Drug development

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https://en.wikipedia.org/wiki/Drug_development

Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regulatory status, such as via the United States Food and Drug Administration 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. 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 typically takes more than a decade.

New chemical entity development

Broadly, the process of drug development can be divided into preclinical and clinical work.

Timeline showing the various drug approval tracks and research phases

Pre-clinical

Main article: Pre-clinical development

New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds that emerge from the process of drug discovery. These have promising activity against a particular biological target that is important in disease. However, little is known about the safety, toxicity, pharmacokinetics, and metabolism of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to recommend the dose and schedule for the first use in a human clinical trial ("first-in-human" [FIH] or First Human Dose [FHD], previously also known as "first-in-man" [FIM]).

In addition, drug development must establish the physicochemical properties of the NCE: its chemical makeup, stability, and solubility. Manufacturers must optimize the process they use to make the chemical so they can scale up from a medicinal chemist producing milligrams, to manufacturing on the kilogram and ton scale. They further examine the product for suitability to package as capsules, tablets, aerosol, intramuscular injectable, subcutaneous injectable, or intravenous formulations. Together, these processes are known in preclinical and clinical development as chemistry, manufacturing, and control (CMC).

Many aspects of drug development focus on satisfying the regulatory requirements for a new drug application. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in humans. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g., the skin if the new drug is to be delivered on or through the skin). Such preliminary tests are made using in vitro methods (e.g., with isolated cells), but many tests can only use experimental animals to demonstrate the complex interplay of metabolism and drug exposure on toxicity.

The information is gathered from this preclinical testing, as well as information on CMC, and submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug (IND) application. If the IND is approved, development moves to the clinical phase.

Clinical phase

Clinical trials involve three or four steps:

• Phase I trials, usually in healthy volunteers, determine safety and dosing.
• Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of patients having the disease targeted by the NCE.
• Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients with the targeted disease. If safety and efficacy are adequately proved, clinical testing may stop at this step and the NCE advances to the new drug application (NDA) stage.
• Phase IV trials are post-approval trials that are sometimes a condition attached by the FDA, also called post-market surveillance studies.

The process of defining characteristics of the drug does not stop once an NCE is advanced into human clinical trials. In addition to the tests required to move a novel vaccine or antiviral drug into the clinic for the first time, manufacturers must ensure that any long-term or chronic toxicities are well-defined, including effects on systems not previously monitored (fertility, reproduction, immune system, among others).

If a vaccine candidate or antiviral compound emerges from these tests with an acceptable toxicity and safety profile, and the manufacturer can further show it has the desired effect in clinical trials, then the NCE portfolio of evidence can be submitted for marketing approval in the various countries where the manufacturer plans to sell it. In the United States, this process is called a "new drug application" or NDA.

Most novel drug candidates (NCEs) fail during drug development, either because they have unacceptable toxicity or because they simply do not prove efficacy on the targeted disease, as shown in Phase II–III clinical trials. Critical reviews of drug development programs indicate that Phase II–III clinical trials fail due mainly to unknown toxic side effects (50% failure of Phase II cardiology trials), and because of inadequate financing, trial design weaknesses, or poor trial execution.

A study covering clinical research in the 1980–90s found that only 21.5% of drug candidates that started Phase I trials were eventually approved for marketing. During 2006–15, the success rate of obtaining approval from Phase I to successful Phase III trials was under 10% on average, and 16% specifically for vaccines. The high failure rates associated with pharmaceutical development are referred to as an "attrition rate", requiring decisions during the early stages of drug development to "kill" projects early to avoid costly failures.

Cost

Main article: Cost of drug development

One 2010 study assessed both capitalized and out-of-pocket costs for bringing a single new drug to market as about US$1.8 billion and $870 million, respectively. A median cost estimate of 2015–16 trials for development of 10 anti-cancer drugs was $648 million. In 2017, the median cost of a pivotal trial across all clinical indications was $19 million.

The average cost (2013 dollars) of each stage of clinical research was US$25 million for a Phase I safety study, $59 million for a Phase II randomized controlled efficacy study, and $255 million for a pivotal Phase III trial to demonstrate its equivalence or superiority to an existing approved drug, possibly as high as $345 million. The average cost of conducting a 2015–16 pivotal Phase III trial on an infectious disease drug candidate was $22 million.

The full cost of bringing a new drug (i.e., new chemical entity) to market – from discovery through clinical trials to approval – is complex and controversial. In a 2016 review of 106 drug candidates assessed through clinical trials, the total capital expenditure for a manufacturer having a drug approved through successful Phase III trials was $2.6 billion (in 2013 dollars), an amount increasing at an annual rate of 8.5%. Over 2003–2013 for companies that approved 8–13 drugs, the cost per drug could rise to as high as $5.5 billion, due mainly to international geographic expansion for marketing and ongoing costs for Phase IV trials for continuous safety surveillance.

Alternatives to conventional drug development have the objective for universities, governments, and the pharmaceutical industry to collaborate and optimize resources. An example of a collaborative drug development initiative is COVID Moonshot, an international open-science project started in March 2020 with the goal of developing an un-patented oral antiviral drug to treat SARS-CoV-2.

Valuation

The nature of a drug development project is characterised by high attrition rates, large capital expenditures, and long timelines. This makes the valuation of such projects and companies a challenging task. Not all valuation methods can cope with these particularities. The most commonly used valuation methods are risk-adjusted net present value (rNPV), decision trees, real options, or comparables.

The most important value drivers are the cost of capital or discount rate that is used, phase attributes such as duration, success rates, and costs, and the forecasted sales, including cost of goods and marketing and sales expenses. Less objective aspects like quality of the management or novelty of the technology should be reflected in the cash flows estimation.

Success rate

Candidates for a new drug to treat a disease might, theoretically, include from 5,000 to 10,000 chemical compounds. On average about 250 of these show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these qualify for tests on humans. A study conducted by the Tufts Center for the Study of Drug Development covering the 1980s and 1990s found that only 21.5 percent of drugs that started Phase I trials were eventually approved for marketing. In the time period of 2006 to 2015, the success rate was 9.6%. The high failure rates associated with pharmaceutical development are referred to as the "attrition rate" problem. Careful decision making during drug development is essential to avoid costly failures. In many cases, intelligent programme and clinical trial design can prevent false negative results. Well-designed, dose-finding studies and comparisons against both a placebo and a gold-standard treatment arm play a major role in achieving reliable data.

Computing initiatives

Novel initiatives include partnering between governmental organizations and industry, such as the European Innovative Medicines Initiative. The US Food and Drug Administration created the "Critical Path Initiative" to enhance innovation of drug development, and the Breakthrough Therapy designation to expedite development and regulatory review of candidate drugs for which preliminary clinical evidence shows the drug candidate may substantially improve therapy for a serious disorder.

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. 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. 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".

Rare disease

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A rare disease is any disease that affects a small percentage of the population. In some parts of the world, an orphan disease is a rare disease whose rarity means there is a lack of a market large enough to gain support and resources for discovering treatments for it, except by the government granting economically advantageous conditions to creating and selling such treatments. Orphan drugs are ones so created or sold.

Most rare diseases are genetic and thus are present throughout the person's entire life, even if symptoms do not immediately appear. Many rare diseases appear early in life, and about 30% of children with rare diseases will die before reaching their fifth birthday. With only four diagnosed patients in 27 years, ribose-5-phosphate isomerase deficiency is considered the rarest known genetic disease.

No single cut-off number has been agreed upon for which a disease is considered rare. A disease may be considered rare in one part of the world, or in a particular group of people, but be common in another.

The US organisation Global Genes has estimated that more than 300 million people worldwide are living with one of the approximately 7,000 diseases they define as "rare" in the United States.

Definition

There is no single, widely accepted definition for rare diseases. Some definitions rely solely on the number of people living with a disease, and other definitions include other factors, such as the existence of adequate treatments or the severity of the disease.

In the United States, the Rare Diseases Act of 2002 defines rare disease strictly according to prevalence, specifically "any disease or condition that affects fewer than 200,000 people in the United States", or about 1 in 1,500 people. This definition is essentially the same as that of the Orphan Drug Act of 1983, a federal law that was written to encourage research into rare diseases and possible cures.

In Japan, the legal definition of a rare disease is one that affects fewer than 50,000 patients in Japan, or about 1 in 2,500 people.

However, the European Commission on Public Health defines rare diseases as "life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them". The term low prevalence is later defined as generally meaning fewer than 1 in 2,000 people. Diseases that are statistically rare, but not also life-threatening, chronically debilitating, or inadequately treated, are excluded from their definition.

The definitions used in the medical literature and by national health plans are similarly divided, with definitions ranging from 1/1,000 to 1/200,000.

Definitions of rare disease in different countries

Country	Patient ratio as defined	Patient ratio standardised for comparison
Brazil	65 in 100,000	1 in 1,538
Argentina	1 in 2,000	1 in 2,000
Australia	5 in 10,000	1 in 2,000
Chile	5 in 10,000	1 in 2,000
Columbia	1 in 2,000	1 in 2,000
European Union	5 in 10,000	1 in 2,000
Mexico	5 in 10,000	1 in 2,000
Panama	1 in 2,000	1 in 2,000
Singapore	1 in 2,000	1 in 2,000
United Kingdom	1 in 2,000	1 in 2,000
Russian Federation	10 in 100,000	1 in 10,000
Peru	1 in 100,000	1 in 100,000

Relationship to orphan diseases

Because of definitions that include reference to treatment availability, a lack of resources, and severity of the disease, the term orphan disease is used as a synonym for rare disease. But in the United States and the European Union, "orphan diseases" have a distinct legal meaning.

The United States' Orphan Drug Act includes both rare diseases and any non-rare diseases "for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will [be] recovered from sales in the United States of such drug" as orphan diseases.

The European Organization for Rare Diseases (EURORDIS) also includes both rare diseases and neglected diseases into a larger category of "orphan diseases".

Prevalence

Prevalence (number of people living with a disease at a given moment), rather than incidence (number of new diagnoses in a given year), is used to describe the impact of rare diseases. The Global Genes Project estimates some 300 million people worldwide are affected by a rare disease.

The European Organization for Rare Diseases (EURORDIS) estimates that as many as 5,000 to 7,000 distinct rare diseases exist, and as much as 6% to 8% of the population of the European Union is affected by one. Only about 400 rare diseases have therapies and about 80% have a genetic component according to Rare Genomics Institute.

Rare diseases can vary in prevalence between populations, so a disease that is rare in some populations may be common in others. This is especially true of genetic diseases and infectious diseases. An example is cystic fibrosis, a genetic disease: it is rare in most parts of Asia but relatively common in Europe and in populations of European descent. In smaller communities, the founder effect can result in a disease that is very rare worldwide being prevalent within the smaller community. Many infectious diseases are prevalent in a given geographic area but rare everywhere else. Other diseases, such as many rare forms of cancer, have no apparent pattern of distribution but are simply rare. The classification of other conditions depends in part on the population being studied: All forms of cancer in children are generally considered rare, because so few children develop cancer, but the same cancer in adults may be more common.

About 40 rare diseases have a far higher prevalence in Finland; these are known collectively as Finnish heritage disease. Similarly, there are rare genetic diseases among the Amish religious communities in the US and among ethnically Jewish people.

Characteristics

A rare disease is defined as one that affects fewer than 200,000 people across a broad range of possible disorders. Chronic genetic diseases are commonly classified as rare. Among numerous possibilities, rare diseases may result from bacterial or viral infections, allergies, chromosome disorders, degenerative and proliferative causes, affecting any body organ. Rare diseases may be chronic or incurable, although many short-term medical conditions are also rare diseases.

Public research and government policy

United States

The NIH's Office of Rare Diseases Research (ORDR) was established by H.R. 4013/Public Law 107-280 in 2002. H.R. 4014, signed the same day, refers to the "Rare Diseases Orphan Product Development Act". Similar initiatives have been proposed in Europe. The ORDR also runs the Rare Diseases Clinical Research Network (RDCRN). The RDCRN provides support for clinical studies and facilitating collaboration, study enrollment and data sharing.

United Kingdom

In 2013, the United Kingdom government published The UK Strategy for Rare Diseases which "aims to ensure no one gets left behind just because they have a rare disease", with 51 recommendations for care and treatment across the UK to be implemented by 2020. Health services in the four constituent countries agreed to adopt implementation plans by 2014, but by October 2016, the Health Service in England had not produced a plan and the all-party parliamentary group on Rare, Genetic and Undiagnosed Conditions produced a report Leaving No One Behind: Why England needs an implementation plan for the UK Strategy for Rare Diseases in February 2017. In March 2017 it was announced that NHS England would develop an implementation plan. In January 2018 NHS England published its Implementation Plan for the UK Strategy for Rare Diseases. In January 2021 the Department of Health and Social Care published the UK Rare Diseases Framework, a policy paper which included a commitment that the four nations would develop action plans, working with the rare disease community, and that "where possible, each nation will aim to publish the action plans in 2021".

Organisations around the world are exploring ways of involving people affected by rare diseases in helping shape future research, including using online methods to explore the perspectives of multiple stakeholders.

Public awareness

Rare Disease Day is held in Europe, Canada, the United States and India on the last day of February to raise awareness for rare diseases.

Orphan drug

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Orphan_drug 

An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.

The assignment of orphan status to a disease and to drugs developed to treat it is a matter of public policy in many countries and has yielded medical breakthroughs that might not otherwise have been achieved, due to the economics of drug research and development.

In the U.S. and the EU, it is easier to gain marketing approval for an orphan drug. There may be other financial incentives, such as an extended period of exclusivity, during which the producer has sole rights to market the drug. All are intended to encourage development of drugs which would otherwise lack sufficient profit motive to attract corporate research budgets and personnel.

Contents

• 1 Definition
• 2 Global statistics
• 3 Effect on investment, sales and profit
• 4 Legislation
  • 4.1 United States
  • 4.2 European Union
  • 4.3 Other countries
  • 4.4 Numbers of new drugs
• 5 Examples for selected diseases
  • 5.1 Cystic fibrosis
  • 5.2 Familial hypercholesterolemia
  • 5.3 Wilson's disease
  • 5.4 Phospholipase 2G6-associated neurodegeneration
  • 5.5 Transthyretin-related hereditary amyloidosis
• 6 Activism, research centers
• 7 Cost
• 8 Public funding
  • 8.1 Evaluation criteria
  • 8.2 Abuse potential
  • 8.3 NICE
• 9 See also
• 10 References
• 11 External links

Definition

According to the US Food and Drug Administration (FDA), an orphan drug is defined as one "intended for the treatment, prevention or diagnosis of a rare disease or condition, which is one that affects less than 200,000 persons in the US" (which equates to approximately 6 cases per 10,000 population) "or meets cost recovery provisions of the act." In the European Union (EU), the European Medicines Agency (EMA) defines a drug as "orphan" if it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically and seriously debilitating condition affecting not more than 5 in 10,000 EU people. EMA also qualifies a drug as orphan if – without incentives – it would be unlikely that marketing the drug in the EU would generate sufficient benefit for the affected people and for the drug manufacturer to justify the investment. As of 2017, there was no official integration of the orphan drug programs between the FDA and EMA.

Global statistics

As of 2014, there were 281 marketed orphan drugs and more than 400 orphan-designated drugs in clinical trials. More than 60% of orphan drugs were biologics. The U.S. dominated development of orphan drugs, with more than 300 in clinical trials, followed by Europe. Cancer treatment was the indication in more than 30% of orphan drug trials.

• Number of orphan drugs in clinical trials: 600
• Number of orphan drugs in phase 2 trial: 231
• Number of orphan drugs in U.S. clinical trials: 350 in the pipeline from research until registration

Effect on investment, sales and profit

According to Thomson Reuters in their 2012 publication "The Economic Power of Orphan Drugs", there has been increased investment in orphan drug research and development, partly due to the U.S. Orphan Drug Act of 1983 (ODA) and similar acts in other regions of the world driven by "high-profile philanthropic funding".

According to Drug Discovery Today, the years 2001 to 2011 were the "most productive period in the history of orphan drug development, in terms of average annual orphan drug designations and orphan drug approvals". For the same decade the compound annual growth rate (CAGR) of the orphan drugs was an "impressive 25.8%, compared to only 20.1% for a matched control group of non-orphan drugs". By 2012, the market for orphan drugs was worth US$637 million, compared with US$638 million for a control group of non-orphan drugs.

By 2012,

the revenue-generating potential of orphan drugs [was] as great as for non-orphan drugs, even though patient populations for rare diseases are significantly smaller. Moreover, we suggest that orphan drugs have greater profitability when considered in the full context of developmental drivers, including government financial incentives, smaller clinical trial sizes, shorter clinical trial times and higher rates of regulatory success.

— Gaze and Breen 2012

According to a 2014 report, the orphan drug market has become increasingly lucrative for a number of reasons. The cost of clinical trials for orphan drugs is substantially lower than for other diseases because trial sizes are naturally much smaller than for more diseases with larger numbers of patients. Small clinical trials and minimal competition place orphan agents at an advantage in regulatory review.

Tax incentives reduce the cost of development. On average the cost per patient for orphan drugs is "six times that of non-orphan drugs, a clear indication of their pricing power". The cost of per-person outlays are large and are expected to increase with wider use of public subsidies.

The 2014 Orphan Drug report stated that the percentage of orphan drug sales as part of all prescription drug sales had been increasing at rapid rate. The report projected a total of US$176 billion by 2020. Although orphan disease populations are the smallest, the cost of per-patient outlays among them are the largest and are expected to increase as more people with rare diseases become eligible for subsidies – in the U.S., for example, through the Affordable Care Act.

Legislation

Orphan drugs generally follow the same regulatory development path as any other pharmaceutical product, in which testing focuses on pharmacokinetics and pharmacodynamics, dosing, stability, safety and efficacy. However, some statistical burdens are lessened to maintain development momentum. For example, orphan drug regulations generally acknowledge the fact that it may not be possible to test 1,000 patients in a phase III clinical trial if fewer than that number are afflicted with the disease.

Government intervention on behalf of orphan drug development takes several forms:

• Tax incentives
• Exclusivity (enhanced patent protection and marketing rights)
• Research subsidies
• Creating a government-run enterprise to engage in research and development as in a Crown corporation

A 2015 study of "34 key Canadian stakeholders, including drug regulators, funders, scientists, policy experts, pharmaceutical industry representatives, and patient advocates" investigated factors behind the pharmaceutical industry growing interest in "niche markets" such as orphan drugs.

United States

The Orphan Drug Act (ODA) of January 1983, passed in the United States, with lobbying from the National Organization for Rare Disorders and many other organizations, is meant to encourage pharmaceutical companies to develop drugs for diseases that have a small market. Under the ODA drugs, vaccines, and diagnostic agents would qualify for orphan status if they were intended to treat a disease affecting fewer than 200,000 American citizens. Under the ODA orphan drug sponsors qualify for seven-year FDA-administered market Orphan Drug Exclusivity (ODE), "tax credits of up to 50% of R&D costs, R&D grants, waived FDA fees, protocol assistance and may get clinical trial tax incentives.

In the U.S., orphan drug designation means that the sponsor qualifies for certain benefits, but it does not mean the drug is safe, effective or legal.

In 2002, the Rare Diseases Act was signed into law. It amended the Public Health Service Act to establish the Office of Rare Diseases. It also increased funding for the development of treatments for people with rare diseases.

European Union

In 2000, the European Union (EU) enacted similar legislation, Regulation(EC) No 141/2000, which refers to drugs developed to treat rare diseases to as "orphan medicinal products". The EU's definition of an orphan condition is broader than that of the US, in that it also covers some tropical diseases that are primarily found in developing nations. Orphan drug status granted by the European Commission gives marketing exclusivity in the EU for 10 years after approval. The EU's legislation is administered by the Committee on Orphan Medicinal Products of the European Medicines Agency (EMA).

In late 2007 the FDA and EMA agreed to use a common application process for both agencies to make it easier for manufacturers to apply for orphan drug status but, while continuing two separate approval processes.

Other countries

Legislation has been implemented by Japan, Singapore, and Australia that offers subsidies and other incentives to encourage the development of drugs that treat orphan diseases.

Numbers of new drugs

Under the ODA and EU legislation, many orphan drugs have been developed, including drugs to treat glioma, multiple myeloma, cystic fibrosis, phenylketonuria, snake venom poisoning, and idiopathic thrombocytopenic purpura.

The Pharmaceutical Executive opines, that the "ODA is nearly universally acknowledged to be a success".

Before the US Congress enacted the ODA in 1983, only 38 drugs were approved in the US specifically to treat orphan diseases. In the US, from January 1983 to June 2004, 249 orphan drugs received marketing authorization and 1,129 received different orphan drug designations, compared to fewer than ten such products in the decade prior to 1983. From 1983 until May 2010, the FDA approved 353 orphan drugs and granted orphan designations to 2,116 compounds. As of 2010, 200 of the roughly 7,000 officially designated orphan diseases have become treatable.

Critics have questioned whether orphan drug legislation was the real cause of this increase, claiming that many of the new drugs were for disorders which were already being researched anyway, and would have had drugs developed regardless of the legislation, and whether the ODA has truly stimulated the production of non-profitable drugs; the act also has been criticised for allowing some pharmaceutical companies to make a large profit off drugs which have a small market but sell for a high price.

While the European Medicines Agency grants orphan drugs market access in all member states, in practice, they only reach the market when a member state decides that its national health system will reimburse for the drug. For example, in 2008, 44 orphan drugs reached the market in the Netherlands, 35 in Belgium, and 28 in Sweden, while in 2007, 35 such drugs reached the market in France and 23 in Italy.

Though not technically an orphan disease, research and development into the treatment for AIDS has been heavily linked to the Orphan Drug Act. In the beginning of the AIDS epidemic the lack of treatment for the disease was often accredited to a believed lack of commercial base for a medication linked to HIV infection. This encouraged the FDA to use the Orphan Drug Act to help bolster research in this field, and by 1995 13 of the 19 drugs approved by the FDA to treat AIDS had received orphan drug designation, with 10 receiving marketing rights. These are in addition to the 70 designated orphan drugs designed to treat other HIV related illnesses.

Examples for selected diseases

Cystic fibrosis

In the 1980s, people with cystic fibrosis rarely lived beyond their early teens. Drugs like Pulmozyme and tobramycin, both developed with aid from the ODA, revolutionized treatment for cystic fibrosis patients by significantly improving their quality of life and extending their life expectancies. Now, cystic fibrosis patients often survive into their thirties and some into their fifties.

Familial hypercholesterolemia

The 1985 Nobel Prize for medicine went to two researchers for their work related to familial hypercholesterolemia, which causes large and rapid increases in cholesterol levels. Their research led to the development of statin drugs which are now commonly used to treat high cholesterol.

Wilson's disease

Penicillamine was developed to treat Wilson's disease, a rare hereditary disease that can lead to a fatal accumulation of copper in the body. This drug was later found to be effective in treating arthritis. Bis-choline tetrathiomolybdate is currently under investigation as a therapy against Wilson's disease.

Phospholipase 2G6-associated neurodegeneration

In 2017, FDA granted RT001 orphan drug designation in the treatment of phospholipase 2G6-associated neurodegeneration (PLAN).

Transthyretin-related hereditary amyloidosis

The FDA granted Patisiran (Onpattro) orphan drug status and breakthrough therapy designation due to its novel mechanism involving RNA therapy to block the production of an abnormal form of transthyretin. Patisiran received full FDA approval in 2018 and its RNA lipid nanoparticle drug delivery system was later used in the Pfizer–BioNTech COVID-19 vaccine and Moderna RNA vaccines.

Activism, research centers

The Center for Orphan Drug Research at the University of Minnesota College of Pharmacy helps small companies with insufficient in-house expertise and resources in drug synthesis, formulation, pharmacometrics, and bio-analysis. The Keck Graduate Institute Center for Rare Disease Therapies (CRDT) in Claremont, California, supports projects to revive potential orphan drugs whose development has stalled by identifying barriers to commercialization, such as problems with formulation and bio-processing.

Numerous advocacy groups such as the National Organization for Rare Disorders, Global Genes Project, Children's Rare Disease Network, Abetalipoproteinemia Collaboration Foundation, Zellweger Baby Support Network, and the Friedreich's Ataxia Research Alliance have been founded in order to advocate on behalf of patients suffering from rare diseases with a particular emphasis on diseases that afflict children.

Cost

According to a 2015 report published by EvaluatePharma, the economics of orphan drugs mirrors the economics of the pharmaceutical market as a whole but has a few very large differences. The market for orphan drugs is by definition very small, but while the customer base is drastically smaller the cost of research and development is very much the same as for non orphan drugs. This, the producers have claimed, causes them to charge extremely high amounts for treatment, sometimes as high as $700,000 a year, as in the case of Spinraza (Biogen), FDA approved in December 2016 for spinal muscular atrophy, placing a large amount of stress on insurance companies and patients. An analysis of 12 orphan drugs that were approved in the US between 1990 and 2000 estimated a price reduction of on average 50% upon loss of marketing exclusivity, with a range of price reductions from 14% to 95%.

Governments have implemented steps to reduce high research and development cost with subsidies and other forms of financial assistance. The largest assistance are tax breaks which can be as high as 50% of research and development costs. Orphan drug manufacturers are also able to take advantage of the small customer base to cut cost on clinical trials due to the small number of cases to have smaller trials which reduces cost. These smaller clinical trials also allow orphan drugs to move to market faster as the average time to receive FDA approval for an orphan drug is 10 months compared to 13 months for non-orphan drugs. This is especially true in the market for cancer drugs, as a 2011 study found that between 2004 and 2010 orphan drug trials were more likely to be smaller and less randomized than their non-orphan counterparts, but still had a higher FDA approval rate, with 15 orphan cancer drugs being approved, while only 12 non-orphan drugs were approved. This allows manufactures to get cost to the point that it is economically feasible to produce these treatments. The subsidies can total up to $30 million per fiscal year in the United States alone.

By 2015, industry analysts and academic researchers agreed, that the sky-high price of orphan drugs, such as eculizumab, was not related to research, development and manufacturing costs. Their price is arbitrary and they have become more profitable than traditional medicines.

Public resources went into understanding the molecular basis of the disease, public resources went into the technology to make antibodies and finally, Alexion, to their credit, kind of picked up the pieces.

— Sachdev Sidhu 2015

Public funding

Evaluation criteria

By 2007 the use of economic evaluation methods regarding public-funding of orphan drugs, using estimates of the incremental cost-effectiveness, for example, became more established internationally. The QALY has often been used in cost-utility analysis to calculate the ratio of cost to QALYs saved for a particular health care intervention. By 2008 the National Institute for Health and Care Excellence (NICE) in England and Wales, for example, operated with a threshold range of £20,000–30,000 per quality-adjusted life year (QALY). By 2005 doubts were raised about the use of economic evaluations in orphan drugs. By 2008 most of the orphan drugs appraised had cost-effectiveness thresholds "well in excess of the 'accepted' level and would not be reimbursed according to conventional criteria". As early as 2005 McCabe et al. argued that rarity should not have a premium and orphan drugs should be treated like other pharmaceuticals in general. Drummond et al. argued that the social value of health technologies should also be included in the assessment along with the estimation of the incremental cost-effectiveness ratio.

Abuse potential

Rosuvastatin (brand name Crestor) is an example of a drug that received Orphan Drug funding but was later marketed to a large consumer base.

The very large incentives given to pharmaceutical companies to produce orphan drugs have led to the impression that the financial support afforded to make these drugs possible is akin to abuse. Because drugs can be used to treat multiple conditions, companies can take drugs that were filed with their government agency as orphan drugs to receive financial assistance, and then market it to a wide population to increase their profit margin. For example AstraZeneca's cholesterol drug Crestor was filed as a treatment for the rare disease pediatric familial hypercholesterolemia. After the drug was approved for orphan drug designation, and AstraZeneca had received tax breaks and other advantages, AstraZeneca later applied and received FDA approval for the drug to be used to treat cholesterol in all diabetics.

NICE

The UK's National Institute for Health and Care Excellence (NICE) can pay from £100,000 to £300,000 per QALY (Quality Adjusted Life Year) for treatments of "very rare conditions". This is compared to under £20,000 for non-orphan drugs.

In 2015, NICE held consultations with "patient groups, the Department of Health, companies, learned societies, charities and researchers" regarding the appraisal of medicines and other technologies. There was a call for more research into new processes, including: 

the model of pharmaceutical research and development, the expectations that companies and patient groups have about how risk and reward is shared between the industry and a publicly funded NHS, and in the arrangements for commissioning expensive new treatments.

— NICE 2014

 

Expanded access

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Expanded_access 

Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug applications (IND) or IDE application for devices, outside of a clinical trial, by people with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress.

These programs go under various names, including early access, special access, or managed access program, compassionate use, compassionate access, named-patient access, temporary authorization for use, cohort access, and pre-approval access.

In general the person and their doctor must apply for access to the investigational product, the company has to choose to cooperate, and the medicines regulatory agency needs to agree that the risks and possible benefits of the drug or device are understood well enough to determine if putting the person at risk has sufficient potential benefit. In some countries the government will pay for the drug or device, but in many countries the person must pay for the drug or device, as well as medical services necessary to receive it.

In the US, compassionate use started with the provision of investigational medicine to certain patients in the late 1970s, and a formal program was established in 1987 in response to HIV/AIDS patients requesting access to drugs in development. An important legal case was Abigail Alliance v. von Eschenbach, in which the Abigail Alliance, a group that advocates for access to investigational drugs for people who are terminally ill, tried to establish such access as a legal right. The Supreme Court declined to hear the case, effectively upholding previous cases that have maintained that there is not a constitutional right to unapproved medical products.

Programs

As of 2016, regulation of access to pharmaceuticals that were not approved for marketing was handled on a country by country basis, including in the European Union, where the European Medicines Agency issued guidelines for national regulatory agencies to follow. In the US, Europe, and the EU, no company could be compelled to provide a drug or device that it was developing.

Companies sometimes provide drugs under these programs to people who were in clinical trials and who responded to the drug, after the clinical trial ends.

United States

In the US as of 2018, people could try obtain unapproved drugs or medical devices that were in development under specific conditions.

These conditions were:

• The person wanting the drug or device and a licensed physician are both willing to participate.
• The person's physician determines that there is no comparable or satisfactory therapy available to diagnose, monitor, or treat the patient's disease or condition.
• That the probable risk to the person from the investigational product is not greater than the probable risk from the disease or condition.
• The FDA determines that there is sufficient evidence of the safety and effectiveness of the investigational product to support its use in the particular circumstance;
• The FDA determines that providing the investigational product will not interfere with the initiation, conduct, or completion of clinical investigations to support marketing approval;
• The sponsor (generally the company developing the investigational product for commercial use) or the clinical investigator (or the patient's physician in the case of a single patient expanded access request) submits a clinical protocol (a document that describes the treatment plan for the patient) that is consistent with FDA's statute and applicable regulations for INDs or investigational device exemption applications (IDEs), describing the use of the investigational product; and
• The person is unable to obtain the investigational drug or device under another IND application (for drugs), IDE application (for devices), or to participate in a clinical trial.

Drugs can be made available to individuals, small groups, or large groups.

In the US, actual provision of the drug depends on the manufacturer's willingness to provide it, as well as the person's ability to pay for it; it is the company's decision whether to require payment or to provide the drug or device for free. The manufacturer can only charge direct costs for individual INDs; it can add some but not all indirect costs for small group or larger expanded access programs. To the extent that a doctor or clinic is required for use of the drug or device, they too may require payment.

In some cases, it may be in the manufacturer's commercial interest to provide access under an EA program; this is a way, for example, for a company to make money before the drug or device is approved. Companies must provide data collected from people getting the drug or device under EA programs to the FDA annually; this data may be helpful with regard to getting the drug or device approved, or may be harmful, should unexpected adverse events occur. The manufacturer remains legally liable as well. If the manufacturer chooses to charge for the investigational product, that price influences later discussions about the price if the product is approved for marketing.

State law

As of February 2019, 41 states have passed right-to-try laws that permit manufacturers to provide experimental medicines to terminally ill people without US FDA authorization. Legal, medical, and bioethics scholars, including Jonathan Darrow and Arthur Caplan, have argued that these state laws have little practical significance because people can already obtain pre-approval access through the FDA's expanded access program, and because the FDA is generally not the limiting factor in obtaining pre-approval access.

Europe

In Europe, the European Medicines Agency issued guidelines that members may follow. Each country has its own regulations, and they vary. In the UK, for example, the program is called "early access to medicine scheme" or EAMS and was established in 2014. If a company that wants to provide a drug under EAMS, it must submit its Phase I data to the Medicines and Healthcare products Regulatory Agency and apply for what is called a "promising innovative medicine" (PIM) designation. If that designation is approved, the data is reviewed, if that review is positive, the National Health Service is obligated to pay for people who fit the criteria to have access to the drug. As of 2016, governments also paid for early access to drugs in Austria, Germany, Greece, and Spain.

Companies sometimes make use of expanded programs in Europe even after they receive EMA approval to market a drug, because drugs also must go through regulatory processes in each member state, and in some countries this process can take nearly a year; companies can start making sales earlier under these programs.

History

Medicinal cannabis farmed by the University of Mississippi for the government

In the US, one of the earliest expanded access programs was a compassionate use IND that was established in 1978, which allowed a limited number of people to use medical cannabis grown at the University of Mississippi. It is administered by the National Institute on Drug Abuse.

The program was started after Robert C. Randall brought a lawsuit (Randall v. U.S) against the FDA, the Drug Enforcement Administration, the National Institute on Drug Abuse, the Department of Justice, and the Department of Health, Education & Welfare. Randall, who had glaucoma, had successfully used the Common Law doctrine of necessity to argue against criminal charges of marijuana cultivation that had been brought against him, because his use of cannabis was deemed a medical necessity (U.S. v. Randall). On November 24, 1976, federal Judge James Washington ruled in his favor.

The settlement in Randall v. U.S. became the legal basis for the FDA's compassionate IND program. People were only allowed to use cannabis under the program who had certain conditions, like glaucoma, known to be alleviated with cannabis. The scope was later expanded to include people with AIDS in the mid-1980s. At its peak, fifteen people received the drug. 43 people were approved for the program, but 28 of the people whose doctors completed the necessary paperwork never received any cannabis. The program stopped accepting new people in 1992 after public health authorities concluded there was no scientific value to it, and due to President George H.W. Bush administration's policies. As of 2011, four people continued to receive cannabis from the government under the program.

The closure of the program during the height of the AIDS epidemic led to the formation of the medical cannabis movement in the United States, a movement which initially sought to provide cannabis for treating anorexia and wasting syndrome in people with AIDS.

In November 2001 the Abigail Alliance for Better Access to Developmental Drugs was established by Frank Burroughs in memory of his daughter, Abigail. The Alliance seeks broader availability of investigational drugs on behalf of people with terminal illnesses. It is best known for a legal case, which it lost, Abigail Alliance v. von Eschenbach, in which it was represented by the Washington Legal Foundation. On August 7, 2007, in an 8–2 ruling, the U.S. Court of Appeals for the District of Columbia Circuit reversed an earlier ruling in favor of the Alliance. In 2008, the Supreme Court of the United States declined to hear their appeal. This decision left standing the appellate court decision that people who are terminal ill patients have no legal right to demand "a potentially toxic drug with no proven therapeutic benefit".

In March 2014, Josh Hardy, a 7-year-old boy from Virginia, made national headlines that sparked a conversation on pediatric access to investigational drugs when his family's request for brincidofovir was declined by the drug manufacturer, Chimerix. The company reversed its decision after pressure from cancer advocacy organizations, and Josh received the drug that saved his life. In 2016 Kids v Cancer, a pediatric cancer advocacy organization, launched the Compassionate Use Navigator to assist physicians and guide families about the application process. Since then, FDA simplified the application process, but stressed that it cannot require a manufacturer to provide a product. FDA receives about 1,500 expanded access requests per year and authorizes 99% of it.

Odds algorithm

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Odds_algorithm#See_also 

The odds-algorithm is a mathematical method for computing optimal strategies for a class of problems that belong to the domain of optimal stopping problems. Their solution follows from the odds-strategy, and the importance of the odds-strategy lies in its optimality, as explained below.

The odds-algorithm applies to a class of problems called last-success-problems. Formally, the objective in these problems is to maximize the probability of identifying in a sequence of sequentially observed independent events the last event satisfying a specific criterion (a "specific event"). This identification must be done at the time of observation. No revisiting of preceding observations is permitted. Usually, a specific event is defined by the decision maker as an event that is of true interest in the view of "stopping" to take a well-defined action. Such problems are encountered in several situations.

Examples

Two different situations exemplify the interest in maximizing the probability to stop on a last specific event.

1. Suppose a car is advertised for sale to the highest bidder (best "offer"). Let n potential buyers respond and ask to see the car. Each insists upon an immediate decision from the seller to accept the bid, or not. Define a bid as interesting, and coded 1 if it is better than all preceding bids, and coded 0 otherwise. The bids will form a random sequence of 0s and 1s. Only 1s interest the seller, who may fear that each successive 1 might be the last. It follows from the definition that the very last 1 is the highest bid. Maximizing the probability of selling on the last 1 therefore means maximizing the probability of selling best.
2. A physician, using a special treatment, may use the code 1 for a successful treatment, 0 otherwise. The physician treats a sequence of n patients the same way, and wants to minimize any suffering, and to treat every responsive patient in the sequence. Stopping on the last 1 in such a random sequence of 0s and 1s would achieve this objective. Since the physician is no prophet, the objective is to maximize the probability of stopping on the last 1. (See Compassionate use.)

Definitions

Consider a sequence of ${\displaystyle n}$ independent events. Associate with this sequence another sequence ${\displaystyle I_{1},\,I_{2},\,\dots ,\,I_{n}}$ with values 1 or 0. Here ${\displaystyle \,I_{k}=1}$, called a success, stands for the event that the kth observation is interesting (as defined by the decision maker), and ${\displaystyle \,I_{k}=0}$ for non-interesting. We observe independent random variables ${\displaystyle I_{1},\,I_{2},\,\dots ,\,I_{n}}$ sequentially and want to select the last success.

Let ${\displaystyle \,p_{k}=P(\,I_{k}\,=1)}$ be the probability that the kth event is interesting. Further let ${\displaystyle \,q_{k}=\,1-p_{k}}$ and ${\displaystyle \,r_{k}=p_{k}/q_{k}}$.Note that ${\displaystyle \,r_{k}}$ represents the odds of the kth event turning out to be interesting, explaining the name of the odds-algorithm.

Algorithmic procedure

The odds-algorithm sums up the odds in reverse order

${\displaystyle r_{n}+r_{n-1}+r_{n-2}\,+\cdots ,\,}$

until this sum reaches or exceeds the value 1 for the first time. If this happens at index s, it saves s and the corresponding sum

${\displaystyle R_{s}=\,r_{n}+r_{n-1}+r_{n-2}+\cdots +r_{s}.\,}$

If the sum of the odds does not reach 1, it sets s = 1. At the same time it computes

${\displaystyle Q_{s}=q_{n}q_{n-1}\cdots q_{s}.\,}$

The output is

1. ${\displaystyle \,s}$, the stopping threshold
2. ${\displaystyle \,w=Q_{s}R_{s}}$, the win probability.

Odds-strategy

The odds-strategy is the rule to observe the events one after the other and to stop on the first interesting event from index s onwards (if any), where s is the stopping threshold of output a.

The importance of the odds-strategy, and hence of the odds-algorithm, lies in the following odds-theorem.

Odds-theorem

The odds-theorem states that

1. The odds-strategy is optimal, that is, it maximizes the probability of stopping on the last 1.
2. The win probability of the odds-strategy equals ${\displaystyle \,w=Q_{s}R_{s}}$
3. If ${\displaystyle \,R_{s}\geq \,1}$, the win probability ${\displaystyle \,w}$ is always at least ${\displaystyle \,1/e=0.368\dots }$, and this lower bound is best possible.

Features

The odds-algorithm computes the optimal strategy and the optimal win probability at the same time. Also, the number of operations of the odds-algorithm is (sub)linear in n. Hence no quicker algorithm can possibly exist for all sequences, so that the odds-algorithm is, at the same time, optimal as an algorithm.

Sources

Bruss 2000 devised the odd-algorithm, and coined its name. It is also known as Bruss-algorithm (strategy). Free implementations can be found on the web.

Applications

Applications reach from medical questions in clinical trials over sales problems, secretary problems, portfolio selection, (one-way) search strategies, trajectory problems and the parking problem to problems in on-line maintenance and others.

There exists, in the same spirit, an Odds-Theorem for continuous-time arrival processes with independent increments such as the Poisson process (Bruss 2000). In some cases, the odds are not necessarily known in advance (as in Example 2 above) so that the application of the odds-algorithm is not directly possible. In this case each step can use sequential estimates of the odds. This is meaningful, if the number of unknown parameters is not large compared with the number n of observations. The question of optimality is then more complicated, however, and requires additional studies. Generalizations of the odds-algorithm allow for different rewards for failing to stop and wrong stops as well as replacing independence assumptions by weaker ones (Ferguson (2008)).

Variations

Bruss & Paindaveine 2000 discussed a problem of selecting the last ${\displaystyle k}$ successes.

Tamaki 2010 proved a multiplicative odds theorem which deals with a problem of stopping at any of the last ${\displaystyle \ell }$ successes. A tight lower bound of win probability is obtained by Matsui & Ano 2014.

Matsui & Ano 2017 discussed a problem of selecting ${\displaystyle k}$ out of the last ${\displaystyle \ell }$ successes and obtained a tight lower bound of win probability. When ${\displaystyle \ell =k=1,}$ the problem is equivalent to Bruss' odds problem. If ${\displaystyle \ell =k\geq 1,}$ the problem is equivalent to that in Bruss & Paindaveine 2000. A problem discussed by Tamaki 2010 is obtained by setting ${\displaystyle \ell \geq k=1.}$

multiple choice problem: A player is allowed ${\displaystyle r}$ choices, and he wins if any choice is the last success. For classical secretary problem, Gilbert & Mosteller 1966 discussed the cases ${\displaystyle r=2,3,4}$. The odds problem with ${\displaystyle r=2,3}$ is discussed by Ano, Kakinuma & Miyoshi 2010. For further cases of odds problem, see Matsui & Ano 2016.

An optimal strategy belongs to the class of strategies defined by a set of threshold numbers ${\displaystyle (a_{1},a_{2},...,a_{r})}$, where ${\displaystyle a_{1}<a_{2}<\cdots <a_{r}}$. The first choice is to be used on the first candidates starting with ${\displaystyle a_{1}}$th applicant, and once the first choice is used, second choice is to be used on the first candidate starting with ${\displaystyle a_{2}}$th applicant, and so on.

When ${\displaystyle r=2}$, Ano, Kakinuma & Miyoshi 2010 showed that the tight lower bound of win probability is equal to ${\displaystyle e^{-1}+e^{-{\frac {3}{2}}}.}$ For general positive integer ${\displaystyle r}$, Matsui & Ano 2016 discussed the tight lower bound of win probability. When ${\displaystyle r=3,4,5}$, tight lower bounds of win probabilities are equal to ${\displaystyle e^{-1}+e^{-{\frac {3}{2}}}+e^{-{\frac {47}{24}}}}$, ${\displaystyle e^{-1}+e^{-{\frac {3}{2}}}+e^{-{\frac {47}{24}}}+e^{-{\frac {2761}{1152}}}}$ and

 ${\displaystyle e^{-1}+e^{-{\frac {3}{2}}}+e^{-{\frac {47}{24}}}+e^{-{\frac {2761}{1152}}}+e^{-{\frac {4162637}{1474560}}},}$ 

 respectively. For further cases that ${\displaystyle r=6,...,10}$, see Matsui & Ano 2016.