Beginning in 2020, FDB partnered with  Amazon  and its  Alexa  devices to provide drug information and answer medication questions. [ 4 ]


During the  COVID-19 pandemic , FDB posted drug data (regarding  remdesivir ,  chloroquine , and  hydroxychloroquine ) and medical device-related coronavirus information to its website. [ 5 ]


In August 2021, the company announced a partnership with RxRevu to provide integrated decision support tools to improve patient access to care, delivering patient-specific pharmacy benefit information to  EHR  workflows via direct connections with pharmacy benefit managers. The technology displays accurate, real-time data at the point of prescribing, allowing physicians to find affordable alternatives for medications specific to a patient's health needs and insurance benefits. FDB will offer RxRevu's prescription cost and coverage solution to current and future hospital, health system, and EHR clients. [ 6 ]


First Databank's MedKnowledge provides prices, descriptions, and collateral clinical information on drugs approved by the US  Food and Drug Administration  (FDA), plus unapproved drugs, commonly used  over-the-counter drugs ,  herbal remedies , medical foods and nutritional supplements.


First Databank has developed a drug ordering knowledge base that enables physicians to look up and order drugs. Drug orders are generated based on patient parameters such as age, weight, renal and hepatic impairment, thereby reducing lists of candidate drugs to a minimum. The database is expected to affect the number of  adverse drug reactions  and side effects at facilities that have adopted the electronic order entry systems.


A web-based software tool that enables institution-specific modification of medication alerts using FDB MedKnowledge clinical modules based on clinician input, localized clinical experience, and other available evidence. The tool allows users to edit or turn off individual alerts, track all alert customizations and create an audit record, and view FDB updates in comparison with the user's own modifications. Users can load the results of their modifications directly into their medication  decision support system  for immediate use in the workflow. The approach follows the normal update process.


The FDB Prizm medical device database provides structured, categorized, and normalized information about medical device products that are implanted into patients; hospital and durable medical equipment; and medical supplies. The medical device content comes from a variety of sources such as the FDA, medical device manufacturers, and industry data pools. Also, it encompasses additional information from clinical, operational, and financial attributes and codes. Use of this database within supply chain and other information systems is designed to help decision makers to build and maintain device libraries, identify and document medical devices in case of recalls and adverse events, and group and analyze medical device utilization.


Meducation comprises simplified medication instructions and medication regimen calendars using patient-specific information from the electronic health record (EHR). All material is written at a 5th to 8th grade reading level with supporting pictograms in more than 20 languages and is designed to help reduce medication errors and improve medication adherence for all patients. [ 7 ]


FDB Targeted Medication Warnings provides patient-specific clinical decision support (CDS) for medications and is integrated directly into the EHR workflow. This content uses lab results, risk scores, and other patient data to suggest clinical guidance that is most relevant to the patient context. The CDS derived from this solution provides specificity for clinical decisions and is linked to the related generic medication alerts which can be filtered out/customized using FDB AlertSpace. [ 8 ]


FDB Pet MedKnowledge is a comprehensive drug database with veterinary FDA approved medications, allowing veterinarians to access pet medication information whenever and wherever is needed. The service is modeled on the FDB MedKnowledge human medication database. [ 9 ]


A consumer coalition filed separate suits in a  Boston, Massachusetts federal court  against drug wholesaler  McKesson Corporation  and First Databank, accusing the companies of artificially inflating drug prices.  The lawsuits say that McKesson and FDB conspired from 2002 through 2005 to set the list prices artificially high.  The suit against First DataBank accused it of limiting its survey of wholesalers to a single company, McKesson. [ 10 ]


First Databank agreed to a settlement, tentatively approved by the federal court, in which it would not pay damages to the plaintiffs, but agreed to reduce  average wholesale prices  (AWPs) listed in its databases by five percent for about 2,033 drugs. [ 11 ]  McKesson chose to fight the suits.


The settlement required First DataBank (FDB) to reduce the AWP mark-up from 1.25 to 1.20 times the Wholesale Acquisition Cost (WAC) for 1,442 NDCs identified in the litigation. FDB set the mark-up at 1.20 for all drugs independent of the litigation on September 26, 2009. The roll back of the WAC-to-AWP spread led to a 4% reduction in their AWP. FDB also stopped publishing AWP data on September 26, 2011, two years after the rollback adjustments were implemented. First DataBank continues to publish non-AWP drug pricing information, including WAC, Direct Price, and suggested wholesale price. [ 12 ]


A  generic drug  is a  pharmaceutical drug  that contains the same chemical substance as a drug that was originally protected by  chemical patents . Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active chemical substance is the same, the medical profile of generics is equivalent in performance compared to their performance at the time when they were patented drugs. [ 1 ] [ 2 ]  A generic drug has the same  active pharmaceutical ingredient  (API) as the original, but it may differ in some characteristics such as the manufacturing process,  formulation ,  excipients , color, taste, and packaging. [ 2 ]


Although they may not be associated with a particular company, generic drugs are usually subject to government regulations in the countries in which they are dispensed. They are labeled with the name of the manufacturer and a generic non-proprietary name such as the  United States Adopted Name  (USAN) or  International Nonproprietary Name  (INN) of the drug. A generic drug must contain the same  active ingredients  as the original brand-name formulation. The  U.S. Food and Drug Administration  (FDA) requires generics to be identical to or within an acceptable  bioequivalent  range of their brand-name counterparts, with respect to  pharmacokinetic  and  pharmacodynamic  properties. [ 3 ]


Biopharmaceuticals , such as  monoclonal antibodies , differ biologically from  small-molecule drugs .  Biosimilars  have active pharmaceutical ingredients that are almost identical to the original product and are typically regulated under an extended set of rules, but they are not the same as generic drugs as the active ingredients are not the same as those of their reference products. [ 4 ]  In most cases, generic products become available after the  patent  protections afforded to the drug's original developer expire. Once generic drugs enter the market, competition often leads to substantially lower prices for both the original brand-name product and its generic equivalents. In most countries, patents give 20 years of protection. However, many countries and regions, such as the  European Union  and the  United States , [ 5 ]  may grant up to five years of additional protection ("patent term restoration") if manufacturers meet specific goals, such as conducting  clinical trials  for  pediatric  patients. [ 6 ]


Manufacturers, wholesalers, insurers, and drugstores can all increase prices at various stages of production and distribution. [ 7 ]  In 2014, according to an analysis by the Generic Pharmaceutical Association, generic drugs accounted for 88 percent of the 4.3 billion prescriptions filled in the United States. [ 8 ] : 2   "Branded generics" on the other hand are defined by the FDA and  National Health Service  as "products that are (a) either novel dosage forms of off-patent products produced by a manufacturer that is not the originator of the molecule, or (b) a molecule copy of an off-patent product with a trade name." [ 9 ]  Since the company making branded generics can spend little on  research and development , it is able to spend on marketing alone, thus earning higher profits and driving costs down. [ 10 ]  For example, the largest revenues of  Ranbaxy , now owned by  Sun Pharma , came from branded generics. [ 11 ] [ 12 ]


Generic drug names are constructed using standardized  affixes  that distinguish drugs between and within classes and suggest their action. [ citation needed ]


When a pharmaceutical company first markets a drug, it is usually under a  patent  that, until it expires, the company can use to exclude competitors by suing them for  patent infringement . [ 13 ]  Pharmaceutical companies that develop new drugs generally only invest in drug candidates with strong patent protection as a strategy to recoup their costs of  drug development  (including the costs of the drug candidates that fail) and to make a profit. [ 14 ]  The average cost to a brand-name company of discovering, testing, and obtaining regulatory approval for a new drug, with a  new chemical entity , was estimated to be as much as US$800 million in 2003 [ 15 ]  and US$2.6  billion  in 2014. [ 16 ]  Drug companies that bring new products have several  product line extension  strategies they use to extend their exclusivity, some of which are seen as gaming the system and labeled " evergreening " by critics, but at some point there is no patent protection available. [ 13 ]  For as long as a drug patent lasts, a brand-name company enjoys a period of market exclusivity, or  monopoly , in which the company is able to set the price of the drug at a level that maximizes profit. This profit often greatly exceeds the development and production costs of the drug, allowing the company to offset the cost of research and development of other drugs that are not profitable or do not pass clinical trials. [ 7 ]  The impact of loss of patent exclusivity on pharmaceutical products varies significantly across different product classes (e.g., biologics vs. small molecules), largely due to regulatory, legal and manufacturing hurdles associated with such products. Indeed, the greater degree of 'brand-brand' competitive dynamics seen in the biologics and complex generics space allows manufacturers of originators to better protect market share following loss of patent exclusivity. [ 17 ]


Large pharmaceutical companies often spend millions protecting their patents from generic competition. [ 7 ]  Apart from litigation, they may reformulate a drug or license a subsidiary (or another company) to sell generics under the original patent. Generics sold under license from the patent holder are known as  authorized generics . [ 18 ]  Generic drugs are usually sold for significantly lower prices than their branded equivalents and at lower  profit margins . [ 19 ]  One reason for this is that competition increases among producers when a drug is no longer protected by patents. [ 19 ]  Generic companies incur fewer costs in creating generic drugs—only the cost of manufacturing, without the costs of  drug discovery  and  drug development —and are therefore able to maintain  profitability  at a lower price. [ 19 ] [ 20 ] [ 21 ]  The prices are often low enough for users in less-prosperous countries to afford them. [ citation needed ]  Generic drug companies may also receive the benefit of the previous marketing efforts of the brand-name company, including advertising, presentations by drug representatives, and distribution of free samples. Many drugs introduced by generic manufacturers have already been on the market for a decade or more and may already be well known to patients and providers, although often under their branded name. [ citation needed ]


India is a leading country in the world's generic drugs market, exporting US$20.0 billion worth of drugs in the 2019–20 (April–March) year. [ 22 ]  India exports generic drugs to the United States and the European Union. [ 23 ]  also the according to market research community the Global Generic Drugs Market was evaluated US$465.96 million in 2021 and is expected to rise with a CAGR of 5.5% from 2022- 2028 during the forecast period. [ 24 ]  In the United Kingdom, generic drug pricing is controlled by the government's reimbursement rate. The price paid by pharmacists and doctors is determined mainly by the number of license holders, the sales value of the original brand, and the ease of manufacture. A typical price decay graph will show a "scalloped" curve, [ 25 ]  which usually starts at the brand-name price on the day of generic launch and then falls as competition intensifies. After some years, the graph typically flattens out at approximately 20% of the original brand price. In about 20% of cases, the price "bounces": Some license holders withdraw from the market when the selling price dips below their cost of goods, and the price then rises for a while until the license holders re-enter the market with new stock. [ 26 ] [ 27 ]  The NHS spent about £4.3 billion on generic medicines in 2016–17. [ 28 ]  In 2012, 84 percent of prescriptions in the US were filled with generic drugs, [ 29 ]  and in 2014, the use of generic drugs in the United States led to US$254 billion in health care savings. [ 8 ] : 2


In the mid-2010s the generics industry began transitioning to the end of an era of giant  patent cliffs  in the pharmaceutical industry; patented drugs with sales of around US$28 billion were set to come off patent in 2018, but in 2019 only about US$10 billion in revenue was set to open for competition, and less the next year. Companies in the industry have responded with  consolidation  or turning to try to generate new drugs. [ 30 ]  Most developed nations require generic drug manufacturers to prove that their formulations are bioequivalent to their brand-name counterparts. [ 31 ] [ 32 ] [ 33 ] [ 34 ] [ 35 ] [ 36 ]  Bioequivalence does not mean generic drugs must be exactly the same as the brand-name product ("pharmaceutical equivalent"). Chemical differences may exist; a different  salt  or  ester  may be used, for instance. Different inactive ingredients means that the generic may look different from the originator brand; [ 37 ]  however, the therapeutic effect of the drug must be the same ("pharmaceutical alternative"). [ citation needed ]  Most small molecule drugs are accepted as bioequivalent if their  pharmacokinetic  parameters of  area under the curve  (AUC) and  maximum concentration  (C max ) are within a 90%  confidence interval  of 80–125%; most approved generics in the US are well within this limit. [ 38 ]  For more complex products—such as  inhalers ,  patch delivery systems ,  liposomal preparations , or biosimilar drugs—demonstrating pharmacodynamic or clinical equivalence is more challenging. [ 39 ]


Enacted in 1984, the  Drug Price Competition and Patent Term Restoration Act , informally known as the Hatch–Waxman Act, standardized procedures for recognition of generic drugs.  In 2007, the FDA launched the Generic Initiative for Value and Efficiency (GIVE): [ 40 ]  an effort to modernize and streamline the generic drug approval process, and to increase the number and variety of generic products available. [ citation needed ]


Before a company can market a generic drug, it needs to file an  Abbreviated New Drug Application  (ANDA) with the Food and Drug Administration, seeking to demonstrate therapeutic equivalence to a previously approved "reference-listed drug" and proving that it can manufacture the drug safely and consistently. [ 41 ]  For an ANDA to be approved, the FDA requires that the 90% confidence interval of the geometric mean test/reference ratios for the total drug exposure (represented by the area under the curve or AUC) and the maximum plasma concentration (Cmax) should fall within limits of 80–125%. [ 42 ]  (This range is part of a statistical calculation, and does not mean that generic drugs are allowed to differ from their brand-name counterparts by up to 25 percent.) The FDA evaluated 2,070 studies conducted between 1996 and 2007 that compared the absorption of brand-name and generic drugs into a person's body. The average difference in absorption between the generic and the brand-name drug was 3.5 percent, comparable to the difference between two batches of a brand-name drug. [ 43 ] [ 44 ]  Non-innovator versions of biologic drugs, or biosimilars, require clinical trials for  immunogenicity  in addition to tests establishing bioequivalency. These products cannot be entirely identical because of batch-to-batch variability and their biological nature, and they are subject to extra rules. [ 45 ]


When an application is approved, the FDA adds the generic drug to its  Approved Drug Products with Therapeutic Equivalence Evaluations  list and annotates the list to show the equivalence between the reference-listed drug and the generic. The FDA also recognizes drugs that use the same ingredients with different bioavailability and divides them into therapeutic equivalence groups. [ 41 ]  For example, as of 2006,  diltiazem hydrochloride  had four equivalence groups, all using the same active ingredient, but considered equivalent only within each group. [ 46 ]


In order to start selling a drug promptly after the patent on innovator drug expires, a generic company has to file its ANDA well before the patent expires. This puts the generic company at risk of being sued for patent infringement, since the act of filing the ANDA is considered "constructive infringement" of the patent. [ 41 ]  In order to incentivize generic companies to take that risk the Hatch-Waxman act granted a 180-day administrative exclusivity period to generic drug manufacturers who are the first to file an ANDA. [ 47 ]


When faced with patent litigation from the drug innovator or patent holder, generic companies will often counter-sue, challenging the validity of the patent. [ 48 ] [ 49 ] [ 50 ] [ 51 ] [ 52 ]  Like any litigation between private parties, the innovator and generic companies may choose to settle the litigation. Some of these settlement agreements have been struck down by courts when they took the form of  reverse payment patent settlement  agreements, in which the generic company basically accepts a payment to drop the litigation, delaying the introduction of the generic product and frustrating the purpose of the Hatch–Waxman Act. [ 53 ] [ 54 ]


Innovator companies sometimes try to maintain some of the revenue from their drug after patents expire by allowing another company to sell an  authorized generic ; a 2011 FTC report found that consumers benefitted from lower costs when an authorized generic was introduced during the 180 day exclusivity period, as it created competition. [ 55 ] [ 56 ]  Innovator companies may also present arguments to the FDA that the ANDA should not be accepted by filing an  FDA citizen petition .  The right of individuals or organizations to petition the federal government is guaranteed by the First Amendment to the United States Constitution. [ 57 ]   For this reason, the FDA has promulgated regulations that provide, among other things, that at any time, any "interested person" can request that the FDA "issue, amend, or revoke a regulation or order," and set forth a procedure for doing so. [ 58 ] [ 59 ]


Some generic drugs are viewed with suspicion by doctors. For example,  warfarin  (Coumadin) has a narrow  therapeutic window  and requires frequent blood tests to make sure patients do not have a subtherapeutic or a toxic level. A study performed in  Ontario  showed that replacing Coumadin with generic warfarin was safe, [ 60 ]  but many physicians are not comfortable with their patients taking branded generic equivalents. [ 61 ]  In some countries (for example, Australia) where a drug is prescribed under more than one brand name, doctors may choose not to allow pharmacists to substitute a brand different from the one prescribed unless the consumer requests it. [ 62 ]


A series of scandals around the approval of generic drugs in the late 1980s shook public confidence in generic drugs; there were several instances in which companies obtained bioequivalence data fraudulently, by using the branded drug in their tests instead of their own product, and a congressional investigation found corruption at the FDA, where employees were accepting bribes to approve some generic companies' applications and delaying or denying others. [ 29 ] [ 63 ] [ 64 ] [ 65 ]


In 2007,  North Carolina Public Radio 's  The People's Pharmacy  began reporting on consumers' complaints that generic versions of  bupropion  (Wellbutrin) were yielding unexpected effects. [ 66 ]  Subsequently,  Impax Laboratories 's 300 mg extended-release tablets, marketed by  Teva Pharmaceutical Industries , were withdrawn from the US market after the FDA determined in 2012 that they were not bioequivalent. [ 67 ] [ 68 ]


Problems with the quality of generic drugs – especially those produced outside the United States – are widespread as of 2019. [ 69 ]  The FDA does infrequent – less than annual – inspections of production sites outside the United States. The FDA normally gives advance notice of inspections, which can lead to cover-ups of problems before inspectors arrive; inspections performed with little or no advance notice have produced evidence of serious problems at a majority of generic drug manufacturing sites in India and China. [ 69 ]


Two women, each claiming to have suffered severe medical complications from a generic version of  metoclopramide , lost their Supreme Court appeal on June 23, 2011. In a 5–4 ruling in  PLIVA, Inc. v. Mensing , [ 70 ] [ 71 ]  the court held that generic companies cannot be held liable for information, or the lack of information, on the originator's label. [ 72 ] [ 73 ] [ 74 ]


The  Indian government  began encouraging more drug manufacturing by Indian companies in the early 1960s, and with the Patents Act in 1970. [ 75 ]  The Patents Act removed composition patents for foods and drugs, and though it kept process patents, these were shortened to a period of five to seven years. The resulting lack of patent protection created a niche in both the Indian and global markets that Indian companies filled by reverse-engineering new processes for manufacturing low-cost drugs. [ 76 ]   The code of ethics issued by the  Medical Council of India  in 2002 calls for physicians to prescribe drugs by their generic names only. [ 77 ]  India is a leading country in the world's generic drugs market, with  Sun Pharmaceuticals  being the largest pharmaceutical company in India.  Indian generics companies exported US$17.3 billion worth of drugs in the 2017–18 (April–March) year. In 1945–2017, bioequivalence studies were only required for generics of drugs that are less than four years old. Since 2017, all generic drugs of certain classes, irrespective of age, require bioequivalence to be approved. [ 78 ]


Generic drug production is a large part of the pharmaceutical industry in China. Western observers have said that China lacks administrative protection for patents. [ 79 ]  However, entry to the  World Trade Organization  has brought a stronger patent system. [ 80 ]  China remains the largest exporter of  active pharmaceutical ingredients , accounting for 40% of the world market per a 2017 estimate. [ 81 ]


Bioequivalence studies are required for new generic drugs starting from 2016, with older drugs planned as well. In addition,  in vitro  dissolution behavior is required to match. [ 82 ]  Since 2018, 44 classes of drugs are exempt from testing (requiring only a dissolution check), and 13 classes only require simplified testing. [ 83 ]


As of 2021, several major companies traditionally dominate the generic drugs market, including  Viatris  (merger of  Mylan  and  Upjohn ),  Teva ,  Novartis' Sandoz , and  Sun Pharma . [ 84 ]  Prices in traditional generic drugs have declined and newer companies such as India-based  Sun Pharma ,  Aurobindo Pharma , and  Dr. Reddy's Laboratories , as well as Canada-based  Apotex , have taken market share, which has led to a focus on  biosimilars .


Generic pharmaceutical price decay  is what happens (in the UK) once the originator brand has lost its  patent exclusivity (patent expiry)  and generic versions of the originator brand have been launched. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ]


The number of license holders entering the market is controlled by the ease of manufacture and the number of companies making the  active pharmaceutical ingredient (API) . For many easy-to-manufacture solid dose tablets and capsules the manufacturing is done in India and China as the costs of production in these countries is significantly lower than in the US or Europe. [ 7 ]


On day one of generic launch the  first to market  the generic product usually gets more market share than late entrants. Both manufacturers (who make their own generic products) and license only holders (who use other companies to do the manufacturing) may be represented. [ 8 ]


If only one company is able to release a generic product into the UK market, the discount against the originator brand is likely to be small, and the price will usually follow the same trend as the brand price. However, in most cases more than one company will release stock at launch and they will compete for market share with other manufacturers and license holders. This means persuading chemists and dispensing doctors to purchase stock. [ 9 ]


As competition drives the price of the generic product down, the average price in the market typically follows a  scalloped curve  which will decline with time at a rate that is driven by the numbers of license holders and manufacturers. [ 10 ] [ 11 ]


Changes in the reimbursement price  drug tariff  will also serve to suppress this curve even more. [ 12 ] [ 13 ] [ 14 ] [ 15 ]


Generic substitution  was planned for the England, but this was rejected in late 2010. Generic substitution would have meant that a prescription written for a branded product by a doctor would result in a pharmacist giving the patient a generic medicine. On Thursday 14 October, the UK's Department of Health announced that it would not be proceeding with the proposals to implement generic substitution. Patient safety was cited as the primary reason for the rejection of this policy. [ 16 ]


In the case of more complex products, such as creams, inhalers and injectables, generic prices decay at a slower rate as fewer companies are able to make the product. [ 17 ]


In the UK, the M category of the drug tariff (reimbursement prices) is used to control the profits of chemists and to reduce the UK's health care tax burden. [ 18 ] [ 19 ] [ 20 ]


The rate of decay of most generic solid dose products has been shown to follow a predictable path and to have some similarity to the decay in price of other non pharmaceutical products. [ 21 ] [ 22 ]


Eventually price decline comes to and end and the price flattens out at approximately 20% of the original brand price.


In about 20% of cases, the average price declines to a low point some months or years after generic launch, and then rises temporarily or  bounces   (Dead Cat Bounce) [ 23 ]  These bounces may then initiate the onset of longer term seasonality or recurrent annual price rises. [ 24 ]


Bounces happen when the average selling price falls below a license holder's manufacturing cost, making the product unprofitable. License holders and manufacturers then withdraw from the market, reducing the amount of competition and allowing the price to rise. They may later re-enter the market when higher prices make the product profitable once more. This usually forces the average price down again to levels lower than that seen before the start of the bounce.


The reasoning behind why some products bounce whereas others do not, is thought to lie in the rapidity of the initial price decline. In these cases manufacturers and license holders either were not able to or did not forecast the levels to which the price might drop.
The period during which their product would be profitable was therefore not known, and the decline into unprofitably left them with stock which could only be sold at a loss. Additionally the product's expiry date might mean that it could not be stored until market prices recovered.


Generic manufacturers and license holders believe that the  seasonality  induced by these bounces may be related to the time taken to manufacture a new product and gain  market access  (get the medicines onto chemist's shelves in the relevant country). The period between the high price peaks in the seasonality induced by price bounces has been shown to be approximately two years. [ 25 ]


It is possible for a product's price to be affected by seasonality in the absence of price bounces. This seasonality is caused by periods of intense competition in the UK market, and periods of calm with much less competition. In the UK traditionally employees  have taken holidays in April, August and January. This is caused by religious holidays like Christmas and Easter, and by spring, summer and winter school holidays.


During holidays, wholesalers, license holders and manufacturers are less competitive than when employees are back at work. During the months when the majority of employees are at work, competing companies continually watch each other's prices and change their own selling prices on a daily or even hourly basis so as to maximize sales and profits.


The pricing trends of some products are believed to be affected by disease patterns, such as the  hay fever  season in May and winter flu in November. It is also possible that the exchange rates between relevant currencies may be another factor in controlling generic prices. However the evidence for this is weak. [ 26 ]


After loss of exclusivity and generic launch the originator brand normally continues to hold at least some market share as either some doctors continue to prescribe the brand or as the originator  equalises  sales prices against the generic. [ 27 ] [ 28 ]


Branded manufactures may build ongoing contracts with wholesalers so that the brand continues to be dispensed in pharmacies even though the prescriptions are generic. This means that an originator may offer an advantageous price to undercut the generic or  parallel import . Wholesalers gets a price and supply guarantee in exchange for taking the risk that they may be paying too much in the long term.


Some companies offer 'branded generics' in the UK market. However, these are no longer common, and are not popular as their reimbursement price may be higher than the generic reimbursement price, costing the tax-payer more than a true generic. [ 29 ] [ 30 ]


Because the generic launch price is often at or close to the originator brand price, more profit can be made in the months following generic launch than in the months later in the product's life cycle. [ 31 ] [ 32 ] [ 33 ]


Generic launch can only occur once all the patents on the originator brand have expired. These may include both product and process patents, and most products can get a further two years of patent life with a SPC  supplementary protection certificate  and a few may get a further six months with a  pediatric extension .


Good documentation practice  (recommended to abbreviate as  GDocP  to distinguish from "good  distribution  practice" also abbreviated GDP) is a term in the pharmaceutical and medical device industries to describe standards by which  documents  are created and maintained. While some GDocP standards are  codified  by various  competent authorities , others are not but are considered  cGMP  (with emphasis on the "c", or "current"). Some competent authorities release or adopt  guidelines , and they may include non-codified GDocP expectations. While not law, authorities will inspect against these guidelines and cGMP expectations in addition to the legal requirements and make comments or observations if departures are seen.
In the past years, the application of GDocP is also expanding to cosmetic industry, excipient and ingredient manufacturers.


From the regulatory guidance above, additional expectations or allowances can be inferred by extension.  Among these are:


The competent authorities are empowered to inspect establishments to enforce the law and the interpretations of the law (e.g., the content of guidance documents and the cGMPs).


Departures from GDocP that involved the regulator have included: documentation not contemporaneous, [ 11 ] [ 12 ]  use of  ditto marks , [ 13 ]  signature stamps., [ 14 ] [ 15 ]  obscured original data, [ 16 ]  Use of pencil, [ 16 ]  inaccurate records, [ 16 ]  and not dating changes. [ 17 ]


Current good manufacturing practices  ( cGMP ) are those conforming to the guidelines recommended by relevant agencies. Those agencies control the authorization and licensing of the manufacture and sale of  food  and  beverages , [ 1 ]   cosmetics , [ 2 ]   pharmaceutical products , [ 3 ]   dietary supplements , [ 4 ]  and  medical devices . [ 5 ]  These guidelines provide minimum requirements that a manufacturer must meet to assure that their products are consistently high in quality, from batch to batch, for their intended use.


Good Manufacturing Practice emerged in response to serious incidents of harm caused by contaminated, adulterated, or improperly manufactured products. Major incidents include:
deaths from  Elixir Sulfanilamide  in 1937,  thalidomide -induced birthdefects 1957–1961,  poliomyelitis  infections from  improperly prepared vaccines  in 1955, and  Dalkon Shield -induced  septicemia  in the 1970s.


These incidents resulted in hundreds of deaths, infections, and birth defects. Complete timelines show the emergence of Good Manufacturing Practices alongside these incidents, starting from 1938 in the US and 1970s internationally. [ 6 ]


The rules that govern each industry may differ significantly; however, the main purpose of GMP is always to prevent harm from occurring to the end user. [ 2 ]  Additional tenets include ensuring the end product is free from contamination, that it is consistent in its manufacture, that its manufacture has been well documented, that personnel are well trained, and that the product has been checked for quality more than just at the end phase. [ 2 ]  GMP is typically ensured through the effective use of a  quality management system  (QMS). [ 1 ] : "The Basis for GMP",   [ 2 ]


Good manufacturing practice, along with  good agricultural practice ,  good laboratory practice  and  good clinical practice , are overseen by regulatory agencies in the United Kingdom, United States, Canada, various European countries, China, India and other countries.


Good manufacturing practice guidelines provide guidance for manufacturing, testing, and quality assurance in order to ensure that a manufactured product is safe for human consumption or use. Many countries have legislated that manufacturers follow GMP procedures and create their own GMP guidelines that correspond with their legislation.


All guidelines follow a few basic principles: [ 2 ] [ 7 ]


Good manufacturing practice is recommended with the goal of safeguarding the health of consumers and patients as well as producing quality products. In the United States, a food or drug may be deemed "adulterated" if it has passed all of the specifications tests but is found to be manufactured in a facility or condition which violates or does not comply with current good manufacturing guideline.


GMP standards are not prescriptive instructions on how to manufacture products. They are a series of performance based requirements that must be met during manufacturing. [ 9 ]  When a company is setting up its quality program and manufacturing process, there may be many ways it can fulfill GMP requirements. It is the company's responsibility to determine the most effective and efficient quality process that both meets business and regulatory needs. [ 1 ] : "Decision Makers' Summary",   [ 2 ]


Regulatory agencies have recently begun to look at more fundamental quality metrics of manufacturers than just compliance with basic GMP regulations. US-FDA has found that manufacturers who have implemented quality metrics programs [ 10 ]  gain a deeper insight into employee behaviors that impact product quality.


In its Guidance for Industry "Data Integrity and Compliance With Drug CGMP" US-FDA states “it is the role of management with executive responsibility to create a quality culture where employees understand that [[data integrity [ 11 ] ]] is an organizational core value and employees are encouraged to identify and promptly report data integrity issues.” [ 12 ]  Australia's Therapeutic Goods Administration has said that recent data integrity failures have raised questions about the role of quality culture in driving behaviors. [ 13 ]  In addition, non-governmental organizations such as the International Society for Pharmaceutical Engineering (ISPE) and the Parenteral Drug Association (PDA) have developed information and resources to help pharmaceutical companies better understand why quality culture is important and how to assess the current situation within a site or organization. [ 14 ]


GMP is enforced in the United States by the U.S.  Food and Drug Administration  (FDA), under Title  21 CFR . The regulations use the phrase "current good manufacturing practices" (CGMP) to describe these guidelines. [ 15 ] [ 16 ] [ 17 ] [ 18 ]  Courts may theoretically hold that a product is  adulterated  even if there is no specific regulatory requirement that was violated as long as the process was not performed according to industry standards. [ 19 ]  However, since June 2007, a different set of CGMP requirements have applied to all manufacturers of  dietary supplements , with additional supporting guidance issued in 2010. [ 4 ]  Additionally, in the U.S., medical device manufacturers must follow what are called "quality system regulations" which are deliberately harmonized with  ISO  requirements, not necessarily CGMPs. [ 17 ]


The  World Health Organization  (WHO) version of GMP is used by pharmaceutical regulators and the  pharmaceutical industry  in over 100 countries worldwide, primarily in the developing world. [ 3 ]  The  European Union 's GMP (EU GMP) enforces similar requirements to WHO GMP, as does the FDA's version in the US. Similar GMPs are used in other countries, with Australia, Canada, Japan, Saudi Arabia, Singapore, Philippines], Vietnam and others having highly developed/sophisticated GMP requirements. [ 20 ]  In the United Kingdom, the Medicines Act (1968) covers most aspects of GMP in what is commonly referred to as "The Orange Guide," which is named so because of the color of its cover; it is officially known as  Rules and Guidance for Pharmaceutical Manufacturers and Distributors . [ 21 ]


Since the 1999 publication of  Good Manufacturing Practice for Active Pharmaceutical Ingredients , by the  International Conference on Harmonization  (ICH), GMPs now apply in those countries and trade groupings that are signatories to ICH (the EU, Japan and the U.S.), and applies in other countries (e.g., Australia, Canada, Singapore) which adopt ICH guidelines for the manufacture and testing of active raw materials. [ 20 ]


Within the European Union GMP inspections are performed by National Regulatory Agencies. GMP inspections are performed in Canada by the Health Products and Food Branch Inspectorate; [ 22 ]  in the United Kingdom by the  Medicines and Healthcare products Regulatory Agency  (MHRA); [ 23 ]  in the Republic of Korea (South Korea) by the  Ministry of Food and Drug Safety  (MFDS); [ 24 ]  in Australia by the  Therapeutic Goods Administration  (TGA); [ 25 ]  in Bangladesh by the Directorate General of Drug Administration (DGDA); [ 26 ]  in South Africa by the Medicines Control Council (MCC); [ 27 ]  in Brazil by the  National Health Surveillance Agency  (ANVISA); [ 28 ]  in India by state Food and Drugs Administrations (FDA), reporting to the  Central Drugs Standard Control Organization ; [ 29 ]  in Pakistan by the  Drug Regulatory Authority of Pakistan ; [ 30 ]  in Nigeria by  NAFDAC ; [ 31 ]  and by similar national organizations worldwide. Each of the  inspectorates  carries out routine GMP inspections to ensure that drug products are produced safely and correctly. Additionally, many countries perform pre-approval inspections (PAI) for GMP compliance prior to the approval of a new drug for marketing.


Regulatory agencies (including the FDA in the U.S. and regulatory agencies in many European nations) are authorized to conduct unannounced inspections, though some are scheduled. [ 15 ] [ 21 ] [ 24 ] [ 25 ] [ 26 ] [ 27 ] [ 29 ] [ 30 ] [ 31 ]  FDA routine domestic inspections are usually unannounced, but must be conducted according to 704(a) of the  Food, Drug and Cosmetic Act  (21 USCS § 374), which requires that they are performed at a "reasonable time". Courts have held that any time the firm is open for business is a reasonable time for an inspection. [ 32 ]


Other good-practice systems, along the same lines as GMP, exist:


Collectively, these and other good-practice requirements are referred to as " GxP " requirements, all of which follow similar philosophies. Other examples include good guidance practice and good tissue practice.


Healthy Skepticism Inc  is an international  non-profit organisation  whose main aim is to "improve health by reducing harm from misleading  drug promotion ".


Healthy Skepticism was founded in 1983 with the name Medical Lobby for Appropriate Marketing (MaLAM). It was begun by an  Australian  medical student,  Peter R. Mansfield ,  who had the idea for the organisation during his final year elective in  Bangladesh  in 1982. MaLAM initially focused on campaigning against questionable  marketing  practices in  developing countries . These included the promotion of  appetite  stimulants, tonics and  anabolic steroids  to parents of malnourished children. MaLAM was modelled on  Amnesty International  and wrote open letters to the international headquarters of  pharmaceutical companies  questioning them about specific advertisements. MaLAM letters were signed by supporters around the world and contributed to many improvements in drug marketing, several products being removed from the market and many  advertising  claims changed. [ 1 ] [ 2 ] [ 3 ]  MaLAM reported more than 450 alleged violations of the voluntary code of conduct of the drug industry in 1987, [ 4 ]  and also questioned drug advertisements in Australia during 1993 to 1997 with funding from the Australian federal government.


In 2001, the organisation's name was changed to Healthy Skepticism and its work widened to include  research ,  education  and  advocacy  about misleading drug promotion in all countries. It has concentrated recently on raising awareness amongst  health professionals  of the influence that marketing techniques have on their decisions, and the psychological factors which make them vulnerable to that influence. [ 5 ]


In  biology  and other experimental sciences, an  in silico  experiment is one performed on a computer or via  computer simulation  software. The phrase is  pseudo-Latin  for 'in silicon' (correct  Latin :  in silicio ), referring to  silicon  in computer chips. It was coined in 1987 as an allusion to the  Latin phrases   in vivo ,  in vitro , and  in situ , which are commonly used in  biology  (especially  systems biology ).  The latter phrases refer, respectively, to experiments done in living organisms, outside living organisms, and where they are found in nature.


The earliest known use of the phrase was by  Christopher Langton  to describe  artificial life , in the announcement of a workshop on that subject at the Center for Nonlinear Studies at the  Los Alamos National Laboratory  in 1987. [ 1 ] [ 2 ]  The expression  in silico  was first used to characterize biological experiments carried out entirely in a computer in 1989, in the workshop "Cellular Automata: Theory and Applications" in Los Alamos, New Mexico, by Pedro Miramontes, a mathematician from  National Autonomous University of Mexico  (UNAM),  presenting the report " DNA  and  RNA  Physicochemical Constraints, Cellular Automata and Molecular Evolution". The work was later presented by Miramontes as his  dissertation . [ 3 ]


In silico  has been used in  white papers  written to support the creation of bacterial genome programs by the Commission of the European Community. The first referenced paper where  in silico  appears was written by a French team in 1991. [ 4 ]  The first referenced book chapter where  in silico  appears was written by Hans B. Sieburg in 1990 and presented during a Summer School on Complex Systems at the Santa Fe Institute. [ 5 ]


The phrase  in silico  originally applied only to computer simulations that modeled natural or laboratory processes (in all the natural sciences), and did not refer to calculations done by computer generically.


In silico study in medicine is thought to have the potential to speed the rate of discovery while reducing the need for expensive lab work and clinical trials.  One way to achieve this is by producing and screening drug candidates more effectively.  In 2010, for example, using the protein docking algorithm EADock (see  Protein-ligand docking ), researchers found potential inhibitors to an enzyme associated with cancer activity  in silico .  Fifty percent of the molecules were later shown to be active inhibitors  in vitro . [ 6 ] [ 7 ]   This approach differs from use of expensive  high-throughput screening  (HTS) robotic labs to physically test thousands of diverse compounds a day, often with an expected hit rate on the order of 1% or less, with still fewer expected to be real leads following further testing (see  drug discovery ).


As an example, the technique was utilized for a  drug repurposing  study in order to search for potential cures for  COVID-19  (SARS-CoV-2). [ 8 ]


Efforts have been made to establish computer models of cellular behavior.  For example, in 2007 researchers developed an in silico model of  tuberculosis  to aid in drug discovery, with the prime benefit of its being faster than real time simulated growth rates, allowing phenomena of interest to be observed in minutes rather than months. [ 9 ]   More work can be found that focus on modeling a particular cellular process such as the growth cycle of  Caulobacter crescentus . [ 10 ]


These efforts fall far short of an exact, fully predictive computer model of a cell's entire behavior.  Limitations in the understanding of  molecular dynamics  and  cell biology , as well as the absence of available computer processing power, force large simplifying assumptions that constrain the usefulness of present in silico cell models.


Digital genetic sequences  obtained from  DNA sequencing  may be stored in  sequence databases , be analyzed (see  Sequence analysis ), be digitally altered or be used as templates for creating new actual DNA using  artificial gene synthesis .


In silico computer-based modeling technologies have also been applied in:


The UCSF  Industry Documents Library  (IDL) is a digital  archive  of internal tobacco, drug, food, chemical and fossil fuel corporate documents, acquired largely through litigation, which illustrate industry efforts to influence policies and regulations meant to protect  public health .  Created and maintained by the  UCSF Library , the mission of the UCSF Industry Documents Library is to "identify, collect, curate, preserve, and make freely accessible internal documents created by industries and their partners which have an impact on public health, for the benefit and use of researchers, clinicians, educators, students, policymakers, media, and the general public at UCSF and internationally". [ 1 ]


The IDL includes the following archives:


The  Influenza Antiviral Drug Search  was a  distributed computing  project that was running on the  BOINC  platform.  It is a project of the  University of Texas Medical Branch .


The Influenza Antiviral Drug Search conducted millions of virtual  docking  experiments in order to discover compounds that may be suitable for real-world  clinical trials  to combat new or  drug resistant   strains  of  influenza  virus.


One vulnerability of all influenza strains is that they need  viral neuraminidase ,  NS1 Influenza Protein  and  hemagglutinin  in order to infect a body.  A  chemical compound  that can disable one of these  molecules  has the potential to be an effective antiviral drug.


This computing article is a  stub . You can help Wikipedia by  expanding it .


The  Innovative Medicines Initiative  (IMI) is a European initiative to improve the competitive situation of the  European Union  in the field of  pharmaceutical research . The IMI is a joint initiative ( public-private partnership ) of the  DG Research  of the  European Commission , representing the European Communities, and the  European Federation of Pharmaceutical Industries and Associations  (EFPIA). IMI is laid out as a  Joint Technology Initiative  within the Seventh Framework Programme. [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ]   Michel Goldman  was the first executive director, from September 2009 until December 2014. [ 9 ]


The Innovative Medicines Initiative is aimed towards removing research  bottlenecks  in the current  drug development  process. The IMI Joint Technology Initiative (IMI JTI), to be implemented by the IMI Joint Undertaking is meant to address these research bottlenecks. Its €2bn budget makes it the largest biomedical public-private partnership in the world.


The funding scheme has been criticised, [ 10 ]  requiring universities to invest more money than with EU FP7 programs. Besides the non-competitive financial aspects of participation in IMI projects for academia, this criticism also discusses that intellectual property is freely flowing to industry.


The  Sixth Framework Programme's  research projects InnoMed AddNeuroMed and InnoMed PredTox acted as pilot projects establishing the feasibility of this particular public-private partnership. [ 11 ]  Since then, the IMI has had four funding rounds: the first call had the topic Safety, while the second call was about Efficacy. Projects for these two calls are ongoing. [ 12 ]


The IMI 2 started in 2014 and will run until 2024, while the IMI 1 is still running. Overall budget is €3.276 billion, taken for half from the European  Horizon 2020  program. Goals of that second calls are to improve clinical trials success rate, deliver clinical proof of concept, biomarkers and new medicines.


In September 2014 IMI-TRAIN, an IMI/ENSO-funded education and training collaboration to support biomedical scientists and professionals, has been launched. IMI-TRAIN will serve as a collaboration platform for the currently IMI-funded education and training projects: [ 13 ]


An  investigational device exemption  ( IDE ) allows an investigational device (i.e. a device that is the subject of a  clinical study [ 1 ] ) to be used in order to collect safety and effectiveness data required to support a  premarket approval  (PMA) application or a
 premarket notification  [510(k)] submission to  Food and Drug Administration  (FDA). [ 2 ]  Clinical studies are most often conducted to support a PMA. Only a small percentage of 510(k)'s require clinical data to support the application. Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated.


Clinical evaluation of devices that have not been cleared for  marketing  requires:


An approved IDE permits a device to be shipped lawfully for the purpose of conducting investigations of the device without complying with other requirements of the  Food, Drug, and Cosmetic Act  that would apply to devices in commercial distribution. Sponsors need not submit a PMA or premarket notification, register their  establishment, or list the device while the device is under investigation. Sponsors of IDEs are also exempt from the Quality System (QS) Regulation except for the requirements for design control.


A commercial sponsor of a significant risk device study must submit a complete IDE application to FDA. There are no preprinted forms for an IDE application; however, an IDE application must include certain required information. The sponsor must demonstrate in the application that there is reason to believe that the risks to human subjects from the proposed investigation are outweighed by the anticipated benefits to subjects and the importance of the knowledge to be gained, that the investigation is scientifically sound, and that there is reason to believe that the device as proposed for use will be effective.


Klick  is a global group of companies in the area of health marketing and advertising.


Klick was founded in 1997. [ 1 ]


The company introduced the  SymPulse  in 2017. Marketed as a "tele-empathy" device, it was designed to transmit the symptoms of  Parkinson's disease  to allow them to be felt and understood by care providers. [ 2 ] [ 3 ] [ 4 ] [ 5 ]


In 2021 it created "Community Unity", a video series with the Vaccine Confidence Project at the  London School of Hygiene & Tropical Medicine  which discusses frequently asked questions about the  COVID-19 vaccines . [ 6 ]


In 2006, Klick Health replaced its internal email systems with a new software program intended for messaging and project management. [ 1 ]  This program, named Genome, incorporates analytics to potentially improve productivity and has been associated with the agency's expansion. [ 7 ] [ 8 ]  Company co-founder Leerom Segal attributed these practices for Klick's low  turnover  rate of three percent, compared to seven percent across Canadian employers As of 2014 [update] . [ 9 ]  The system was marketed to external clients as SenseiOS. [ 10 ]


The organizational structure of Klick Health has not included a  human resources  department, which was a point of concern for some employees. [ 11 ] [ 7 ]


Its research and development division is Klick Labs. [ 12 ]  The division developed an AI program able to analyze people's voices to determine whether or not they have  type 2 diabetes . [ 12 ]


Klick Health is described by the  Yale School of Management  as the "largest private health marketing company in the world". [ 13 ]


The  pharmaceutical lobby  refers to the representatives of  pharmaceutical drug  and  biomedicine  companies who engage in  lobbying  in favour of  pharmaceutical companies  and their products.


The largest pharmaceutical companies and their two trade groups,  Pharmaceutical Research and Manufacturers of America  (PhRMA) and  Biotechnology Innovation Organization , lobbied on at least 1,600 pieces of legislation between 1998 and 2004. According to the non-partisan  OpenSecrets , pharmaceutical companies spent $900 million on lobbying between 1998 and 2005, more than any other industry. During the same period, they donated $89.9 million to federal candidates and political parties, giving approximately three times as much to  Republicans  as to  Democrats . [ 1 ]  According to the  Center for Public Integrity , from January 2005 through June 2006 alone, the pharmaceutical industry spent approximately $182 million on federal lobbying in the United States. [ 2 ]  In 2005, the industry had 1,274 registered lobbyists in Washington, D.C. [ 3 ]


A 2020 study found that, from 1999 to 2018, the pharmaceutical industry and health product industry together spent $4.7 billion lobbying the United States federal government, an average of $233 million per year. [ 4 ]


Critics of the pharmaceutical lobby argue that the drug industry's influence allows it to promote legislation friendly to drug manufacturers at the expense of patients. [ 5 ] [ failed verification ]  The lobby's influence in securing the passage of the  Medicare Prescription Drug, Improvement, and Modernization Act  of 2003 was considered a major and controversial [ according to whom? ]  victory for the industry, as it prevents the government from directly negotiating prices with drug companies who provide those prescription drugs covered by  Medicare . Price negotiations are instead conducted between manufacturers and the pharmacy benefit managers providing Medicare Part D benefits under contract with Medicare.  In 2010 the  Congressional Budget Office  estimated the average discount negotiated by pharmacy benefit managers at 14%. [ 6 ]


The high price of U.S. prescription drugs has been a source of ongoing controversy. Pharmaceutical companies state that the high costs are the result of pricey research and development programs. Critics point to the development of drugs having only small incremental benefit. [ 5 ] [ 7 ]  According to  Marcia Angell , former editor-in-chief of the  New England Journal of Medicine , "The United States is the only advanced country that permits the pharmaceutical industry to charge exactly what the market will bear." [ 8 ]  In contrast, the  RAND Corporation  and authors from the  National Bureau of Economic Research  have argued that price controls stifle innovation and are economically counterproductive in the long term. [ 9 ] [ 10 ]


In 2021, during the height of COVID-19, vaccine makers increased lobbying and public-relations efforts to oppose  a proposal that would temporarily waive their patents  in Germany, Japan and other countries. This proposal would allow COVID-19 vaccine patents to be licensed to international vaccine makers or otherwise sold entirely. The Biden presidential administration in the U.S. supported the waiver proposal; however, pharmaceutical industry trade groups supported Germany, Japan, and other countries that expressed opposition. Pharmaceutical industry representatives have been lobbying members of Congress to pressure the Biden administration to reverse its support of the waiver, arguing that the patents protect its innovations. However, proponents of the proposal see the patent as giving companies a monopoly over sales of vaccines during a world crisis. [ 11 ]


Mean kinetic temperature  ( MKT ) is a simplified way of expressing the overall effect of  temperature  fluctuations during storage or transit of perishable goods. The MKT is used to predict the overall effect of temperature fluctuations on perishable goods.  It has more recently been applied to the  pharmaceutical industry .


The mean kinetic temperature can be expressed as:


When the temperature readings are taken at the same interval (i.e.,

 t

 1

 {\displaystyle t_{1}\,\!}

  =

 t

 2

 {\displaystyle t_{2}\,\!}

  =

 ⋯

 {\displaystyle \cdots }

  =

 t

 n

 {\displaystyle t_{n}\,\!}

 ), the above equation is reduced to:


A  medical science liaison  ( MSL ) is a  healthcare  consulting professional who is employed by  pharmaceutical ,  biotechnology , medical device, and managed care companies. Other job titles for medical science liaisons may include medical liaisons, clinical science liaisons, medical science managers, regional medical scientists, and regional medical directors.


The term "MSL" was originally trademarked by  Upjohn  as "Education services – namely, initiation of drug studies in laboratory and clinical settings and development of workshops, symposia, and seminars for physicians, medical societies, specialty organizations, academicians, in concert, concerned with drug related medical topics" in 1967 and with first use in commerce in 1967. [ 1 ]


As the number of MSL programs in healthcare increased, subsequent peer-reviewed journal publications and books became available to examine the emerging role of medical affairs [ 2 ] [ 3 ]  and the use of MSLs in an increasingly vertically integrated biotechnology industry. [ 4 ]


MSLs build relationships with key opinion leaders or  thought leaders  and  health care providers , providing critical windows of insight into the market and competition. Through such monitoring, MSLs can gain access to key influencers by interacting with national and regional societies and organizations. Moreover, as MSLs specialize in a particular therapeutic area and have scientific knowledge related to it. The educational background of MSLs consists primarily of MDs, DMSc, PharmD, and PhD professionals.  Other professions who work as MSLs include Physician Assistants and Nurses.  According to the program's advocates, the Board Certified Medical Affairs Specialist (BCMAS) program is the recognized MSL board certification for MSL professionals. [ 5 ]   They are now highly involved in activities related to  clinical trials . [ citation needed ]


The medical science liaison role is varied and day-to-day activities include (but are not limited to); [ 6 ]


The  Mexican barbasco trade  was the trade of the  diosgenin -rich  yam  species  Dioscorea mexicana ,  Dioscorea floribunda  and  Dioscorea composita  which emerged in Mexico in the 1950s as part of the  Mexican steroid industry . The trade consisted in Mexican  campesinos  harvesting the root in the jungle, selling it to middlemen who brought it to processing plants where the root was fermented and the diosgenin extracted and sold to pharmaceutical companies such as  Syntex  who used it to produce  synthetic hormones .


The trade started when  Russell Marker , a chemist looking for a plant source from which to extract  diosgenin  and  saponin , traveled to  Veracruz  looking for the yam  Dioscorea mexicana  which he suspected might be suitable. He hired two Mexican campesinos to bring him exemplars of the  tuber . When he discovered that the root was indeed a significant source of diosgenin, he established Syntex, the first Mexican fine chemical company dedicated to producing  semisynthetic  hormones from Barbasco. Before this development, natural hormones were extracted from animal sources, such as urine from pregnant mares or women, or from bull testes; prices were consequently very high. With the development of the process of  Marker degradation  which allowed the production of hormones from vegetable  saponin  sources, Marker began a search for a plant  steroid  of the sapogenin class with a ring structure more like  progesterone . With the discovery of the chemical properties of the barbasco root, world market prices for steroids and other synthetic hormones plummeted, making them feasible for large-scale production of medicines for common ailments such as  arthritis  or  Addison's disease , and eventually as the basis for the  combined oral contraceptive pill . [ 1 ] [ 2 ]


This development sparked a barbasco extraction industry centered on the barbasco-rich areas of southeastern Mexico, in Northern  Oaxaca , Southern  Veracruz  and  Puebla  states. Especially the area called  Chinantla  in Northern Oaxaca, around the cities of  Tuxtepec  and  Valle Nacional . The root was extracted in the wild by  barbasqueros , often poor  Indigenous   Chinantecs , who ventured into the jungle to dig out the tuber with digging sticks or with their bare hands. Before becoming used industrially, the tuber was used by  Chinantec  healers in northern  Oaxaca  as an  abortifacient  and in cures for aching joints. It was also used by Chinantecs as a poison for fishing in the  Papaloapan river . [ 3 ]


By the mid-1970s, 125,000 Mexican peasants depended on the barbasco trade for their livelihood, and ten tons of barbasco per week were extracted from the wild. [ 4 ]


Quickly, a system of middlemen appeared, as those who had enough means to pay  barbasqueros , started buying large quantities, often using a system of  debt peonage . They would start by giving the  barbasquero  a loan, which he or she would then have to pay off with barbasco. These middlemen would eventually establish  acopios , recollection and distribution centers where large quantities of barbasco are gathered and shipped on to the  beneficios , the processing plants. [ 5 ]


At the processing plants, the tuber is inspected, washed, chopped up, and mixed with water to produce a thick paste. The paste is then put into fermentation vats, where it remains for several days, after which it is taken out and sun-dried on a concrete floor, where it is turned by workers using rakes. In the process of drying, the paste crystallizes into diosgenin granules, also called flour. The flour is then bagged and sent to laboratories where the diosgenin content is measured and the price is calculated based on the diosgenin percentage, which varies from 4–6%. [ 5 ]


Knowledge of the uses and purposes of the barbasco tuber was highly stratified, and barbasqueros often did not know the true purpose of the root they were gathering; they were frequently told that it was used for soap. [ 5 ]  The acopio owners knew more about the process and eventually invented ways of improving the diosgenin concentration in roots collected by adding different solvents to the tubers before shipping them to the beneficios.


In the late 1970s, populist President  Luis Echeverría  sought to organize and nationalize the barbasco trade in order to provide more benefits to the barbasqueros and to the Mexican state. He established the organization PROQUIVEMEX (Productos Químicos Vegetales de México). However, at this point, Mexico had lost its status as a world leader in the synthetic hormone market, and the barbasco trade was declining, just as the root was becoming depleted in the wild. [ 5 ]


Also during the 1970s, it became possible to produce steroids from soy  phytosterols , including  progesterone . This meant that barbasco was no longer necessary as a base product, and international reliance on Mexican yams stopped. Today, only a few communities in Northern Oaxaca continue to produce barbasco, and the few existing beneficios process only a few tons per year. In 1999, 65% of families in the municipio of  Santiago Jocotepec  depended on barbasco production, whereas in the municipios of  San Juan Lalana  it was 29.2%, in  San Felipe Usila  28.3%, and in  San Lucas Ojitlán  24.4%. [ 6 ]


The relationship between water content and equilibrium relative humidity of a material can be displayed graphically by a curve, the so-called  moisture sorption isotherm .
For each  humidity  value, a  sorption isotherm  indicates the corresponding  water content  value at a given temperature. If the composition or quality of the material changes, then its sorption behaviour also changes. Because of the complexity of sorption process the isotherms cannot be determined explicitly by calculation, but must be recorded experimentally for each product. [ 1 ]


The relationship between water content and  water activity  (a w ) is complex. An increase in a w  is usually accompanied by an increase in water content, but in a non-linear fashion. This relationship between water activity and moisture content at a given temperature is called the moisture sorption isotherm. These curves are determined experimentally and constitute the fingerprint of a  food system . [ 2 ]


BET theory  (Brunauer-Emmett-Teller) provides a calculation to describe the physical adsorption of gas molecules on a solid surface.  Because of the complexity of the process, these calculations are only moderately successful; however,  Stephen Brunauer  was able to classify sorption isotherms into five generalized shapes as shown in Figure 2.


He found that Type II and Type III isotherms require highly porous materials or desiccants, with first monolayer adsorption, followed by multilayer adsorption and finally leading to capillary condensation, explaining these materials high moisture capacity at high relative humidity. [ 3 ]


Care must be used in extracting data from isotherms, as the representation for each axis may vary in its designation. Brunauer provided the vertical axis as moles of gas adsorbed divided by the moles of the dry material, and on the horizontal axis he used the ratio of partial pressure of the gas just over the sample, divided by its partial pressure at saturation. More modern isotherms showing the sorption of water vapor, on the vertical axis, provide the ratio of the weight of water adsorbed  divided by its dry weight, or that ratio converted into a percentage. On the horizontal axis they provide relative humidity or water activity of the air presented to the material.


Sorption Isotherms are named as such because the equilibrium established must be for a constant temperature and this temperature should be specified.  Normally, materials hold less moisture when they are hotter, and more moisture when they are colder.  Occasionally, a set of isotherms are provided on one graph that shows each curve at a different temperature. Such a set of adsorption isotherms is provided in Figure 3 as measured by Dini on a Type V silica gel. [ 4 ]


Molecular phenotyping  describes the technique of quantifying pathway reporter genes,  i.e.  pre-selected genes that are modulated specifically by metabolic and  signaling pathways , in order to infer activity of these pathways. [ 1 ] [ 2 ]


In most cases, molecular phenotyping quantifies changes of pathway reporter  gene expression  to characterize modulation of pathway activities induced by perturbations such as therapeutic agents or stress in a cellular system  in vitro . In such contexts, measurements at early time points are often more informative than later observations because they capture the primary response to the perturbation by the cellular system. [ 3 ]  Integrated with quantified changes of  phenotype  induced by the perturbation, molecular phenotyping can identify pathways that contribute to the phenotypic changes.


Currently molecular phenotyping uses  RNA sequencing  and  mRNA  expression to infer pathway activities. Other technologies and readouts such as  mass spectrometry  and protein abundance or phosphorylation levels can be potentially used as well. [ 4 ]


Current data suggest that by quantifying pathway reporter  gene expression , molecular phenotyping is able to cluster compounds based on pathway profiles and dissect associations between pathway activities and disease  phenotypes  simultaneously. [ 5 ]  Furthermore, molecular phenotyping can be applicable to compounds with a range of binding specificities and is able to triage false positives derived from high-content screening assays. Furthermore, molecular phenotyping allows integration of data derived from  in vitro  and  in vivo  models as well as patient data into the drug discovery process. [ citation needed ]


The  National Institute for Pharmaceutical Technology and Education  ( NIPTE ) is a  non-profit  scientific and research and development organization that was established in 2005 and incorporated in June 2007 in the State of  Indiana . [ citation needed ]  Its offices are currently located in  Minneapolis , Minnesota.


NIPTE's current membership includes 18 leading schools and colleges of  pharmacy  and  chemical engineering  from the following universities:  University of Mississippi ,  Duquesne University ,  University of Rochester ,  Illinois Institute of Technology ,  Purdue University ,  Rutgers University ,  University of Puerto Rico ,  Long Island University ,  University of Connecticut ,  University of Texas at Austin ,  University of Iowa ,  University of Kentucky ,  University of Maryland ,  Texas A&M University ,  University of Michigan ,  University of Minnesota ,  University of Kansas  and  University of Wisconsin .


The pharmaceutical industry is currently facing increased pricing pressures globally and rising  manufacturing  costs. Cost of Goods (COGS) for Brand-Name  pharmaceutical drugs  can be higher than 30% of the total sales revenues of these companies. In comparison, the percentage of sales revenues spent on  R&D  by these pharmaceutical companies is only 10-15%. For  generic drugs , COGS can be as high as 50% of their total sales revenues. [ 1 ]  Traditionally, pharmaceutical companies preferred to manufacture their own products internally. [ 2 ]  They were keen on "making" what they "sold" because it provided them with more control of the quality of their products. However, since the pressures to reduce cost these days are high, to save money, the pharmaceutical industry is increasingly outsourcing manufacturing to countries in Asia – where the regulatory standards are evolving and sometimes could lag several years behind the U.S. [ 3 ]


The science required to transform a new discovery to a marketable new  drug  has definitely not kept pace with advances on the drug discovery side. [ 4 ]  Pharmaceutical product development today is more of an art than science. Once the new drug discovery is made, product development and manufacturing are left to traditional "tried and true" practices. Marked advances in  chemistry ,  chemical engineering ,  computer modeling  & simulation,  instrumentation , analytical science, and product formulations that could be used to increase efficiency may also be more gainfully applied in pharmaceutical product development and manufacturing. The cost savings achievable by outsourcing can be easily exceeded by improving the science and technology for developing and manufacturing pharmaceutical products. Other industries, such as the  semiconductor  industry have examined their manufacturing technologies and have modernized them. This has allowed these industries to become more competitive and to have products of superior value. [ 4 ]


Manufacturing is a critical step in the chain of very complex events before a drug reaches the pharmacy shelves. When that critical link is broken, it opens the door for something like the  heparin  crisis. [ 5 ]  And heparin may just be the tip of the iceberg. The ultimate answer is not costly inspections of foreign manufacturing sites. [ 6 ]  If that remains the answer, the  U.S. Food and Drug Administration  (FDA) will need a lot more resources and millions of dollars from the  United States Congress  to ensure that all drugs and drug components manufactured in foreign countries are safe and effective. [ 7 ]  Our goal should be to improve the quality of pharmaceutical manufacturing such that drugs can be produced safely and cost-effectively no matter where they are produced. We need to build in manufacturing quality with front-end design – not back-end inspection. If the U.S. wants to increase medication safety and reduce the cost of drugs, it must invest in the basic science of drug development and manufacturing.


The  public/private partnership model  for drug discovery (known as the  NIH Roadmap ) shows success by spurring advances with strong basic science research investment. Between 1999 and 2006, research and development investments in the  United States  grew 5 times the initial investment while in  Europe  it grew 2.9 times. However, since 2006  Asia  has markedly outpaced the U.S. in the opening of new research sites for pharmaceuticals.


NIPTE's goal is to increase science and engineering-based understanding of this area such that novel state-of-the-art technologies can be developed and science-based regulations can be implemented. These technologies will also enable new drug discoveries to be brought to market faster with less variability, higher predictability of performance and at a significantly lower cost.
NIPTE's research agenda [ citation needed ]  is to conduct fundamental and basic research that will:


NIPTE has developed Strategic Roadmap for Research and Technology which outlines current and future challenges and proposed solutions in pharmaceutical science.


NIPTE's membership includes leading schools and colleges of pharmacy and chemical and  pharmaceutical engineering , and has overlapping scientific interests with pharmaceutical scientists (e.g. American Association of Pharmaceutical Sciences).


Current academic programs in pharmaceutical technology are disappearing despite the continued and growing needs of today's industry leading to too few good teacher/mentors and very few qualified graduates. NIPTE comprises leading educational institutions in the pharmaceutical science and engineering, NIPTE's goal is to create a "pipeline" of diverse talent that commences at the undergraduate level and continues throughout  graduate ,  postgraduate , and continuing education, augmenting the available workforce in academia, industry, and government. This goal is being addressed by developing and implementing an integrated Education and Training plan which incorporates NIPTE research programs. By that, NIPTE will create and deliver educational and training programs that will prepare the technical cadre needed by the industry and the FDA to implement and regulate new technologies. [ citation needed ]


The  Newhouse Research Site  is a  drug research  facility situated 15 miles (24 km) east of  Glasgow  in central Scotland. It is located beside the  M8 motorway  in  Newhouse ,  North Lanarkshire . The site is an early  drug discovery  research centre with a track record of generating a succession of products in the areas of  anaesthesia  and  psychiatry . In 2007, the  Royal Society of Chemistry  Malcolm Campbell Memorial Prize was awarded to researchers for its work on a new anaesthesia drug,  sugammadex . [ 1 ] [ failed verification ]  It currently employs 250 scientists across a range of disciplines including  medicinal chemistry ,  molecular biology  and  drug metabolism . The site is currently the largest private drug discovery centre in  Scotland , and one of the biggest in the UK. [ 2 ] [ failed verification ]


The 20-acre (8.1 ha) campus was acquired by  Organon  in 1948 and has continued to grow throughout the years. [ 3 ] [ 4 ]  Scientists at the site are responsible for the invention of a succession of successful products, two of which have recently received approval. Organon was acquired by  Schering-Plough  in 2007, [ 5 ]  and the site was further expanded with the addition of one of the largest compound management facilities in the industry. [ 6 ]  Schering-Plough merged with  Merck  (known as MSD outside of North America) at the end of 2009. [ 7 ]


The site has a long history of research in the area of  neuromuscular blockers , which are commonly used during surgery, and was responsible for the identification of  rocuronium  as well as a number of other drugs. [ citation needed ]  In another major advance the reversal agent  sugammadex  was the first  selective relaxant binding agent  (SRBA) for Neuromuscular Block Reversal to be identified, [ 8 ]  and has recently entered the market in Europe. [ 9 ]  On the psychiatric front researchers at Newhouse supported the development of  mirtazepine , a novel  tetracyclic   anti-depressant  which has become widely prescribed throughout the world. More recently the site was closely involved in supporting the introduction of the  anti-psychotic   asenapine  which has just been launched for the treatment of  schizophrenia  and  bipolar disorder . [ 10 ]


The  osmotic-controlled release oral delivery system (OROS)  is an advanced  controlled release  oral drug delivery system in the form of a rigid  tablet  with a semi-permeable outer membrane and one or more small  laser drilled  holes in it. As the tablet  passes through the body , water is absorbed through the  semipermeable membrane  via  osmosis , and the resulting  osmotic pressure  is used to push the active  drug  through the laser drilled opening(s) in the tablet and into the  gastrointestinal tract . OROS is a trademarked name owned by  ALZA Corporation , which pioneered the use of osmotic pumps for oral drug delivery. [ 1 ] [ 2 ] [ 3 ]


Osmotic release systems have a number of major advantages over other controlled-release mechanisms. They are significantly less affected by factors such as  pH , food intake,  GI motility , and differing intestinal environments. Using an osmotic pump to deliver drugs has additional inherent advantages regarding control over drug delivery rates. This allows for much more precise drug delivery over an extended period of time, which results in much more predictable  pharmacokinetics . However, osmotic release systems are relatively complicated, somewhat difficult to manufacture, and may cause irritation or even blockage of the GI tract due to prolonged release of irritating drugs from the non-deformable tablet. [ 1 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ] [ 8 ] [ 9 ]


The Elementary Osmotic Pump (EOP) was developed by  ALZA  in 1974, and was the first practical example of an osmotic pump based drug release system for oral use. [ 1 ] [ 2 ] [ 10 ] [ 11 ] [ 12 ]  It was introduced to the market in the early 1980s in Osmosin ( indomethacin ) and Acutrim ( phenylpropanolamine ), but unexpectedly severe issues with GI irritation and cases of  GI perforation  led to the withdrawal of Osmosin. [ 1 ]


Merck & Co.  later developed the Controlled-Porosity Osmotic Pump (CPOP) with the intention of addressing some of the issues that led to Osmosin's withdrawal via a new approach to the final stage of the release mechanism. [ 1 ]  Unlike the EOP, the CPOP had no pre-formed hole in the outer shell for the drug to be expelled out of. Instead, the CPOP's semipermeable membrane was designed to form numerous small pores upon contact with water through which the drug would be expelled via osmotic pressure. The pores were formed via the use of a pH insensitive  leachable  or  dissolvable  additive such as  sorbitol . [ 13 ]


Both the EOP and CPOP were relatively simple designs, and were limited by their inability to deliver poorly  soluble  drugs. [ 1 ]  This led to the development of an additional internal "push layer" composed of material (a swellable  polymer ) that would expand as it absorbed water, which then pushed the drug layer (which incorporates a  viscous  polymer for suspension of poorly soluble drugs) out of the exit hole at a controlled rate. [ 1 ] [ 4 ]  Osmotic agents such as  sodium chloride ,  potassium chloride , or  xylitol  are added to both the drug and push layers to increase the  osmotic pressure . [ 1 ] [ 4 ] [ 5 ]  The initial design developed in 1982 by ALZA researchers was designated the Push-Pull Osmotic Pump (PPOP), and Procardia XL ( nifedipine ) was one of the first drugs to utilize this PPOP design. [ 1 ] [ 2 ]


In the early 1990s, an ALZA-funded research program began to develop a new dosage form of  methylphenidate  for the treatment of children with  attention deficit hyperactivity disorder  (ADHD). [ 14 ]  Methylphenidate's short  half-life  required multiple doses to be administered each day to attain long-lasting coverage, which made it an ideal candidate for the OROS technology. Multiple candidate  pharmacokinetic  profiles were evaluated and tested in an attempt to determine the optimal way to deliver the drug, which was especially important given the puzzling failure of an existing extended-release formulation of methylphenidate (Ritalin SR) to act as expected. The zero-order (flat) release profile that the PPOP was optimal at delivering failed to maintain its efficacy over time, which suggested that acute tolerance to methylphenidate formed over the course of the day. This explained why Ritalin SR was inferior to twice-daily Ritalin IR, and led to the  hypothesis  that an ascending pattern of drug delivery was necessary to maintain clinical effect. Trials designed to test this hypothesis were successful, and ALZA subsequently developed a modified PPOP design that utilized an overcoat of methylphenidate designed to release immediately and rapidly raise serum levels, followed by 10 hours of first-order (ascending) drug delivery from the modified PPOP design. This design was called the Push-Stick Osmotic Pump (PSOP), and utilized two separate drug layers with different concentrations of methylphenidate in addition to the (now quite robust) push layer. [ 1 ] [ 14 ]


OROS medications include: [ 1 ] [ 3 ] [ 4 ] [ 7 ]


The  Pharmaceutical Accountability Foundation  (in Dutch  Stichting Farma Ter Verantwoording ) was established in  Amsterdam  in July 2018 to deal with pharmaceutical companies that demand excessive prices for medicines in the Netherlands. This followed a report by the  Raad voor de Volksgezondheid en Zorg  [ nl ]  in 2017. Wilbert Bannenberg, an epidemiologist, is the chairman. [ 1 ]  The group plans to deploy both health and pharmaceutical expertise and lawyers.


They have investigated 12 cases all with the same business model, which they describe as: "buy an old, cheap product, get the old versions off the market, win orphan drug designation, and put up the price as high as you can." They say that European orphan drug legislation needs to be reformed. [ 2 ]


It plans to make a referral to the  Netherlands Authority for Consumers and Markets  in respect of the pricing policy of  Leadiant Biosciences  Ltd, formerly known as Sigma-Tau Rare Disease, for  chenodeoxycholic acid  which is used to treat about 60 children with  cerebrotendineous xanthomatosis  in the Netherlands. The company now sells this medicine at €140 per capsule, about €153,300 per patient per year. Previously it was sold under the name Chenofalk for the treatment of gallstones at a cost of €0.28 per capsule and used off label for the treatment of cerebrotendineous xanthomatosis.  Sigma-Tau  acquired the rights in 2008.  [ 3 ]  The  European Medicines Agency  approved chenodeoxycholic acid for the treatment of cerebrotendinous xanthomatosis. Leadiant, having secured orphan drug designation, and bought up rival suppliers, raised the price, as they were entitled to ten years market exclusivity in the European Union. Bannenberg claims that Leadiant is abusing its dominant market position. [ 4 ]  The  VU University Medical Center  are proposing to manufacture their own version at cost price, and this has been supported by Dutch health insurers. [ 5 ]  Leadiant has been compared to  Martin Shkreli . [ 6 ]  Bannanberg is quoted as saying “This may be legal but it’s not socially acceptable.” [ 7 ]  The foundation's complaints have been echoed by  Bruno Bruins , Minister for Medical Care. The track record of the  Netherlands Authority for Consumers and Markets  and previously of the Netherlands Competition Authority in the medicines sector has been described as poor.  [ 8 ]


Under political pressure, the pharmaceutical companies in the Netherlands have been working on a code of conduct which they say will provide guarantees for responsible pricing, and keep speculators out of the door. [ 9 ]


In April 2020, Bannenberg said that the Netherlands' vulnerability to medicine shortages had been exposed by the  COVID-19 pandemic in the Netherlands  because the country was too dependent on medicines from low-wage countries and vaccines from big pharma. The Netherlands was not a priority for supply. He wanted to see more local production and different manufacturers, even if this meant that generic drugs would be more expensive. [ 10 ]


Pharmaceutical fraud  is when pharmaceutical companies engage in illegal,  fraudulent  activities to the detriment of patients and/or insurers. Examples include  counterfeit  drugs that do not contain the active ingredient, false claims in packaging and marketing, suppression of negative information regarding the efficacy or safety of the drug, and violating pricing regulations.


Pharma fraud refers to:


Because of a lack of regulation and enforcement, the quality, safety and efficacy of both imported and locally manufactured medicines in many developing countries cannot be guaranteed. Subsequently, smuggling and illegal importation of drugs are common. Substandard and counterfeit drugs are then not only sold in these countries but also exported or re-exported. [ 10 ]  According to the  World Customs Organization , counterfeit drugs are a $200 billion a year industry that kills hundreds of thousands of people annually. [ 11 ]


In the United States, there are several different schemes [ 12 ]  used to defraud the  health care system  which are particular to the pharmaceutical industry.


Involve fraud with the Good Manufacturing Practice (GMP) Regulations which require manufacturers to have adequately equipped manufacturing facilities, adequately trained personnel, stringent control over the manufacturing process, appropriate laboratory controls, complete and accurate records, reports, appropriate finished product examination, and so on. Certain violations of the Good Manufacturing Practice Regulations may be the basis for a False Claims Act lawsuit. [ 13 ]


Though physicians may prescribe drugs for off-label usage known as off-label marketing, the  Food and Drug Administration  (FDA) prohibits drug manufacturers from marketing or promoting a drug for a use that the FDA has not approved. A manufacturer illegally “misbrands” a drug if the drug's labeling includes information about its unapproved uses. A drug is deemed misbranded unless its labeling bears adequate directions for use. The courts have agreed with the FDA that the  Food, Drug, and Cosmetic Act  (FDCA) requires information not only on how a product is to be used (e.g., dosage and administration), but also on all the intended uses of the product. In 2004, whistleblower  David Franklin  prevailed in a suit under the  False Claims Act  against  Warner-Lambert , resulting in a $430 million settlement in the  Franklin v. Parke-Davis  case. It was the  first off-label promotion case  successfully brought under the False Claims Act in U.S. history. Oral statements and materials presented at industry-support scientific and educational activities may provide evidence of a product's intended use. If these statements or materials promote a use that is inconsistent with the product's approved labeling, the product is misbranded under the FDCA for failure to bear labeling with adequate directions for all intended uses. [ 14 ]


A figure reported by the manufacturer to CMS in quarterly reports under the Medicaid Rebate Program, it is used to calculate the Medicaid reimbursement rate. It is defined as the lowest price available to any wholesaler, retailer, provider, health maintenance organization (HMO), nonprofit entity, or the government. BP excludes prices to the Indian Health Service (IHS), Department of Veterans Affairs (DVA), Department of Defense (DOD), the Public Health Service (PHS), 340B covered entities, Federal Supply Schedule (FSS), state pharmaceutical assistance programs, depot prices, and nominal pricing. BP includes cash discounts and free goods that are contingent upon purchase, volume discounts, and rebates. The fraud occurs as the manufacturer falsely self-reports its Best Price. [ 15 ]


In order to decrease the amounts owed to states under the  Medicaid Drug Rebate Program , some companies misrepresented material facts regarding the regulatory origin/status of their brand name drugs, the AMP, and/or the best price. Despite the Government's good faith reliance to charge manufacturers a unit rebate amount based upon the manufacturer's own representation of drug status, and price, some manufacturers have deceptively and fraudulently, breached their duty to deal honestly with the Government. [ 16 ]


FDA guidelines authorize pharmacists to “compound” or mix medications only in response to a physician's valid prescription. This assumes, of course, that the physician intends that the medication be compounded. The regulations further require that the mixed or compounded medications are medically necessary and not commercially available. Illegal compounding includes compounding of ingredients such that the compounded drug is tantamount to commercially available medications, involving mass manufacturing of drugs under the guise of compounding.


Federal law, including the Centers for Medicare and Medicaid Services (CMS) guidelines and the regulations of other Government Healthcare Programs, prohibit coverage of claims for “compounded” medications when the claims are submitted by a company that is mass manufacturing large amounts of unapproved drugs in violation of the Federal Food, Drug and Cosmetic Act (FFDCA), under the guise of “compounding.” [ 17 ]


Kickbacks  are rewards such as cash, jewelry, free vacations, corporate sponsored retreats, or other lavish gifts used to entice medical professionals into using specific medical services. This could be a small cash kickback for the use of an MRI when not required, or a lavish doctor/patient retreat that is funded by a pharmaceutical company to entice the prescription and use of a particular drug. [ 12 ]


People engaging in this type of fraud are also subject to the federal Anti-Kickback statute.


Drug discovery  and  development  requires the integration of multiple scientific and technological disciplines. These include  chemistry ,  biology ,  pharmacology ,  pharmaceutical technology  and extensive use of  information technology . The latter is increasingly recognised as  Pharmacoinformatics . Pharmacoinformatics relates to the broader field of  bioinformatics .


The main idea behind the field is to integrate different informatics branches (e.g. bioinformatics, chemoinformatics, immunoinformatics, etc.) into a single platform, resulting in a seamless process of drug discovery. The first reference of the term "Pharmacoinformatics" can be found in the year of 1993. [ 1 ]


The first dedicated department for Pharmacoinformatics was established at the  National Institute Of Pharmaceutical Education And Research , S.A.S. Nagar, India in 2003. [ 2 ]   This has been followed by different universities worldwide including a program by European universities named the  European Pharmacoinformatics Initiative  (Europin [ 3 ] ).


Pharmacoinformatics is also referred to as pharmacy informatics. According to the article "Pharmacy Informatics: What You Need to Know Now" by the University of Illinois at Chicago Pharmacoinformatics may be defined as: “the scientific field that focuses on medication-related data and knowledge within the continuum of healthcare systems. [ 4 ] ” It is the application of computers to the storage, retrieval and analysis of drug and prescription information. Pharmacy informaticists work with pharmacy information management systems that help the pharmacist safe decisions about patient drug therapies with respect to, medical insurance records, drug interactions, as well as prescription and patient information.


Pharmacy informatics can be thought of as a sub-domain of the larger professional discipline of health informatics. Health informatics is the study of interactions between people, their work processes and engineered systems within health care with a focus on pharmaceutical care and improved patient safety. For example, the Health Information Management Systems Society (HIMSS) defines pharmacy informatics as, "the scientific field that focuses on medication-related data and knowledge within the continuum of healthcare systems - including its acquisition, storage, analysis, use and dissemination - in the delivery of optimal medication-related patient care and health outcomes"


Pharmacometrics  is a field of study of the methodology and application of models for  disease  and  pharmacological   measurement . It uses mathematical models of  biology , pharmacology, disease, and  physiology  to describe and quantify interactions between  xenobiotics  and patients (human and non-human), including beneficial effects and adverse effects. [ 1 ]  It is normally applied to quantify drug, disease and trial information to aid efficient drug development, regulatory decisions and rational drug treatment in patients.


Pharmacometrics uses models based on pharmacology, physiology, and disease for quantitative analysis of interactions between drugs and patients. This involves  Systems pharmacology ,  pharmacokinetics ,  pharmacodynamics  and  disease progression  with a focus on  populations  and  variability .


Mould and Upton provide an overview of basic concepts in population modeling, simulation, and model-based drug development. [ 2 ]


A major focus of pharmacometrics is to understand variability in drug response. Variability may be predictable (e.g. due to differences in body weight or kidney function) or apparently unpredictable (a reflection of the current lack of knowledge).


The term "pharmacometrics" first appeared in literature in the preface of the 1964 book "Evaluation of Drug Activities: Pharmacometrics" [ 3 ] :


The sub-title of the book is, as far as we are aware, a  neologism , coined by one of us (A.L.B.), and the word is defined by the main title of the book, which could have been even more explicitly, if more verbosely, expressed as "The Identification and the Comparative Evaluation, Qualitative and Quantitative, of Drug Activities". The term has an etymological precedent in the now widely accepted " Econometrics ". We hope it will prove useful for distinguishing the kind of measurement discussed and described in this book from what is nowadays called  bioassay ; although the same techniques sometimes serve for both, their objectives are not at all identical.


However, the editors later state at the end of the preface:


...we have learned with interest and humility that Dr. Karl Beyer, a vice-president of  Merck, Sharpe and Dohme , Rahway, New Jersey, U.S.A., and current president of the American Pharmacological Society, "coined the word (Pharmacometrics) in the early '50s and has been using it in internal reports ever since" (J. R. Vane, personal communication). Moreover, one of the laboratories in the pharmacological department of his Company is "labeled 'Pharmacometrics'"!
We do not know in exactly what sense Dr. Beyer has been using the word, though we find it difficult to think of any other legitimate one than that advanced above. We can only hope that he also thinks so and that its use in the title of this book may help to give it the wider currency that we believe it to deserve and all the "priority" rights to Dr. Beyer.


Pharmacokinetic  models are constructs aimed at characterizing the average pharmacokinetic behavior of a drug within a population. By incorporating inter-individual variability, these models provide insights into central tendencies and variabilities in drug responses across diverse patient groups. Their application extends to the optimization of dosing regimens at a population level.


Pharmacodynamic  models focus on elucidating the intricate relationship between drug concentration and its effects on the body. This includes both the desired therapeutic effects and potential side effects. By delineating the time course of drug effects, these models contribute to the prediction of efficacy and adverse events, aiding in the identification of optimal dosing strategies.