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Drug Industry

Drug industry

A pharmaceutical company (or drug company) is a company licensed to discover, develop, market and distribute drugs.

History

Most large pharmaceutical companies were founded in the late 19th and early 20th century, and derive their market share from a few well-marketed preparations. There are currently more than 200 major pharmaceutical companies. [http://www.pharmacy.org/company.html see list] As in some other industries, economic pressures are forcing pharmaceutical companies toward greater efficiency.[http://www.infosys.com/industries/Lifesciences/SETLabs_Life_Sciences_Challenge.pdf]

Biotechnology company

A biotechnology company is any company that uses biological systems, living organisms, or derivatives thereof, to make or modify products or processes for specific use. Often biotechnology companies produce pharmaceuticals. Typically a biopharmaceutical made in this manner is composed of very large molecules that are unstable and must be administered by injection in a physician's office.

Drug discovery

Drug discovery is the process by which drugs are discovered and/or designed. In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery. The new approach has been to understand how disease and infection are controlled at the molecular and physiology level and to target specific entities based on this knowledge. New drugs begin in the laboratory with chemists, scientists and pharmacologists who identify cellular and genetic factors that play a role in specific diseases[http://www.ppdi.com/corporate/faq/about_drug_development/home.htm]. "They search for chemical and biological substances that target these biological markers and are likely to have drug-like effects. Out of every 5,000 new compounds identified during the discovery process, only five are considered safe for testing in human volunteers after preclinical evaluations. After three to six years of further clinical testing in patients, only one of these compounds is ultimately approved as a marketed drug for treatment. The following sequence of research activities begins the process that results in development of new medicines:"

Target identification

"Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease. Scientists use a variety of techniques to identify and isolate a target and learn more about its functions and how these influence disease. Compounds are then identified that have various interactions with drug targets helpful in treatment of a specific disease."

Target prioritization/validation

"To select targets most likely to be useful in the development of new treatments for disease, researchers analyze and compare each drug target to others based on their association with a specific disease and their ability to regulate biological and chemical compounds in the body. Tests are conducted to confirm that interactions with the drug target are associated with a desired change in the behavior of diseased cells. Research scientists can then identify compounds that have an effect on the target selected."

Lead identification

"A lead compound or substance is one that is believed to have potential to treat disease. Laboratory scientists can compare known substances with new compounds to determine their likelihood of success. Leads are sometimes developed as collections, or libraries, of individual molecules that possess properties needed in a new drug. Testing is then done on each of these molecules to confirm its effect on the drug target."

Lead optimization

"Lead optimization compares the properties of various lead compounds and provides information to help pharmaceutical and biotechnology companies select the compound or compounds with the greatest potential to be developed into safe and effective medicines. Often during this same stage of development, lead prioritization studies are conducted in living organisms (in vivo) and in cells in the test tube (in vitro) to compare various lead compounds and how they are metabolized and affect the body."

Drug development

Drug development is considered a costly and intensive process. Of all compounds investigated for use in humans only a small fraction is eventually approved, and only after heavy investment in pre-clinical development, clinical data acquisition, clinical trials, and safety monitoring to determine the safety and efficacy of a compound. Most clinical trials are randomized. The cost for a new drug (new chemical entity) is estimated to be about $1 billion US$. This figure is however hotly disputed.[http://www.ppdi.com/corporate/faq/about_drug_development/home.htm] Depending on a number of considerations, a company may apply for and be granted a patent for the drug or the process of producing the drug for about 20 years. Only after rigorous study and testing, which can take as long as 12 years, will governmental authorities grant permission for the company to market and sell the drug. In special circumstances, such as the search for effective drugs to treat AIDS, the Food and Drug Administration (FDA) has encouraged an abbreviated process for drug testing and approval called fast-tracking.[http://www.ppdi.com/corporate/faq/about_drug_development/home.htm] Clinical testing is usually described as consisting of Phase I, Phase II and Phase III clinical studies.[http://www.ppdi.com/corporate/faq/about_drug_development/home.htm] In each successive phase, increasing numbers of patients are tested. There are a large number of [http://www.healtheconomics.com/consulting.cfm firms] that support clinical trials.

Phase I Clinical Studies

"Phase I studies are designed to verify safety and tolerability of the candidate drug in humans and typically take six to nine months. These are the first studies conducted in humans. A small number of subjects, usually from 20 to 100 healthy volunteers, take the investigational drug for short periods of time. Testing includes observation and careful documentation of how the drug acts in the body -- how it is absorbed, distributed, metabolized and excreted."

Phase II Clinical Studies

"Phase II studies are designed to determine effectiveness and further study the safety of the candidate drug in humans. Depending upon the type of investigational drug and the condition it treats, this phase of development generally takes from six months up to three years. Testing is conducted with up to several hundred patients suffering from the condition the investigational drug is designed to treat. This testing determines safety and effectiveness of the drug in treating the condition and establishes the minimum and maximum effective dose. Most Phase II clinical trials are randomized, or randomly divided into groups, one of which receives the investigational drug, one of which gets a placebo containing no medication and sometimes a third that receives a current standard treatment to which the new investigational drug will be compared. In addition, most Phase II studies are double-blinded, meaning that neither patients nor researchers evaluating the compound know who is receiving the investigational drug or placebo."

Phase III Clinical Studies

"Phase III studies provide expanded testing of effectiveness and safety of an investigational drug, usually in randomized, and blinded clinical trials. Depending upon the type of drug candidate and the condition it treats, this phase usually requires one to four years of testing. In Phase III, safety and efficacy testing is conducted with several hundred to thousands of volunteer patients suffering from the condition the investigational drug treats."

New Drug Application

"(NDA)/Marketing Authorization Application (MAA) NDAs (in the U.S.) and MAAs (in the U.K.) are examples of applications to market a new drug. Such applications document safety and efficacy of the investigational drug and contain all the information collected during the drug development process. At the conclusion of successful preclinical and clinical testing, this series of documents is submitted to the FDA in the U.S. or to the applicable regulatory authorities in other countries. The application must present substantial evidence that the drug will have the effect it is represented to have when people use it or under the conditions for which it is prescribed, recommended or suggested in the labeling. Obtaining approval to market a new drug frequently takes between six months and two years."

Orphan drug

There are special rules for certain rare diseases ("orphan diseases") involving fewer than 200,000 people in the United States. Because medical research and development of drugs to treat such diseases is financially disadvantageous, companies that do so are rewarded with tax reductions and a monopoly on that orphan drug for a limited time (seven years).

Post-approval surveillance

Some medications only show to have safety issues after they are marketed, as clinical trials are of a limited size, such as the 3,000 test subjects required by the FDA. Post-marketing surveillance ensures that after marketing the safety of a drug is monitored closely. In certain instances, its indication may need to be limited to particular patient groups, and in others the substance is withdrawn from the market completely. After the FDA (or other regulatory agency for drugs marketed outside the U.S.) approves a new drug, pharmaceutical companies may conduct additional studies, including Phase IIIb and Phase IV studies.[http://www.ppdi.com/corporate/faq/about_drug_development/home.htm] "Late-stage drug development studies of approved, marketed drugs may continue for several months to several years."

Phase IIIb/IV Studies

"Phase IIIb trials, which often begin before approval, may supplement or complete earlier trials by providing additional safety data or they may test the approved drug for additional conditions for which it may prove useful. Phase IV studies expand testing of a proven drug to broader patient populations and compare the long-term effectiveness and/or cost of the drug to other marketed drugs available to treat the same condition."

Post-Market Studies

"Post-market studies test a marketed drug in new age groups or patient types. Some studies focus on previously unknown side effects or related risk factors. As with all stages of drug development testing, the purpose is to ensure the safety and effectiveness of marketed drugs."

Products

Drug information

Drug information and data are provided by the FDA and are located at the [http://www.fda.gov/cder/ob/default.htm Orange Book] site. Drug information is commercially available at [http://www.pharmalive.com/subscriptions/ekb.cfm?from=%23urlEncodedFormat('/ekb') eKnowledgebase].

ICD and DRG

Diseases are classified by ICD-9 codes. These ICD codes are aggregated into approximately 500 diagnosis-related groupss (DRG) expected to have similar hospital use. In 1991, the top 10 DRGs overall were:
- normal newborn,
- vaginal delivery,
- heart failure,
- psychoses,
- cesarean section,
- neonate with significant problems,
- angina pectoris,
- specific cerebrovascular disorders,
- pneumonia, and
- hip/knee replacement. These DRGs comprised nearly 30 percent of all hospital discharges. The complete list with prevalence rates is given in [http://www.rcgp.org.uk/journal/supp/v55/Fleming-S1.pdf].
- List of diseases

Revenues

Industry revenues

2004 global dollar volume was $550 billion, a 7 percent increase over 2003—which in turn represented a 9 percent increase over 2002. US sales grew to $235.4 billion, a growth rate of 8.3 percent compared with 11.5 percent growth from 2002 to 2003 [http://www.pharmexec.com/pharmexec/article/articleDetail.jsp?id=177964]. The United States accounts for 46 percent of the world's pharmaceutical market. According to Teradata Magazine,[http://www.teradata.com/t/page/131951/] "By 2007, $40 billion in U.S. sales will be lost at the top 10 pharma companies as a result of the slowdown in R&D innovation and the expiry of patents on major products," ... "Taking a broader look across the industry, no fewer than 19 blockbuster drugs are expected to hit patent crisis by 2008. Analysis suggests that 150 mid-sized new compounds will be needed by 2007-2008 in the U.S. alone to plug this gap."

Top 10 pharmaceutical companies by sales

The top 10 pharmaceutical companies by 2004 sales are: [http://www.pharmexec.com/pharmexec/data/articlestandard/pharmexec/282005/169778/article.pdf]

Patents and Generics

Drugs are patentable. A typical patent lasts for 20 years. However, it often takes as long as 12 years to approve a drug for patient use. Patent protection allows the owner of the patent to charge high margins for the branded drug. When the patent for the drug runs out, a generic drug [http://www.fda.gov/oc/speeches/2005/GPhA0301.html] is usually created by a competing company and released, causing the price to drop markedly. Often the owner of the branded drug will introduce a generic version before the patent runs out in order to get a head start in the generic market.

Medicare Part D

In 2003 the United States enacted the Medicare Prescription Drug, Improvement, and Modernization Act (MMA), a program to provide prescription drug benefits to the elderly and disabled. This program is a component of Medicare (United States) and is known as "Medicare Part D." This program, set to begin in January 2006, will significantly alter the revenue models for pharmaceutical companies. Revenues from the program are expected to be $724 Billion between 2006 and 2015 [http://www.kff.org/medicare/upload/7044-02.pdf]. Pharmaceuticals developed by biotechnological processes often must be injected in a physician's office rather than be delivered in the form of a capsule taken orally. Medicare payments for these drugs are usually made through Medicare Part B (physician office) rather than Part D (prescription drug plan).

Sales and marketing

The pharmaceutical industry is different

The pharmaceutical industry is different from most industries in that the products are usually not chosen by the consumers or paid for by the consumers. Physicians control the choice of many drugs through prescription writing. Private or public insurance often pays for most of the drugs. Moreover, insurance companies restrict the drugs that can be prescribed through the use of formularies. This along with the high margins for the industry make pharmaceutical marketing a complex discipline.

Advertising to physicians

Physicians are perhaps the most important players in pharmaceutical sales. They write the prescriptions that determine which drugs will be used by the patient. Influencing the physician is key to pharmaceutical sales. Historically, this was done with large pharmaceutical sales forces. A medium-sized pharmaceutical company might have a sales force of 1000 representaives. The largest companies have tens of thousands of representatives. Currently, there are approximately 100,000 pharmaceutical sales reps in the United States pursuing some 120,000 pharmaceutical prescribers.[http://www.teradata.com/t/page/131951/] Drug companies spend $5 billion annually sending representatives to physician offices.

Direct to consumer

Since the 1980s new methods of marketing for prescription drugs to consumers have become important. Patients are far less deferential to doctors and will inquire about, or even demand, to receive a medication they have seen advertised on television. In the United States recent years have seen an increase in mass media advertisements for pharmaceuticals.

The payers

Public and private insurers affect the writing of prescriptions by physicians through formularies that restrict the number and types of drugs that the insurer will cover. Not only can the insurer affect drug sales by including or excluding a particular drug from a formulary, they can affect sales by tiering, or placing bureacratic hurdles to prescribing certain drugs. In January 2006, the U.S. will institute a new public prescription drug plan through its Medicare program. Known as Medicare Part D, this program engages private insurers to negotiate with pharmaceutical companies for the placement of drugs on tiered formularies.

Mergers, acquisitions, and co-marketing of drugs

A merger, acquisition, or co-marketing deal between pharmaceutical companies can occur if the companies have complementary capabilities. A small biotechnology company might have a new drug but no sales or marketing capability. Conversely, a large pharmaceutical company might have unused capacity in a large sales force due to a gap in the company pipeline of new products. It may be in both company's interest to enter into a deal to capitalize on the synergy between the companies. The difference between the value of the two companies after the deal and before the deal is known as the synergy value of the deal. News affecting the value of a pharmaceutical company can be obtained through [http://welcome.pharmasentry.com/ PharmaSentry].

Controversy

- Accusations of forging or suppressing clinical trial results to maximise uptake of some medications;
- Accusations of manipulating the market for their products by showering doctors with free gifts[http://www.nofreelunch.org/].
- Too much advertising materials in the doctor's office, such as clocks, poster ads, etc.
- Aggressive representation by pharmaceutical companies' salespeople (detailmen).
- Sponsorship of medical schools, with influence on the curriculum to discourage the teaching of alternative medicines.
- Increased number of drug tests on animals before FDA approval
- Criticism for the price of patented AIDS medication, which could limit therapeutic options for patients in the Third World, where the most people have AIDS. Under World Trade Organization rules, a developing country has options for obtaining needed medications under compulsory licensing or importation of cheaper versions of the drugs, even before patent expiration[http://www.wto.org/english/news_e/pres03_e/pr350_e.htm (WTO Press Release)]. Pharmaceutical companies often offer much needed medication at no or reduced cost to the developing countries. Proposals to allow the manufacture generic AIDS drugs are not without controversy; it is sometimes claimed that this might cause pharmaceutical companies to move away from AIDS drug research and focus their research on other, more profitable areas. In March of 2001, South Africa was sued by 41 pharmaceutical companies for their Medicines Act, which allowed the import and generic production of cheap AIDS drugs. The case was later dropped after protest around the world.
- Between 1980 and 1997, drug industry funding for academic research rose x8, as research costs rose, and the rate of federal support fell. Drug researchers not employed by pharmaceutical companies often look to companies for grants, and companies often look to researchers for studies that will make their products look good. 79% of papers written by independent researchers are favorable to new drugs. 98% of papers written by researchers sponsored by the drug companies are favorable. Sponsored researchers are rewarded by drug companies by putting them on symposium circuits to lecture, with the lecture scripts written by pharmaceutical companies. Some researchers who have tried to publish papers that show harmful effects of new drugs or cheaper alternatives have been threatened by drug companies with lawsuits.
- Drug companies spent $900 million on consumer ads in the first half of 1999 alone. Pharmaceutical companies often fund non-profit "patient groups" that consume their drugs. Patient groups can advertise for the drug companies, and are unregulated by the Food and Drug Administration (FDA). Advertising directly to consumers, however, is strictly regulated in the United States by the FDA, as described in [http://www.fda.gov/cder/guidance/1804fnl.htm FDA Guidance for Industry on Consumer-Directed Broadcast Advertisements].
- Where pharmaceutics have been shown to cause side-effects, civil action has occurred, especially in countries where tort payouts are likely to be large. Due to high-profile cases leading to large compensations, most pharmaceutical companies endorse tort reform.

Bibliography

Controversy

- Ray Moynihan, Alan Cassels: Selling sickness: How the world's biggest pharmaceutical companies are turning us all into patients". Nation Books, New York, 2005.
- Merrill Goozner: The $800 million pill. [http://www.businessweek.com/magazine/content/04_16/b3879046_mz005.htm] University of California Press, Berkeley, 2004, 297 S. ISBN 0-520-23945-8.
- Marcia Angell: The truth about the drug companies. Random House, New York, 2004, 305 S. ISBN 0-375-50846-5.
- [http://www.amazon.com/exec/obidos/tg/detail/-/0195300041/qid=1129321038/sr=8-4/ref=pd_bbs_4/002-2335749-2056041?v=glance&s=books&n=507846 On The Take: How Medicine's Complicity With Big Business Can Endanger Your Health (Paperback)]
Drug discovery and development

- [http://www.amazon.com/exec/obidos/tg/detail/-/0849342112/qid=1129321513/sr=8-1/ref=pd_bbs_1/002-2335749-2056041?v=glance&s=books&n=507846 The Process of New Drug Discovery and Development (Hardcover)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/0471899801/qid=1129321513/sr=8-2/ref=pd_bbs_2/002-2335749-2056041?v=glance&s=books&n=507846 Drug Discovery : A History (Paperback)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/0415282888/qid=1129321513/sr=8-3/ref=pd_bbs_3/002-2335749-2056041?v=glance&s=books&n=507846 Textbook of Drug Design and Discovery, Third Edition (Paperback)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/3540423966/qid=1129321513/sr=8-8/ref=pd_bbs_8/002-2335749-2056041?v=glance&s=books&n=507846 Drug Discovery and Evaluation (Hardcover)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/0471213845/qid=1129321513/sr=8-9/ref=pd_bbs_9/002-2335749-2056041?v=glance&s=books&n=507846 Drug Discovery Handbook (Hardcover)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/0471601500/qid=1129321513/sr=8-4/ref=pd_bbs_4/002-2335749-2056041?v=glance&s=books&n=507846 Drugs-From Discovery to Approval (Hardcover)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/B000063N91/qid=1129321513/sr=8-7/ref=pd_bbs_7/002-2335749-2056041?v=glance&s=books&n=507846 Speeding Drug Discovery [DOWNLOAD: PDF]]
- [http://www.amazon.com/exec/obidos/tg/detail/-/B00006KC61/qid=1129321513/sr=8-10/ref=sr_8_xs_ap_i1_xgl153/002-2335749-2056041?v=glance&s=magazines&n=507846 Drug Discovery & Development [MAGAZINE SUBSCRIPTION]]
- [http://www.amazon.com/exec/obidos/tg/detail/-/B0009VL0MW/qid=1129321513/sr=8-11/ref=sr_8_xs_ap_i2_xgl229/002-2335749-2056041?v=glance&s=office-products&n=507846 Ethnomedicine and Drug Discovery]
- [http://www.amazon.com/exec/obidos/tg/detail/-/047146127X/qid=1129321513/sr=8-12/ref=sr_8_xs_ap_i3_xgl14/002-2335749-2056041?v=glance&s=books&n=507846 Integrated Strategies for Drug Discovery Using Mass Spectrometry (Hardcover)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/B000071FL0/qid=1129321513/sr=8-13/ref=sr_8_xs_ap_i4_xgl153/002-2335749-2056041?v=glance&s=magazines&n=507846 Drug Discovery Today [MAGAZINE SUBSCRIPTION]]
- [http://www.amazon.com/exec/obidos/tg/detail/-/B000071FFQ/qid=1129321513/sr=8-14/ref=sr_8_xs_ap_i5_xgl153/002-2335749-2056041?v=glance&s=magazines&n=507846 Current Opinion In Drug Discovery And Development [MAGAZINE SUBSCRIPTION]]
- [http://www.amazon.com/exec/obidos/tg/detail/-/1566769736/qid=1129321513/sr=8-18/ref=sr_8_xs_ap_i9_xgl14/002-2335749-2056041?v=glance&s=books&n=507846 Pharmacokinetics in Drug Discovery and Development (Hardcover)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/0471668273/qid=1129321513/sr=8-19/ref=sr_8_xs_ap_i10_xgl14/002-2335749-2056041?v=glance&s=books&n=507846 Antiviral Drug Discovery for Emerging Diseases and Bioterrorism Threats (Hardcover)]
Management, mergers, acquisitions, co-marketing deals

- [http://www.amazon.com/exec/obidos/tg/detail/-/0973467622/qid=1129321513/sr=8-5/ref=pd_bbs_5/002-2335749-2056041?v=glance&s=books&n=507846 Building Biotechnology: Starting, Managing, And Understanding Biotechnology Companies (Hardcover)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/186067464X/qid=1129322940/sr=1-1/ref=sr_1_1/002-2335749-2056041?v=glance&s=books Mergers and Acquisitions in Pharmaceuticals - Why and How? (Spiral-bound)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/1578515556/qid=1129322940/sr=1-3/ref=sr_1_3/002-2335749-2056041?v=glance&s=books Harvard Business Review on Mergers & Acquisitions (Paperback)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/B0001EYIPI/qid=1129323132/sr=1-1/ref=sr_1_1/002-2335749-2056041?v=glance&s=books Optimizing Promotional Alliances: Benchmarking Co-marketing and Co-promotion Strategies in the Pharmaceutical Industry [DOWNLOAD: PDF]]
- [http://www.amazon.com/exec/obidos/tg/detail/-/0333930983/qid=1129323132/sr=1-3/ref=sr_1_3/002-2335749-2056041?v=glance&s=books Brand Medicine : The Role of Branding in the Pharmaceutical Industry (Hardcover)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/0658000063/qid=1129323132/sr=1-6/ref=sr_1_6/002-2335749-2056041?v=glance&s=books The Co-Marketing Solution: Strategic Marketing Through Better Branding, Improved Trade Relationships, Superior Promotions, Effective Fact-Bases Selling, ... Analyses O (American Marketing Association) (Hardcover)]
Sales and marketing

- [http://www.amazon.com/exec/obidos/tg/detail/-/0970415362/qid=1129321038/sr=8-2/ref=pd_bbs_2/002-2335749-2056041?v=glance&s=books&n=507846 Insider's Guide to the World of Pharmaceutical Sales, Seventh Edition (Paperback)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/0595174183/ref=pd_sim_b_1/002-2335749-2056041?%5Fencoding=UTF8&v=glance Be Brief, Be Bright, Be Gone: Career Essentials for Pharmaceutical Representatives (Paperback)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/0972467513/ref=pd_sim_b_3/002-2335749-2056041?%5Fencoding=UTF8&v=glance PharmRepSelect-Your Complete Guide to Getting a Pharmaceutical Sales Job (Pharmrepselect, 1) (Paperback)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/0803993781/qid=1129323132/sr=1-4/ref=sr_1_4/002-2335749-2056041?v=glance&s=books The Rx Factor : Strategic Creativity in Pharmaceutical Marketing (Response Book) (Hardcover)]
- [http://www.amazon.com/exec/obidos/tg/detail/-/078901582X/qid=1129323132/sr=1-5/ref=sr_1_5/002-2335749-2056041?v=glance&s=books Pharmaceutical Marketing: Principles, Environment, and Practice (Hardcover)]
See also

- List of pharmaceutical companies or a [http://www.pharmacy.org/company.html better list]
- List of drugs
- Medicine
- Pharmaceutical marketing
- List of diseases for a huge list of 6000+ diseases, many very rare.
- Pharmaceuticals (China)
- Pharmaceuticals (India)
- Medicine (China)
- Traditional Chinese medicine
- Pharmacology
- Biotechnology
- Medicare Part D
- Medicare Prescription Drug, Improvement, and Modernization Act
- Food and Drug Administration
- Prescription drug prices in the United States
- National pharmaceuticals policy
- Chilean pharmaceutical policy
- Seneka Bibile
- Sri Lanka National Pharmaceuticals Policy
- State Pharmaceuticals Corporation of Sri Lanka
- clinical trial
- Protein structure prediction
- Drug design
- Rational drug design
- Bioinformatics
- Cheminformatics
- Biomedical informatics
- Orphan drug
- Physiologically-based pharmacokinetic modelling
- Big killers
- Complementary and alternative medicine
- Health profession
- Healthcare system
- Iatrogenesis (ill health caused by medical treatment)
- List of diseases
- List of medical abbreviations
- List of medical schools
- Important publications in medicine
- Medical equipment
- Rare diseases
External links

- [http://www.washingtonmonthly.com/features/2000/0005.pomper.html/ Drug Rush]
- [http://www.pharmexec.com/pharmexec/ Pharmaceutical Executive Magazine]
- [http://www.phrma.org/ Pharmaceutical Research and Manufacturers of America]
- [http://www.ppdi.com/corporate/faq/about_drug_development/home.htm PPD]
- [http://www.pharmalive.com/ PharmaLive]
- [http://www.micromedex.com/products/drugknowledge/drugknowledge_costjust.pdf Cost Justification: Pharmaceutical]
- [http://www.chemlin.de/chemistry/drug_design.htm WWW-Information resources: Drug Discovery]
- [http://www.ich.org ICH Website]
- [http://www.fda.gov/ FDA Website]
- [http://www.nofreelunch.org No Free Lunch]
- Category:Biotechnology category:pharmacology category:pharmacy category:Clinical research category:Pharmaceutical industry Category:Industries Category:Pharmaceuticals Policy

Medication
A medication is a licenced drug taken to cure or reduce symptoms of an illness or medical condition. Medications are generally divided into two groups -- over the counter (OTC) medications, which are available in pharmacies and supermarkets without special restrictions, and Prescription only medicines (POM), which must be prescribed by a physician. Most OTC medication is generally considered to be safe enough that most persons will not hurt themselves accidentally by taking it as instructed. Many countries, such as the UK have a third category of pharmacy medicines which can only be sold in registered pharmacies, by or under the supervision of a pharmacist. However, the precise distinction between OTC and prescription depends on the legal jurisdiction. Medications are typically produced by pharmaceutical companies and are often patented. Those that are not patented are called generic drugs.
Some common medications

- Anti-diabetic drugs
- Asthma medication
- Cough medicine
- Diarrhea relief medicine (such as Loperamide)
- Nasal spray (such as Xylometazoline)
- Anti-Inflammatory Medications
- Anti-Pyretic Medications
- Gastrointestinal Medications
- Psychiatric Medications
- Hair Medications
See also

- Pharmacology
- Herbology
- Herbalism
External links

- [http://www.rxlist.com Medication list or vademecum]
- [http://www.theacpa.org/ American Chronic Pain Association (ACPA)]
- [http://www.fda.gov/cder/drug/DrugSafety/DrugIndex.htm Consumer drug information from the FDA]
- [http://www.dmoz.org/Health/Medicine/ Medicinal directory] Category:Pharmacology als:Medikament th:ยา

Biopharmaceutical

Biopharmaceuticals are medical drugs (see pharmacology) produced by biotechnology. The first such substance approved for therapeutic use was recombinant insulin in 1982. ---- The term biopharmacology also describes a field of research closely related to pharmacokinetics. Category:Pharmacology Category:Pharmaceutical industry

Medication

A medication is a licenced drug taken to cure or reduce symptoms of an illness or medical condition. Medications are generally divided into two groups -- over the counter (OTC) medications, which are available in pharmacies and supermarkets without special restrictions, and Prescription only medicines (POM), which must be prescribed by a physician. Most OTC medication is generally considered to be safe enough that most persons will not hurt themselves accidentally by taking it as instructed. Many countries, such as the UK have a third category of pharmacy medicines which can only be sold in registered pharmacies, by or under the supervision of a pharmacist. However, the precise distinction between OTC and prescription depends on the legal jurisdiction. Medications are typically produced by pharmaceutical companies and are often patented. Those that are not patented are called generic drugs.

Some common medications

- Anti-diabetic drugs
- Asthma medication
- Cough medicine
- Diarrhea relief medicine (such as Loperamide)
- Nasal spray (such as Xylometazoline)
- Anti-Inflammatory Medications
- Anti-Pyretic Medications
- Gastrointestinal Medications
- Psychiatric Medications
- Hair Medications

External links

- [http://www.rxlist.com Medication list or vademecum]
- [http://www.theacpa.org/ American Chronic Pain Association (ACPA)]
- [http://www.fda.gov/cder/drug/DrugSafety/DrugIndex.htm Consumer drug information from the FDA]
- [http://www.dmoz.org/Health/Medicine/ Medicinal directory] Category:Pharmacology als:Medikament th:ยา

Serendipity

Serendipity is finding something unexpected and useful while searching for something else entirely. For instance, the discovery of the antibacterial properties of penicillin by Alexander Fleming is often said to have been serendipitous, because he was merely cleaning up his laboratory when he discovered that the Penicillium mold had contaminated one of his old experiments (it should be realized, however, that Fleming had been researching common substances for several years in the hopes of discovering antibacterial properties, and thus was prepared to understand what he was seeing). The word was coined by Horace Walpole in 1754, from the Persian fairy tale The Three Princes of Serendip. (Serendip is an old Persian name for Sri Lanka.) The episode in the story involves a case of spectacular abductive reasoning (as used by Sherlock Holmes), which later leads to unsought "serendipitous" rewards from the king. Serendipity is used as a sociological method in Anselm L. Strauss' and Barney G. Glasers Grounded Theory, building on ideas by sociologist Robert K. Merton, who in Social Theory and Social Structure (1949) claimed that serendipity was an Indian concept. This word has been voted as one of the ten English words that were hardest to translate in June 2004 by a British translation company. However, due to its sociological use, the word has been imported into many other languages (Portuguese serendipicidade or serendipidade; French sérendipicité or sérendipité; Spanish serendipia; Italian serendipità; Dutch serendipiteit).

Serendipitous discoveries and inventions

- Alexander Fleming's discovery of penicillin
- The discovery of the cosmic microwave background radiation
- Alfred Nobel's discovery of blasting gelatin
- The discovery of polyethylene
- The invention of Silly Putty
- The invention of Post-it notes
- The discovery of the psychedelic effects of LSD by Dr. Albert Hofmann

Origin of the term

The fairy tale The Three Princes of Serendip is based upon the life of Persian king Bahram Gur who ruled the Sasanian Empire from ca. 420-440 AD. Stories of his rule are told in epic poetry of the region (Firdausi's Shahnameh 1010 AD, Nizami's Haft Paykar 1197 AD, Khusrau's Hasht Bihisht 1302 AD), parts of which are based upon historical facts with embellishments derived from folklore going back hundreds of years to oral traditions in India and The Book of One Thousand and One Nights. With the exception of the well-known camel story, English translations are very hard to come by. In the camel story, the Three Princes use trace clues to precisely identify a camel they have never seen (lame; blind in one eye; missing a tooth; carrying a pregnant maiden; bearing honey on one side and butter on the other). This result of abductive reasoning is not what is meant by serendipity (the discovery of something NOT sought). Because of their cleverness and sagacity, they are accused of stealing the camel and are about to be put to death by Bahram Gur. Suddenly and without anyone seeking him out, a traveler steps forward to say that he has just seen the missing camel wandering in the desert. Bahram spares the lives of the Three Princes, lavishes them with rich rewards and appoints them as advisors. These rewards are the unsought (serendipitous) results of their sagacious insights. There are other examples of the Princes receiving unsought rewards (marriage to a beautiful princess, kingdoms, wealth, etc.) from their accidental discoveries. The fact that they can make clever or accidental discoveries and breakthroughs is a result of their intelligence, wisdom and reasoning. The unsought rewards come later. Thus, stumbling upon a captive slave girl in a forest is a serendipitous occurrence. Deducing that the slave girl they rescued is actually a Princess is not the serendipitous moment – rather, this occurs later when they receive lavish gifts as a reward. More contemporaneously, because we put great value on scientific breakthroughs and insights themselves (e.g., the waxy polymer residue (Teflon) in an uncooperative gas cylinder), these are considered to be the unsought serendipitous rewards of clever reasoning, hard work and luck.

Related terms

William Boyd coined the term zemblanity to mean somewhat the opposite of serendipity: "making unhappy, unlucky and expected discoveries occurring by design". It derives from Novaya Zemlya (or Nova Zembi), a cold, barren land with many features opposite to the lush Sri Lanka (Serendip). Bahramdipity is derived directly from Bahram Gur as characterized in the "Three Princes of Serendip". It describes the suppression of serendipitous discoveries or research results by powerful individuals.

Bibliography

- Robert K. Merton, Elinor Barber: The Travels and Adventures of Serendipity : A Study in Sociological Semantics and the Sociology of Science. Princeton University Press, 2003. ISBN 0691117543.
- Royston M. Roberts: Serendipity: Accidental Discoveries in Science. Wiley, 1989. ISBN 0471602035
- Pek Van Andel: "Anatomy of the unsought finding : serendipity: origin, history, domains, traditions, appearances, patterns and programmability." British Journal for the Philosophy of Science, 1994, 45(2), 631-648.

References

# Boyd, William. Armadillo, Chapter 12, Knopf, New York, 1998. ISBN 0375402233 # #
- Sommer, Toby J. "'Bahramdipity' and Scientific Research", The Scientist, 1999, 13(3), 13. http://www.the-scientist.com/yr1999/feb/opin_990201.html #
- Sommer, Toby J. "Bahramdipity and Nulltiple Scientific Discoveries," Science and Engineering Ethics, 2001, 7(1), 77-104. (Free download) http://www.uow.edu.au/arts/sts/bmartin/dissent/documents/Sommer.pdf

External links

- [http://www.thebakken.org/education/SciMathMN/polymers-serendipity/polymer1.htm Polymers & Serendipity: Case Studies] -- rayon, nylon, and more examples in chemistry
- [http://max.ipv.pt Max] - A software agent built to induce serendipity.
- [http://livingheritage.org/three_princes.htm The Three Princes of Serendip] – one version of the story.
- [http://serendip.brynmawr.edu Serendip] - a website continually evolving using the principles of serendipity ko:세렌디피티 ja:セレンディピティ Category:Epistemology

Disease

A disease is any abnormal condition of the body or mind that causes discomfort, dysfunction, or distress to the person affected or those in contact with the person. Sometimes the term is used broadly to include injuries, disabilities, syndromes, symptoms, deviant behaviors, and atypical variations of structure and function, while in other contexts these may be considered distinguishable categories. Pathology is the study of diseases. The subject of systematic classification of diseases is referred to as nosology. The broader body of knowledge about diseases and their treatments is medicine.

Syndromes, illness and disease

Medical usage sometimes distinguishes a disease, which has a known specific cause or causes (called its etiology), from a syndrome, which is a collection of signs or symptoms that occur together. However, many conditions have been identified, yet continue to be referred to as "syndromes". Furthermore, numerous conditions of unknown etiology are referred to as "diseases" in many contexts. Illness, although often used to mean disease, can also refer to a person's perception of their health, regardless of whether they in fact have a disease. A person without any disease may feel unhealthy and believe he has an illness. Another person may feel healthy and believe he does not have an illness even though he may have a disease such as dangerously high blood pressure which may lead to a fatal heart attack or stroke.

Transmission of disease

Some diseases, such as influenza, are contagious or infectious, and can be transmitted by any of a variety of mechanisms, including droplets from coughs and sneezes, by bites of insects or other vectors, from contaminated water or food, etc. Other diseases, such as cancer and heart disease are not considered to be due to infection, although micro-organisms may play a role.

Social significance of disease

The identification of a condition as a disease, rather than as simply a variation of human structure or function, can have significant social or economic implications. The controversial recognitions as diseases of post-traumatic stress disorder, also known as "shell shock"; repetitive motion injury or repetitive stress injury (RSI); and Gulf War syndrome has had a number of positive and negative effects on the financial and other responsibilities of governments, corporations and institutions towards individuals, as well as on the individuals themselves. The social implication of viewing aging as a disease could be profound, though this classification is not yet widespread. A condition may be considered to be a disease in some cultures or eras but not in others. Oppositional-defiant disorder, attention-deficit hyperactivity disorder, and, increasingly, obesity are conditions considered to be diseases in the United States and Canada today, but were not so-considered decades ago and are not so-considered in some other countries. Conversely, the number of people in the West who consider homosexuality to be a disease became widespread in the 20th century but has been decreasing in the last two decades. To consider a condition to be a disease can sometimes involve a negative social value judgement. Lepers were a group of afflicted individuals who were historically shunned and the term "leper" still evokes social stigma. Fear of disease can still be a widespread social phenomena, though not all diseases evoke extreme social stigma.

Other uses of the term

In biology, disease refers to any abnormal condition of an organism that impairs function. The term disease is often used metaphorically for disordered, dysfunctional, or distressing conditions of other things, as in disease of society.

External links

- [http://www.nlm.nih.gov/medlineplus/healthtopics.html Health Topics], MedlinePlus descriptions of most diseases, with access to current research articles.
- [http://www.cdc.gov/health/default.htm Center for Disease Control Health Topics A-Z], fact sheets about many common diseases
- [http://rarediseases.about.com/ Rare/Orphan Diseases]
- [http://www.national-health.org/rarediseases/ National Organization for Rare Disorders] Extensive, useful information on rare diseases.
- [http://www.merck.com/pubs/mmanual/sections.htm The Merck Manual], detailed description of most diseases, freely searchable online. Category:Diseases Category:Medical terms als:Krankheit zh-min-nan:Pīⁿ ms:Penyakit ja:病気 simple:Disease th:โรค

Molecular biology

Molecular biology is the study of biology at a molecular level. The field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry. Molecular biology chiefly concerns itself with understanding the interactions between the various systems of a cell, including the interrelationship of DNA, RNA and protein synthesis and learning how these interactions are regulated. Writing in Nature, William Astbury described molecular biology as:

"... not so much a technique as an approach, an approach from the viewpoint of the so-called basic sciences with the leading idea of searching below the large-scale manifestations of classical biology for the corresponding molecular plan. It is concerned particularly with the forms of biological molecules and ..... is predominantly three-dimensional and structural - which does not mean, however, that it is merely a refinement of morphology - it must at the same time inquire into genesis and function"

Relationship to other "molecular-scale" biological sciences

William Astbury Researchers in molecular biology use specific techniques native to molecular biology (see Techniques section later in article), but increasingly combine these with techniques and ideas from genetics, biochemistry and biophysics. There is not a hard-line between these disciplines as there once was. The following figure is a schematic that depicts one possible view of the relationship between the fields:
- Biochemistry is the study of the chemical substances and vital processes occurring in living organisms.
- Genetics is the study of the effect of genetic differences on organisms. Often this can be inferred by the absence of a normal component (e.g. one gene). The study of "mutants" – organisms which lack one or more functional components with respect to the so-called "wild type" or normal phenotype. Genetic interactions such as epistasis can often confound simple interpretations of such "knock-out" studies.
- Molecular biology is the study of molecular underpinnings of the process of replication, transcription and translation of the genetic material. The central dogma of molecular biology where genetic material is transcribed into RNA and then translated into protein, despite being an oversimplified picture of molecular biology, still provides a good starting point for understanding the field. This picture, however, is undergoing revision in light of emerging novel roles for RNA. Much of the work in molecular biology is quantitative, and recently much work has been done at the interface of molecular biology and computer science in bioinformatics and computational biology. As of the early 2000s, the study of gene structure and function, molecular genetics, has been amongst the most prominent sub-field of molecular biology. Increasingly many other fields of biology focus on molecules, either directly studying their interactions in their own right such as in cell biology and developmental biology, or indirectly, where the techniques of molecular biology are used to infer historical attributes of populations or species, as in fields in evolutionary biology such as population genetics and phylogenetics. There is also a long tradition of studying biomolecules "from the ground up" in biophysics.

Techniques of molecular biology

Since the late 1950s and early 1960s, molecular biologists have learned to characterise, isolate, and manipulate the molecular components of cells and organisms. These components include DNA, the repository of genetic information; RNA, a close relative of DNA whose functions range from serving as a temporary working copy of DNA to actual structural and enzymatic functions as well as a functional and structural part of the translational apparatus; and proteins, the major structural and enzymatic type of molecule in cells.

Expression cloning

One of the most basic techniques of molecular biology to study protein function is expression cloning. In this technique, DNA coding for a protein of interest is cloned (using PCR and/or restriction enzymes) into a plasmid (known as an expression vector). This plasmid may have special promoter elements to drive production of the protein of interest, and may also have antibiotic resistance markers to help follow the plasmid. This plasmid can be inserted into either bacterial or animal cells. Introducing DNA into bacterial cells is called transformation, and can be completed with several methods, including electroporation, microinjection, passive uptake and conjugation. Introducing DNA into eukaryotic cells, such as animal cells, is called transfection. Several different transfection techniques are available, including calcium phosphate transfection, liposome transfection, and proprietary transfection reagents such as Fugene. DNA can also be introduced into cells using viruses or pathenogenic bacteria as carriers. In such cases, the technique is called viral/bacterial transduction, and the cells are said to be transduced. In either case, DNA coding for a protein of interest is now inside a cell, and the protein can now be expressed. A variety of systems, such as inducible promoters and specific cell-signaling factors, are available to help express the protein of interest at high levels. Large quantities of a protein can then be extracted from the bacterial or eukaryotic cell. The protein can be tested for enzymatic activity under a variety of situations, the protein may be crystallized so its tertiary structure can be studied, or, in the pharmaceutical industry, the activity of new drugs against the protein can be studied.

Polymerase chain reaction (PCR)

Main article: Polymerase chain reaction The polymerase chain reaction is an extremely versatile technique for copying DNA. In brief, PCR allows a single DNA sequence to be copied (millions of times), or altered in predetermined ways. For example, PCR can be used to introduce restriction enzyme sites, or to mutate (change) particular bases of DNA. PCR can also be used to determine whether a particular DNA fragment is found in a cDNA library.

Gel electrophoresis

Main article: Gel electrophoresis Gel electrophoresis is one of the principal tools of molecular biology. The basic principle is that DNA, RNA, and proteins can all be separated using an electric field. In agarose gel electrophoresis, DNA and RNA can be separated based on size by running the DNA through an agarose gel. Proteins can be separated based on size using an SDS-PAGE gel. Proteins can also be separated based on their electric charge, using what is known as an isoelectric gel...

Southern blotting

Main article: Southern blot The Southern blot is a technique employed to ascertain information about the molecular weight and relative amount of a DNA sequence of interest. The assay was first developed by Edwin Southern and is a combination of gel electrophoresis of DNA (often first fragmented by restriction_enzyme digestion), transfer of the same to a charged membrane, and hybridization of a labeled DNA probe. Following hybridization, the membrane is washed to remove unbound probe, and an image obtained via autoradiography or using equipment such as a phosphoimager. The image will indicate the location(s) to which the probe hybridized, with the intensity of the signal observed serving as a measure of relative abundance.

Northern blotting

Main article: Northern blot The Northern blot is used to study the expression patterns a specific type of RNA molecule as relative comparison among of a set of different samples of RNA. It is essentially a combination of denaturing RNA gel electrophoresis, and a blot. In this process RNA is separated based on size and is then transferred to a membrane that is then probed with a labeled complement of a sequence of interest. The results may be visualized through a variety of ways depending on the label used, however, most result in the revelation of bands representing the sized of the RNA detected in sample. The intensity of these bands is related to the amount of the target RNA in the samples analyzed. The procedure is commonly used to study when and how much gene expressing is occurring by measuring how much of that RNA is present in different samples. It is one of the most basic tools for determing at what time certain genes are expressed in living tissues.

Western blotting and immunochemistry

Main article: Western blot Antibodies to most proteins can be created by injecting small amounts of the protein into an animal such as a mouse, rabbit, sheep, or donkey. These antibodies can be used for a variety of analytical and preprative techniques. In Western blotting, proteins are first separated by size, in a thin gel sandwiched between two glass plates. This technique is called SDS-PAGE (for Sodium Dodecyl Sulfate Poly-Acrylamide Gel Electrophoresis). The proteins in the gel are then transferred to a PVDF, nitrocellulose, nylon or other support membrane. This membrane can then be probed with solutions of antibodies. Antibodies that specifically bind to the protein of interest can then be visualized by a variety of techniques, including chemoluminescence or radioactivity. Antibodies can also be used to purify proteins. Antibodies to a protein are generated and are often then coupled to "beads". After the antibody has bound to the protein of interest, this antibody-protein complex can be separated from all other proteins by centrifugation. During centrifugation, the beads, to which the antibody is coupled, will pellet (bringing the protein of interest down with it) whereas all other proteins will remain in the solution. Alternatively, antibodies coupled to a solid support matrix like Sephadex or Sepharose beads, for example, can be used to remove a protein of interest from a complex solution. After washing unbound and non-specifically bound materials away from the "beads", the protein of interest is then eluted from the matrix, usually by adding a solution with a high salt concentration, or by varying the pH of the solution in which the matrix is contained. The beads can either be suspended in solution (batch processing) or packed into a tube (column processing).

History

Molecular biology was established in the 1930s, the term was first coined by Warren Weaver in 1938 however. Warren was director of Natural Sciences for the Rockefeller Foundation at the time and believed that biology was about to undergo a period of significant change given recent advances in fields such as X-ray crystallography. He therefore channeled significant amounts of (Rockefeller Institute) money into biological fields.

References

- Cohen, S.N., Chang, A.C.Y., Boyer, H. & Heling, R.B. Construction of biologically functional bacterial plasmids in vitro. Proc. Natl. Acad. Sci. USA 70, 3240 – 3244 (1973).
- Rodgers, M. The Pandora's box congress. Rolling Stone 189, 37 – 77 (1975).
- ko:분자생물학 ms:Biologi skala molekul ja:分子生物学 th:อณูชีววิทยา

Drug development

Drug Development or Preclinical Development is defined in many pharmaceutical companies as the process of taking a new chemical lead through the stages necessary to allow it to be tested in human clinical trials, although a broader definition would encompass the entire process of drug discovery and clinical testing of novel drug candidates. Novel chemical entities (NCEs) are compounds which emerge from the process of drug discovery. These will have promising activity against a particular biological target thought to be important in disease, however little will be known about the safety, toxicity, pharmacokinetics and metabolism of this NCE in man. 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 make a recommendation of the dose and schedule to be used the first time an NCE is used in a human clinical trial ("First-in-Man", FIM). In addition, drug development is required to establish the physicochemical properties of the NCE: its chemical makeup, stability, solubility. The process by which the chemical is made will be optimised so that from being made at the bench on a milligram scale by a synthetic chemist, it can be manufactured on the kilogram and then on the ton scale. It will be further examined for its suitability to be made into capsules, tablets or intravenous formulations. Together these processes are known in preclinical development as CMC: Chemistry, Manufacturing and Control. Many aspects of drug development are focussed on satisfying the regulatory requirements of drug licensing authorities. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in man. 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 (eg. the skin if the new drug is to be delivered through the skin). While, increasingly, these tests can be made using in vitro methods (eg. with isolated cells), many tests can only be made by using experimental animals, since it is only in an intact organism that the complex interplay of metabolism and drug exposure on toxicity can be examined. The use of animals for this purpose is considered controversial in many countries (see Animal rights and Animal welfare). The process of drug development does not stop once an NCE begins human clinical trials. In addition to the tests required to move a novel drug into the clinic for the first time it is also important to ensure that long-term or chronic toxicities are determined, as well as effects on systems not previously monitored (fertility, reproduction, immune system, etc). The compound will also be tested for its ability to cause cancer (carcinogenicity testing). If a compound emerges from these tests with an acceptable toxicity and safety profile, and it can further be demonstrated to have the desired effect in clinical trials, then it can be submitted for marketing approval in the various countries where it will be sold. In the US, this process is called a New Drug Application or NDA. Most NCEs, however, will fail during drug development, either because they have some unacceptable toxicity, or because they simply do not work in clinical trials.

Approved drugs

In the United States, the FDA approves prescription drugs. Before a drug can be prescribed, it must undergo an extensive FDA approval process. This process involves first testing the drug on animals or in medical labs. If found to be safe by the FDA and approved for the next phase of study, the drug is then tested for safety and effectiveness in humans (clinical trials). The drug manufacturer then files a New Drug Application to the FDA, which reviews the application and either approves or rejects it. The U.S. and Canadian systems of new drug approvals are perhaps the most rigorous in the world. On average, it costs a company $359 million to get one new medicine from the laboratory to the pharmacist's shelf, according to a February 1993 report by the Congressional Office of Technology Assessment. It takes 12 years on average for an experimental drug to travel from lab to medicine chest. Only five in 5,000 compounds that enter preclinical testing make it to human testing. One of these five tested in people is approved.

External links

- [http://www.clinicaltrials.gov/ ClinicalTrials.gov] from US National Library of Medicine
- [http://www.ich.org ICH Website]
- [http://www.fda.gov/ FDA Website]
- [http://www.kriger.com/training/index.htm Clinical Research Training]
- [http://www.biorole.com/ Careers in Clinical Research]
- [http://www.clinqua.com/ Clinical Research Services]
- [http://www.ibpassociation.com Clinical Research Companies Listings]
- [http://www.kriger.com/ International Clinical Research Services and Corporate Trainings]
- [http://www.krctraining.com/ACRONYMS/index.htm Clinical Research Abbreviations and Acronyms]
- [http://www.krctraining.com/CRA%20Definitions/index.htm Clinical Research Glossary / Definitions]
- [http://www.kriger.com/international_modules/index.htm List of Food and Drugs Regulatory Agencies]
- [http://www.krctraining.com/faq/faq.htm Clinical Research: Frequently asked questions] category:clinical research Category:Pharmaceutical industry

Pre-clinical development

Pre-clinical development is a period in development when activities that need to be performed and results to be obtained before a clinical trial in humans can begin. Typically, both in vitro and in vivo tests will be performed. Areas covered are pharmacology, toxicology, toxokinetics, dose-response studies, genotoxicity, reproductive toxicity and, at a later stage, carcinogenicity studies. These areas are agreed on by the ICH and implemented by the three ICH parties, i.e. Europe, Japan and the US, as their national law. There is much misinformation about the use of animals in preclinical testing of new drug candidates. Animal testing in the research-based pharmaceutical industry has been reduced in recent years both for cost reasons and in response to protests by animal rights groups. Typically animal testing involves 2 species (often rodent and dog) to determine the absorption, distribution, metabolism, and excretion of the drug. This information is necessary so that safe human testing can commence. Category:Pharmaceutical industry

Clinical trial

In medicine, a clinical trial (synonyms: clinical studies, research protocols, medical research) is a research study.

Types of clinical trials

The most commonly performed clinical trials evaluate new drugs, medical devices, biologics, or other interventions to patients in strictly scientifically controlled settings, and are required for Food and Drug Administration approval of new therapies. Trials may be designed to assess the safety and efficacy of an experimental therapy, to assess whether the new intervention is better than standard therapy, or to compare the efficacy of two standard or marketed interventions. To be ethical, they must involve the full and informed consent of participating human subjects. They are closely supervised by appropriate regulatory authorities. All interventional studies must be approved by an ethics committee before permission is granted to run the trial. The study design that provides the most compelling evidence of a causal relationship between the treatment and the effect, is the randomized controlled trial. Studies in epidemiology such as the cohort study and the case-control study are clinical studies in that they involve human participants, but provide less compelling evidence than the randomized controlled trial. The major difference between clinical trials and epidemiological studies is that, in clinical trials, the investigators manipulate the administration of a new intervention and measure the effect of that manipulation, whereas epidemiological studies only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. Currently some Phase II and most Phase III drug trials are designed to be randomized, double-blind, and placebo-controlled. This means that each study subject is randomly assigned to receive one of the treatments, which might be the placebo. Neither the subjects nor scientists involved in the study know which study treatment is being administered to any given subject; and, in particular, none of those involved in the study know which subjects are being administered a placebo. Of note, during the last ten years or so it has become a common practice to conduct "active comparator" trials - in other words, when a treatment exists that is clearly better than doing nothing (i.e. the placebo) for the subject, the alternate treatment would be a standard-of-care therapy. While the term clinical trials is most commonly associated with large randomized studies, many clinical trials are small. They may be initiated by single physicians or a small group of physicians, and are designed to test simple questions. Other clinical trials require large numbers of participants followed over long periods of time. It is sometimes necessary to organize multicentre clinical trials. Often the centres taking part in such trials are in different countries (in which case they may be termed international clinical trials). The number of patients enrolled in the study also has a large bearing on the ability of the trial to reliably detect an effect of a treatment. This is described as the "power" of the trial. It is usually expressed as the probability that, if the treatments differ in their effect on the outcome of interest, the statistical analysis of the trial data will detect that difference. The larger the sample size or number of participants, the greater the statistical power. However, in designing a clinical trial, this consideration must be balanced with the greater costs associated with larger studies. The power of a trial is not a single, unique value; it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated and control groups. For example, of a lipid lowering drug with 100 patients per group, might have a power of .90 to detect a difference between active and placebo of 10 mg/dL or more, but only have a power of .70 to detect a difference of 5 mg/dL.

Phases

Drug clinical trials are commonly classified into four phases, and the drug-development process will normally proceed through all four stages over many years. If the drug successfully passes through the first three phases, it will usually be successfully approved for use in the general population. Before embarking on costly clinical trials, pharmaceutical companies will perform pre-clinical development to ensure that their investment is wise.

Phase I

Phase I trials are the first-stage of testing in human subjects. Normally a small (20-80) group of healthy volunteers will be selected. This phase includes trials designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a therapy. These trials are almost always conducted in an inpatient clinic, where the subject can be observed by full-time medical staff. The subject is usually observed until several half-lives of the drug have passed. Phase I trials also normally include dose-ranging studies such that doses for clinical use can be refined. The tested range of doses will usually be a small fraction of the dose that causes harm in animal testing. Phase I trials most often include healthy subjects. Other groups commonly tested include subjects who are renally or hepatically impaired. Phase I trials of new cancer drugs are a little different. These studies are ususally carried out in patients with advanced (metastatic) cancer. These trials are usually offered to patients who have had other types of therapy and who have few other treatment choices. There are two specific kinds of Phase I trials - SAD studies, and MAD studies. SAD - Single Ascending Dose studies are those in which groups of three or six patients are given a small dose of the drug and observed for a specific period of time. If they do not exhibit any adverse side effects, a new group of patients is then given a higher dose. This is continued until intolerable side effects start showing up, at which point the drug is said to have reached the Maximum tolerated dose (MTD). MAD - Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics/pharmacodynamics of the drug. In these studies, a group of patients receives a low dose of the drug and the dose is subsequently escalated upto a predetermined level. Samples (of blood, and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body.

Phase II

Once the initial safety of the therapy has been confirmed in Phase I trials, Phase II trials are performed on larger groups (100-300) and are designed to assess clinical efficacy of the therapy; as well as to continue Phase I assessments in a larger group of volunteers and patients. The development process for a new drug commonly fails during Phase II trials due to the discovery of poor efficacy or toxic effects.

Phase III

Phase III studies are large double-blind randomized controlled trials on large patient groups (1000-3000 or more) and are aimed at being the definitive assessment of the efficacy of the new therapy, especially in comparison with currently available alternatives. Phase III trials are the most expensive, time-consuming and difficult trials to design and run; especially in therapies for chronic conditions. Once a drug has proven satisfactory over Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to various regulatory authorities in different countries (such as the Therapeutic Goods Administration (TGA) in Australia, the European Medicines Agency (EMEA) or the Food and Drug Administration (FDA) in the United States) for marketing approval.

Phase IV

Phase IV trials involve the post-launch safety surveillance and ongoing technical support of a drug. Phase IV studies may be mandated by regulatory authorities or may be undertaken by the sponsoring company for competitive or other reasons. Post-launch safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and timescale than was possible during the initial clinical trials. Such adverse effects detected by Phase IV trials may result in the withdrawal or restriction of a drug - recent examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).

References

- Rang HP, Dale MM, Ritter JM, Moore PK (2003). Pharmacology 5 ed. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4
- Finn R, (1999). "Cancer Clinical Trials: Experimental Treatments and How They Can Help You." Sebastopol: O'Reilly & Associates. ISBN 1-56592-566-1

External links

- [http://www.cancer.gov/clinicaltrials/learning/what-is-a-clinical-trial What is a Clinical Trial?] from National Cancer Institute, US National Institutes of Health
- [http://www.clinicaltrials.gov/ ClinicalTrials.gov] from US National Library of Medicine
- [http://www.centerwatch.com/ Thomson CenterWatch] Industry Sponsored Clinical Trial Listings
- [http://www.cochrane.org/ The Cochrane collaboration]
- [http://www.globalizationandhealth.com/content/1/1/11 Can context justify an ethical double standard for clinical research in developing countries?] category:experimental design category:pharmacology category:clinical research Category:Pharmaceutical industry ja:治験

Randomized controlled trial

A randomized controlled trial (RCT) is a form of clinical trial, or scientific procedure used in the testing of the efficacy of medicines or medical procedures. It is widely considered the most reliable form of scientific evidence because it is the best known design for eliminating the variety of biases that regularly compromise the validity of medical research. Sellers of medicines throughout the ages have had to convince their patients that the medicine works. As science has progressed, public expectations have risen, and government health budgets have become ever tighter, pressure has grown for a reliable system to do this. Moreover, the public's concern for the dangers of medical interventions has spurred both legislators and administrators to provide an evidential basis for licensing or paying for new procedures and medications. In most modern health-care systems all new medicines and surgical procedures therefore have to undergo trials before being approved. Trials are used to establish average efficacy of a treatment as well as learn about its most frequently occurring side-effects. This is meant to address the following concerns. First, effects of a treatment may be small and therefore undetectable except when studied systematically on a large population. Second, biological organisms (including humans) are complex, and do not react to the same stimulus in the same way, which makes inference from single clinical reports very unreliable and generally unacceptable as scientific evidence. Third, some conditions will spontaneously go into remission, with many extant reports of miraculous cures for no discernible reason. Finally, it is well-known and has been proven that the simple process of administering the treatment may have direct psychological effects on the patient, sometimes very powerful, what is known as the placebo effect.

Types of trials

Randomized trials are employed to test efficacy while avoiding these factors. Trials may be open, blind or double-blind.

Open trial

In an open trial, the researcher knows the full details of the treatment, and so does the patient. These trials are open to challenge for bias, and they do nothing to reduce the placebo effect. However, sometimes they are unavoidable, particularly in relation to surgical techniques, where it may not be possible or ethical to hide from the patient which treatment he or she received.

Blind trials

Single-blind trial

In a single-blind trial, the researcher knows the details of the treatment but the patient does not. Because the patient does not know which treatment is being administered (the new treatment or another treatment) there should be no placebo effect. In practice, since the researcher knows, it is possible for them to treat the patient differently or to subconsciously hint to the patient important treatment-related details, thus influencing the outcome of the study.

Double-blind trial

In a double-blind trial, one researcher allocates a series of numbers to 'new treatment' or 'old treatment'. The second researcher is told the numbers, but not what they have been allocated to. Since the second researcher does not know, they cannot possibly tell the patient, directly or otherwise, and cannot give in to patient pressure to give them the new treatment. In this system, there is also often a more realistic distribution of sexes and ages of patients. Therefore double-blind (or randomized) trials are preferred, as they tend to give the most accurate results.

Triple-blind trial

Some randomized controlled trials are considered triple-blinded, although the meaning of this may vary according to the exact study design. The most common meaning is that the subject, researcher and person administering the treatment (often a pharmacist) are blinded to what is being given. Alternately, it may mean that the patient, researcher and statistician are blinded. These additional precautions are often in place with the more commonly accepted term "double blind trials", and thus the term "triple-blinded" is infrequently used. However, it connotes an additional layer of security to prevent undue influence of study results by anyone directly involved with the study.

Controlled aspect

The 'controlled' aspect comes from three main sources. The first is another member of the research team, who will typically review the test to try to remove any factors which might skew the results. For example, it is important to have a test group which is reasonably balanced for ages and sexes of the subjects (unless this is a treatment which will never be used on a particular sex or age group). The second source of control is inherent in having a 'control' group, that is, a group which is undergoing the same routine (seeing a doctor, taking pills at the same time, etc.) but is not receiving the same treatment. This control group will be receiving either no treatment (e.g., sugar pills) or will be receiving the current standard treatment (if, for example, it would be unethical not to treat their ailment at all). The third source of control is via peer review and/or review by government regulators, who will examine the trial when it is presented for publication or when the drug manufacturer applies for a licence for the drug. The importance of having a control group cannot be overstated. Merely being told that one is receiving a miraculous cure can be enough to cure a patient—even if the pill contains nothing more than sugar. Additionally, the procedure itself can produce ill effects. For example, in one study on rabbits where these subjects were receiving daily injections of a drug, it was found that they were developing cancer. If this was a result of the treatment, it would obviously be unsuitable for testing in humans. Because this result was reflected equally between the control and test groups, the source of the problem was investigated and it was shown in this case that the administration of daily injections was the cancer risk—not the drug itself. The analysis of the trial results is a great skill in itself, and pharmaceutical firms employ groups of statisticians to try to make sense of the data. Likewise, regulators pay keen attention to the statistics, which can be used to hide serious deficiencies in the effectiveness of a treatment.

Difficulties

A major difficulty in dealing with trial results comes from commercial, political and/or academic pressure. Most trials are expensive to run, and will be the result of significant previous research, which is itself not cheap. There may be a political issue at stake (compare MMR vaccine) or vested interests (compare homeopathy). In such cases there is great pressure to interpret results in a way which suits the viewer, and great care must be taken by researchers to maintain emphasis on clinical facts. Most studies start with a 'null hypothesis' which is being tested (usually along the lines of 'Our new treatment x cures as many patients as existing treatment y) and an alternative hypothesis (x cures more patients than y). The analysis at the end will give a statistical likelihood, based on the facts, of whether the null hypothesis can be safely rejected (saying that the new treatment does, in fact, result in more cures). Nevertheless this is only a statistical likelihood, so false negatives and false positives are possible. These are generally set an acceptable level (e.g., 1% chance that it was a false result). However, this risk is cumulative, so if 200 trials are done (often the case for contentious matters) about 2 will show contrary results. There is a tendency for these two to be seized on by those who need that proof for their point of view.
See also

- randomization
- medicine
- hypothesis testing
- statistical inference
- evidence-based medicine
- systematic review
- meta-analysis
- double-blind
External links

- [http://bmj.bmjjournals.com/cgi/content/full/327/7429/1459 A humorous look at problems with requiring randomized studies in medicine]
- [http://www-users.york.ac.uk/~mb55/guide/randsery.htm Directory of randomization software and services] category:experimental design category:pharmacology category:clinical research category:pharmaceutical industry

Randomized controlled trial

Types of trials

Randomized trials are employed to test efficacy while avoiding these factors. Trials may be open, blind or double-blind.

Open trial

Blind trials

Single-blind trial

Double-blind trial

Triple-blind trial

Controlled aspect

Difficulties

Randomized controlled trial

Types of trials

Randomized trials are employed to test efficacy while avoiding these factors. Trials may be open, blind or double-blind.

Drug industry

History

Biotechnology company

Drug discovery

Target identification

Target prioritization/validation

Lead identification

Lead optimization

Drug development

Phase I Clinical Studies

Phase II Clinical Studies

Phase III Clinical Studies

New Drug Application

Orphan drug

Post-approval surveillance

Phase IIIb/IV Studies

Post-Market Studies

Products

Drug information

ICD and DRG

Revenues

Industry revenues

Top 10 pharmaceutical companies by sales

Patents and Generics

Medicare Part D

Sales and marketing

The pharmaceutical industry is different

Advertising to physicians

Direct to consumer

The payers

Mergers, acquisitions, and co-marketing of drugs

Controversy

Bibliography

Controversy

Drug discovery and development

Management, mergers, acquisitions, co-marketing deals

Sales and marketing

See also

External links

Medication

Some common medications

See also

External links

Biopharmaceutical

Medication

Some common medications

See also

External links

Serendipity

Serendipitous discoveries and inventions

Origin of the term

Related terms

Bibliography

References

External links

Disease

Syndromes, illness and disease

Transmission of disease

Social significance of disease

Other uses of the term

See also

External links

Molecular biology

Relationship to other "molecular-scale" biological sciences

Techniques of molecular biology

Expression cloning

Polymerase chain reaction (PCR)

Gel electrophoresis

Southern blotting

Northern blotting

Western blotting and immunochemistry

History

Further reading

Notes

See also

Notable molecular biologists

See also

In fiction and games

External links

References