of the product in the United States- A 50% tax credit on the cost of clinical trials undertaken in the US. Seven years of marketing exclusivity after the marketing approval. Some recommendations by the FDA regarding clinical as well as preclinical trials to be completed to register the new drug. A fast-track process for the FDA for evaluation of registration files. Orphan Drug Designation in Europe In the European Union (EU), applications for orphan drug designation are examined by the EMA's Committee for Orphan Medicinal Products, using the network of specialists that the Committee has built up. The evaluation takes a maximum of three months from validation. Sponsors who obtain an orphan designation from EMA getbenefit from protocol assistance and market exclusivity once the medicine is available in the market. Fee reductions are also available depending on the status of the sponsor and the type of service needed. Orphan Drug Designation in Japan In Japan, drugs & medical devices are designated as orphan drugs or medical devices based on Article 77-2 of the Pharmaceutical Affairs Law. Medicines are designated by the Minister of Health, Labour and Welfare (MHLW) based on the judgment of the PAFSC (Pharmaceutical Affairs & Food Sanitation Council). After receiving applications for ODD application from the applicants, MHLW may give the orphan designation to drugs or medical devices after assessing the drug against the following points: The number of patients. Medical requirements. Possibility of development. What is the Orphan Products Development (OOPD) Program? The Orphan Products Development (OOPD) mission of the FDA is to advance the evaluation as well as the development of products such as drugs, biologics, medical devices, or foods used to diagnosis and/or treatment of orphan or rare diseases. The program offers incentives for sponsors to develop products for rare diseases. Since 1983, this program has facilitated development and commercialization of over 600 drugs and biologic products for orphan indications. The OOPD program provides orphan status to medicines and biologics that are described as those meant for the treatment, prevention as well as diagnosis of a rare condition or disease. In the United States, a sponsor seeking orphan designation for medicine or device must submit an application for designation to OOPD with the information necessary in 21 CFR 316.20 and 316.21. Sponsors requesting designation of a similar drug for a related rare disease or condition as a previously designated product must submit their information to support their designation request.
What are Biosimilars? A biosimilar drug is a biological formulation developed in a way similar to an already-approved biologic, also known as the reference product. Biologics offer relatively cheaper treatment alternatives for patients suffering from chronic and often disabling indication like autoimmune disease, diabetes, and cancers. While one might think that biosimilars are akin to generic drugs, there are significant differences between the two. Generics are chemically identical to the branded drugs. However, a biosimilar is not a replica of another biological product. There is a level of natural variability in all biological products, and it is not possible to make an exact copy of a product that comes from living cells. All biologic, including reference products, indicate a few variations in batch-to-batch formulations. Most of the biosimilars are likely to include biotechnology-derived proteins as an active moiety. Biosimilars are anticipated to cost from 10-40% less as compared to their reference products. How are Biosimilars Regulated? The EMA (European Medicines Agency) was the first body to develop an overarching structure for approving biosimilars. Biosimilars have been authorized for use in the European Union since 2006. They also have been licensed for use in Australia, Latin America, and Japan. In the US, a regulatory pathway for approval of biosimilars was made possible by the BCPI act or Biologics Price Competition & Innovation Act. This act is a provision comprised in the Patient Protection and Affordable Care Act of 2010. The Food and Drug Administration (FDA) gauges the safety as well as the efficacy of all the new, original biologics. Evaluation of biologics is the same as for new conventional medications. The purpose of developing a biosimilar is to determine that the proposed biosimilar is highly comparable to the reference product, with similar safety and efficacy. What is the Approval Process for Biosimilars? Biosimilars are approved as per the similar requirements of pharmaceutical safety, quality, and efficacy that apply to all biological medicines. In the United States, the FDA approves biosimilar products and provides the scientific and regulatory advice needed to bring safe and effective biosimilars to the market. Biosimilars can only be approved after the expiration of data exclusivity on the reference biological drug. Biosimilar products approval could improve access to care for patients by increasing the number of alternatives for medication at potentially lower costs. Approval by the FDA The FDA pathway for approving reference biologics emphasizes large clinical trials that determine safety and efficacy. In contrast, the approval pathway for biosimilars places more importance on biological and physicochemical characterizations of the biosimilar molecule, because the safety & efficacy information for the reference product are readily available. The objective of a biosimilar development program is to establish biosimilarity between the proposed biosimilar and the reference product. The program does not independently determine the safety and effectiveness of the proposed product. Approval by the EMA In the European Union, scientific boards of the EMA assess the majority of marketing authorization applications for biosimilar medicines earlier than they can be approved and marketed in the EU. The European Medical Agency has issued scientific guidelines to assist developers of biosimilars confirm to the strict regulatory requirements for biosimilars approval. The guidelines also assist in providing transparency on the requirements for the approval of biosimilars. Approval by the TGA In Australia, biosimilars are approved by the Therapeutic Goods Administration (TGA). Some biosimilar medicines are listed on the Pharmaceutical Benefits Scheme (PBS). In August 2008, the TGA adopted several European guidelines on similar biological medicinal products. In Australia, so far, 20 biosimilars have been approved by the TGA. Out of these 20, nine are listed under PBS and available as subsidized medicine. What Information is Required for the Approval of a Biosimilar? The application for approval of biosimilar drug must include data supporting biosimilarity with the reference product. This generally comprises data from: Analytical studies proving that a biologic drug is highly identical to the reference drug, despite a few differences in clinically inactive components. Animal trials, including toxicity assessment. A clinical trial sufficient to establish safety, purity, as well as the potency of the proposed biosimilar product in one or more of the conditions for which the reference product is licensed. This typically includes evaluation of immunogenicity, pharmacokinetics. In some cases, it may also include pharmacodynamics and a comparative clinical trial. Differences between Biosimilars and Generics? Biosimilar drugs are often confused with generic drugs. Both are marketed as lower cost as of branded drugs. These are designed to have the same clinical effect as their pricier counterparts. But biosimilars and generics are very different. The critical difference is that generic drugs are a copy of synthetic medicines, while biosimilars are developed after drugs that use living organisms as an active ingredient. Few key differences between biosimilar drugs and generic drugs are-
What is MHRA? MHRA, or Medicines and Healthcare products Regulatory Agency, is an essential part of the United Kingdom’s Department of Health. Founded in 2003, the agency is responsible for regulating drugs, medical devices, along with blood elements for transfusions across the UK. MHRA is involved in the protection and maintaining public health, supporting the development and innovation in this field. The agency manages both the CPRD (Clinical Practice Research Datalink) and the NIBSC (National Institute for Biological Standards and Control). The London-headquartered agency employs over 1,200 individuals across England. Three main centres of the MHRA: CPRD provides a data research service that intends to make public health better by utilising NHS clinical information (anonymised). The NIBSC is engaged in the standardisation and management of biologics (biological medicines). MHRA is the regulator for the pharmaceutical and medical devices industries. Regulates medicines, medical devices, and blood components for transfusion, responsible for safeguarding their safety, quality, and efficacy in the UK. Advisory bodies of the MHRA- The MHRA has established several independent advisory committees for providing impartial advice to ministers related to the medicines and medical devices regulation. The committees may also create working groups to focus on specific challenges. The eight advisory bodies are as follows: What does the MHRA do? The MHRA ensures that any medicine or medical device is safe to use as well as meets the regulatory standards and required quality. A medical device could be a plaster, an inhaler for asthma, or a ventilator that is used in a hospital. All medicines require a licence from the agency before their prescription within the United Kingdom. This makes sure that the medicines are effective and safe to use. The MHRA also monitors the application of new medicines. Doctors or patients can record any issues with the agency that might need further inquiry through the Yellow Card scheme. The MHRA is accountable for the regulation of medical devices, equipment used in healthcare, medicines, along with the harmful incidents’ investigation. The agency regulates blood and blood-related products, working with UK based healthcare providers, blood services, and some other relevant organisations for improving blood quality and safety. What are the roles & responsibilities of MHRA? The key responsibilities of the MHRA are highlighted below: The agency makes sure that medical devices, medicines, and any blood components for transfusion meet the safety, quality, and efficacy applicable standards. MHRA ensures that the safety and security of the supply chain for medicines, medical devices, and blood components. The agency helps to promote international harmonisation & standardisation to ensure the safety and efficacy of biological medicines. MHRA helps to educate healthcare professionals (HCPs) and public about the risks and benefits of medical devices, medicines, and blood components. This way, the agency leads to safer and more efficient use. The agency provides support to the innovation, including the R&D that is performed for the benefit of public health. Priorities of the MHRA Some key focus areas for the Medicines and Healthcare products Regulatory Agency are- To make regulation more supportive of safe and reliable innovation. To support the growth agenda of the government through the life science strategy, which comprises the adaptive licensing pilot and early access to medicines schemes. To introduce a combined reporting system for adverse reactions, medical devices, medicines, blood & counterfeit products under the YC brand to make sure of the safety of the patient. To work with its partners across the United Kingdom, Europe and worldwide for preventing substandard therapeutic products entering into the supply chain. To establish a centre of excellence for advanced and innovative therapies, including stem cells. To engage more with patients, HCPs, and the public, including by working together with others in the healthcare system. To grow the volume of observational and interventional research, together with clinical trials, by using the Clinical Practice Research Datalink (CPRD) data. What is the role of the MHRA in clinical studies? Medicines and Healthcare products Regulatory Agency (MHRA) plays a vital role in the drug development process. For a clinical trial for a new drug to commence, it must first be assessed and authorised by the MHRA. The agency examines sites where the clinical trials are conducted to ensure they are carried out in accordance with good clinical practice. The clinical trials are designed to demonstrate the effect of new medicines as per the anticipations. The results from the clinical trials are sent to the MHRA. After the assessment of the clinical trial results, the agency decides whether to allow the sponsor or healthcare company manufacturing the medicine to market it for a particular indication.