Products manufactured for medical or food use must be produced in facilities designed and operated according to   Good Manufacturing Practice (GMP)  regulations.   Cleanrooms  are often required to control the levels of particulates and microorganisms.   Sterilization  and  aseptic  processing equipment are required for production of  injectable  products.


Skilled professionals are required for positions throughout the life cycle of a biomanufacturing product, which includes:


Details for some of these positions are listed in “The Model Employee,” published by the  North Carolina Biotechnology Center . [ 1 ]  In addition, the North Carolina Association for Biomedical Research (NCABR) maintains the website  About Bioscience  that offers free online videos on various careers. [ 2 ]


Several academic institutions have developed curricula and built facilities to provide education and training in biomanufacturing to students from community colleges, universities, and/or industry.    NCBioImpact , established in 2004, is an example of a comprehensive state-wide training network.  Member institutions  Golden LEAF Biomanufacturing Training and Education Center (BTEC)  at  North Carolina State University , (BRITE) at  North Carolina Central University , and  North Carolina Community College System’s  BioNetwork operate multidisciplinary centers dedicated to workforce development for the biomanufacturing industry.


MiraCosta College  and  Solano College  in California developed the first bachelor of science degree in biomanufacturing.  The degree is largely lab-based and is built on a contextualized science and statistics backbone.  The upper division classes recognize the unique environment of biological production where the process sciences and technology thrive in partnership with quality and regulatory compliance.


A  biosimilar  (also known as  follow-on biologic  or  subsequent entry biologic ) is a  biologic medical product  that is almost an identical copy of an original product that is manufactured by a different company. [ 1 ]  Biosimilars are officially approved versions of original "innovator" products and can be manufactured when the original product's  patent  expires. [ 2 ]  Reference to the innovator product is an integral component of the approval. [ 3 ]


Unlike with  generic drugs  of the more common  small-molecule  type, biosimilar drugs generally exhibit high molecular complexity and may be quite sensitive to changes in manufacturing processes. Despite this heterogeneity, all  biopharmaceuticals , including biosimilars, must maintain consistent quality and clinical performance throughout their lifecycle. [ 4 ]


Drug-related authorities such as the  European Medicines Agency  (EMA) of the European Union, the United States  Food and Drug Administration  (FDA), and the  Health Products and Food Branch  of  Health Canada  hold their own guidance on requirements for demonstration of the similar nature of two biological products in terms of safety and efficacy. According to them, analytical studies demonstrate that the biological product is highly similar to the reference product, despite minor differences in clinically inactive components, animal studies (including the assessment of toxicity), and a clinical study or studies (including the assessment of  immunogenicity  and  pharmacokinetics  or  pharmacodynamics ). They are sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and is intended to be used and for which licensure is sought for the biological product. [ citation needed ]


The  World Health Organization  (WHO) published its "Guidelines for the evaluation of similar biotherapeutic products (SBPs)" in 2009. The purpose of this guideline is to provide an international norm for evaluating biosimilars. [ 5 ] [ 6 ] [ 7 ] [ 8 ]


The EMA has granted marketing authorizations for more than 50 biosimilars since 2006. The first biosimilar of a  monoclonal antibody  to be approved worldwide was a biosimilar of  infliximab  in the EU in 2013. [ 9 ]  On March 6, 2015, the FDA approved the United States' first biosimilar product, the biosimilar of  filgrastim  called filgrastim-sndz (trade name Zarxio) by  Sandoz .


In the United States, the  Food and Drug Administration  (FDA) held that new legislation was required to enable them to approve biosimilars to those biologics originally approved through the PHS Act pathway. [ 10 ]  Additional Congressional hearings have been held. [ 11 ]  On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House. [ 2 ]  Since 2004 the FDA has held a series of public meetings on biosimilars. [ 12 ] [ 13 ]


The FDA gained the authority to approve biosimilars (including interchangeables that are substitutable with their reference product) as part of the  Patient Protection and Affordable Care Act  signed into law by President Obama on March 23, 2010. [ citation needed ]


The FDA has previously approved biologic products using comparability, for example,  Omnitrope  in May 2006, but this like  Enoxaparin  was also to a reference product,  Genotropin , originally approved as a  biologic  under the FD&C Act. [ 14 ]


On March 6, 2015,  Zarxio  obtained the first approval of FDA. [ 15 ]  Sandoz's Zarxio is biosimilar to Amgen's Neupogen (filgrastim), which was originally licensed in 1991. This is the first product to be passed under the Biologics Price Competition and Innovation Act of 2009 (BPCI Act), which was passed as part of the Affordable Healthcare Act. But Zarxio was approved as a biosimilar, not as an interchangeable product, the FDA notes. And under the BPCI Act, only a biologic that has been approved as an "interchangeable" may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product. The FDA said its approval of Zarxio is based on review of evidence that included structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamics data, clinical immunogenicity data and other clinical safety and effectiveness data that demonstrates  Zarxio  is biosimilar to Neupogen. [ citation needed ]


In March 2020, most protein products that were approved as drug products (including every insulin currently on the market as of December 2019 [update] ) are scheduled to open up to biosimilar and interchangeable competition in the United States. [ 16 ]  However, "chemically synthesized polypeptides" are excluded from this transition, which means that a product that falls within this category won't be able to come to market as a biosimilar or interchangeable product, but will have to come to the market under a different pathway. [ 16 ]


Cloning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any  recombinant DNA  based biological substance for eventual development of a drug.  Monoclonal antibody  technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines.  Gene-  and  cell-based  therapies are emerging as new approaches.


Recombinant therapeutic  proteins  are of a complex nature (composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells (bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug.


After the expiry of the patent of approved recombinant drugs (e.g.,  insulin , human  growth hormone ,  interferons ,  erythropoietin , monoclonal antibodies and more) any other biotech company can develop and market these  biologics  (thus called biosimilars).


The typical reference product has undergone numerous changes in its manufacturing processes, and such changes in the manufacturing process (ranging from a change in the supplier of cell culture media to new purification methods or new manufacturing sites) was substantiated with appropriate data and was approved by the EMA.


The current concept of development of biosimilar  monoclonal antibodies  follows the principle that an extensive state of the art physicochemical, analytical and functional comparison of the molecules is complemented by comparative non-clinical and clinical data that establish equivalent efficacy and safety in a clinical "model" indication that is most sensitive to detect any minor differences (if these exist) between the biosimilar and its reference monoclonal antibody also at the clinical level.


The EMA has recognized this fact, which has resulted in the establishment of the term "biosimilar" in recognition that, whilst biosimilar products are similar to the original product, they are not exactly the same. [ 17 ]


Originally the complexity of biological molecules led to requests for substantial efficacy and safety data for a biosimilar approval. This has been progressively replaced with a greater dependence on assays, from quality through to clinical, that show assay sensitivity sufficient to detect any significant difference in dose. [ 18 ]  However, the safe application of biologics depends on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed  pharmacovigilance  plan. It is difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified. In contrast, small molecule drugs made up of a chemically based compound can be easily replicated and are considerably less expensive to reproduce. In order to be released to the public, biosimilars must be shown to be as close to identical to the parent innovator biologic product based on data compiled through clinical, animal, analytical studies and conformational status. [ 19 ] [ 20 ]


Generally, once a drug is released in the market by the FDA, it has to be re-evaluated for its safety and efficacy once every six months for the first and second years. Afterward, re-evaluations are conducted yearly, and the result of the assessment should be reported to authorities such as FDA. Biosimilars are required to undergo pharmacovigilance (PVG) regulations as its reference product. Thus biosimilars approved by the EMA are required to submit a risk management plan (RMP) along with the marketing application and have to provide regular safety update reports after the product is in the market. The RMP includes the safety profile of the drug and proposes the prospective pharmacovigilance studies.


Several PK studies, such as studies conducted by Committee for Medicinal Products for Human Use (CHMP), have been conducted under various ranges of conditions; Antibodies from an originator's product versus antibodies from a biosimilar; combination therapy and monotherapy; various diseases, etc. on the purpose to verify comparability in pharmacokinetics of the biosimilar with the reference medicinal product in a sufficiently sensitive and homogeneous population.


In the European Union, no unique identifier of a biosimilar medicine product is required, as the same rules are followed as for all biologics. [ citation needed ]


The US decided on a different approach, requiring the assignment of a four-letter suffix to the nonproprietary name of the original product to distinguish between innovator drugs and their biosimilars. [ 21 ]  Japan has similar requirements. [ 22 ]  The suffix approach has been criticized on the grounds of compromising the INN system and delaying the marketing of biosimilars. [ 22 ]  Australia decided not to use a 4-letter suffix. [ 23 ] [ 24 ] [ 25 ]


A version of the four-letter suffix has been proposed to the WHO as the biological qualifier (BQ). It is not part of the  international nonproprietary name  (INN), but is proposed to be managed under the same registry. [ 26 ]  The report 1 of the May 2017 WHO Expert Consultation on Improving Access to and Use of Similar Biotherapeutic Products, published in October 2017, revealed on page 4, that following the outcome arising from the meeting: "No consensus was reached on whether WHO should continue with the BQ... WHO will not be proceeding with this at present." [ 27 ]


Biosimilars available in Australia include adalimumab, bevacizumab, enoxaparin, epoetin lambda, etanercept, filgrastim, follitropin alfa, infliximab, insulin aspart, insulin glargine, pegfilgrastim, rituximab, teriparatide, and trastuzumab. [ 28 ]


A research article about "Maximizing the benefits of using biosimilars in Egypt" proposed a regulatory framework for biosimilars in Egypt. The article summarized the recommendations of a number of stakeholders. [ 29 ]


Biosimilar medicines approved in the European Union (EU) are interchangeable with their reference medicine or with an equivalent biosimilar. [ 30 ]


As of October 2024, the US FDA has approved 60 biosimilars. [ 132 ] [ 133 ]


The  Biologics Price Competition and Innovation Act  of 2009 (BPCI Act) was originally sponsored and introduced on June 26, 2007, by Senator  Edward Kennedy  (D-MA). It was formally passed under the  Patient Protection and Affordable Care Act  (PPAC Act), signed into law by President Barack Obama on March 23, 2010. The BPCI Act was an amendment to the Public Health Service Act (PHS Act) to create an abbreviated approval pathway for biological products that are demonstrated to be highly similar (biosimilar) to a  Food and Drug Administration  (FDA) approved biological product. [ 134 ]  The BPCI Act is similar, conceptually, to the Drug Price Competition and Patent Term Restoration Act of 1984 (also referred to as the "Hatch-Waxman Act") which created biological drug approval through the Federal Food, Drug, and Cosmetic Act (FFD&C Act). The BPCI Act aligns with the FDA's longstanding policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing. The FDA has released a total of four draft guidelines related to biosimilar or follow-on biologics development. Upon the release of the first three guidance documents the FDA held a public hearing on May 11, 2012. [ 135 ]


In 2018, the FDA released a Biosimilars Action Plan to implement regulations from the BPCI, including limiting the abuse of the Risk Evaluation and Mitigation Strategy (REMS) system for  evergreening  and transitioning insulin and human growth hormone to regulation as biologics rather than drugs. [ 136 ]


Bovhyaluronidase azoximer , sold under the brand name Longidaze, is a  conjugate  of  proteolytic   enzyme   hyaluronidase  with high- molecular weight  copolymer  that forms a component of combination therapy regimens for treatment and prevention of diseases associated with  connective tissue   hyperplasia . [ 1 ]
The most frequently observed adverse reactions seen with bovhyaluronidase azoximer include pain at site of injection and  injection site reactions  such as skin redness, itching and  oedema . Local reactions typically resolve themselves in 48–72 hours. [ medical citation needed ]


Type: Hyaluronidases


Other names: hyaluronidase conjugate with co-polymer of N-oxide 1,4-ethylenepiperazine and (N-carboxymethyl)-1,4- ethylenepiperazine bromide


Pharmaceutical form: suppositories


Pharmacotheapeutic group: enzymes


ATC Code: V03AX


Bovhyaluronidase azoximer is a porous white or white with a yellowish or brownish tint mass and prepared in ampules 1500 IU or 3000 IE with mannitol excipient (up to 15 mg [for 1500 IE dos] or up to 20 mg (for 3000 IE dose).


The active ingredient belongs to the  hyaluronidases  family of  enzymes  that  catalyse  the degradation of  hyaluronic acid . By catalyzing the  hydrolysis  of  hyaluronan , a constituent of the body's  extracellular matrix  (ECM), hyaluronidase lowers the  viscosity  of hyaluronan, thereby increasing tissue  permeability ... [ 2 ]  It is, therefore, often used in medicine in conjunction with other drugs to speed their dispersion and delivery. It also increases the absorption rate of parenteral fluids given by  hypodermoclysis , and is an adjunct in subcutaneous urography for improving resorption of radiopaque agents. Hyaluronidases are also used for  extravasation  of hyperosmolar solutions. [ 3 ]


Approved applications include:


Gynaecology: treatment and prevention of adhesive process in lesser pelvis during inflammatory diseases of internal genital organs, including tubo-peritoneal  infertility ,  intrauterine synechiae , chronic  endometritis . [ 4 ] [ 5 ] [ 6 ]


Urology: treatment of chronic  prostatitis ,  interstitial cystitis . [ 7 ]


Pulmonology and  phthisiology : treatment of pneumosclerosis,
 fibrosing alveolitis , and  tuberculosis  (fibro-cavity, infiltrative, tuberculoma). [ 8 ] [ 1 ]


Orthopaedics: treatment of joint contracture,  arthrosis , Marie-Striinipell disease,  haematomas . [ 1 ] [ 9 ]


Medicines incorporating hyaluronidase have been used in medical applications for over 60 years. [ 10 ]  The  US Food and Drug Administration  has approved hyaluronidase for the following indications: (1) subcutaneous fluid infusion ( hypodermoclysis ), (2) as an adjuvant to accelerate the absorption and dispersion of drugs in subcutaneous tissue or to manage extravasation, and (3) as an adjunct to promote the absorption of contrast media in urinary tract  angiography  (subcutaneous urography). [ 2 ]  They have also been approved and used for the purpose of increasing hematoma absorption in Europe. [ 2 ]  Hyaluronidase has a variety of uses in addition to its approved indications. Its current off-label uses include dissolving hyaluronic acid fillers, treating granulomatous foreign body reactions, and treating skin  necrosis  associated with filler injections. [ 2 ] [ 11 ]


Recognised limitations for hyaluronidase-based medicines include allergenic properties, presence of ballast impurities, loss of enzymatic activity due to temperature and inhibitors of blood serum. [ 12 ]  Since administration is via a  parenteral  route of administration, the enzyme is inactivated by blood serum inhibitors, which shortens its half-life. [ 11 ]


Conjugation ( covalent binding ) of hyaluronidase with polymeric carriers prevents the unfolding of enzyme globule  Hyal , increasing resistance to denaturation and the action of inhibitors while preserving the enzymes native structure and activity, thus prolonging its activity. [ 13 ]  The water-soluble copolymer 1,4-ethylene-piperazine N-oxide and (N-carboxymethyl)-1,4-ethylene-piperazinium bromide, itself an  immunomodulator  with anti-inflammatory properties, [ 14 ]  was found to confer increased stability. A comparative study of the stability of commercial hyaluronidase (Lydase®) and bovhyaluronidase azoximer showed a 20-fold increase in length of activity at 37 °C (24 hours vs. 20 days, respectively). [ 11 ]


Frequently observed adverse events include (≥ 1/100 to < 1/10) – pain at injection site. Less frequent adverse events (≥ 1/1,000 to < 1/100) include injection site reaction such as skin redness, itching and oedema. All local reactions resolve themselves in 48 – 72 hours. Very rare (< 1/10000) – allergic reactions.
Use of bovhyaluronidase azoximer is contraindicated in known cases of hypersensitivity to hyaluronidase, acute infectious diseases, pulmonary haemorrhage and haemoptysis, recent vitreous haemorrhage, malignant neoplasms, acute renal failure, age under 18 years (no clinical study data available). It should also be used with caution in cases of chronic liver failure (administer not more than once per week) and is contraindicated for use in pregnant and breast-feeding women. [ 1 ]


Bovhyaluronidase azoximer can be prescribed with other medications such as antifungal drugs, bronchial spasmolytics, antibiotics and antivirals. When administered in combination with other medicinal product (antibiotics, local anesthetics, diuretics) bovhyaluronidase azoximer increases their bioavailability and enhances their effect. In case of co-administration with high doses of salicylates, cortisone, adrenocorticotrophic hormone (ACTH), estrogens or antihistaminic drugs bovhyaluronidase azoximer enzymatic activity can decrease. It is advised that bovhyaluronidase azoximer is not administered with medicinal products containing furosemide, benzodiazepines, phenytoin. [ 1 ]


Catridecacog , sold under the brand name  Tretten  in the US and  NovoThirteen  in the EU [ 1 ] ) is a class of  recombinant   factor XIII  A-subunit based  biopharmaceutical  medicine, indicated in patients with a rare clotting disorder, congenital factor XIII A-subunit deficiency, which is a kind of  Factor XIII deficiency . The medication prevents bleeding in patients with this condition, and has been approved by the U.S.  Food and Drug Administration  (FDA) for this use in the US in 2014. [ 2 ]   It was brought to market by  Novo Nordisk . [ 1 ]


This  drug  article relating to the  blood  and  blood forming organs  is a  stub . You can help Wikipedia by  expanding it .


Condoliase  ( Hernicore ) is a  biopharmaceutical  for the treatment of  lumbar disc herniation . Clinical trials have shown its benefit in alleviation of lumbar disc herniation associated low back pain and disability, although some concerns have been suggested with regard to promotion of disc degeneration. [ 1 ] [ 2 ]


Condoliase is derived from the enzyme  mucopolysaccharidase  from the  Gram-negative bacteria   Proteus vulgaris . [ 3 ] [ 4 ]   It functions as an enzymatic  chemonucleolysis  product, specifically designed to reduce the size of the protruded herniation. [ 5 ]  It is an enzyme that specifically degrades  glycosaminoglycans . [ 6 ] [ 7 ] [ 4 ]


It was approved for use in Japan in 2018 as a treatment for lumbar disc herniation. [ 8 ]


The  Golden LEAF Biomanufacturing Training and Education Center (BTEC)  is a multidisciplinary instructional center at  North Carolina State University  that provides education and training to develop skilled professionals for the  biomanufacturing  industry. Biomanufacturing refers to the use of living organisms or other biological material to produce commercially viable products. Examples include therapeutic proteins,  monoclonal antibodies , and  vaccines  for medical use; amino acids and enzymes for food manufacturing; and biofuels and biochemicals for industrial applications. BTEC provides hands-on education and training in bioprocessing concepts and biomanufacturing methods that comply with  cGMP  (current Good Manufacturing Practice), a set regulations published by the United States  Food and Drug Administration (FDA) .


BTEC reports administratively through the university's  College of Engineering  and is guided by an advisory board made up of representatives from the biomanufacturing industry and other organizations interested in biotechnology and biomanufacturing.


In 2003, North Carolina's  Golden LEAF Foundation  provided almost $39 million to build BTEC, as part of a larger grant to establish a statewide public-private partnership now called  NCBioImpact . [ 1 ] [ 2 ]  The state of North Carolina provided funds for process equipment and supports the operation of the facility.  The NCBioImpact partnership now includes BTEC, BRITE (Biomanufacturing Research Institute and Technology Enterprise) at  North Carolina Central University , North Carolina BioNetwork of the  North Carolina Community College System , NCBIO (North Carolina Biosciences Organization), the  North Carolina Biotechnology Center , and the Golden LEAF Foundation.  It was created to provide workforce training and development for the biotechnology industry, thereby fostering the growth of this economic sector in the state. According to the North Carolina Biotechnology Center, North Carolina is home to 528 biotechnology companies that provide 57,000 jobs and $1.92 billion in taxes for state and local government. [ 3 ]   Employment in the industry has grown 4.1% from 2008 to 2010, when other industries shed thousands of jobs. [ 4 ]  In recent years some of the world's largest pharmaceutical companies, e.g.  Novartis  and  Merck & Co , have located and/or expanded manufacturing operations in North Carolina. [ 5 ] [ 6 ]


BTEC opened in fall 2007 and was the first facility dedicated to biomanufacturing training. [ 7 ]  BTEC is 82,500 gross square feet and contains 63,000-gross square feet of laboratories, which range from small or bench scale to large-scale suites that simulate a biomanufacturing pilot plant capable of producing  biopharmaceutical  products.  Upstream processes utilize bacteria, yeast, animal  cells , and insect cells.  Equipment in these spaces includes the following:


The main BTEC facility is home to the North Carolina Community College System's BioNetwork Capstone Center, which operates an aseptic processing/filling suite and several bench-scale labs. [ 8 ]  In 2012, BTEC completed construction of additional laboratories in a nearby facility for cell culture, purification, and processing of active virus.


BTEC delivers undergraduate and graduate courses to North Carolina State University students. Academic programs include the following:


Curriculum was created with extensive input from industry professionals, and most courses include substantial hands-on laboratory work. Most BTEC courses are offered in a half-semester (eight-week) format, which enables students to complete a series of courses in one academic year.


BTEC collaborates with industry partners to design, develop and deliver courses that provide professionals working for biomanufacturing companies, equipment vendors, or regulatory agencies with continuing education opportunities.  Open-enrollment courses are offered throughout the year and are available to all interested parties.  BTEC also regularly delivers courses customized to meet a client's specific needs for training.


BTEC provides biomanufacturing training specified in contracts of grants to provide training for government agencies.  In 2007, the  FDA  awarded BTEC a 5-year contract to develop and deliver biomanufacturing training for FDA inspectors. [ 9 ]   In 2010, BTEC received a grant for almost $900,000 from  Biomedical Advanced Research and Development Authority  (BARDA), part of the  United States Department of Health and Human Services . [ 10 ]  With funding from this grant, a team of instructors from BTEC,  Duke University , and industry provide a three-week course on influenza vaccine manufacturing. Trainees were selected by institutions participating in a U.S. government-sponsored program to build vaccine production capacity among countries with developing economies. Countries represented included Egypt, India, Indonesia, Mexico, Romania, Serbia, Russia, South Korea, Thailand, and Vietnam.


When laboratories are not being used for training, BTEC uses them to perform a variety of services for scientists from industry, government, and academia.  Projects involve technology development, process improvement/scale-up, analytical testing, and preparation of material for preclinical studies.  These services allow scientists to advance their research projects toward commercialization.  In turn, these advancements stimulate the North Carolina economy.


BTEC is located on the  Centennial Campus  of  North Carolina State University  in  Raleigh, North Carolina , United States. The campus is approximately 15 miles east of  Research Triangle Park  and  Raleigh-Durham International Airport .


A  living medicine  is a type of  biologic  that consists of a living organism that is used to treat a disease. This usually takes the form of a cell (animal, bacterial, or fungal) or a virus that has been  genetically engineered  to possess  therapeutic  properties that is injected into a patient. [ 2 ] [ 3 ]  Perhaps the oldest use of a living medicine is the use of  leeches  for  bloodletting , though living medicines have advanced tremendously since that time.


Examples of living medicines include  cellular therapeutics  (including  immunotherapeutics ),  phage therapeutics , and  bacterial therapeutics , a subset of the latter being  probiotics .


Development of living medicines is an extremely active research area in the fields of  synthetic biology  and  microbiology . [ 6 ] [ 7 ] [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ] [ 13 ] [ 14 ]  Currently, there is a large focus on: 1) identifying microbes that naturally produce therapeutic effects (for example, probiotic bacteria), and 2)  genetically programming  organisms to produce therapeutic effects. [ 15 ] [ 16 ] [ 17 ]


There is tremendous interest in using bacteria as a therapy to treat tumors. In particular,  tumor-homing bacteria  that thrive in  hypoxic  environments are particularly attractive for this purpose, as they will tend to migrate to, invade (through the  leaky vasculature  in the  tumor microenvironment ) and  colonize  tumors. This property tends to increase their residence time in the tumor, giving them longer to exert their therapeutic effects, in contrast to other bacteria that would be quickly cleared by the immune system. [ 19 ] [ 20 ] [ 21 ] [ 22 ]


Metazym  is an experimental recombinant  enzyme  that was studied in patients with late infantile  metachromatic leukodystrophy , [ 1 ]  but found to be ineffective under the conditions of that trial. A subsequent clinical trial is ongoing. [ 2 ]  The drug became a source of controversy when a family attempted to purchase the drug for their child before it was approved. [ 3 ]  Jonckheere, Kingma, Eyskens, Bordon, & Jansen (2023) highlight the shift towards the need for newborn screening for metachromatic leukodystrophy as it allows for improved early detection and timely treatment as well. [ 4 ]


This  enzyme -related article is a  stub . You can help Wikipedia by  expanding it .


Patisiran , sold under the brand name  Onpattro , is a  medication  used for the treatment of  polyneuropathy  in people with  hereditary transthyretin-mediated amyloidosis , [ 7 ]  a fatal  rare disease  that is estimated to affect 50,000 people worldwide. [ 8 ] [ 9 ]


It is the first  small interfering RNA -based drug approved by the U.S.  Food and Drug Administration  (FDA) and the first drug approved by the FDA to treat this condition. [ 8 ]  It is a  gene silencing  drug that interferes with the production of an abnormal form of  transthyretin . [ 10 ]  Patisiran utilizes a novel approach to target and reduce production of the  TTR  protein in the liver via the RNAi pathway. [ 11 ]


Patisiran was developed and is marketed by  Alnylam . [ 12 ]  The FDA considers it to be a  first-in-class medication . [ 13 ]


Patisiran was granted  orphan drug status ,  fast track designation ,  priority review  and  breakthrough therapy designation  due to its novel mechanism and the rarity of the condition it treats. [ 14 ] [ 15 ]  It was approved for medical use in the United States and in the European Union in August 2018. [ 16 ] [ 17 ]  The per-patient cost is between  US$451,430  and  US$677,145  per year, depending on the number of vials needed. [ 18 ]


[ 19 ] [ 20 ]


The  siRNA  active component of Patisiran is formulated into  lipid nanoparticles , which protect the  RNA  and facilitate its delivery to target tissues. The lipid  nanoparticle  formulation includes buffer components, as well as the  lipid  components DLin-MC3-DMA,  Distearoylphosphatidylcholine ,  cholesterol , and the PEGylated lipid  DMG-PEG 2000 . [ 21 ]


As of 2020, there were 1050 people globally receiving patisiran, generating $65.5M in net-revenues for  Alnylam Pharmaceuticals . [ 22 ] [ 23 ]


Plasminogen , sold under the brand name  Ryplazim , is a  biologic medication  for the treatment of  hypoplasminogenemia  (plasminogen deficiency type 1). [ 1 ] [ 2 ] [ 4 ]  It is purified from human plasma [ 1 ] [ 2 ]  and is administered  intravenously . [ 1 ] [ 5 ]


The most common side effects include abdominal pain, bloating, nausea, bleeding, limb pain, fatigue, constipation, dry mouth, headache, dizziness, joint pain, and back pain. [ 1 ] [ 2 ]


Individuals with hypoplasminogenemia lack a protein called plasminogen, which is responsible for the ability of the body to break down fibrin clots. [ 2 ]  Plasminogen deficiency leads to an accumulation of fibrin, causing the development of growths (lesions) that can impair normal tissue and organ function and may lead to blindness when these lesions affect the eyes. [ 2 ]


Plasminogen, human-tvmh was approved for medical use in the United States in June 2021. [ 2 ]  It is the first therapy for hypoplasminogenemia approved by the U.S.  Food and Drug Administration  (FDA). [ 2 ]


Plasminogen, human-tvmh is  indicated  for the treatment of people with plasminogen deficiency type 1, also referred to as hypoplasminogenemia, a disorder that can impair normal tissue and organ function and may lead to blindness. [ 1 ] [ 2 ]


The effectiveness and safety of plasminogen is primarily based on one single-arm, open-label (unblinded) clinical trial enrolling 15 adult and pediatric participants with plasminogen deficiency type 1. [ 2 ]  All participants received plasminogen administered every two to four days for 48 weeks. [ 2 ]  The effectiveness of plasminogen was demonstrated by at least 50% improvement of their lesions in all 11 participants who had lesions at baseline, and absence of recurrent or new lesions in any of the 15 participants through the 48 weeks of treatment. [ 2 ]


The U.S.  Food and Drug Administration  (FDA) granted the application for plasminogen   orphan drug  designation, [ 6 ]   fast track  designation,  priority review , and a rare pediatric disease priority review voucher. [ 2 ]  The FDA granted approval of Ryplazim to ProMetic Biotherapeutics Inc. [ 2 ]


Recombinant DNA  ( rDNA ) molecules are  DNA  molecules formed by laboratory methods of  genetic recombination  (such as  molecular cloning ) that bring together genetic material from multiple sources, creating  sequences  that would not otherwise be found in the  genome .


Recombinant DNA is the general name for a piece of DNA that has been created by combining two or more fragments from different sources. Recombinant DNA is possible because DNA molecules from all organisms share the same chemical structure, differing only in the  nucleotide  sequence. Recombinant DNA molecules are sometimes called  chimeric DNA  because they can be made of material from two different species like the mythical  chimera . rDNA technology uses  palindromic sequences  and leads to the production of  sticky and blunt ends .


The DNA sequences used in the construction of recombinant DNA molecules can originate from any  species . For example, plant DNA can be joined to bacterial DNA, or human DNA can be joined with fungal DNA. In addition, DNA sequences that do not occur anywhere in nature can be created by the  chemical synthesis of DNA  and incorporated into recombinant DNA molecules. Using recombinant DNA technology and synthetic DNA, any DNA sequence can be created and introduced into living organisms.


Proteins that can result from the expression of recombinant DNA within living cells are termed  recombinant proteins . When recombinant DNA encoding a protein is introduced into a host organism, the recombinant protein is not necessarily produced. [ 1 ]  Expression of foreign proteins requires the use of specialized expression vectors and often necessitates significant restructuring by
foreign coding sequences. [ 2 ]


Recombinant DNA differs from genetic recombination in that the former results from artificial methods while the latter is a normal biological process that results in the remixing of existing DNA sequences in essentially all organisms.


Molecular cloning is the laboratory process used to produce recombinant DNA. [ 3 ] [ 4 ] [ 5 ] [ 6 ]  It is one of two most widely used methods, along with  polymerase chain reaction  (PCR), used to direct the replication of any specific DNA sequence chosen by the experimentalist. There are two fundamental differences between the methods. One is that molecular cloning involves replication of the DNA within a living cell, while PCR replicates DNA in the test tube, free of living cells. The other difference is that cloning involves cutting and pasting DNA sequences, while PCR amplifies by copying an existing sequence.


Formation of recombinant DNA requires a  cloning vector , a DNA molecule that replicates within a living cell. Vectors are generally derived from  plasmids  or  viruses , and represent relatively small segments of DNA that contain necessary genetic signals for replication, as well as additional elements for convenience in inserting foreign DNA, identifying cells that contain recombinant DNA, and, where appropriate, expressing the foreign DNA. The choice of vector for molecular cloning depends on the choice of host organism, the size of the DNA to be cloned, and whether and how the foreign DNA is to be expressed. [ 7 ]  The DNA segments can be combined by using a variety of methods, such as restriction enzyme/ligase cloning or  Gibson assembly . [ citation needed ]


In standard cloning protocols, the cloning of any DNA fragment essentially involves seven steps: (1) Choice of host organism and cloning vector, (2) Preparation of vector DNA, (3) Preparation of DNA to be cloned, (4) Creation of recombinant DNA, (5) Introduction of recombinant DNA into the host organism, (6) Selection of organisms containing recombinant DNA, and (7) Screening for clones with desired DNA inserts and biological properties. [ 6 ]
 These steps are described in some detail in a related article ( molecular cloning ).


DNA expression requires the transfection of suitable host cells. Typically, either bacterial, yeast, insect, or mammalian cells (such as  Human Embryonic Kidney cells  or  CHO cells ) are used as host cells. [ 8 ]


Following transplantation into the host organism, the foreign DNA contained within the recombinant DNA construct may or may not be  expressed . That is, the DNA may simply be replicated without expression, or it may be  transcribed  and  translated  and a recombinant protein is produced. Generally speaking, expression of a foreign gene requires restructuring the gene to include sequences that are required for producing an  mRNA  molecule that can be used by the host's  translational apparatus  (e.g.  promoter ,  translational initiation signal , and  transcriptional terminator ). [ 9 ]  Specific changes to the host organism may be made to improve expression of the ectopic gene. In addition, changes may be needed to the coding sequences as well, to optimize translation, make the protein soluble, direct the recombinant protein to the proper cellular or extracellular location, and stabilize the protein from degradation. [ 10 ] [ 11 ] [ 12 ]


In most cases, organisms containing recombinant DNA have apparently normal  phenotypes . That is, their appearance, behavior and metabolism are usually unchanged, and the only way to demonstrate the presence of recombinant sequences is to examine the DNA itself, typically using a polymerase chain reaction (PCR) test. [ 13 ]  Significant exceptions exist, and are discussed below.


If the rDNA sequences encode a gene that is expressed, then the presence of RNA and/or protein products of the recombinant gene can be detected, typically using  RT-PCR  or  western hybridization  methods. [ 13 ]  Gross phenotypic changes are not the norm, unless the recombinant gene has been chosen and modified so as to generate biological activity in the host organism. [ 14 ]  Additional phenotypes that are encountered include toxicity to the host organism induced by the recombinant gene product, especially if it is  over-expressed  or expressed within inappropriate cells or tissues. [ citation needed ]


In some cases, recombinant DNA can have deleterious effects even if it is not expressed. One mechanism by which this happens is  insertional inactivation , in which the rDNA becomes inserted into a host cell's gene. In some cases, researchers use this phenomenon to " knock out " genes to determine their biological function and importance. [ 15 ]  Another mechanism by which rDNA insertion into chromosomal DNA can affect gene expression is by inappropriate activation of previously unexpressed host cell genes. This can happen, for example, when a recombinant DNA fragment containing an active promoter becomes located next to a previously silent host cell gene, or when a host cell gene that functions to restrain gene expression undergoes insertional inactivation by recombinant DNA. [ citation needed ]


Recombinant DNA is widely used in  biotechnology , medicine and research. Today, recombinant proteins and other products that result from the use of DNA technology are found in essentially every pharmacy, physician or veterinarian office, medical testing laboratory, and biological research laboratory. In addition, organisms that have been manipulated using recombinant DNA technology, as well as products derived from those organisms, have found their way into many farms,  supermarkets ,  home medicine cabinets , and even pet shops, such as those that sell  GloFish  and other  genetically modified animals .


The most common application of recombinant DNA is in basic research, in which the technology is important to most current work in the biological and biomedical sciences. [ 13 ]  Recombinant DNA is used to identify, map and sequence genes, and to determine their function. rDNA probes are employed in analyzing gene expression within individual cells, and throughout the tissues of whole organisms. Recombinant proteins are widely used as reagents in laboratory experiments and to generate antibody probes for examining protein synthesis within cells and organisms. [ 4 ]


Many additional practical applications of recombinant DNA are found in industry, food production, human and veterinary medicine, agriculture, and bioengineering. [ 4 ]  Some specific examples are identified below.


Found in  rennet ,  chymosin  is the enzyme responsible for hydrolysis of  κ - casein  to produce para- κ -casein and  glycomacropeptide , which is the first step in formation of  cheese , and subsequently  curd , and  whey . [ 16 ]  It was the first genetically engineered food additive used commercially. Traditionally, processors obtained chymosin from rennet, a preparation derived from the fourth stomach of milk-fed calves. Scientists engineered a non-pathogenic strain (K-12) of  E. coli  bacteria for large-scale laboratory production of the enzyme. This microbiologically produced recombinant enzyme, identical structurally to the calf derived enzyme, costs less and is produced in abundant quantities. Today about 60% of U.S. hard cheese is made with genetically engineered chymosin. In 1990, FDA granted chymosin " generally recognized as safe " (GRAS) status based on data showing that the enzyme was safe. [ 17 ]


Recombinant human  insulin  has almost completely replaced insulin obtained from animal sources (e.g. pigs and cattle) for the treatment of  type 1 diabetes . A variety of different recombinant insulin preparations are in widespread use. [ 18 ]  Recombinant insulin is synthesized by inserting the human insulin gene into  E. coli , or yeast (Saccharomyces cerevisiae) [ 19 ]  which then produces insulin for human use. [ 20 ]  Insulin produced by E. coli requires further  post translational modifications  (e.g. glycosylation) whereas yeasts are able to perform these modifications themselves by virtue of being more complex host organisms. The advantage of recombinant human insulin is after chronic use patients don't develop an immune defence against it the way animal sourced insulin stimulates the human immune system. [ 21 ]


Administered to patients whose pituitary glands generate insufficient quantities to support normal growth and development. Before recombinant HGH became available, HGH for therapeutic use was obtained from pituitary glands of cadavers. This unsafe practice led to some patients developing  Creutzfeldt–Jakob disease . Recombinant HGH eliminated this problem, and is now used therapeutically. [ 22 ]  It has also been misused as a performance-enhancing drug by athletes and others. [ 23 ] [ 24 ]


It is the recombinant form of  factor VIII , a blood-clotting protein that is administered to patients with the bleeding disorder  hemophilia , who are unable to produce factor VIII in quantities sufficient to support normal blood coagulation. [ 25 ]  Before the development of recombinant factor VIII, the protein was obtained by processing large quantities of human blood from multiple donors, which carried a very high risk of transmission of  blood borne infectious diseases , for example HIV and hepatitis B.


Hepatitis B  infection can be successfully controlled through the use of a recombinant  subunit   hepatitis B vaccine , which contains a form of the hepatitis B virus surface antigen that is produced in yeast cells. The development of the recombinant subunit vaccine was an important and necessary development because hepatitis B virus, unlike other common viruses such as  polio virus , cannot be grown  in vitro . [ 26 ]


Recombinant antibodies  (rAbs) are produced in vitro by the means of expression systems based on mammalian cells. Their monospecific binding to a specific epitope makes rAbs eligible not only for research purposes, but also as therapy options against certain cancer types, infections and autoimmune diseases. [ 27 ]


Each of the three widely used methods for  diagnosing HIV infection  has been developed using recombinant DNA. The antibody test ( ELISA  or  western blot ) uses a recombinant HIV protein to test for the presence of  antibodies  that the body has produced in response to an HIV infection. The DNA test looks for the presence of HIV genetic material using  reverse transcription polymerase chain reaction  (RT-PCR). Development of the RT-PCR test was made possible by the molecular cloning and sequence analysis of HIV genomes.  HIV testing page from US Centers for Disease Control (CDC)


Golden rice  is a recombinant variety of rice that has been engineered to express the enzymes responsible for  β-carotene  biosynthesis. [ 14 ]  This variety of rice holds substantial promise for reducing the incidence of  vitamin A deficiency  in the world's population. [ 28 ]  Golden rice is not currently in use, pending the resolution of regulatory and intellectual property issues. [ 29 ]


Commercial varieties of important agricultural crops (including soy, maize/corn, sorghum, canola, alfalfa and cotton) have been developed that incorporate a recombinant gene that results in resistance to the herbicide  glyphosate  (trade name  Roundup ), and simplifies weed control by glyphosate application. [ 30 ]  These crops are in common commercial use in several countries.


Bacillus thuringiensis  is a bacterium that naturally produces a protein ( Bt toxin ) with insecticidal properties. [ 28 ]  The bacterium has been applied to crops as an insect-control strategy for many years, and this practice has been widely adopted in agriculture and gardening. Recently, plants have been developed that express a recombinant form of the bacterial protein, which may effectively control some insect predators. Environmental issues associated with the use of these  transgenic  crops have not been fully resolved. [ 31 ]


The idea of recombinant DNA was first proposed by Peter Lobban, a graduate student of Prof.  Dale Kaiser  in the Biochemistry Department at Stanford University Medical School. [ 32 ]  The first publications describing the successful production and intracellular replication of recombinant DNA appeared in 1972 and 1973, from  Stanford  and  UCSF . [ 33 ] [ 34 ] [ 35 ] [ 36 ]  In 1980  Paul Berg , a professor in the Biochemistry Department at Stanford and an author on one of the first papers [ 33 ]  was awarded the Nobel Prize in Chemistry for his work on nucleic acids "with particular regard to recombinant DNA".  Werner Arber ,  Hamilton Smith , and  Daniel Nathans  shared the 1978  Nobel Prize in Physiology or Medicine  for the discovery of  restriction endonucleases  which enhanced the techniques of rDNA technology. [ citation needed ]


Stanford University  applied for a U.S. patent on recombinant DNA on November 4, 1974, listing the inventors as  Herbert W. Boyer  (professor at the  University of California, San Francisco ) and  Stanley N. Cohen  (professor at  Stanford University ); this patent, U.S. 4,237,224A, was awarded on December 2, 1980. [ 37 ] [ 38 ]  The first licensed drug generated using recombinant DNA technology was human insulin, developed by  Genentech  and licensed by  Eli Lilly and Company . [ 39 ]


Scientists associated with the initial development of recombinant DNA methods recognized that the potential existed for organisms containing recombinant DNA to have undesirable or dangerous properties. At the 1975  Asilomar Conference on Recombinant DNA , these concerns were discussed and a voluntary moratorium on recombinant DNA research was initiated for experiments that were considered particularly risky. This moratorium was widely observed until the US  National Institutes of Health  developed and issued formal guidelines for rDNA work. Today, recombinant DNA molecules and recombinant proteins are usually not regarded as dangerous. However, concerns remain about some organisms that express recombinant DNA, particularly when they leave the laboratory and are introduced into the environment or food chain. These concerns are discussed in the articles on  genetically modified organisms  and  genetically modified food controversies . Furthermore, there are concerns about the by-products in biopharmaceutical production, where recombinant DNA result in specific protein products. The major by-product, termed  host cell protein , comes from the host expression system and poses a threat to the patient's health and the overall environment. [ 40 ] [ 41 ]


Sebelipase alfa , sold under the brand name  Kanuma ,  is a  recombinant form  of  the  enzyme   lysosomal acid lipase  (LAL) that is used as a  medication  for the treatment of  lysosomal acid lipase deficiency  (LAL-D). [ 6 ] [ 7 ]  It is administered via intraveneous infusion. [ 5 ]  It was approved for medical use in the European Union and in the United States in 2015. [ 8 ] [ 6 ] [ 5 ] [ 7 ]


Sebelipase alfa is indicated for long-term enzyme replacement therapy (ERT) in people of all ages with lysosomal acid lipase (LAL) deficiency. [ 6 ]


Sebelipase was developed by  Synageva  that became part of  Alexion Pharmaceuticals  in 2015. For its production,  chickens  are  genetically modified  to  produce the recombinant form of LAL (rhLAL) in their  egg white . After extraction and purification it becomes available as the medication. [ 9 ]   On 8 December 2015 the  FDA  announced that its approval came from two centers: The  Center for Drug Evaluation and Research  (CDER) approved the human therapeutic application of the medication, while the  Center for Veterinary Medicine  (CVM) approved the application for a recombinant DNA construct in genetically engineered chicken to produce rhLAL in their egg whites. [ 10 ]  At the time it gained FDA approval Kanuma was the first only drug manufactured in chicken eggs and intended for use in humans. [ 9 ]


Sebelipase alfa is an  orphan drug ; its effectiveness was published after a  phase 3 trial  in 2015. [ 11 ]  The disease of LAL affects < 0.2 in 10,000 people in the EU. [ 8 ]


Specialty drugs  or  specialty pharmaceuticals  are a recent designation of pharmaceuticals [ 1 ] [ 2 ]  classified as high-cost, [ 3 ] [ 4 ] [ 5 ]  high complexity and/or  high touch . [ 4 ]  Specialty drugs are often  biologics [ 3 ] [ 6 ] —"drugs derived from living cells" [ 7 ]  that are injectable or infused (although some are oral medications). [ 4 ]  They are used to treat complex or rare chronic conditions such as  cancer ,  rheumatoid arthritis ,  hemophilia ,  H.I.V. [ 5 ]   psoriasis , [ 3 ]   inflammatory bowel disease [ 3 ]  and  hepatitis C . [ 4 ] [ 8 ]  In 1990 there were 10 specialty drugs on the market, [ 9 ]  around five years later nearly 30, [ 10 ]  by 2008 200, [ 10 ]  and by 2015 300. [ 11 ]


Drugs can be defined as specialty because of their high price. [ 3 ] [ 4 ] [ 5 ]   Medicare  defines any drug with a negotiated price of $670 per month or more as a specialty drug. These drugs are placed in a specialty tier requiring a higher patient cost sharing. [ 11 ] [ 12 ]  Drugs are also identified as specialty when there is a special handling requirement [ 3 ]  or the drug is only available via a limited distributions network. [ 3 ]  By 2015 "specialty medications accounted for one-third of all spending on drugs in the United States, up from 19 percent in 2004 and heading toward 50 percent in the next 10 years", [ 5 ]  according to  IMS Health .


According to a 2010 article in  Forbes , specialty drugs for rare diseases became more expensive "than anyone imagined" and their success came "at a time when the traditional drug business of selling medicines to the masses" was "in decline". [ 13 ]  In 2015 analysis by  The Wall Street Journal  suggested the large premium was due to the perceived value of rare disease treatments which usually are very expensive when compared to treatments for more common diseases. [ 14 ]


Medications must be either identified as high cost, high complexity or high touch to be classified as a specialty medication by Magellan Rx Management. [ 4 ]  Specialty pharmaceuticals are defined as "high-cost oral or injectable medications used to treat complex chronic conditions". [ 4 ]  According to a 2013 article in the  Journal of Managed Care & Specialty Pharmacy , on the increasingly important role of specialty drugs in the treatment of chronic conditions and their cost, drugs are most typically defined as specialty because they are expensive. [ 3 ]  Other criteria used to define a drug as specialty include "biologic drugs, the need to inject or infuse the drug, the requirement for special handling, or drug availability only via a limited distribution network". [ 3 ]  The price of specialty drugs compared to non-specialty drugs is very high, "more than $1,000 per 30-day supply". [ 4 ] [ 5 ]


Specialty drugs cover over forty therapeutic categories and special disease states with over 500 drugs. [ 4 ]


Vogenberg claims that there is no standard definition of a specialty drug which is one of the reasons they are difficult to manage. [ 6 ]  "[T]hose pharmaceuticals that usually require special handling, administration, unique inventory management, and a high level of patient monitoring and support to consumers with specific chronic conditions, acute events, or complex therapies, and provides comprehensive patient education services and coordination with the patient and prescriber." [ 15 ]


Drugs are most typically defined as specialty because they are expensive. [ 3 ]  They are high cost "both in total and on a per-patient basis". [ 16 ]  High-cost medications are typically priced at more than $1,000 per 30-day supply. [ 4 ] [ 5 ]  The Medicare Part D program "defines a specialty drug as one that costs more than $600 per month". [ 16 ] [ 17 ]  Most of the prescriptions filled by Pennsylvania-licensed  Philidor Rx Services , a specialty online mail-order pharmacy, which mainly sold [ 18 ] [ 19 ] [ 20 ]   Valeant Pharmaceuticals International Inc  expensive drugs directly to patients and handled insurance claims on the customers' behalf, [ 21 ] [ 22 ]  such as  Solodyn ,  Jublia , [ 14 ] [ 23 ] [ 24 ]  and  Tretinoin , would be considered specialty drugs. [ 25 ]


Specialty drugs are more complex to manufacture. [ 16 ]  They are "highly complex medications, typically biology-based, that structurally mimic compounds found within the body". [ 4 ]  Specialty drugs are often biologics [ 3 ] [ 6 ] —"drugs derived from living cells"—but biologics are "not always deemed to be specialty drugs". [ 7 ]  Biologics "may be produced by biotechnology methods and other cutting-edge technologies. Gene-based and cellular biologics, for example, often are at the forefront of biomedical research, and may be used to treat a variety of medical conditions for which no other treatments are available." [ 26 ]


"In contrast to most drugs that are chemically synthesized and their structure is known, most biologics are complex mixtures that are not easily identified or characterized. Biological products, including those manufactured by biotechnology, tend to be heat sensitive and susceptible to microbial contamination. Therefore, it is necessary to use aseptic principles from initial manufacturing steps, which is also in contrast to most conventional drugs. Biological products often represent the cutting-edge of biomedical research and, in time, may offer the most effective means to treat a variety of medical illnesses and conditions that presently have no other treatments available."


According to the  U.S. Food and Drug Administration  (FDA) biologics, or [ 26 ]


"Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources—human, animal, or microorganism..."


Some specialty drugs can be oral medications or self-administered injectables. Others may be professionally administered or injectables/infusions. [ 4 ]  High-touch patient care management is usually required to control side effects and ensure compliance. Specialized handling and distribution are also necessary to ensure appropriate medication administration. [ 4 ]  Specialty drugs patient care management is meant to be both high technology and high touch care, or  patient-centered care  with "more face-to-face time, more personal connections". Patient-centered care is defined by the  Institute of Medicine  as "care that is respectful of and responsive to individual patient preferences, needs and values". [ 27 ]


Specialty drugs may be "difficult for patients to take without ongoing clinical support". [ 16 ]


Specialty drugs might have special requirements for handling procedures and administration including the necessity of having controlled environments such as highly specific temperature controls to ensure product integrity. [ 16 ]  They are often only available via a limited distributions network such as a special pharmacy. [ 3 ]  Specialty drugs may be "challenging for providers to manage". [ 16 ]


Specialty drugs may be taken "by relatively small patient populations presenting with complex medical conditions". [ 16 ]


"Specialty pharmacies have their roots in the 1970s, when they began delivering temperature-controlled drugs to treat cancer, HIV, infertility and hemophilia." [ 28 ]


"The business grew as more drugs became available for patients to inject themselves and as insurers sought to manage expenses for patients with chronic conditions, according to areport from IMS Health. Manufacturers have increasingly relied on these pharmacies when it comes to fragile medicines that need special handling or have potentially dangerous side effects that require them to be taken under a management program."


According to  The American Journal of Managed Care , in 1990 there were 10 specialty drugs on the market. [ 9 ]  According to the  National Center for Biotechnology Information , by the mid-1990s, there were fewer than 30 specialty drugs on the market, but by 2008 that number had increased to 200. [ 10 ]


Specialty drugs may also be designated as orphan drugs or ultra-orphan drugs under the U. S.  Orphan Drug Act of 1983 . This was enacted to facilitate development of orphan drugs—drugs for rare diseases such as  Huntington's disease ,  myoclonus ,  amyotrophic lateral sclerosis ,  Tourette syndrome  and  muscular dystrophy  which affect small numbers of individuals residing in the United States. [ 29 ]


Not all specialty drugs are orphan drugs. According to  Thomson Reuters  in their 2012 publication "The Economic Power of Orphan Drugs", there has been increased investing in  orphan drug  research and development partly since the U.S. Congress enacted the Orphan Drug Act, giving an extra monopoly for drugs for "orphan diseases" that affected fewer than 200,000 people in the country. [ 13 ]  Similar acts came into existence in other regions of the world, many driven by "high-profile philanthropic funding". [ 30 ] [ 31 ]  According to a 2010 article in  Forbes , prior to 1983 drug companies largely ignored rare diseases and focused on drugs that affected millions of patients. [ 13 ]


The term  specialty drugs  was used as early as 1988 in a  New York Times  article about  Eastman Kodak Company 's acquisition of the New York-based  Sterling Drug Inc. , maker of specialty drugs along with many and diverse other products. [ 2 ]  When  Shire Pharmaceuticals  acquired BioChem Pharma in 2000 they created a specialty pharmaceuticals company. [ 32 ]  By 2001 Shire was one of the fastest growing specialty pharmaceutical companies in the world. [ 33 ]


By 2001  CVS 's specialty pharmacy ProCare was the "largest integrated retail/mail provider of specialty pharmacy services" in the United States. [ 34 ] : 10   It was consolidated with their pharmacy benefit management company PharmaCare in 2002. In their 2001 annual report, CVS anticipated that the "$16 billion specialty pharmacy market" would grow at "an even faster rate than traditional pharmacy due in large part to the robust pipeline of biotechnology drugs". [ 34 ]  By 2014 CVS Caremark,  Express Scripts  and  Walgreens  represented more than 50% of the specialty drug market in the United States. [ 35 ] : 4


When an increasing number of oral oncology agents first entered the market between 2000 and 2010, most cancer care was provided in a community oncology practices. By 2008 many other drugs had been developed to treat cancer, and drug development had grown into a multibillion-dollar industry. [ 36 ]


In 2003 the  Medicare Prescription Drug, Improvement, and Modernization Act [ 37 ]  was enacted [ 38 ] —the largest overhaul of  Medicare  in the public health program's 38-year history—included  Medicare Part D  an  entitlement  benefit for  prescription drugs , through tax breaks and subsidies. In 2004 the U. S.  Centers for Medicare and Medicaid Services  (CMS) prepared a report on final guidance regarding access to drug coverage enacted under in which they included the specialty drugs tier in the prescription drug formulary. [ 1 ]  At that time CMS guidelines included four tiers: tier 1 includes preferred generics, tier 2 includes preferred brands, tier 3 includes non-preferred brands and generics and tier 4 included specialty drugs. [ 1 ]  By January 1, 2006, the controversial [ according to whom? ]   Medicare Part D  was put in effect. It was a massive [ clarification needed ]  expansion of the federal government's provision of prescription drug coverage to previously uninsured Americans, particularly seniors. [ 39 ] : 69   In 2006 in the United States there was no standard nomenclature, so sellers could call the plan anything they wanted and cover whatever drugs they wanted. [ 40 ]


By 2008 most prescription medication plans in the United States used specialty drug tiers, and some had a separate benefit tier for injectable drugs. Beneficiary cost sharing was higher for drugs in these tiers. [ 41 ]


By 2011 in the United States a growing number of Medicare Part D health insurance plans—which normally include generic, preferred, and non-preferred tiers with an accompanying rate of cost-sharing or co-payment—had added an "additional tier for high-cost drugs which is referred to as a specialty tier". [ 42 ] : 1


By 2014 in the United States, in the new  Health Insurance Marketplace —following the implementation of the U.S.  Affordable Care Act , also known as Obamacare [ 43 ] —most health plans had a four- or five-tier prescription drug formulary with specialty drugs in the highest of the tiers. [ 44 ]


According to an  AARP  2015 report, "All but 4 of the 46 therapeutic categories of specialty drug products had average annual retail price increases that exceeded the rate of general inflation in 2013. Price increases by therapeutic category ranged from 1.7 percent to 77.2 percent." [ 45 ]


On September 27, 2007 President  George W. Bush  amended the  Food and Drug Administration Amendments Act of 2007  (FDAAA) to authorize the FDA to require  Risk Evaluation and Mitigation Strategies  (REMS) on medications if necessary to minimize the risks associated with some drugs". These medications were designated as specialty drugs and required specialty pharmacies. When the FDA approves a new drug they may require a REMS program which "may contain any combination of 5 criteria: Medication Guide, Communication Plan, Elements to Assure Safe Use, Implementation System, and Timetable for Submission of Assessments". [ 46 ]  "In 2010, 48% of all new molecular entities, and 60% of all new specialty drug approvals, required a REMS program." Risk-reduction mechanisms can include the "use of specialized distribution partners", special pharmacy. [ 47 ]


In 2013 the FDA introduced the  breakthrough therapy  designation program which cut the development process of new therapies by several years. This meant that the FDA could "introduce important medicines to the market based on very promising phase 2 rather than phase 3 clinical trial results". Shortly after the law was enacted,  Ivacaftor , in January 2013, became the first drug to receive the breakthrough therapy designation. [ 48 ]


On February 3, 2015 New York-based  Pfizer 's drug  Ibrance  was approved through the FDA's  Breakthrough Therapy  designation program as a treatment for advanced breast cancer. [ 49 ]  It can only be ordered through specialty pharmacies and sells for "$9,850 for a month or $118,200 per year". [ 50 ]  According to a statement by the New York-based  Pfizer  the price "is not the cost that most patients or payors pay" since most prescriptions are dispensed through health plans, which negotiate discounts for medicines or get government-mandated price concessions. [ 50 ]


According to Express Scripts, [ 51 ]


"[T]he pharmacy landscape [in the United States] underwent a seismic change, and the budgetary impact to healthcare payers was significant. U.S. prescription drug spend increased 13.1% in 2014 – the largest annual increase since 2003 – and this was largely driven by an unprecedented 30.9% increase in spending on specialty medications. Utilization of traditional medications stayed flat (-0.1%), while the use of specialty drugs increased 5.8%. The largest factors contributing to the increased spending, however, were the price increases for these medication categories – 6.5% for traditional and 25.2% for specialty. While specialty medications represent only 1% of all U.S. prescriptions, these medications represented 31.8% of all 2014 drug spend – an increase from 27.7% in 2013."


By 2015 "specialty medications account for one-third of all spending on drugs in the United States, up from 19 percent in 2004 and heading toward 50 percent in the next 10 years, according to IMS Health, which tracks prescriptions". [ 5 ]  The specialty pharmacy business had $20 billion in sales in 2005. By 2014 it had grown to "$78 billion in sales". [ 5 ]  In Canada by 2013 "specialty drugs made up less than 1.3 percent of all Canadian prescriptions, but accounted for 24 percent of Canada's total spending on prescription drugs". [ 52 ]


When Randy Vogenberg of the  Institute for Integrated Healthcare  in Massachusetts and a co-leader of the Midwest Business Group initiative, began investigating specialty drugs in 2003, it "wasn't showing up on the radar". By 2009 specialty drugs had started doubling in cost and payers such as employers began to question. [ 6 ]  Vogenberg observed that by 2014 health care reform had changed the landscape for specialty drugs. There is a shift away from a marketplace based on a predominately clinical perspective, to one that puts economics first and clinical second. [ 53 ] : 15


Many factors contribute to the continuing increase in price of specialty drugs.  Development of specialty drugs not only costs more, but they also take longer to develop than other large market pharmaceuticals [ 54 ]  (See  Drug development ).  In addition, there are often fewer drug choices for rare or hard-to-treat diseases. [ 55 ]   This results in less competition in the marketplace for these drugs due to patent protection, which allows these firms to act as monopolists (See  Drug Price Competition and Patent Term Restoration Act ).  Due to this lack of competition, policies that serve to limit prices in other markets can be ineffective or even counter-productive when applied to specialty drugs. [ 56 ]


High prices for specialty drugs are a problem for both patients and payers.  Patients frequently have difficulty paying for these medications, which can lead to lack of access to treatment. [ 57 ]   Specialty drugs are now so expensive that they are leading to increases in insurance premiums. [ 58 ]   Control of specialty drug prices will require research to identify effective policy options, which may include: decreasing regulation, limiting patent protection, allowing negotiation of drug prices by Medicare, or pricing drugs based on their effectiveness. [ 59 ]


In the United States, private insurance payers will favour a lower-cost agent preferring generics and biosimilars to the more expensive specialty drugs if there is no peer-reviewed or evidence-based justification for them. [ 53 ]


According to a 2012 report by  Sun Life Financial  the average cost of specialty drug claims was $10,753 versus $185 for non-specialty drugs and the cost of specialty drugs continues to rise. With such steep prices by 2012 specialty drugs represented 15-20% of prescription drug reimbursement claims. [ 60 ]


Patient advocacy groups that lobby for payment for specialty drugs include the  Alliance for Patient Access  (AfPA), formed in 2006 and which according to a 2014 article in the  Wall Street Journal  "represents physicians and is largely funded by the pharmaceutical industry. The contributors mostly include brand-name drug makers and biotechs, but some—such as Pfizer and Amgen—are also developing biosimilars." [ 61 ]


In 2013 AfPA director  David Charles  published an article on specialty drugs in which he agreed with the findings of the  Congressional Budget Office  that spending on prescription medications "saves costs in other areas of healthcare spending". [ 62 ]  He observed that specialty drugs are so high priced that many patients do not fill prescriptions resulting in more serious health problems increasing. His article referred to specialty drugs such as "new cancer drugs specially formulated for patients with specific genetic markers". [ 62 ]  He explained the high cost of these "individualized medications based on diagnostic testing; and "biologics", or medicines created through biologic processes, rather than chemically synthesized like most pharmaceuticals". [ 62 ]  He argued that there should be a slight increase in co-pays for the more commonly using lower-tier medications to allow a lower co-pay for those who "require high-cost specialty tier medications". [ 62 ]


According to the 2014 Express Scripts Drug Trend Report, [ 51 ]  the most significant increase in prescription drugs in the United States in 2014 was due to "increased inflation and utilization of hepatitis C and compounded medications". [ 51 ]  "Excluding those two therapy classes, overall drug spend would have increased only 6.4%. [ 51 ]


The cost of "the top three specialty therapy classes—inflammatory conditions, multiple sclerosis and oncology—contributed 55.9% of the spend for all specialty medications billed through the pharmacy benefit in 2014. The U.S. spent 742.6% more on hepatitis C medications in 2014 than it did in 2013; this therapy class was not among the top 10 specialty classes in 2013. [ 51 ]


As the market demanded specialization in drug distribution and clinical management of complex therapies, specialized pharma (SP) evolved. [ 63 ]  By 2001  CVS ' specialty pharmacy ProCare was the "largest integrated retail/mail provider of specialty pharmacy services" in the United States. [ 34 ] : 10   It was consolidated with their pharmacy benefit management company, PharmaCare in 2002 to In their 2001 annual report CVS anticipated that the "$16 billion specialty pharmacy market" would grow at "an even faster rate than traditional pharmacy due in large part to the robust pipeline of biotechnology drugs". [ 34 ]  By 2014 CVS Caremark,  Express Scripts  and  Walgreens  represented more than 50% of the specialty drug market in the United States. [ 35 ] : 4


The  specialty pharmacy  business had $20 billion in sales in 2005. By 2014 it had grown to "$78 billion in sales". [ 5 ]


Specialty pharmacies came into existence to as a result of unmet needs. According to the  National Comprehensive Cancer Network  the "primary goals of specialty pharmacies are to ensure the appropriate use of medications, maximize drug adherence, enhance patient satisfaction through direct interaction with healthcare professionals, minimize cost impact, and optimize pharmaceutical care outcomes and delivery of information". [ 64 ]


McKesson Specialty Care Solutions, a division of McKesson Corporation, is "one of the largest distributors of specialty drugs, biologics and rheumatology drugs to community-based specialty practices". It is "a leader in the development, implementation and management of FDA-mandated Risk Evaluation and Mitigation Strategies (REMS) for manufacturers". [ 65 ]  For example, in order ProStrakan Group plc, an international pharmaceutical company based in the UK works with McKesson Specialty Care Solutions to administer its FDA-approved Risk Evaluation and Mitigation Strategy (REMS) program for  Abstral . [ 65 ]


URAC's Specialty Pharmacy Accreditation "provides an external validation of excellence in Specialty Pharmacy Management and provides Continuous Quality Improvement (CQI) oriented processes that improve operations and enhance compliance". [ 15 ]


Specialty pharmaceuticals or biologics are a significant part of the treatment market, yet there is still additional work that should be done to manage costs.  Defining biologics has been described as a matter of perspective, with variation between chemists, physicians, payers, microbiologists and regulators. [ 66 ]  A payer may define a biologic by cost, while a biochemist may look at composition and structure and a provider at means of delivery or action on the body. [ 66 ]   The FDA generally defines biologics as, "a wide range of products [that] ...can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources—human, animal, or microorganism—and may be produced by biotechnology methods and other cutting-edge technologies". [ 67 ]


Due to the complexity, risk of adverse events and allergic reactions associated with biologics, management is very important for the safety of patients. [ 68 ]   Management includes areas from patient education and adherence to the delivery of the medication.  These medications often require very specific storage conditions and monitoring of temperature, the level of agitation and proper reconstitution of the drug . [ 68 ]   Because of the high risk of error and adverse events, provider management of delivery is required, especially for injection or infusion of some biologic medications. Such biologics are often coded in a way that ties reimbursement to delivery by a provider—either a specialty pharmacist or medical care provider with those skills. [ 69 ]    As more biologics are being designed to be self-administered pharmacists are supporting the management of these drugs.  They make calls to remind patients of the need for refills, provide education to patients, monitor patients for adverse events and work with primary care provider offices to monitor the outcomes of the medication. [ 69 ]


The high cost of specialty pharmaceuticals is one of their defining characteristics; as such, cost-containment is high on the list of all the players in the arena.  For physician-administered biologics, cost-containment is often handled by volume purchasing of biologic drugs for discounted pricing, formularies, step therapy to attempt other treatment before beginning biologics and administrative fees by insurers to keep physicians from artificially inflating requested reimbursement from insurance companies. [ 70 ] [ 69 ] [ 68 ]   Cost-containment for self-administered biologics tends to occur via requiring authorization to be prescribed those drugs and benefit design, such as coinsurance for cost-sharing. [ 70 ] [ 69 ]


The 21st Century Cures Act which addressed fast-tracking approval of specialty pharmaceuticals was particularly beneficial for dealing with the development of 2nd run biologics (which might be more easily understood as "generic biologics", though they do not exist). [ 71 ]   Debate around the act raised some important questions about the efficacy of biologics and their continued high costs. Some call for insurers to pay only the cost of production to manufacturers until the benefit of these biologics can be proven long-term, stating that insurers should not bear the full cost of products that may be unreliable or have only limited efficacy. [ 71 ]


Achieving this would require conducting studies that assess value, such as comparative effectiveness studies and using those studies to determine pricing. Comparative effectiveness would examine all aspects of the use of biologics, from outcomes such as clinical benefits and potential harms, to efficiency of administration, public health benefits and patient productivity after treatment. [ 72 ]   This is a new direction in managing the high costs of specialty pharmaceuticals and not without challenges.  One of the barriers is strict regulation by the Food and Drug Administration of what pharmaceutical manufacturers may communicate to the public, limiting that communication to formulary committees for managed care, for example. [ 73 ]    Additionally, studies tend to be constructed using observational design, instead of as randomized controlled trials, limiting their usefulness for real-world application. [ 73 ]


Difficulties experienced with patient adherence to specialty pharmaceuticals also limit the availability of real-world outcomes data for biologics. [ 71 ] [ 69 ]   In 2016, real world data evaluating the efficacy of biologics was only publicly available for multiple myeloma through ICER (where biologics were found to be overpriced for their outcomes) [ 72 ]  and for hepatitis C treatment (which achieved high cure rates—90%—for patients co-infected with HIV and Hep C) through Curant Health. [ 71 ]    These studies show how useful value-based pricing may become for cost-containment in the field.  The good news is that there are effectiveness studies on biologics currently underway aiming to provide more of this data. [ 71 ]


Biologics or biological products for human use are regulated by the  Center for Biologics Evaluation and Research  (CBER), overseen by the  Office of Medical Products and Tobacco , within the U.S. Food and Drug Administration which includes the  Public Health Service Act  and the  Federal Food, Drug and Cosmetic Act . [ 74 ]  "CBER protects and advances the public health by ensuring that biological products are safe and effective and available to those who need them. CBER also provides the public with information to promote the safe and appropriate use of biological products."


There are multiple players in specialty drugs including the employer, the health plan, the  pharmacy benefits manager  and it is unclear who should be in charge of controlling costs and monitoring care. [ 6 ]  Pharmacies generally buy a product from a wholesaler and sell (Buy & Bill) it to the patient and provide basic drug use information and counseling. According to Maria Hardin, vice president of patient services for the  National Organization for Rare Disorders , an alliance of voluntary health and patient advocacy groups working with rare diseases, "As the cost of drugs increases, management of the financial side has gotten more complex... The issues range from Medicare Part D to tiered benefits, prior authorizations, and no benefits. These patients need a pharmacy with the expertise and the clout to go to bat for them. If the patient doesn't get treated, the specialty pharmacy doesn't get paid." [ 75 ]


Alexion Pharmaceuticals was one of the pioneers in the use of a business model of developing drugs to combat rare diseases. "Knowing the value of specialty drugs as well as its own stock is Alexion's business." [ 76 ]  Since other big pharmaceutical companies had tended to ignore these markets, Alexion had minimal competition at first. Insurance companies have generally been willing to pay high prices for such drugs; since few of their customers need the drugs, a high price does not significantly impact the insurance companies outlays. [ 76 ]  Alexion is thus seeking a stronger position in the lucrative rare disease market, and is willing to pay a premium to obtain that position. [ 14 ] [ 76 ]   The rare disease market is seen as desirable because insurers have minimal motive to deny claims (due to small population sizes of patients) and are unable to negotiate better drug prices due to lack of competition. of May 2015, Alexion is currently seeking approval of its second drug, Strensiq.  It will be used to treat hypophosphatasia, a rare metabolic disorder. In 2015 Alexion estimated that Synageva, its specialty drug for  lysosomal acid lipase deficiency , a fatal genetic disorder, could eventually have annual sales of more than $1 billion. [ 14 ] [ 77 ]


Companies like Magellan RX Management provide a "single source for high-touch patient care management to control side effects, patient support and education to ensure compliance or continued treatment, and specialized handling and distribution of medications directly to the patient or care provider. Specialty medications may be covered under either the medical or pharmacy benefit." [ 4 ]


According to an article published in 2014 in the journal  Pharmacoeconomics , [ 78 ]  "[s]pecialty pharmacies combine medication dispensing with clinical disease management. Their services have been used to improve patient outcomes and contain costs of specialty pharmaceuticals. These may be part of independent pharmacy businesses, retail pharmacy chains, wholesalers, pharmacy benefit managers, or health insurance companies. Over the last several years, payers have been transitioning to obligate beneficiaries to receive self-administered agents from contracted specialty pharmacies, limiting the choice of acceptable specialty pharmacy providers (SPPs) for patient services." [ 78 ]


Managed care organizations  contract with Specialty Pharmacy vendors. "Managed care organizations (MCOs) are using varied strategies to manage utilization and costs. For example, 58% of 109 MCOs surveyed implement prior authorizations for MS specialty therapies." [ 78 ]  The  Academy of Managed Care Pharmacy  (AMCP) designates a product as a specialty drug if "[i]t requires a difficult or unusual process of delivery to the patient (preparation, handling, storage, inventory, distribution, Risk Evaluation and Mitigation Strategy (REMS) programs, data collection, or administration) or, Patient management prior to or following administration (monitoring, disease or therapeutic support systems)". [ 79 ]  Health plans consider "high cost" (on average a minimum monthly costs of $US1,200) to be is a determining factor in identifying a specialty drug. [ 79 ]


Tom Westrich, of St. Louis, Missouri-based Centric Health Resources, a specialty pharmacy, described how their specialty drugs treat  ultra-orphan diseases  with a total patient population of 20,000 nationwide. [ 75 ]


The top ten specialty pharmacies in 2014 were CVS Specialty parent company  CVS Health  with $20.5B in sales,  Express Scripts 's  Accredo  at $15B,  Walgreens Boots Alliance 's Walgreens Specialty at $8.5B,  UnitedHealth Group 's  OptumRx  at $2.4B, Diplomat Pharmacy at $2.1B,
 Catamaran 's BriovaRx at $2.0B, Specialty Prime Therapeutics's  Prime Therapeutics  at $1.8B,  Omnicare 's Advanced Care Scripts at $1.3B,  Humana 's RightsourceRx at $1.2B, Avella at $0.8B. All the other specialty pharmacies accounted for $22.4B of sales in 2014 with a total of $78B. [ 80 ]


In 2010 the United States enacted a new health law which had unintended consequences. Because of the 2010 law, drug companies like  Genentech  informed children's hospitals that they would no longer get discounts for certain cancer medicines such as the orphan drugs  Avastin ,  Herceptin ,  Rituxan ,  Tarceva , or  Activase . This cost hospitals millions of dollars. [ 81 ]


There is a debate about whether specialty drugs should be managed as a medical benefit or a pharmaceutical benefit. Infused or injected medications are usually covered under the medical benefit and oral medications are covered under the pharmacy benefit. Self-injected medications may be either. [ 82 ]  "Many biologics, such as chemotherapy drugs, are administered in a doctor's office and require extensive monitoring, further driving up costs." [ 6 ]  Chemotherapy is usually  delivered   intravenously , although a number of agents can be administered orally (e.g. specialty drugs,  melphalan  (trade name Alkeran),  busulfan ,  capecitabine ).  Delcath Systems, Inc.  (NASDAQ: DCTH) a specialty pharmaceutical and medical device company manufactures melphalan. [ 83 ]


By 2011 the oral medications for cancer patients represented approximately 35% of cancer medications. Prior to the increase in cancer oral drugs community cancer centers were used to managing office-administered  chemotherapy  treatments. At that time "the majority of community oncology practices were unfamiliar with the process of prescribing and obtaining drugs that are covered under the pharmacy benefit" and "conventional retail pharmacy chains were ill-prepared to stock oral oncology agents, and were not set up to deliver the counseling that often accompanies these medications". [ 84 ]


According to  IMS Health  "Specialty pharmaceutical spending is on the rise and is expected to increase from approximately $55 billion in 2005 to $1.7 trillion in 2030, according to the Pharmaceutical Care Management Association. That reflects an increase from 24% of total drug spend in 2005 to an estimated 44% of a health plan's total drug expenditure in 2030." [ 35 ]


While CVS, Accredo, and Walgreens led the Specialty Pharmacies (SP) market in revenue in 2014, there are constant changes through mergers and acquisitions in terms of SPs and specialty distributors (SDs). [ 85 ]  The SP/SD network faces common strengths such as "in-depth clinical management, coordinated/comprehensive care, and early limited distribution network success" and common weaknesses, "lack of ability to customize services, poor integration experience and outcomes, and strained pharma relations". [ 85 ]   BioScrip  was acquired by Walgreens in 2012. [ 86 ]  Specialty companies like Genzyme and MedImmune were acquired and are transitioning to a new business model. [ 53 ] : 12


According to Nicolas Basta, by 2013 there was "a spate of new entities" called hub services, "mechanisms by which manufacturers can keep a grip on the marketplace" in specialty pharma. The "biggest and oldest of these organizations" are "offshoots of insurance companies or [Pharmacy benefit managers] PBMs, such as Express Scripts' combination of  Accredo  and CuraScript (both specialty pharmacies) and HealthBridge (physician and patient support). UnitedHealth, an insurance company, operates OptumRx, a PBM, which has a specialty unit within it. Cigna has Tel-Drug, a mail-order pharmacy and support system." [ 87 ]  Basta described how Hubs have been around since about 2002 "starting out as "reimbursement hubs"", usually provided as a service by manufacturers to help patients and providers navigate the process of obtaining permission to use, and reimbursement for, expensive specialty therapies". Industry observers look to pioneering efforts by  Genentech  and  Genzyme  under the tenure of  Henri Termeer , "when some of their earliest biotech products entered the marketplace". [ 87 ]  Specialty hubs provide reimbursement support to physicians and patients as well as patient education including medical hotlines. There is a voluntary program enrollment and registry intake with Patient Assistance Program management.


According to a 2007 study by employees of  Express Scripts  or its wholly owned subsidiary  CuraScript  on specialty pharmacy costs, if payers manage cost control through copayments with patients, there is an increased risk that patients will forego essential but expensive specialty drugs. [ 88 ] : 6   and health outcomes were compromised. [ 39 ] : 69   In 2007 these researchers suggested in the adoption of formularies and other traditional drug-management tools. They also recommended specialty drug utilization management programs that guide treatment plans and improve outpatient compliance. [ 88 ] : 88


By 2010  Alexion Pharmaceuticals 's  Soliris , was considered to be the most expensive drug in the world. [ 13 ]


In a 2012 article in the  New York Times,  journalist Andrew Pollack described how  Don M. Bailey , a mechanical engineer by training who became interim president of Questcor Pharmaceuticals, Inc. (Questcor) in May 2007, initiated a new pricing model for  Acthar  in August 2007 [ 89 ]  when it was classified by FDA as an  orphan drug  and a specialty drug to treat infantile spasms. [ 90 ]  Questcor, a biopharmaceutical company, focuses on the treatment of patients with "serious, difficult-to-treat autoimmune and inflammatory disorders". Its primary product is FDA-approved Acthar, an injectable drug that is used for the treatment of 19 indications. [ 91 ]  At the same time Questcor created "an expanded safety net for patients using Acthar", provided a "group of  Medical Science Liaisons  to work with health care providers who are administering Acthar" and limited distribution to its sole specialty distributor,  Curascript . The 2007 pricing model brought "Acthar in line with the cost of treatments for other very rare diseases". [ 89 ]  The cost for a course of treatment in 2007 was estimated at about "$80,000–$100,000". [ 89 ]  Acthar is now manufactured through a contractor on  Prince Edward Island , Canada. [ 91 ]  The price increased from $40 a vial to $700 and continued to increase. [ 90 ]  By 2012 the price of a vial of Acthar was $28,400. [ 90 ]  and was considered to be one of the world's most expensive drugs in 2013.


By 2014 the price of  Gilead 's specialty drug for hepatitis C,  Sovaldi  or  sofosbuvir , was $84,000 to $168,000 for a course of treatment in the U.S., £35,000 in the UK for 12 weeks. [ 92 ]  Sovaldi is on the  World Health Organization's most important medications needed  in a basic health system and the steep price is highly controversial. [ 93 ] [ 94 ] [ 95 ]  In 2014 the U.S. spent 742.6% more on hepatitis C medications than it did in 2013. [ 51 ]


In September 2015,  Martin Shkreli  was criticized by several health organizations [ 96 ]  for obtaining manufacturing licenses on old,  out-of-patent , [ 97 ]  life-saving medicines including pyrimethamine (brand name  Daraprim ), which is used to treat patients with  toxoplasmosis ,  malaria , some cancers, and  AIDS , [ 98 ]  and then increasing the price of the drug in the US from $13.50 to $750 per pill, a 5,455% increase. [ 99 ] [ 100 ]  In an interview with  Bloomberg News , Shkreli claimed that despite the price increase, patient co-pays would be lower, that many patients would get the drug at no cost, that the company has expanded its free drug program, and that it sells half of the drugs for one dollar. [ 101 ] [ 102 ]


In 2015  Bloomberg News  used the term 'captive pharmacies' to describe the alleged exclusive agreements such as that between the specialty mail-order pharmacy  Philodor  and  Valeant , mail-order pharmacy  Linden Care  and  Horizon Pharma Plc . In November 2015  Express Scripts  Holding Co.—the largest U.S. manager of prescription drug benefits—"removed the mail-order pharmacy Linden Care LLC from its network after concluding it dispensed a large portion of its medications from Horizon Pharma Plc and didn't fulfill its contractual agreements". Express Scripts was "evaluating other 'captive pharmacies' that it said are mostly distributing Horizon drugs". In 2015 specialty pharmacies like "Philidor drew attention for the lengths they went to fill prescriptions with brand-name drugs and then secure insurance reimbursement. [ 28 ]


According to Pfenex, a clinical-stage biotechnology company, the proposed terms in the Trans-Pacific Partnership, a trade agreement between twelve  Pacific Rim  countries, meant that all participating countries had to adopt the United States' lengthy drug patent exclusivity protection period of 12 years for biologics and specialty drugs. [ 103 ]


In 1981 an episode of the television series  Quincy, M.E.  starring star,  Jack Klugman  as Quincy, entitled "Seldom Silent, Never Heard" brought the plight of children with orphan diseases to public attention. In the episode, Jeffrey, a young boy with  Tourette syndrome , died after falling from a building. Dr. Arthur Ciotti ( Michael Constantine ), a medical doctor who had been researching Tourette syndrome for years wanted to study Jeffrey's brain to discover the cause and cure for the rare disease. He explained to Quincy that drug companies, like the one where he worked, were not interested in doing the research because so few people were afflicted with them that it was not financially viable. [ 104 ]  In 1982 another episode "Give Me Your Weak" Klugman as Quincy testified before Congress in an effort to get the Orphan Drug Act passed. He was moved by the dilemma of a young mother with  myoclonus . [ 13 ] [ 105 ] [ 106 ] [ 107 ] [ 108 ]


Stem-cell therapy  uses  stem cells  to treat or prevent a disease or condition. [ 1 ]  As of 2024 [update] , the only FDA-approved therapy using stem cells is  hematopoietic stem cell transplantation . [ 2 ] [ 3 ]  This usually takes the form of a  bone marrow  or  peripheral blood stem cell  transplantation, but the cells can also be derived from  umbilical cord blood . Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for  neurodegenerative diseases [ 4 ]  and conditions such as  diabetes  and  heart disease .


Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture  embryonic stem cells , to create stem cells using  somatic cell nuclear transfer , and their use of techniques to create  induced pluripotent stem cells . This controversy is often related to  abortion politics  and   human cloning . Additionally, efforts to market treatments based on transplant of stored umbilical  cord blood  have been controversial.


For over 90 years,  hematopoietic stem cell transplantation  (HSCT) has been used to treat people with conditions such as  leukemia  and  lymphoma ; this is the only widely practiced form of stem-cell therapy. [ 5 ] [ 6 ] [ 7 ]  During  chemotherapy , most growing cells are killed by the  cytotoxic  agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the  hematopoietic stem cells  within the bone marrow. This is the side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to  graft vs host disease , the most serious side effect of this treatment. [ 8 ]


Another stem-cell therapy, called  Prococvhymal , was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids. [ 9 ]  It is an  allogenic stem therapy  based on  mesenchymal stem cells  (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed. [ 10 ]


The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases. [ 11 ]


In 2014, the  European Medicines Agency  recommended approval of  limbal stem cells  for people with severe limbal stem cell deficiency due to burns in the eye. [ 12 ]


Stem cells are being studied for several reasons. The molecules and  exosomes  released from stem cells are also being studied in an effort to make medications. [ 13 ]  In addition to the functions of the cells themselves,  paracrine soluble factors  produced by stem cells, known as the  stem cell secretome , have been found to be another mechanism by which stem cell-based therapies mediate their effects in  degenerative ,  autoimmune , and  inflammatory  diseases. [ 14 ]