Lithium  was discovered in the 19th century for nervous disorders and its possible mood-stabilizing or prophylactic effect; it was cheap and easily produced. As lithium fell out of favor in France,  valpromide  came into play. This antibiotic was the origin of the drug that eventually created the mood stabilizer category. Valpromide had distinct psychotrophic effects that were of benefit in both the treatment of acute manic states and in the maintenance treatment of manic depression illness.  Psychotropics  can either be  sedative  or  stimulant ; sedatives aim at damping down the extremes of behavior. Stimulants aim at restoring normality by increasing tone. Soon arose the notion of a tranquilizer which was quite different from any sedative or stimulant. The term tranquilizer took over the notions of sedatives and became the dominant term in the West through the 1980s. In Japan, during this time, the term tranquilizer produced the notion of a psyche-stabilizer and the term mood stabilizer vanished. [ 30 ]


Premarin  (conjugated estrogens, introduced in 1942) and  Prempro  (a combination estrogen-progestin pill, introduced in 1995) dominated the  hormone replacement therapy  (HRT) during the 1990s. HRT is not a life-saving drug, nor does it cure any disease. HRT has been prescribed to improve one's quality of life. Doctors prescribe estrogen for their older female patients both to treat short-term menopausal symptoms and to prevent long-term diseases. In the 1960s and early 1970s, more and more physicians began to prescribe estrogen for their female patients. Between 1991 and 1999, Premarin was listed as the most popular prescription and best-selling drug in America. [ 30 ]


The first oral contraceptive,  Enovid , was approved by FDA in 1960. Oral contraceptives inhibit ovulation and so prevent conception. Enovid was known to be much more effective than alternatives including the condom and the diaphragm. As early as 1960, oral contraceptives were available in several different strengths by every manufacturer. In the 1980s and 1990s, an increasing number of options arose including, most recently, a new  delivery system  for the oral contraceptive via a  transdermal patch . In 1982, a new version of  "the pill"  was introduced, known as the  biphasic pill . By 1985, a new  triphasic pill  was approved. Physicians began to think of "the pill" as an excellent means of birth control for young women. [ 30 ]


Stimulants such as  Ritalin  (methylphenidate) came to be pervasive tools for behavior management and modification in young children. Ritalin was first marketed in 1955 for  narcolepsy ; its potential users were middle-aged and the elderly. It was not until some time in the 1980s along with hyperactivity in children that Ritalin came onto the market. Medical use of methylphenidate is predominantly for symptoms of  attention deficit hyperactivity disorder  (ADHD). Consumption of methylphenidate in the U.S. out-paced all other countries between 1991 and 1999. Significant growth in consumption was also evident in Canada, New Zealand, Australia, and Norway. Currently, 85% of the world's methylphenidate is consumed in America. [ 30 ]


The first minor tranquilizer was  meprobamate . Only fourteen months after it was made available, meprobamate had become the country's largest-selling prescription drug. By 1957, meprobamate had become the fastest-growing drug in history. The popularity of meprobamate paved the way for  Librium  and  Valium , two minor tranquilizers that belonged to a new chemical class of drugs called the  benzodiazepines . These were drugs that worked chiefly as  anti-anxiety agents  and  muscle relaxants . The first benzodiazepine was Librium. Three months after it was approved, Librium had become the most prescribed tranquilizer in the nation. Three years later, Valium hit the shelves and was ten times more effective as a muscle relaxant and anti-convulsant. Valium was the most versatile of the minor tranquilizers. Later came the widespread adoption of major tranquilizers such as  chlorpromazine  and the drug  reserpine . In 1970, sales began to decline for Valium and Librium, but sales of new and improved tranquilizers, such as  Xanax , introduced in 1981 for the newly created diagnosis of panic disorder, soared. [ 30 ]


Mevacor  (lovastatin) is the first and most influential  statin  in the American market. The 1991 launch of  Pravachol  (pravastatin), the second available in the United States, and the release of  Zocor  (simvastatin) made Mevacor no longer the only statin on the market.
In 1998,  Viagra  was released as a treatment for erectile dysfunction. [ 30 ]


Using plants and plant substances to treat all kinds of diseases and medical conditions is believed to date back to  prehistoric medicine . [ citation needed ]


The  Kahun Gynaecological Papyrus , the oldest known medical text of any kind, dates to about 1800 BC and represents the first documented use of any kind of drug. [ 31 ] [ 32 ]  It and other  medical papyri  describe  Ancient Egyptian medical practices , such as using  honey  to treat infections and the legs of bee-eaters to treat neck pains.


Ancient  Babylonian medicine  demonstrated the use of medication in the first half of the  2nd millennium BC .  Medicinal creams  and  pills  were employed as treatments. [ 33 ]


On the Indian subcontinent, the  Atharvaveda , a sacred text of  Hinduism  whose core dates from the second millennium BC, although the hymns recorded in it are believed to be older, is the first Indic text dealing with medicine. It describes plant-based drugs to counter diseases. [ 34 ]  The earliest foundations of  ayurveda  were built on a synthesis of selected ancient herbal practices, together with a massive addition of theoretical conceptualizations, new  nosologies  and new therapies dating from about 400 BC onwards. [ 35 ]  The student of Āyurveda was expected to know ten arts that were indispensable in the preparation and application of his medicines: distillation, operative skills, cooking, horticulture, metallurgy, sugar manufacture, pharmacy, analysis and separation of minerals, compounding of metals, and preparation of  alkalis .


The  Hippocratic Oath  for physicians, attributed to fifth century BC Greece, refers to the existence of "deadly drugs", and  ancient Greek physicians  imported drugs from Egypt and elsewhere. [ 36 ]  The  pharmacopoeia   De materia medica , written between 50 and 70 CE by the Greek physician  Pedanius Dioscorides , was widely read for more than 1,500 years. [ 37 ]


Al-Kindi 's ninth century AD book,  De Gradibus  and  Ibn Sina  (Avicenna)'s  The Canon of Medicine , covers a range of drugs known to the practice of  medicine in the medieval Islamic world .


Medieval medicine of Western Europe  saw advances in surgery compared to previously, but few truly effective drugs existed, beyond  opium  (found in such extremely popular drugs as the "Great Rest" of the  Antidotarium Nicolai  at the time) [ 38 ]  and  quinine . Folklore cures and potentially poisonous metal-based compounds were popular treatments.  Theodoric Borgognoni , (1205–1296), one of the most significant surgeons of the medieval period, responsible for introducing and promoting important surgical advances including basic  antiseptic  practice and the use of  anaesthetics .  Garcia de Orta  described some herbal treatments that were used. [ vague ]


For most of the 19th century, drugs were not highly effective, leading  Oliver Wendell Holmes Sr.  to famously comment in 1842 that "if all medicines in the world were thrown into the sea, it would be all the better for mankind and all the worse for the fishes". [ 27 ] : 21


During the  First World War ,  Alexis Carrel  and  Henry Dakin  developed the Carrel-Dakin method of treating wounds with an irrigation, Dakin's solution, a germicide which helped prevent  gangrene .


In the inter-war period, the first anti-bacterial agents such as the  sulpha  antibiotics were developed. The Second World War saw the introduction of widespread and effective antimicrobial therapy with the development and mass production of  penicillin  antibiotics, made possible by the pressures of the war and the collaboration of British scientists with the American  pharmaceutical industry .


Medicines commonly used by the late 1920s included  aspirin ,  codeine , and  morphine  for pain;  digitalis ,  nitroglycerin , and  quinine  for heart disorders, and  insulin  for diabetes. Other drugs included  antitoxins , a few biological vaccines, and a few synthetic drugs. In the 1930s, antibiotics emerged: first  sulfa drugs , then  penicillin  and other antibiotics. Drugs increasingly became "the center of medical practice". [ 27 ] : 22   In the 1950s, other drugs emerged including  corticosteroids  for  inflammation ,  rauvolfia alkaloids  as tranquilizers and antihypertensives,  antihistamines  for nasal allergies,  xanthines  for asthma, and typical  antipsychotics  for psychosis. [ 27 ] : 23–24   As of 2007, thousands of approved drugs have been  developed . Increasingly,  biotechnology  is used to discover  biopharmaceuticals . [ 27 ]  Recently, multi-disciplinary approaches have yielded a wealth of new data on the development of novel antibiotics and antibacterials and on the use of biological agents for antibacterial therapy. [ 39 ]


In the 1950s, new psychiatric drugs, notably the antipsychotic  chlorpromazine , were designed in laboratories and slowly came into preferred use. Although often accepted as an advance in some ways, there was some opposition, due to serious adverse effects such as  tardive dyskinesia . Patients often opposed psychiatry and refused or stopped taking the drugs when not subject to psychiatric control.


Governments have been heavily involved in the regulation of drug development and drug sales. In the U.S., the  Elixir Sulfanilamide disaster  led to the establishment of the  Food and Drug Administration , and the 1938 Federal Food, Drug, and Cosmetic Act required manufacturers to file new drugs with the FDA. The 1951 Humphrey-Durham Amendment required certain drugs to be sold by prescription. In 1962, a subsequent amendment required new drugs to be tested for efficacy and safety in  clinical trials . [ 27 ] : 24–26


Until the 1970s, drug prices were not a major concern for doctors and patients. As more drugs became prescribed for chronic illnesses, however, costs became burdensome, and by the 1970s nearly every U.S. state required or encouraged the substitution of  generic drugs  for higher-priced brand names. This also led to the 2006 U.S. law,  Medicare Part D , which offers Medicare coverage for drugs. [ 27 ] : 28–29


As of 2008, the United States is the leader in  medical research , including pharmaceutical development. U.S. drug prices are among the highest in the world, and drug innovation is correspondingly high. In 2000, U.S.-based firms developed 29 of the 75 top-selling drugs; firms from the second-largest market, Japan, developed eight, and the United Kingdom contributed 10. France, which imposes price controls, developed three. Throughout the 1990s, outcomes were similar. [ 27 ] : 30–31


Controversies concerning pharmaceutical drugs include patient access to drugs under development and not yet approved, pricing, and environmental issues.


Governments worldwide have created provisions for granting access to drugs prior to approval for patients who have exhausted all alternative treatment options and do not match clinical trial entry criteria. Often grouped under the labels of compassionate use,  expanded access , or named patient supply, these programs are governed by rules which vary by country defining access criteria, data collection, promotion, and control of drug distribution. [ 40 ]


Within the United States, pre-approval demand is generally met through  treatment IND  (investigational new drug) applications (INDs), or single-patient INDs. These mechanisms, which fall under the label of expanded access programs, provide access to drugs for groups of patients or individuals residing in the US. Outside the US, Named Patient Programs provide controlled, pre-approval access to drugs in response to requests by physicians on behalf of specific, or "named", patients before those medicines are licensed in the patient's home country.  Through these programs, patients are able to access drugs in late-stage clinical trials or approved in other countries for a genuine, unmet medical need, before those drugs have been licensed in the patient's home country. [ citation needed ]


Patients who have not been able to get access to drugs in development have organized and advocated for greater access.  In the United States,  ACT UP  formed in the 1980s, and eventually formed its  Treatment Action Group  in part to pressure the US government to put more resources into discovering treatments for AIDS and then to speed release of drugs that were under development. [ 41 ]


The  Abigail Alliance  was established in November 2001 by Frank Burroughs in memory of his daughter, Abigail. [ 42 ]  The Alliance seeks broader availability of investigational drugs on behalf of terminally ill patients.


In 2013,  BioMarin Pharmaceutical  was at the center of a high-profile debate regarding expanded access of cancer patients to experimental drugs. [ 43 ] [ 44 ]


Essential medicines, as defined by the  World Health Organization  (WHO), are "those drugs that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in appropriate dosage forms, at a price the community can afford." [ 45 ]   Recent studies have found that most of the medicines on the WHO essential medicines list, outside of the field of HIV drugs, are not patented in the developing world, and that lack of widespread  access to these medicines  arise from issues fundamental to economic development – lack of infrastructure and poverty. [ 46 ]   Médecins Sans Frontières  also runs a  Campaign for Access to Essential Medicines  campaign, which includes advocacy for greater resources to be devoted to currently untreatable diseases that primarily occur in the developing world. The  Access to Medicine Index  tracks how well pharmaceutical companies make their products available in the developing world. [ citation needed ]


World Trade Organization  negotiations in the 1990s, including the  TRIPS Agreement  and the  Doha Declaration , have centered on issues at the intersection of international trade in pharmaceuticals and  intellectual property rights , with developed world nations seeking strong intellectual property rights to protect investments made to develop new drugs, and developing world nations seeking to promote their generic pharmaceuticals industries and their ability to make medicine available to their people via  compulsory licenses .


Some have raised ethical objections specifically with respect to pharmaceutical patents and the high prices for drugs that they enable their proprietors to charge, which poor people around the world, cannot afford. [ 47 ] [ 48 ]  Critics also question the rationale that exclusive patent rights and the resulting high prices are required for pharmaceutical companies to recoup the large investments needed for research and development. [ 47 ]  One study concluded that marketing expenditures for new drugs often doubled the amount that was allocated for research and development. [ 49 ]  Other critics claim that patent settlements would be costly for consumers, the health care system, and state and federal governments because it would result in delaying access to lower cost generic medicines. [ 50 ]


Novartis  fought a protracted battle with the government of India over the patenting of its drug,  Gleevec , in India, which ended up in a Supreme Court in a case known as  Novartis v. Union of India & Others .  The Supreme Court ruled narrowly against Novartis, but opponents of patenting drugs claimed it as a major victory. [ 51 ]


Pharmaceutical medications are commonly described as "ubiquitous" in nearly every type of environmental medium (i.e.  lakes ,  rivers ,  streams ,  estuaries ,  seawater , and  soil ) worldwide. [ 52 ] [ 53 ] [ 54 ] [ 55 ]  Their chemical components are typically present at relatively low  concentrations  in the ng/L to μg/L ranges. [ 56 ] [ 54 ]  The primary avenue for medications reaching the environment are through the  effluent  of wastewater  treatment plants , both from  industrial plants  during production, and from  municipal plants  after consumption. [ 57 ]   Agricultural pollution  is another significant source derived from the prevalence of  antibiotic use in livestock . [ 56 ]


Scientists generally divide environmental impacts of a chemical into three primary categories: persistence,  bioaccumulation , and  toxicity . [ 53 ]  Since medications are inherently bio-active, most are naturally degradable in the environment, however they are classified as "pseudopersistent" because they are constantly being replenished from their sources. [ 52 ]  These  Environmentally Persistent Pharmaceutical Pollutants  (EPPPs) rarely reach toxic concentrations in the environment, however they have been known to bioaccumulate in some species. [ 58 ]  Their effects have been observed to compound gradually across  food webs , rather than becoming acute, leading to their classification by the  US Geological Survey  as "Ecological Disrupting Compounds." [ 52 ]


In an  adaptive design  of a  clinical trial , the parameters and conduct of the trial for a candidate  drug  or  vaccine  may be changed based on an  interim analysis . [ 2 ] [ 1 ] [ 3 ]  Adaptive design typically involves advanced statistics to interpret a clinical trial  endpoint . [ 1 ]  This is in contrast to traditional single-arm (i.e. non-randomized) clinical trials or  randomized clinical trials  (RCTs) that are static in their protocol and do not modify any parameters until the trial is completed. The adaptation process takes place at certain points in the trial, prescribed in the trial protocol. Importantly, this trial protocol is set before the trial begins with the adaptation schedule and processes specified. Adaptions may include modifications to: dosage, sample size, drug undergoing trial, patient selection criteria and/or "cocktail" mix. [ 4 ] [ 5 ]  The PANDA (A Practical Adaptive & Novel Designs and Analysis toolkit) provides not only a summary of different adaptive designs, but also comprehensive information on adaptive design planning, conduct, analysis and reporting. [ 6 ]


The aim of an adaptive trial is to more quickly identify drugs or devices that have a therapeutic effect, and to zero in on patient populations for whom the drug is appropriate. [ 7 ]  When conducted efficiently, adaptive trials have the potential to find new treatments while minimizing the number of patients exposed to the risks of clinical trials. Specifically, adaptive trials can efficiently discover new treatments by reducing the number of patients enrolled in treatment groups that show minimal efficacy or higher adverse-event rates. Adaptive  trials  can adjust almost any part of its design, based on pre-set rules and statistical design, such as sample size, adding new groups, dropping less effective groups and changing the probability of being randomized to a particular group, for example.


In 2004, a Strategic Path Initiative was introduced by the United States  Food and Drug Administration  (FDA) to modify the way drugs travel from lab to market. This initiative aimed at dealing with the high attrition levels observed in the clinical phase. It also attempted to offer flexibility to investigators to find the optimal clinical benefit without affecting the study's validity. Adaptive clinical trials initially came under this regime. [ 8 ]


The FDA issued draft guidance on adaptive trial design in 2010. [ 7 ]  In 2012, the  President's Council of Advisors on Science and Technology  (PCAST) recommended that the FDA "run pilot projects to explore adaptive approval mechanisms to generate evidence across the lifecycle of a drug from the pre-market through the post-market phase." While not specifically related to clinical trials, the council also recommended that they "make full use of accelerated approval for all drugs meeting the statutory standard of addressing an unmet need for a serious or life-threatening disease, and demonstrating an impact on a clinical endpoint other than survival or irreversible morbidity, or on a surrogate endpoint, likely to predict clinical benefit." [ 9 ]


By 2019, the FDA updated their 2010 recommendations and issued "Adaptive Design Clinical Trials for Drugs and Biologics Guidance". [ 10 ]   In October of 2021, the FDA Center for Veterinary Medicine issued the Guidance Document "Adaptive and Other Innovative Designs for Effectiveness Studies of New Animal Drugs". [ 11 ]


Traditionally, clinical trials are conducted in three steps: [ 1 ]


Any trial design that can change its design, during active enrollment, could be considered an adaptive clinical trial. There are a number of different types, and real life trials may combine elements from these different trial types: [ 1 ] [ 12 ] [ 13 ] [ 14 ] [ 15 ] [ 16 ]  In some cases, trials have become an ongoing process that regularly adds and drops therapies and patient groups as more information is gained. [ 8 ]


Phase I  of clinical research focuses on selecting a particular dose of a drug to carry forward into future trials. Historically, such trials have had a "rules-based" (or "algorithm-based") design, such as the 3+3 design. [ 17 ]  However, these "A+B" rules-based designs are not appropriate for phase I studies and are inferior to adaptive, model-based designs. [ 18 ]  An example of a superior design is the continual reassessment method (CRM). [ 19 ] [ 20 ] [ 21 ]


Group sequential design is the application of  sequential analysis  to clinical trials. At each interim analysis, investigators will use the current data to decide whether the trial should either stop or should continue to recruit more participants. The trial might stop either because the evidence that the treatment is working is strong ("stopping for benefit") or weak ("stopping for futility"). Whether a trial may stop for futility only, benefit only, or either, is stated in advance. A design has "binding stopping rules" when the trial must stop when a particular threshold of (either strong or weak) evidence is crossed at a particular interim analysis. Otherwise it has "non-binding stopping rules", in which case other information can be taken into account, for example safety data. The number of interim analyses is specified in advance, and can be anything from a single interim analysis (a "two-stage" design") to an interim analysis after every participant ("continuous monitoring").


For trials with a binary (response/no response) outcome and a single treatment arm, a popular and simple group sequential design with two stages is the Simon design. In this design, there is a single interim analysis partway through the trial, at which point the trial either stops for futility or continues to the second stage. [ 22 ]  Mander and Thomson also proposed a design with a single interim analysis, at which point the trial could stop for either futility or benefit. [ 23 ]


For single-arm, single-stage binary outcome trials, a trial's success or failure is determined by the number of responses observed by the end of the trial. This means that it may be possible to know the conclusion of the trial (success or failure) with certainty before all the data are available. Planning to stop a trial once the conclusion is known with certainty is called  non-stochastic curtailment . This reduces the sample size on average. Planning to stop a trial when the probability of success, based on the results so far, is either above or below a certain threshold is called  stochastic curtailment . This reduces the average sample size even more than non-stochastic curtailment. Stochastic and non-stochastic curtailment can also be used in two-arm binary outcome trials, where a trial's success or failure is determined by the number of responses observed on each arm by the end of the trial.


The adaptive design method developed mainly in the early 21st century. [ 1 ]  In November 2019, the US  Food and Drug Administration  provided guidelines for using adaptive designs in clinical trials. [ 3 ]


In April 2020, the  World Health Organization  published an "R&D Blueprint (for the)  novel Coronavirus " (Blueprint). The Blueprint documented a "large, international, multi-site, individually randomized controlled clinical trial" to allow "the concurrent evaluation of the benefits and risks of each promising candidate vaccine within 3–6 months of it being made available for the trial." The Blueprint listed a  Global Target Product Profile  (TPP) for COVID‑19, identifying favorable attributes of safe and effective vaccines under two broad categories: "vaccines for the long-term protection of people at higher risk of COVID-19, such as healthcare workers", and other vaccines to provide rapid-response immunity for new outbreaks. [ 24 ]


The international TPP team was formed to 1) assess the development of the most promising candidate vaccines; 2) map candidate vaccines and their clinical trial worldwide, publishing a frequently-updated "landscape" of vaccines in development; [ 25 ]  3) rapidly evaluate and screen for the most promising candidate vaccines simultaneously before they are tested in humans; and 4) design and coordinate a multiple-site, international  randomized controlled trial  – the "Solidarity trial" for vaccines [ 24 ] [ 26 ]  – to enable simultaneous evaluation of the benefits and risks of different vaccine candidates under clinical trials in countries where there are high rates of COVID‑19 disease, ensuring fast interpretation and sharing of results around the world. [ 24 ]  The WHO vaccine coalition prioritized which vaccines would go into Phase   II and III clinical trials, and determined harmonized Phase   III protocols for all vaccines achieving the  pivotal trial  stage. [ 24 ]


The global  "Solidarity"  and European "Discovery" trials of hospitalized people with severe COVID‑19 infection applied adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge. [ 27 ] [ 28 ] [ 29 ] [ 30 ]  The US  National Institute of Allergy and Infectious Diseases  (NIAID) initiated an adaptive design, international Phase III trial (called "ACTT") to involve up to 800 hospitalized COVID‑19 people at 100 sites in multiple countries. [ 31 ]


An adaptive trial design enabled two experimental  breast cancer  drugs to deliver promising results after just six months of testing, far shorter than usual. Researchers assessed the results while the trial was in process and found that cancer had been eradicated in more than half of one group of patients. The trial, known as  I-Spy 2 , tested 12 experimental drugs. [ 7 ]


For its predecessor I-SPY 1, 10 cancer centers and the National Cancer Institute (NCI SPORE program and the NCI Cooperative groups) collaborated to identify response indicators that would best predict survival for women with high-risk breast cancer. During 2002–2006, the study monitored 237 patients undergoing  neoadjuvant therapy  before surgery. Iterative  MRI  and tissue samples monitored the biology of patients to chemotherapy given in a neoadjuvant setting, or presurgical setting. Evaluating chemotherapy's direct impact on tumor tissue took much less time than monitoring outcomes in thousands of patients over long time periods. The approach helped to standardize the imaging and tumor sampling processes, and led to miniaturized assays. Key findings included that tumor response was a good predictor of patient survival, and that tumor shrinkage during treatment was a good predictor of long-term outcome. Importantly, the vast majority of tumors identified as high risk by molecular signature. However, heterogeneity within this group of women and measuring response within tumor subtypes was more informative than viewing the group as a whole. Within genetic signatures, level of response to treatment appears to be a reasonable predictor of outcome. Additionally, its shared database has furthered the understanding of drug response and generated new targets and agents for subsequent testing. [ 32 ]


I-SPY 2 is an adaptive clinical trial of multiple Phase 2 treatment regimens combined with standard chemotherapy. I-SPY 2 linked 19 academic cancer centers, two community centers, the FDA, the NCI, pharmaceutical and biotech companies, patient advocates and philanthropic partners. The trial is sponsored by the Biomarker Consortium of the Foundation for the NIH (FNIH), and is co-managed by the FNIH and QuantumLeap Healthcare Collaborative. I-SPY 2 was designed to explore the hypothesis that different combinations of cancer therapies have varying degrees of success for different patients. Conventional clinical trials that evaluate post-surgical tumor response require a separate trial with long intervals and large populations to test each combination. Instead, I-SPY 2 is organized as a continuous process. It efficiently evaluates multiple therapy regimes by relying on the predictors developed in I-SPY 1 that help quickly determine whether patients with a particular genetic signature will respond to a given treatment regime. The trial is adaptive in that the investigators learn as they go, and do not continue treatments that appear to be ineffective. All patients are categorized based on tissue and imaging markers collected early and iteratively (a patient's markers may change over time) throughout the trial, so that early insights can guide treatments for later patients. Treatments that show positive effects for a patient group can be ushered to confirmatory clinical trials, while those that do not can be rapidly sidelined. Importantly, confirmatory trials can serve as a pathway for FDA  Accelerated Approval . I-SPY 2 can simultaneously evaluate candidates developed by multiple companies, escalating or eliminating drugs based on immediate results. Using a single standard arm for comparison for all candidates in the trial saves significant costs over individual Phase 3 trials. All data are shared across the industry. [ 32 ]  As of January 2016 [update]  I-SPY 2 is comparing 11 new treatments against 'standard therapy', and is estimated to complete in Sept 2017. [ 33 ]  By mid 2016 several treatments had been selected for later stage trials. [ 34 ]


Researchers under the EPAD project by the  Innovative Medicines Initiative  are utilizing an adaptive trial design to help speed development of  Alzheimer's disease  treatments, with a budget of 53 million euros. The first trial under the initiative was expected to begin in 2015 and to involve about a dozen companies. [ 7 ] [ 35 ]  As of 2020, 2,000 people over the age of 50 have been recruited across Europe for a long term study on the earliest stages of Alzheimer's. [ 36 ]  The EPAD project plans to use the results from this study and other data to inform 1,500 person selected adaptive clinical trials of drugs to prevent Alzheimer's. [ 37 ]


The adjustable nature of adaptive trials inherently suggests the use of  Bayesian statistical analysis . Bayesian statistics inherently address updating information such as that seen in adaptive trials that change from updated information derived from interim analysis. [ 38 ]  The problem of adaptive clinical trial design is more or less exactly the  bandit problem  as studied in the field of  reinforcement learning .


According to FDA guidelines, an adaptive Bayesian clinical trial can involve: [ 39 ]


The Bayesian framework  Continuous Individualized Risk Index  which is based on dynamic measurements from cancer patients can be effectively used for adaptive trial designs.  Platform trials  rely heavily on Bayesian designs.


For regulatory submission of Bayesian clinical trial design, there exist two Bayesian decision rules that are frequently used by trial sponsors. [ 40 ]  First, posterior probability approach is mainly used in decision-making to quantify the evidence to address the question, "Does the current data provide convincing evidence in favor of the alternative hypothesis?" The key quantity of the posterior probability approach is the posterior probability of the alternative hypothesis being true based on the data observed up to the point of analysis. Second, predictive probability approach is mainly used in decision-making is to answer the question at an interim analysis: "Is the trial likely to present compelling evidence in favor of the alternative hypothesis if we gather additional data, potentially up to the maximum sample size (or current sample size)?" [ 38 ]  The key quantity of the predictive probability approach is the posterior predictive probability of the trial success given the interim data.


In most regulatory submissions, Bayesian trial designs are calibrated to possess good frequentist properties. In this spirit, and in adherence to regulatory practice, regulatory agencies typically recommend that sponsors provide the frequentist type I and II error rates for the sponsor's proposed Bayesian analysis plan. In other words, the Bayesian designs for the regulatory submission need to satisfy the type I and II error requirement in most cases in the frequentist sense. Some exception may happen in the context of external data borrowing where the type I error rate requirement can be relaxed to some degree depending on the confidence of the historical information. [ 38 ]


The problem of adaptive clinical trial design is more or less exactly the  bandit problem  as studied in the field of  reinforcement learning .


The logistics of managing traditional, non-adaptive design clinical trials may be complex. In adaptive design clinical trials, adapting the design as results arrive adds to the complexity of design, monitoring, drug supply, data capture and randomization. [ 8 ]  Furthermore, it should be stated in the trial's  protocol  exactly what kind of adaptation will be permitted. [ 1 ]  Publishing the trial protocol in advance increases the validity of the final results, as it makes clear that any adaptation that took place during the trial was planned, rather than ad hoc. According to PCAST "One approach is to focus studies on specific subsets of patients most likely to benefit, identified based on validated biomarkers. In some cases, using appropriate biomarkers can make it possible to dramatically decrease the sample size required to achieve statistical significance—for example, from 1500 to 50 patients." [ 41 ]


Adaptive designs have added statistical complexity compared to traditional clinical trial designs. For example, any multiple testing, either from looking at multiple treatment arms or from looking at a single treatment arm multiple times, must be accounted for. Another example is  statistical bias , which can be more likely when using adaptive designs, and again must be accounted for.


While an adaptive design may be an improvement over a non-adaptive design in some respects (for example, expected sample size), it is not always the case that an adaptive design is a better choice overall: in some cases, the added complexity of the adaptive design may not justify its benefits. An example of this is when the trial is based on a measurement that takes a long time to observe, as this would mean having an interim analysis when many participants have started treatment but cannot yet contribute to the interim results. [ 42 ]


Shorter trials may not reveal longer term risks, such as a cancer's return. [ 7 ]


The  Anatomical Therapeutic Chemical  ( ATC )  Classification System  is a  drug classification  system that classifies the  active ingredients  of  drugs  according to the  organ  or  system  on which they act and their  therapeutic ,  pharmacological  and  chemical  properties. Its purpose is an aid to  monitor drug use  and for  research  to improve quality medication use. It does not imply  drug recommendation  or  efficacy . [ 1 ]  It is controlled by the  World Health Organization  Collaborating Centre for Drug Statistics Methodology (WHOCC), and was first published in 1976. [ 2 ] [ 3 ] [ 4 ]


This  pharmaceutical coding system  divides drugs into different groups according to the organ or system on which they act, their  therapeutic  intent or nature, and the drug's  chemical characteristics . Different brands share the same code if they have the same active substance and indications. Each bottom-level ATC code stands for a pharmaceutically used substance, or a combination of substances, in a single indication (or use). This means that one drug can have more than one code, for example  acetylsalicylic acid  (aspirin) has  A01AD05  ( WHO ) as a drug for local  oral  treatment,  B01AC06  ( WHO ) as a  platelet inhibitor , and  N02BA01  ( WHO ) as an  analgesic  and  antipyretic ; as well as one code can represent more than one active ingredient, for example  C09BB04  ( WHO ) is the combination of perindopril with amlodipine, two active ingredients that have their own codes ( C09AA04  ( WHO ) and  C08CA01  ( WHO ) respectively) when prescribed alone.


The ATC classification system is a strict hierarchy, [ 5 ]  meaning that each code necessarily has one and only one parent code, except for the 14 codes at the topmost level which have no parents. The codes are semantic identifiers, [ 5 ]  meaning they depict information by themselves beyond serving as identifiers (namely, the codes depict themselves the complete lineage of parenthood). As of 7 May 2020, there are 6,331 codes in ATC; the table below gives the count per level. [ 6 ]


The ATC system is based on the earlier Anatomical Classification System, which is intended as a tool for the pharmaceutical industry to classify pharmaceutical products (as opposed to their active ingredients). [ 7 ]  This system, confusingly also called ATC, was initiated in 1971 by the  European Pharmaceutical Market Research Association  (EphMRA) and is being maintained by the EphMRA and Intellus. Its codes are organised into four levels. [ 8 ]  The WHO's system, having five levels, is an extension and modification of the EphMRA's. It was first published in 1976. [ 2 ]


In this system, drugs are classified into groups at five different levels: [ 9 ]


The first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups: [ 10 ]


Example :  C   Cardiovascular system


The second level of the code indicates the therapeutic subgroup and consists of two digits. [ 11 ]


Example :  C 03   Diuretics


The third level of the code indicates the therapeutic/pharmacological subgroup and consists of one letter.


Example : C03 C  High-ceiling diuretics


The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter.


Example : C03C A   Sulfonamides


The fifth level of the code indicates the chemical substance and consists of two digits.


Example : C03CA 01   furosemide


The  Anatomical Therapeutic Chemical Classification System for veterinary medicinal products  (ATCvet) is used to classify  veterinary  drugs. ATCvet codes can be created by placing the letter Q in front of the ATC code of most human medications. For example, furosemide for veterinary use has the code  Q C03CA01.


Some codes are used exclusively for veterinary drugs, such as  QI  Immunologicals ,  QJ51  Antibacterials for intramammary use  or  QN05AX90  amperozide . [ 12 ]


The Herbal ATC system (HATC) is an ATC classification of  herbal substances ;  it differs from the regular ATC system by using 4 digits instead of 2 at the 5th level group. [ 13 ]


The herbal classification is not adopted by WHO. The  Uppsala Monitoring Centre  is responsible for the Herbal ATC classification, and it is part of the  WHODrug Global  portfolio available by  subscription . [ 14 ]


The ATC system also includes defined daily doses (DDDs) for many drugs. This is a measurement of drug consumption based on the usual daily dose for a given drug. According to the definition, "[t]he DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults." [ 15 ]


National issues of the ATC classification, such as the  German   Anatomisch-therapeutisch-chemische Klassifikation mit Tagesdosen , may include additional codes and DDDs not present in the WHO version. [ 16 ]


ATC follows guidelines [ 17 ]  in creating new codes for newly approved drugs. An application is submitted to WHO for ATC classification and DDD assignment. A preliminary or temporary code is assigned and published on the website and in the  WHO Drug Information  for comment or objection.  New ATC/DDD codes are discussed at the semi-annual Working Group meeting. If accepted it becomes a final decision and published semi-annually on the website and  WHO Drug Information  and implemented in the annual print/on-line ACT/DDD Index on January 1. [ 18 ]


Changes to existing ATC/DDD follow a similar process to become temporary codes and if accepted become a final decision as ATC/DDD alterations.  ATC and DDD alterations are only valid and implemented in the coming annual updates; the original codes must continue until the end of the year. [ 19 ] [ 20 ]  An updated version of the complete on-line/print ATC index with DDDs is published annually on January 1. [ 21 ]


An  astringent  (sometimes called  adstringent ) is a chemical that shrinks or constricts  body tissues . The word derives from the  Latin   adstringere , which means "to bind fast".  Astringency , the dry, puckering or numbing  mouthfeel  caused by the  tannins [ 1 ] [ 2 ]  in unripe fruits, lets the fruit mature by deterring eating. Tannins, being a kind of  polyphenol , bind salivary  proteins  and make them precipitate and  aggregate , [ 3 ] [ 4 ] [ 5 ]  producing a rough, "sandpapery", or dry sensation in the mouth.


Smoking tobacco  is also reported to have an astringent effect. [ 6 ]


In a scientific study, astringency was still detectable by subjects who had  local anesthesia  applied to their taste nerves, but not when both these and the  trigeminal nerves  were disabled. [ 7 ]


In medicine, astringents cause constriction or contraction of  mucous membranes  and exposed tissues and are often used internally to reduce discharge of  blood serum  and mucous secretions. [ 8 ]  This can happen with a  sore throat ,  hemorrhages ,  diarrhea , and  peptic ulcers . Externally applied astringents, which cause mild coagulation of skin  proteins , dry, harden, and protect the  skin . [ 9 ]  People with  acne  are often advised to use astringents if they have oily skin. [ 10 ]  Mild astringents relieve such minor skin irritations as those resulting from superficial cuts;  allergies ;  insect bites ; [ 9 ]   anal hemorrhoids ; [ 11 ]  and  fungal infections  such as  athlete's foot . [ 12 ]  Redness-reducing eye drops contain an astringent. Use of  Goulard's Extract  has been discontinued due to  lead poisoning . [ citation needed ]


Some common astringents are  alum ,  acacia ,  sage , [ 13 ]   yarrow , [ 14 ]   witch hazel ,  bayberry ,  distilled vinegar , very cold  water , and  rubbing alcohol . Astringent preparations include  silver nitrate ,  potassium permanganate ,  zinc oxide ,  zinc sulfate ,  Burow's solution ,  tincture of benzoin , and such vegetable substances as  tannic  and  gallic acids .  Balaustines  are the red  rose -like  flowers  of the  pomegranate , which are very bitter to the taste. In medicine, their dried form has been used as an astringent. [ 15 ]   Some metal  salts  and acids have also been used as astringents. [ 16 ]


Calamine lotion ,  witch hazel , and  yerba mansa , are astringents, [ 17 ]  as are the powdered leaves of the  myrtle . [ 18 ]  Ripe fruits and fruit parts including  blackthorn  (sloe berries),  Aronia  chokeberry,  chokecherry ,  bird cherry ,  rhubarb ,  quince ,  jabuticaba  and  persimmon  fruits (especially when unripe),  banana  skins (or unripe bananas),  cashew  fruits and acorns are astringent. [ 19 ]  Citrus fruits, like lemons, are somewhat astringent. The tannins in some  teas ,  coffee , and red grape  wines  like  Cabernet Sauvignon  and  Merlot  produce mild astringency. [ citation needed ]   Astringency  is used in classifications of  white wine .


Biodiversity  plays a vital role in maintaining human and animal health because numerous plants, animals, and fungi are used in medicine to produce vital  vitamins ,  painkillers ,  antibiotics , and other medications. [ 1 ] [ 2 ] [ 3 ]  Natural products have been recognized and used as medicines by ancient cultures all around the world. [ 4 ]  Some animals are also known to  self-medicate  using plants and other materials available to them. [ 5 ]


Many plant species have been studied thoroughly for their value as a source of medicine. [ 6 ] [ 7 ]  They have a wide range of benefits such as anti-fever and anti-inflammatory properties, can treat diseases such as  malaria  and  diabetes , and are used as vitamins and  antibiotic  and  antifungal  medications. [ 7 ] [ 8 ] [ 9 ] [ 10 ]  More than 60% of the world's population relies almost entirely on plant medicine for primary health care, [ 11 ]  and about 119 pure chemicals such as  caffeine ,  methyl salicylate , and  quinine  are extracted from less than 90 species of higher plants and used as medicines throughout the world. [ 4 ]


In China, Japan, India, and Germany, there is a great deal of interest in and support for the search for new drugs from higher plants. [ 4 ]  For example, the Herbalome Project was launched in China in 2008 and aims to use  high throughput sequencing  and  toxicity testing  to identify active components in traditional herbal remedies. [ 12 ]


Sweet Wormwood ( Artemisia annua ) grows in all continents besides Antarctica. [ 13 ]  It is the only known source of  artemisinin , a drug that has been used to treat  fevers  due to  malaria , exhaustion, or many other causes, since ancient times. [ 14 ]  Upon further study, scientists have found that Sweet Wormwood inhibits activity of various bacteria, viruses, and parasites and exhibits anti-cancer and anti-inflammatory properties. [ 14 ] [ 15 ] [ 16 ]


Animal-derived drugs are a major source of modern medications used around the world. [ 2 ] [ 17 ]  The use of these drugs can cause certain animals to become  endangered  or  threatened ; however, it is difficult to identify the animal species used in medicine since animal-derived drugs are often processed, which degrades their  DNA . [ 2 ]


Cells from animal horns and shells are included in a group of medications call Medicinal Animal Horns and Shells (MAHS). [ 2 ] [ 18 ]  These drugs are often used in  dermatology  and have been reported to have anti-fever and anti-inflammatory properties and treat some diseases. [ 18 ] [ 19 ]


Certain animals have obtained many adaptations of toxic substances due to a  coevolutionary arms race  between them and their predators. [ 20 ]  Some components of these toxins such as  enzymes  and inorganic salts are used in modern medicine. [ 21 ]  For example, drugs such as  Captopril  and  Lisinopril  are derived from snake venom and inhibit the  angiotensin-converting enzyme . [ 22 ] [ 21 ]  Another example is  Ziconotide , a drug from the cone snail,  Conus magus , that is used to reduce pain. [ 21 ] [ 23 ]


Edible fungi can contain important nutrients and  biomolecules  that can be used for medical applications. [ 3 ]  For example, medicinal fungi have  polysaccharides  that can be used to prevent the spread of cancer by activating different types of immune cells (namely  T lymphocytes ,  macrophages , and  NK cells ), which inhibit cancer cell reproduction and  metastasis  (the process by which cancer can spread to different parts of the body). [ 3 ] [ 24 ]


Fungi have been used to make many antibiotics since Sir Alexander Flemming discovered Penicillin from the mold,  Penicillium notatum . [ 25 ] [ 26 ]  Recently, there has been a renewed interest in using fungi to create antibiotics since many bacteria have obtained  antibiotic resistance  due to the heavy selection pressures that antibiotics cause. [ 25 ]  The diversity of  marine fungi  makes them a potential new source of antibiotic compunds; however, most are difficult to cultivate in a laboratory setting. [ 25 ] [ 27 ]


Countries in Asia such as Egypt and China have been using fungi for medical uses for centuries. [ 3 ] [ 24 ]


Toxoplasmosis  is a disease caused by an infection by the parasite:  Toxoplasma gondii  (T. gondii). [ 28 ] [ 29 ]  Current drugs used to treat this disease have many side effects and do not inhibit all forms of T. gondii. [ 30 ]  An  in vitro  study by Sharma et al. suggests that Turkey Tail mushroom extract could be used to treat Toxoplasmosis since it inhibited T. gondii growth. [ 28 ]


Pestalone is an antibiotic created from the marine fungus:  Pestalotia sp . [ 25 ] [ 31 ]  M. Cueto et al. (2001–11) found that it has antibiotic activity against two bacteria species that have gained resistance to antibiotics: vancomycin-resistant  Enterococcus faecium  and methicillin-resistant  Staphylococcus aureus . [ 32 ]


Zoopharmacognosy  is the study of how animals select certain plants as self-medication to treat or prevent disease. [ 5 ]  Usually, this behavior is a result of  coevolution  between the animal and the plant that it uses for self-medication. [ 5 ]  For example, apes have been observed selecting a particular part of a medicinal plant by taking off leaves and breaking the stem to suck out the juice. [ 33 ]  In an interview with the late  Neil Campbell ,  Eloy Rodriguez  describes the importance of biodiversity:


"Some of the compounds we've identified by zoopharmacognosy kill parasitic worms, and some of these chemicals may be useful against tumors. There is no question that the templates for most drugs are in the natural world." [ 33 ]


A  botanical drug  is defined in the United States  Federal Food, Drug, and Cosmetic Act  as a botanical product that is marketed as diagnosing, mitigating, treating, or curing a  disease ; a botanical product in turn, is a finished, labeled product that contains ingredients from  plants . Chemicals that are purified from plants, like  paclitaxel , and highly purified products of  industrial fermentation , like  biopharmaceuticals , are not considered to be botanical products.


In 2006 the  Food and Drug Administration  approved the first botanical drug in the United States:  sinecatechins , a  green tea extract  for  genital warts . [ 1 ]


A botanical drug product is defined in the United States  Federal Food, Drug, and Cosmetic Act  (FD&C) as a botanical drug that is marketed as diagnosing, mitigating, treating, or curing a  disease ; a botanical product in turn, is a finished, labeled product that contains vegetable matter as ingredients. [ 2 ] : 2–3   Chemicals that are purified from plants, like  paclitaxel  or  artemisinin , and highly purified products of  industrial fermentation , like  biopharmaceuticals , are not considered to be botanical products. [ 2 ] : 3


The FD&C act separately regulates uses of botanical products as food (including  dietary supplements ),  medical devices  (e.g.,  gutta-percha ), and  cosmetics . [ 2 ] : 2


Like other drugs, botanical drugs may be sold  over the counter  (OTC) or by prescription only. For OTC drugs, a  monograph  must be created by the company that wants to market the drug and then approved by the FDA, after which it is published in the  Federal Register . For prescription drugs, a  New Drug Application  (NDA) must be filed with and approved by the FDA; clinical data included in the NDA is gathered under an  Investigational New Drug  Application which the FDA also must approve before clinical testing begins. [ 2 ] : 3–4


Assessment of the safety and toxicity of botanical drugs in clinical trials, and in ensuring their quality once the drug is on the market, is complicated by the nature of the raw ingredients; problems arise in identifying the correct plants to harvest, in the quality of plants harvested, in their processing, and in the stability of the active components, which are often poorly understood. [ 3 ]


The FDA relies on a combination of tests and controls to ensure the identity and quality of botanical drugs. The tests include "fingerprinting" using  spectroscopy  or  chromatography , chemical or biological assays, and  process controls  on raw material collection and processing. [ 2 ] : 5   The standards are higher for botanical drugs than for extracts or plant matter used in  dietary supplements . [ 2 ] : 5


If the substance being developed as a botanical drug has been used in  traditional medicine , it may be possible to begin initial, small clinical trials without conducting extensive  toxicology testing . [ 2 ] : 13  [ 4 ] [ 5 ]  However, toxicity testing is required before beginning larger clinical trials and trials that will be used to get approval to sell a botanical drug. [ 4 ]


The endogenous  Chinese pharmaceutical industry  is made up mostly of companies that make herbal  traditional chinese medicines  and sell them over the counter; the US regulatory pathway is similar to that established by the  China Food and Drug Administration . [ 6 ] : 15, 20


The European regulatory pathway is also similar. [ 7 ]


As of 2012, the  pharmaceutical industry  had expressed strong interest in developing botanical drugs, with more than 500 applications pending at the FDA. [ 15 ]  Part of the interest stems from a desire to address the Chinese market, where herbal medicines remain widely used and had $13 billion in sales in 2011. [ 15 ]


Commonly prescribed drugs  are drugs that are frequently provided by doctors in a prescription to treat a certain disease. These drugs are often first-line treatment for the target diseases and are effective in tackling the symptoms. An example of the target disease is ischemic heart disease. Some examples of commonly prescribed drugs for this disease are  beta-blockers ,  calcium-channel blockers  and  nitrates.


In accordance with the pharmacological effects, commonly prescribed drugs can be divided into different groups. Drugs in the same group exert nearly identical effects, and can be utilized for treating the prevailing disease and sometimes, preventing complications of the existing diseases.


The use of commonly prescribed drugs can be reflected from the number of prescriptions of the drugs. Countries have their own dataset in recording the trend of commonly prescribed drugs. For example, the United States uses the Medical Expenditure Panel Survey (MEPS) [ 1 ]  and England uses the English Prescribing Dataset [ 2 ]  to record the prescription data for showing which drugs are commonly prescribed.


Understanding commonly prescribed drugs allows healthcare professionals to react to symptoms quickly and new treatment strategies can be developed. However, the data for commonly prescribed drugs may be outdated due to the time lag between data collection and publication as well as errors in data collection process.


Commonly prescribed drugs are prescribed according to guidelines around the world. For instance, for ischemic heart disease, the American College of Cardiology/American Heart Association (ACC/AHA) guideline is used in the United States and the European Society of Cardiology (ESC) guideline is used in Europe. Western guidelines are more commonly used for reference during the development of local practice guidelines due to the large number of western guidelines stored in guideline databases. [ 3 ]  The data of prescriptions are collected through the government, such as Medical Expenditure Panel Survey (MEPS) in America and the Pharmaceutical Benefit Scheme (PBS) in Australia, providing information on the actual prescription volume of drugs.


The  Medical Expenditure Panel Survey (MEPS)  conducted by the Agency for Healthcare Research and Quality (AHRQ) via the United States government is used to collect prescription data and data for other healthcare services, including home healthcare, children's health and preventive care in America. The survey started in 1996 and was the predecessor of the National Medical Expenditure Survey (NMES) and the National Medical Care Utilization and Expenditure Survey (NMCUES), [ 4 ]  which were conducted in 1977 (NMES-1), 1980 (NMCUES), and 1987 (NMES-2). The survey is updated every year with the renewed data from the country. The prescription data is published in the Prescribed Medicines File of the MEPS. [ 5 ]  The collection of data involves two components: Household component and the Medical Provider component. The household component collects self-reported data of the prescribed medicines and the demographic information of the respondents. The Medical Provider component acts as a piece of follow-back information provided by the pharmacy including a computerized printout for all prescription filled for the patient. [ 6 ]


The English Prescribing Dataset (EPD) from the  NHS Business Services Authority  (NHSBSA) provides prescription data in the United Kingdom. [ 2 ]  The dataset was created in 2014. EPD is a combination of the Detailed Prescribing Information (DPI) and the Practice Level Prescribing in England (PLP). Both DPI and PLP are previous datasets from NHSBSA and NHS Digital respectively and EPD aims to replace them both in the future, but no specific date of replacement is given. EPD collects data from England, Wales, Scotland, Guernsey, Alderney, Jersey and the Isle of Man. EPD provides the item, quantity, net ingredient cost, actual cost, average daily quantity (ADQ), practice name and address details of the prescription. [ 7 ]


The  Pharmaceutical Benefits Scheme  (PBS) from the Australian Government Department of Health provides the prescription data of prescriptions under PBS. PBS started in 1948 and the under co-payment prescriptions were added into the dataset from 1 April 2012. It publishes the PBS expenditure and prescriptions report every year recording prescription data in the past 12 months. The examples of data it provides are the top 50 drugs by total prescription volume and the top 50 drugs by government cost. [ 8 ]


Understanding commonly prescribed drugs for different diseases can allow healthcare professionals to be more confident and decisive when choosing the most suitable treatment for the patient. This can also help develop new treatment strategies by researchers for more effective treatments. [ 9 ]  By enriching the knowledge of commonly prescribed drugs, pharmacy students will be more familiar with their mechanism of action, first-line therapy indications and side effects. [ 10 ]


Limitations include time lag for the conducted survey. The Medical Expenditure Panel Survey (MEPS) shows data recorded two years before the publishing of the survey. The time lag may lead to a difference in representing the current prescribing practice with the recorded data in the survey. Questionnaires which are self-reported tend to create  recall bias . Respondents are likely to underreport the number of prescription drugs they have as those drugs are usually for short-term use and intermittent use, such as analgesics and topical agents. [ 11 ]


Two diseases from the top 10 causes of death introduced by the World Health Organization (WHO) in 2019 are used as examples, namely ischemic heart disease (ranked 1st) from cardiovascular diseases and Chronic Obstructive Pulmonary Disease from respiratory diseases (ranked 3rd). [ 12 ]  Although stroke is ranked 2nd by WHO, drugs used are similar to ischemic heart disease. Moreover, surgical interventions are commonly required, so it will be out of the scope of this article and it will not be introduced. [ 13 ] [ 14 ]


Ischemic Heart Disease (IHD) or coronary heart disease is the lack of supply of blood to an area in the heart, often due to plaque formation (atherosclerosis), causing inadequacy of oxygen to heart muscle and eventually leading to myocardial infarction. This disease can be classified into acute and chronic coronary heart disease. This disease caused 8.9 million deaths in 2019 and was ranked 1st in the top 10 causes of death globally by the World Health Organization (WHO). [ 12 ]


The treatment of Ischemic Heart Disease can be divided into two directions: risk factor control and symptomatic relief.


Commonly prescribed drugs for Ischemic Heart Disease


anti-inflammatory drugs (NSAID)


Chronic Obstructive Pulmonary Disease (COPD)  is a disease that causes chronic respiratory problems by gradually blocking the respiratory tracts. The continuous exposure to toxic fumes produced by cigarettes, vehicle engines and other human activities leads to inflammation of the respiratory tract, causing the development of COPD. The problem will deteriorate over time if it is not well managed. It will eventually cause respiratory failure and death in the late stage. [ 28 ]  It is the third deadliest disease reported by WHO in 2019 and it accounted for 6% of total deaths. [ 12 ]


There are two types of management plan in COPD, namely  regular treatment  and  acute exacerbation . In acute exacerbation, new medications will be added to the existing prescription and they will be stopped once the exacerbation is managed.


Clavulanic acid [ 45 ] [ 46 ]


Macrolides [ 45 ] [ 46 ] [ 47 ] [ 48 ]


Tetracycline [ 45 ] [ 46 ] [ 47 ] [ 49 ]


In patients with COPD, multiple inhalers need to be used at a time. There are two major types of inhaler, namely dry-powder inhaler(DPI) and metered-dose inhaler(MDI), and many more subtypes with different techniques for using them. [ 51 ]   Adherence  is also an issue with the use of multiple inhalers. Generally with different types of inhalers, the adherence will be lowered. [ 52 ] [ 53 ]  Proper inhaler technique and adherence are two of the factors that affect the management of COPD. Other factors include  smoking cessation  and participation in physical activities, to name but a few. [ 54 ]  With inappropriately applied inhaler technique and low adherence, there will be ineffective management of COPD, thus increasing in the burden on the healthcare sector. [ 31 ] [ 55 ]  As a result, inhalers combining multiple medications are invented to tackle the problem.


A  drug coupon  is a  coupon  intended to help consumers save money on  pharmaceutical drugs . They are offered by  drug companies  or distributed to consumers via  doctors  and  pharmacists , and most can be obtained online. There are drug coupons for drugs from many categories such as  cholesterol ,  acne ,  migraine ,  allergies , etc.


Direct-to-consumer or "DTC" marketing of prescription drugs is common in the  United States . Patients frequently inquire about or request medications they have seen advertised in print or on television.


Pharmaceutical companies use drug coupons as a marketing tool to stimulate demand for their products.


Drug coupons are commonly offered for new products to stimulate demand or ameliorate high co-pays for non-formulary (non-preferred products) as a way to level the playing field and remove the disincentive for using a drug that is not covered by insurance.


In an effort to avoid unregulated resale of drugs, the  Prescription Drug Marketing Act  of 1988 banned the traffic or  counterfeiting  of redeemable drug coupons. [ 1 ]


Most drug coupons are printed by consumers using their personal computers and printers. Drug coupons reduce out-of-pocket costs for consumers in a variety of ways such as instant savings offers, free trial offers (also known as try-before-you-buy offers),  copay  reduction or rebates.


Generic drug  companies rarely offer coupons, though insurance companies occasionally offer discounts on generic drugs. [ 2 ]


In addition  PBMs  (Pharmacy Benefit Managers) offer discount cards that act similarly to coupons.  These cards work for both generic and brand medications and can save cash paying customers up to 75% on their prescription medication.


Critics of prescription drug coupon programs have argued that these programs lead to higher healthcare costs for consumers. Typically, American patients with health insurance pay a percentage of the cost of a prescription drug out of pocket, with insurance companies responsible for the rest of the medication's cost. Insurance companies charge higher  copayments  for brand-name drugs than for generics in order to encourage patients to choose less expensive alternative medications when they are available. However, by reducing a patient's copayment, prescription drug coupons also reduce a patient's incentive to choose a less expensive generic medication. As an example,  NPR  reported in 2009 that the generic  acne  medication  Minocin  cost $109 a month while a newer alternative called  Solodyn  cost $514 a month. Solodyn can be taken only once daily, while Minocin must be taken twice daily. Since Solodyn's manufacturer offers a coupon to reduce copays, patients may believe that both drugs cost the same amount. [ 3 ]


Drug coupon advocates argue that coupon programs enhance medication adherence by reducing or eliminating drug copays. [ 2 ]


As of 2008, the  U.S. Food and Drug Administration  (FDA) was planning a study to see if coupons make patients overlook drug risks and side effects in their effort to save money. [ 2 ]  All medicines come with a certain level of risk. This is why all prescription drugs include information reviewed and approved by the U.S. Food and Drug Administration (FDA) about how the medication works in the body, its uses and when it should not be used, possible side effects, the recommended dosage, and other facts about the appropriate use of the drug. Most Americans have never heard of “Risk Evaluation and Mitigation Strategies” (REMS); yet, these drug safety protections give millions of Americans with serious diseases, such as cancer and multiple sclerosis, access to medicines that would otherwise be too dangerous to be allowed on the market. [ 4 ]  REMS programs exist because certain medicines can cause serious side effects, life-threatening infections, allergic reactions, liver damage or birth defects. Before patients take one of these drugs, they and their prescriber should be aware of the risks, and may need to take certain steps that lessen these risks, in order to ensure they benefit from the treatment.


Unions have filed several lawsuits seeking to ban drug coupons, characterizing them as illegal kickbacks.  As of June, 2013 Three of these lawsuits have been dismissed.  Six more are pending.  This ruling is seen as vindication for the Pharmaceutical industry that drug coupons are an acceptable business practice. [ 5 ]


COVID-19 drug development  is the research process to develop preventative therapeutic  prescription drugs  that would alleviate the severity of  coronavirus disease 2019  (COVID-19). From early 2020 through 2021, several hundred  drug companies ,  biotechnology  firms, university research groups, and health organizations were developing therapeutic candidates for COVID-19 disease in various stages of  preclinical  or  clinical research  (506 total candidates in April 2021), with 419 potential COVID-19 drugs in  clinical trials , as of April 2021. [ 1 ]


As early as March 2020, the  World Health Organization  (WHO), [ 2 ]   European Medicines Agency  (EMA), [ 3 ]  US  Food and Drug Administration  (FDA), [ 4 ]  and the Chinese government and drug manufacturers [ 5 ] [ 6 ]  were coordinating with academic and industry researchers to speed development of vaccines,  antiviral drugs , and post-infection therapies. [ 7 ] [ 8 ] [ 9 ] [ 10 ]  The  International Clinical Trials Registry Platform  of the WHO recorded 536 clinical studies to develop post-infection therapies for COVID-19 infections, [ 11 ] [ 12 ]  with numerous established antiviral compounds for treating other infections  under clinical research to be repurposed . [ 7 ] [ 13 ] [ 14 ] [ 15 ]


In March 2020, the WHO initiated the " SOLIDARITY Trial " in 10 countries, enrolling thousands of people infected with COVID-19 to assess treatment effects of four existing antiviral compounds with the most promise of efficacy. [ 2 ] [ 16 ]  A dynamic, systematic review was established in April 2020 to track the progress of registered clinical trials for COVID-19 vaccine and therapeutic drug candidates. [ 12 ]


Drug development is a multistep process, typically requiring more than five years to assure safety and efficacy of the new compound. [ 17 ]   Several national regulatory agencies, such as the EMA and the FDA, approved procedures to expedite clinical testing. [ 4 ] [ 18 ]  By June 2021, dozens of potential post-infection therapies were in the final stage of human testing –  phase III–IV clinical trials . [ 19 ]


Drug development  is the process of bringing a new infectious disease vaccine or  therapeutic drug  to the market once a  lead compound  has been identified through the process of  drug discovery . [ 17 ]  It includes  laboratory research  on microorganisms and animals, filing for regulatory status, such as via the FDA, for an  investigational new drug  to initiate  clinical trials  on humans, and may include the step of obtaining  regulatory approval  with a  new drug application  to market the drug. [ 20 ] [ 21 ]  The entire process – from concept through preclinical testing in the laboratory to clinical trial development, including Phase I–III trials – to approved vaccine or drug normally takes more than a decade. [ 17 ] [ 20 ] [ 21 ]


The term "preclinical research" is defined by laboratory studies  in vitro  and  in vivo , indicating a beginning stage for development of a preventative vaccine, antiviral or other post-infection therapies, [ 7 ]  such as experiments to determine  effective doses  and  toxicity  in animals, before a candidate compound is advanced for safety and efficacy evaluation in humans. [ 22 ]  To complete the preclinical stage of drug development – then be tested for safety and efficacy in an adequate number of people infected with COVID-19 (hundreds to thousands in different countries) – is a process likely to require 1–2 years for COVID-19 therapies, according to several reports in early 2020. [ 9 ] [ 23 ] [ 24 ] [ 25 ]  Despite these efforts, the success rate for drug candidates to reach eventual regulatory approval through the entire drug development process for treating  infectious diseases  is only 19%. [ 26 ]


Phase I trials test primarily for safety and preliminary dosing in a few dozen healthy subjects, while Phase II trials – following success in Phase I – evaluate therapeutic efficacy against the COVID-19 disease at ascending dose levels (efficacy based on  biomarkers ), while closely evaluating possible  adverse effects  of the candidate therapy (or combined therapies), typically in hundreds of people. A common trial design for Phase II studies of possible COVID-19 drugs is  randomized ,  placebo -controlled,  blinded , and conducted at multiple sites, while determining more precise, effective doses and monitoring for adverse effects. [ 27 ]


The success rate for Phase II trials to advance to Phase III (for all diseases) is about 31%, and for infectious diseases specifically, about 43%. [ 26 ]  Depending on its duration (longer more expensive) – typically a period of several months to two years [ 27 ]  – an average-length Phase II trial costs  US$57  million (2013 dollars, including preclinical and Phase I costs). [ 28 ]  Successful completion of a Phase II trial does not reliably forecast that a candidate drug will be successful in Phase III research. [ 29 ]


Phase III trials for COVID-19 involve hundreds-to-thousands of hospitalized participants, and test effectiveness of the treatment to reduce effects of the disease, while monitoring for adverse effects at the optimal dose, such as in the multinational Solidarity and Discovery trials. [ 2 ] [ 17 ] [ 30 ]


According to one source (as of August 2020), diverse categories of preclinical or early-stage clinical research for developing COVID-19 therapeutic candidates included: [ 19 ]


Pivotal Phase III trials  assess whether a candidate drug has efficacy specifically against a disease, and – in the case of people hospitalized with severe COVID-19 infections – test for an effective dose level of the repurposed or new drug candidate to improve the illness (primarily pneumonia) from COVID-19 infection. [ 2 ] [ 11 ] [ 32 ]  For an already-approved drug (such as  hydroxychloroquine  for malaria),  Phase III–IV trials  determine in hundreds to thousands of COVID-19-infected people the possible extended use of an already-approved drug for treating COVID-19 infection. [ 32 ]  As of August 2020, over 500 candidate therapeutics were in preclinical or a stage of Phase I–IV development, with new Phase II–III trials announced for hundreds of therapeutic candidates during 2020. [ 19 ]


Numerous candidate drugs under study as "supportive" treatments to relieve discomfort during illness, such as  NSAIDs  or  bronchodilators , are not included in the table below. Others in early-stage Phase II trials or numerous treatment candidates in Phase I trials, [ 19 ]  are also excluded. Drug candidates in Phase I–II trials have a low rate of success (under 12%) to pass through all trial phases to gain eventual approval. [ 20 ] [ 29 ]  Once having reached Phase III trials, therapeutic candidates for diseases related to COVID-19 infection –  infectious  and  respiratory diseases  – have a success rate of about 72%. [ 26 ]


Drug repositioning  (also called drug repurposing) – the investigation of existing drugs for new therapeutic purposes – is one line of scientific research followed to develop safe and effective COVID-19 treatments. [ 15 ] [ 59 ]  Several existing antiviral medications, previously developed or used as treatments for  Severe acute respiratory syndrome  (SARS),  Middle East respiratory syndrome  (MERS),  HIV/AIDS , and  malaria , are being researched as COVID-19 treatments, with some moving into clinical trials. [ 13 ]


During the COVID-19 pandemic, drug repurposing is the  clinical research  process of rapidly screening and defining the safety and efficacy of existing drugs already approved for other diseases to be used for people with COVID-19 infection. [ 13 ] [ 15 ] [ 60 ]  In the usual drug development process, [ 17 ]  confirmation of repurposing for new disease treatment would take many years of clinical research – including  pivotal Phase III clinical trials  – on the candidate drug to assure its safety and efficacy specifically for treating COVID-19 infection. [ 13 ] [ 60 ]  In the emergency of a growing COVID-19 pandemic, the drug repurposing process was being accelerated during March 2020 to treat people hospitalized with COVID-19. [ 2 ] [ 13 ] [ 15 ]


Clinical trials using repurposed, generally safe, existing drugs for hospitalized COVID-19 people may take less time and have lower overall costs to obtain endpoints proving safety (absence of serious  side effects ) and post-infection efficacy, and can rapidly access existing drug  supply chains  for manufacturing and worldwide distribution. [ 2 ] [ 13 ] [ 61 ]  In an international effort to capture these advantages, the WHO began in mid-March 2020 expedited international  Phase II–III trials  on four promising treatment options – the SOLIDARITY trial [ 2 ] [ 62 ] [ 63 ]  – with numerous other drugs having potential for repurposing in different disease treatment strategies, such as anti-inflammatory,  corticosteroid , antibody,  immune , and  growth factor  therapies, among others, being advanced into Phase II or III trials during 2020. [ 19 ] [ 13 ] [ 60 ] [ 64 ]


In March 2020, the United States  Centers for Disease Control and Prevention  (CDC) issued a physician advisory concerning remdesivir for people hospitalized with  pneumonia  caused by COVID-19: "While clinical trials are critical to establish the safety and efficacy of this drug, clinicians without access to a clinical trial may request remdesivir for  compassionate use  through the manufacturer for patients with clinical pneumonia." [ 37 ]


Passive immunization  with  convalescent plasma  or  hyperimmune serum  has been proposed as a potential treatment for COVID-19. As of May 2021, there is strong evidence that convalescent plasma treatment is not associated with clinical improvements for people with moderate or severe disease and does not decrease the risk of dying. [ 65 ]  The potential for adverse effects associated with convalescent plasma treatment is unknown. [ 65 ]


In the United States, the FDA has granted temporary authorization to convalescent plasma (plasma from the blood of people who have recovered from COVID-19, which thus contains antibodies against SARS-CoV-2) as an experimental treatment in cases where the person's life is seriously or immediately threatened. [ 66 ]  As of May 2021, at least 12 randomized controlled trials on the effectiveness of convalescent plasma treatment were published in peer-reviewed medical journals. [ 65 ]  In addition, as of May 2021, 100 additional trials were 'ongoing' and 33 studies were reported as 'competed' but not yet published. [ 65 ]


Argentina, Brazil, Costa Rica, and Mexico have pursued development of  antisera . [ 67 ]  Brazil began development of an equine hyperimmune serum, obtained by inoculating  horses  with recombinant SARS-CoV-2  spike protein , in mid-2020. A consortium of Instituto Vital Brazil,  UFRJ , the  Oswaldo Cruz Foundation  and the D'Or Institute for Research and Education in Rio de Janeiro began preclinical trials in May 2020, [ 68 ]  while  Instituto Butantan  in São Paulo completed animal testing in September. [ 67 ]  In December 2020, Argentina granted emergency authorization to CoviFab, a locally developed formulation of equine hyperimmune serum, for use in cases of moderate to severe COVID-19, based on the initial results of a single phase 2/3 trial which suggested reductions in mortality, ICU admission, and mechanical ventilation requirements in patients who received the serum. [ 69 ] [ 70 ]  This was harshly criticized by the Argentine Intensive Care Society, which stated that the trial failed to achieve its primary or secondary endpoints and did not demonstrate any  statistically significant  differences between the serum and placebo groups. [ 70 ]


Bamlanivimab/etesevimab  is a combination of two  monoclonal antibodies ,  bamlanivimab  and  etesevimab , administered together via intravenous infusion as a treatment for  COVID-19 . [ 71 ] [ 72 ] [ 73 ] [ 74 ]  Both types of antibody target the  surface spike protein  of  SARS‑CoV‑2 . [ 75 ] [ 76 ]


Bamlanivimab and etesevimab, administered together, are authorized in the United States for the treatment of mild-to-moderate COVID-19 in people aged twelve years of age and older weighing at least 40 kilograms (88 lb) with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death. [ 77 ] [ 78 ]  They are also authorized, when administered together, for use after exposure to the SARS-CoV-2 virus for  post-exposure prophylaxis  (PEP) for COVID-19 and are not authorized for pre-exposure prophylaxis to prevent COVID-19 before being exposed to the SARS-CoV-2 virus. [ 77 ] [ 78 ]


Bebtelovimab  is a  monoclonal antibody  developed by  AbCellera  and  Eli Lilly  as a treatment for  COVID-19 . [ 80 ] [ 81 ] [ 82 ] [ 83 ]


Possible side effects include itching, rash, infusion-related reactions, nausea and vomiting. [ 80 ]


Bebtelovimab works by binding to the spike protein of the virus that causes COVID-19, similar to other monoclonal antibodies that have been authorized for the treatment of high-risk people with mild to moderate COVID-19 and shown a benefit in reducing the risk of hospitalization or death. [ 80 ]  Bebtelovimab is a neutralizing human immunoglobulin G1 (IgG1) monoclonal antibody, isolated from a patient who has recovered from the Coronavirus disease 2019 (COVID-19), directed against the spike (S) protein of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), that can potentially be used for immunization against COVID-19. [ 84 ]


Casirivimab/imdevimab , sold under the brand name REGEN‑COV among others, [ 86 ] [ 87 ]  is a combination  medicine  used for the treatment and prevention of  COVID‑19 . [ 87 ]  It consists of two  human monoclonal antibodies , casirivimab and imdevimab that must be mixed together and administered as an infusion or subcutaneous injection. [ 88 ] [ 86 ] [ 87 ]  The combination of two antibodies is intended to prevent  mutational escape . [ 89 ]  It is also available as a  co-formulated  product. [ 88 ]  It was developed by the American biotechnology company  Regeneron Pharmaceuticals . [ 90 ] [ 91 ]


The most common side effects include allergic reactions, which include infusion related reactions, injection site reactions, [ 87 ]  brief pain, weakness and others. [ 92 ]


The combination is approved under the brand name Ronapreve for medical use in Japan, the United Kingdom, the European Union, and Australia. [ 93 ] [ 94 ] [ 87 ] [ 95 ] [ 96 ] [ 97 ]


Pemivibart , sold under the brand name Pemgarda, is a  monoclonal antibody  medication authorized for the  pre-exposure prophylaxis  (prevention) of  COVID‑19 . [ 99 ]  Pemivibart was developed by  Invivyd . [ 100 ] [ 101 ]


Regdanvimab , sold under the brand name Regkirona, is a  human monoclonal antibody  used for the treatment of  COVID-19 . [ 102 ]  The antibody is directed against the  spike protein  of  SARS-CoV-2 . It is developed by  Celltrion . [ 103 ] [ 104 ]  The medicine is given by infusion (drip) into a vein. [ 102 ] [ 105 ]


The most common side effects include infusion-related reactions, including allergic reactions and anaphylaxis. [ 102 ]


Sotrovimab , sold under the brand name Xevudy, is a human neutralizing  monoclonal antibody  with activity against severe acute respiratory syndrome coronavirus 2, known as  SARS-CoV-2 . [ 107 ] [ 108 ] [ 109 ]  It was developed by  GlaxoSmithKline  and Vir Biotechnology, Inc. [ 108 ] [ 110 ]  Sotrovimab is designed to attach to the  spike protein  of SARS-CoV-2. [ 108 ] [ 109 ] [ 111 ]


The most common side effects include hypersensitivity (allergic) reactions and infusion-related reactions. [ 107 ]


Vilobelimab , sold under the brand name Gohibic, is an investigational  medication  that is used for the treatment of  COVID-19 . [ 119 ]  It is a human-mouse chimeric  IgG4   kappa  antibody that targets human  C5a  in plasma. [ 120 ]


The most common adverse reactions include pneumonia, sepsis, delirium, pulmonary embolism, hypertension, pneumothorax, deep vein thrombosis, herpes simplex, enterococcal infection, bronchopulmonary aspergillosis, hepatic enzyme increased, urinary tract infection, hypoxia, thrombocytopenia, pneumomediastinum, respiratory tract infection, supraventricular tachycardia, constipation, and rash. [ 119 ]


Molnupiravir , sold under the brand name Lagevrio, is an  antiviral medication  that inhibits the replication of certain  RNA viruses . [ 124 ]  It is used to treat  COVID‑19  in those infected by  SARS-CoV-2 . [ 124 ]  It is taken  by mouth . [ 124 ]


Molnupiravir is a  prodrug  of the synthetic  nucleoside  derivative  N 4 -hydroxy cytidine  and exerts its antiviral action by introducing copying errors during viral RNA replication. [ 125 ] [ 126 ]


Molnupiravir was originally developed to treat  influenza  at  Emory University  by the university's drug innovation company, Drug Innovation Ventures at Emory (DRIVE), but was reportedly abandoned for  mutagenicity  concerns. [ 127 ] [ 128 ]  It was then acquired by the Miami-based company  Ridgeback Biotherapeutics , which later partnered with  Merck & Co.  to develop the drug further. [ 129 ]


Ensitrelvir , sold under the brand name Xocova is an  antiviral medication  used as a treatment for  COVID-19 . [ 140 ] [ 141 ] [ 142 ] [ 143 ]  It was developed by  Shionogi  in partnership with  Hokkaido University  and acts as an orally active  3C-like   protease inhibitor . [ 144 ] [ 145 ]  It is taken by mouth. [ 146 ] [ 147 ] [ 148 ]


Nirmatrelvir/ritonavir , sold under the brand name Paxlovid, is a co-packaged  medication  used as a  treatment  for  COVID‑19 . [ 149 ] [ 150 ] [ 151 ] [ 152 ]  It contains the  antiviral medications   nirmatrelvir  and  ritonavir  and was developed by  Pfizer . [ 149 ] [ 151 ]  Nirmatrelvir inhibits  SARS-CoV-2 main protease , while ritonavir is a strong  CYP3A inhibitor , slowing down nirmatrelvir  metabolism  and therefore boosting its effect. [ 151 ] [ 153 ]  It is taken  by mouth . [ 151 ]


In unvaccinated high-risk people with COVID‑19, nirmatrelvir/ritonavir can reduce the risk of hospitalization or death by 88% if taken within five days of symptom onset. [ 154 ]  People who take nirmatrelvir/ritonavir also test negative for COVID‑19 about two and a half days earlier than people who do not. [ 155 ]   Side effects  of nirmatrelvir/ritonavir include changes in sense of taste ( dysgeusia ),  diarrhea , high blood pressure ( hypertension ), and muscle pain ( myalgia ). [ 151 ]


Sabizabulin  is an  investigational new drug  that is being evaluated for the treatment of  castration-resistant prostate cancer [ 166 ]  and in  SARS-CoV-2  ( COVID-19 ) infections. [ 167 ]  It is a  tubulin  polymerization inhibitor. [ 168 ] [ 169 ]


Over 2018–20, new initiatives to stimulate vaccine and antiviral drug development included partnerships between governmental organizations and industry, such as the European  Innovative Medicines Initiative , [ 171 ]  the US  Critical Path Initiative  to enhance innovation of drug development, [ 172 ]  and the  Breakthrough Therapy  designation to expedite development and regulatory review of promising candidate drugs. [ 173 ]  To accelerate refinement of  diagnostics  for detecting COVID-19 infection, a global diagnostic pipeline tracker was formed. [ 174 ]


According to a tracker of clinical trial progress on potential therapeutic drugs for COVID-19 infections, 29 Phase II–IV efficacy trials were concluded in March 2020 or scheduled to provide results in April from hospitals in China – which experienced the first outbreak of COVID-19 in late 2019. [ 19 ]  Seven trials were evaluating repurposed drugs already approved to treat  malaria , including four studies on hydroxychloroquine or chloroquine phosphate. [ 19 ]  Repurposed antiviral drugs make up most of the Chinese research, with 9 Phase III trials on remdesivir across several countries due to report by the end of April. [ 19 ]  Other potential therapeutic candidates under pivotal clinical trials concluding in March–April are  vasodilators ,  corticosteroids ,  immune therapies ,  lipoic acid ,  bevacizumab , and  recombinant   angiotensin-converting enzyme 2 , among others.


The COVID-19 Clinical Research Coalition has goals to 1) facilitate  rapid reviews  of clinical trial proposals by  ethics committees  and national regulatory agencies, 2) fast-track approvals for the candidate therapeutic compounds, 3) ensure standardised and rapid analysis of emerging efficacy and safety data, and 4) facilitate sharing of clinical trial outcomes before publication. [ 11 ]  A dynamic review of clinical development for COVID-19 vaccine and drug candidates was in place, as of April. [ 12 ]


By March 2020, the international  Coalition for Epidemic Preparedness Innovations  (CEPI) committed to research investments of US$100 million across several countries, [ 175 ]  and issued an urgent call to raise and rapidly invest $2 billion for vaccine development. [ 176 ]  Led by the  Bill and Melinda Gates Foundation  with partners investing  US$125  million and coordinating with the World Health Organization, the COVID-19 Therapeutics Accelerator began in March, facilitating drug development researchers to rapidly identify, assess, develop, and  scale up  potential treatments. [ 177 ]  The COVID-19 Clinical Research Coalition formed to coordinate and expedite results from international clinical trials on the most promising post-infection treatments. [ 11 ]  In early 2020, numerous established antiviral compounds for treating other infections were being repurposed or developed in new clinical research efforts to alleviate the illness of COVID-19. [ 7 ] [ 13 ] [ 19 ]


During March 2020, the  Coalition for Epidemic Preparedness Innovations  (CEPI) initiated an international COVID-19 vaccine development fund, with the goal to raise  US$2 billion  for vaccine research and development, [ 178 ]  and committed to investments of  US$100 million  in vaccine development across several countries. [ 175 ]  The  Canadian government  announced  CA$275 million  in funding for 96 research projects on medical countermeasures against COVID-19, including numerous vaccine candidates at Canadian universities, [ 179 ] [ 180 ]  with plans to establish a "vaccine bank" of new vaccines for implementation if another COVID-19 outbreak occurs. [ 180 ] [ 181 ]  The  Bill & Melinda Gates Foundation  invested  US$ 150 million in April for development of COVID-19 vaccines, diagnostics, and therapeutics. [ 182 ]


In March 2020, the  United States Department of Energy ,  National Science Foundation ,  NASA , industry, and nine universities pooled resources to access supercomputers from  IBM , combined with cloud computing resources from  Hewlett Packard Enterprise ,  Amazon ,  Microsoft , and  Google , for drug discovery. [ 183 ] [ 184 ]  The COVID-19 High Performance Computing Consortium also aims to forecast disease spread, model possible vaccines, and screen thousands of chemical compounds to design a COVID-19 vaccine or therapy. [ 183 ] [ 184 ]  The Consortium used up 437 peta FLOPS  of computing power by May 2020. [ 185 ]


The C3.ai Digital Transformation Institute, an additional consortium of Microsoft, six universities (including the  Massachusetts Institute of Technology , a member of the first consortium), and the  National Center for Supercomputer Applications  in Illinois, working under the auspices of C3.ai, an artificial intelligence software company, are pooling supercomputer resources toward drug discovery, medical protocol development and public health strategy improvement, as well as awarding large grants to researchers who proposed by May to use AI to carry out similar tasks. [ 186 ] [ 187 ]


In March 2020, the  distributed computing  project  Folding@home  launched a program to assist drug developers, initially simulating protein targets from SARS-CoV-2 and the related SARS-CoV virus, which has been studied previously. [ 188 ] [ 189 ] [ 190 ] [ 191 ] [ 192 ] [ 193 ]


Distributed computing project  Rosetta@home  also joined the effort in March. The project uses computers of volunteers to model SARS-CoV-2 virus proteins to discover possible drug targets or create new proteins to neutralize the virus. Researchers revealed that with the help of Rosetta@home, they had been able to "accurately predict the atomic-scale structure of an important coronavirus protein weeks before it could be measured in the lab." [ 194 ]


In May 2020, the OpenPandemics – COVID-19 partnership between  Scripps Research  and IBM's  World Community Grid  was launched. The partnership is a distributed computing project that "will automatically run a simulated experiment in the background [of connected home PCs] which will help predict the effectiveness of a particular chemical compound as a possible treatment for COVID-19". [ 195 ]


In March, the World Health Organization (WHO) launched the coordinated "Solidarity Trial" in 10 countries on five  continents  to rapidly assess in thousands of COVID-19 infected people the potential efficacy of existing antiviral and  anti-inflammatory  agents not yet evaluated specifically for COVID-19 illness. [ 2 ] [ 16 ]  By late April, hospitals in over 100 countries were involved in the trial. [ 196 ]


The individual or combined drugs undergoing initial studied are 1)  lopinavir – ritonavir  combined, 2) lopinavir–ritonavir combined with  interferon-beta , 3)  remdesivir  or 4) (hydroxy) chloroquine  in separate trials and hospital sites internationally. [ 2 ] [ 16 ]  Following a study published by  The Lancet  on safety concerns with hydroxychloroquine, the WHO suspended use of it from the Solidarity trial in May 2020, [ 197 ] [ 198 ]  reinstated it after the research was retracted, [ 199 ]  then abandoned further use of the drug for COVID-19 treatment when analysis showed in June that it provided no benefit. [ 43 ]


With about 15% of people infected by COVID-19 having severe illness, and hospitals being overwhelmed during the pandemic, WHO recognized a rapid clinical need to test and repurpose these drugs as agents already approved for other diseases and recognized as safe. [ 2 ]  The Solidarity project is designed to give rapid insights to key clinical questions: [ 2 ] [ 200 ]


Enrolling people with COVID-19 infection is simplified by using data entries, including  informed consent , on a WHO website. After the trial staff determines the drugs available at the hospital, the WHO website  randomizes  the hospitalized subject to one of the trial drugs or to the hospital standard of care for treating COVID-19. The trial physician records and submits follow-up information about the subject status and treatment, completing data input via the WHO Solidarity website. The design of the Solidarity trial is not  double-blind  – which is normally the standard in a high-quality clinical trial – but the WHO needed speed with quality for the trial across many hospitals and countries. [ 2 ]  A global  safety monitoring board of WHO physicians  examine  interim results  to assist decisions on safety and effectiveness of the trial drugs, and alter the trial design or recommend an effective therapy. [ 2 ] [ 200 ]  A similar web-based study to Solidarity, called "Discovery", was initiated in March across seven countries by  INSERM  ( Paris, France ). [ 2 ] [ 34 ]


The Solidarity trial seeks to implement coordination across hundreds of hospital sites in different countries – including those with poorly-developed infrastructure for clinical trials – yet needs to be conducted rapidly. According to  John-Arne Røttingen , chief executive of the  Research Council of Norway  and chairman of the Solidarity trial international  steering committee , the trial would be considered effective if therapies are determined to "reduce the proportion of patients that need ventilators by, say, 20%, that could have a huge impact on our national health-care systems." [ 30 ]


During March, funding for the Solidarity trial reached  US$108  million from 203,000 individuals, organizations and governments, with 45 countries involved in financing or trial management. [ 197 ]


A clinical trial design in progress may be modified as an "adaptive design" if accumulating data in the trial provide early insights about positive or negative efficacy of the treatment. [ 201 ] [ 202 ]  The global Solidarity and European Discovery trials of hospitalized people with severe COVID-19 infection apply adaptive design to rapidly alter trial parameters as results from the four experimental therapeutic strategies emerge. [ 11 ] [ 34 ] [ 203 ]  Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations. [ 29 ] [ 202 ] [ 204 ]


The US  National Institute of Allergy and Infectious Diseases  (NIAID) initiated an adaptive design, international Phase III trial (called "ACTT") to involve up to 800 hospitalized COVID-19 people at 100 sites in multiple countries. Beginning with use of remdesivir as the primary treatment over 29 days, the trial definition of its adaptive protocol states that "there will be interim monitoring to introduce new arms and allow early stopping for futility, efficacy, or safety. If one therapy proves to be efficacious, then this treatment may become the control arm for comparison(s) with new experimental treatment(s)." [ 38 ]


Operation Warp Speed  (OWS) was a  public–private partnership  initiated by the United States government to facilitate and accelerate the development, manufacturing, and distribution of  COVID-19 vaccines , therapeutics, and diagnostics. [ 205 ] [ 206 ]  The first news report of Operation Warp Speed was on April 29, 2020, [ 207 ] [ 208 ] [ 209 ]  and the program was officially announced on May 15, 2020. [ 205 ]  It was headed by  Moncef Slaoui  from May 2020 to January 2021 and by  David A. Kessler  from January to February 2021. [ 210 ]  At the end of February 2021, Operation Warp Speed was transferred into the responsibilities of the  White House COVID-19 Response Team . [ 211 ]


The program promoted mass production of multiple vaccines, and different types of vaccine technologies, based on preliminary evidence. Then there were clinical trials. The plan anticipated that some of these vaccines would not prove safe or effective, making the program more costly than typical vaccine development, but potentially leading to the availability of a viable vaccine several months earlier than typical timelines. [ 212 ]


A large-scale,  randomized controlled trial  named the  RECOVERY Trial  was set up in March 2020, in the UK to test possible treatments for COVID-19. It is run by the Nuffield Departments of Public Health and of Medicine at the  University of Oxford  and is testing five repurposed drugs and also  convalescent plasma . The trial enrolled more than 11,500 COVID-19 positive participants in the U.K by June 2020. [ 44 ] [ 213 ] [ 214 ]


During April, the British RECOVERY (Randomised Evaluation of COVid-19 thERapY) trial was launched initially in 132 hospitals across the UK, [ 215 ]  expanding to become one of the world's largest COVID-19 clinical studies, involving 5400 infected people under treatment at 165 UK hospitals, as of mid-April. [ 216 ]  The trial is examining different potential therapies for severe COVID-19 infection: lopinavir/ritonavir, low-dose  dexamethasone  (an anti-inflammatory  steroid ), hydroxychloroquine, and  azithromycin  (a common  antibiotic ). [ 213 ]  In June, the trial arm using hydroxychloroquine was discontinued when analyses showed it provided no benefit. [ 44 ]


On 16 June the trial group released a statement that dexamethasone had been shown to reduce mortality in patients receiving respiratory support. [ 217 ]  In a  controlled trial  around 2,000 hospital patients were given dexamethasone and were compared with more than 4,000 who did not receive the drug. For patients on ventilators, it cut the risk of death from 40% to 28% (1 in 8). For patients needing oxygen, it cut the risk of death from 25% to 20% (1 in 5). [ 218 ]