Pharmaceutical research

from Wikipedia, the free encyclopedia

As a pharmaceutical research in is pharmaceutical company operated and universities targeted search for new drugs , new drug combinations, new pharmaceutical form , new applications for existing drugs and the development of new drugs called. Candidates for new drugs must be tested for quality, safety and effectiveness in prescribed preclinical and clinical studies before they are approved for marketing by the drug authorities.

Preclinical research

Active ingredient search

Every innovative drug starts with the search for a new active ingredient. In contrast to earlier, often random approaches, efforts are now being made to identify new substances as lead structures in a systematic, multi-stage and iterative process , which are then further developed and optimized into active ingredient candidates.

Target molecules for new active ingredients

The techniques of molecular biology are used to understand disease processes and to identify possible endogenous target molecules, so-called targets , on which a drug can attach and thus influence the course of the disease. Most existing drugs have only a few hundred different endogenous target molecules that they act on. Most of such target molecules are receptors , enzymes and ion channels . In the course of genome research, many new potential target molecules were identified, for which suitable drugs are only being developed.

Search for lead structures

In the search for new lead structures, large molecule libraries are used, in which molecules from older research projects, molecules from combinatorial chemistry but also natural substances are combined. Such libraries of often several million different molecules can be searched in a few days by special robots with the help of automated high-throughput screening (HTS).

A prerequisite for such a systematic search for new lead structures is the development of a biochemical test system that can be used in high-throughput screening. Such test systems or assays are mostly biochemical reactions in which the interaction between a target molecule and the various molecules from the library to be searched can be examined. These assays are carried out hundreds of thousands of times in high-throughput screening on a microliter scale.

Lead structure development

Only a few molecules found in such a screening , also known as hits , have the quality to be classified as lead structures. In medicinal chemistry, their structure is optimized in the course of an active ingredient design so that in the end there is a molecule that has a favorable potency , high specificity and suitable molecular properties that make the molecule a candidate for an active ingredient. These properties are a prerequisite for a successful drug. If the potency is too low, too high a dose must be used, if the specificity is insufficient, there is a risk that the drug will show unacceptable side effects and without suitable pharmacokinetic properties the substance would not be absorbed, distributed, metabolized or excreted in the body as desired.

In addition to chemical and biochemical experiments, chemoinformatics methods are also used for lead structure optimization . By means of analyzes of the quantitative structure-effect relationship, predictions about the pharmacological effect or bioavailability can be made. If a crystal structure analysis is available for the target structure , suggestions for modified molecular structures can also be made by means of molecular design . To improve binding affinity and specificity, pharmacophore hypotheses are often developed, which can also be used to search for active substances in databases. A simple method for predicting the oral bioavailability of a new substance is the Rule of Five .

In this phase, the narrower circle of candidates is already on the most important side effects, e.g. B. unintentional interactions with the hERG channel (with the help of the patch clamp technique ), tested.

In the end, however, neither the biochemical nor the cheminformatical analyzes can predict with certainty how a new active ingredient will behave in vivo . Therefore, new active ingredients have to be tested in further preclinical studies.

Search for active ingredients in biotechnological active ingredients

The search for active substances in the development of biotechnological active substances such as peptide hormones , growth factors or monoclonal antibodies is significantly different . The search for monoclonal antibodies, for example, is described in the relevant article. But biotechnological active ingredients must also be tested in further prescribed preclinical and clinical studies.

Preclinical testing of new active ingredients

Animal experiments in preclinical testing

After a new active ingredient has been identified, it must be tested for effectiveness and harmlessness in suitable animal experiments . These must be registered or approved and carried out in accordance with the applicable animal welfare laws . Not only mandatory, but also technically necessary for meaningful results, is a species-appropriate keeping of the laboratory animals as well as the proven expertise of the employees.

The aim of these animal experiments is to make predictions about how people will react to the new active ingredient. This assumes that the experiments are carried out with animal species that behave particularly similar to humans in this respect. This has to be checked on a case-by-case basis, and in practice the agreement between the toxic effects observed in animals and humans is high, so that a relatively reliable risk assessment can be made from the animal test data. This is also proven by the fact that only 10% of all active substances in clinical studies fail because of unexpected side effects in humans; the vast majority of projects are terminated due to a lack of effectiveness or poor pharmacokinetics. But there remains an inevitable residue of uncertainty; accordingly, very careful action must be taken when first using it on humans.

Toxicological test

In particular, testing for toxicity is prescribed in detail by guidelines from the FDA , the ICH and the European Medicines Agency . According to the Association of Research-Based Pharmaceutical Manufacturers (vfa), these mandatory studies make up 86% of all animal studies carried out in the pharmaceutical sector.

The safety of new active ingredients must be proven in the following studies.

  • Acute toxicity of single doses in two mammalian species (one rodent and one non-rodent - typically rat and dog; in the case of biotechnologically produced active substances, e.g. monoclonal antibodies , also monkeys)
  • Repeated dose toxicity over a long period of time
  • Toxicokinetic and Pharmacokinetic Tests
  • Mutagenicity testing
  • Safety pharmacology tests to check for interactions with vital organ systems (heart / circulation, nervous system, lungs, kidneys)
  • Local compatibility tests
  • Reproductive toxicology

Studies on the carcinogenicity of the substance may still have to be carried out, the results of which, however, are only required for approval. The results of immunotoxicology studies also have to be available for approval . All essential toxicology studies must be conducted according to the rules of Good Laboratory Practice . The aim of the toxicological studies is to establish a safe starting dose for the clinical studies and to identify possible target organs for toxic effects as well as safety parameters for monitoring during the clinical studies. Usually the maximum recommended starting dose is calculated according to an FDA guideline from the NOAEL of the most sensitive animal species.

Proof of effectiveness in animal experiments

Preclinical studies are often also carried out in suitable disease models ( e.g. knockout mice ) in order to prove the effectiveness of the active ingredient in vivo. However, the relevance of such disease models is often difficult to prove. Proof of effectiveness in such animal models is not required, but it is a valuable milestone in project planning for companies.

At the end of all these preclinical test series, in many cases only one substance out of several drug candidates comes into question, which can be tested further in clinical research.

Manufacture of investigational drugs

For further clinical research, the new active ingredient must be processed in a suitable dosage form into a drug, the test preparation . This process of pharmaceutical technology or galenics runs parallel to clinical research because the optimal dose and dosage form must first be found in clinical studies. The dosage form can be used to control how quickly the active ingredient is absorbed and distributed in the body and how it reaches the site of action. A more targeted drug form can also reduce or avoid side effects. Innovations in drug development are therefore not limited to the search for new active ingredients.

Only for the phase III studies does the investigational product match the drug to be marketed in terms of dose, dosage form and, as far as possible, packaging. In the European Union, all investigational medicinal products for clinical studies must be manufactured in accordance with the rules of Good Manufacturing Practice .

Clinical research

After preclinical research, new drugs must be tested for their safety and effectiveness in suitable clinical studies. The mandatory test in clinical trials is divided into several phases. Clinical studies must be approved by the relevant drug authorities; The authority checks, among other things, the data from the preclinical development and the data on the pharmaceutical quality of the investigational product. In addition, a positive vote from the responsible ethics committee is required; the ethics committee reviews the qualifications of the investigators and the study plan to protect the study participants . Details on the approval and implementation of clinical studies are set out in pharmaceutical law. All clinical studies must be carried out according to the rules of Good Clinical Practice .

Phase 0

Phase 0 studies are a newer, non-mandatory concept for testing the pharmacokinetic properties of a new drug in humans. The smallest doses of the active ingredient, which are far below the threshold for a pharmacological effect, are tested on test subjects , i.e. healthy volunteers. In this approach, also known as microdosing , the active ingredient distribution, the active ingredient breakdown and individual breakdown products are then analyzed using mass spectrometry . Only a few preclinical studies are required for phase 0 studies, so that several drug candidates can be tested quickly in this way. This should increase the success rate in the following clinical studies.

Phase I.

The classic first use of a new drug in humans, also known as first-in-human , are phase I studies. The aim of these studies is to test the initial safety and tolerability as well as to measure pharmacokinetic values. When used for the first time in humans, particular care must be taken, as at that point in time only data from animal experiments are available, the transferability of which to humans is subject to a residual degree of uncertainty. Possible precautionary measures for initial use include, for example, a very low starting dose and sequential use on individual subjects.

Phase I studies are generally conducted on 10 to 80 male subjects. When it comes to an oncological agent, these early studies are often already carried out on patients, since the administration of a cytotoxic drug to test subjects is not ethically justifiable.

Phase I studies investigate whether the active ingredient behaves in the human organism exactly as predicted in the preclinical animal experiments, especially with regard to absorption, distribution, conversion, excretion (ADME) and tolerability. Appropriate monitor devices are used to continuously monitor how vital clinical parameters - for example blood pressure, heart and respiratory rate and body temperature - change. In the course of the phase I study, the dose of the active ingredient is slowly increased in order to find out when and how severe a reaction occurs. In addition, all events during the study are recorded and examined for a possible connection with the active ingredient in order to obtain initial indications of side effects.

Phase II

The focus of phase II studies is initial evidence of medical effectiveness and thus confirmation of the therapeutic concept. Phase II studies are therefore carried out on patients. The duration of treatment is usually limited to a few months; at most a few hundred patients are treated. In addition to the effectiveness, the tolerance is also carefully monitored here.

As soon as there are initial indications of effectiveness, the optimal therapeutic dose will be sought in further partial studies, also known as phase IIb, which will then be used in phase III studies. In this phase too, the dosage form often has to be optimized or changed; for this it may be necessary to carry out phase I studies on the pharmacokinetics of the new dosage form.

Phase III

Phase III comprises the studies that determine the data that are decisive for approval and for the proof of efficacy.

Usually at least two independent controlled clinical studies, each of which provide evidence of the statistical significance of the effectiveness, are necessary. Phase III studies can include many thousands of patients and span several years. As a rule, these are randomized, double-blind studies . In exceptions, in which a comparison group is not possible for ethical reasons, open studies are carried out, such as with imatinib . Depending on availability for the respective indication, either already approved drugs or placebos are used as comparator drugs . While superiority over placebo has to be demonstrated in any case, proof of a comparable effect over other drugs may be sufficient.

In phase III, data on drug safety are consistently collected from all patients. The risk-benefit assessment is one of the most important criteria for approval. In addition, further investigations can be carried out in phase III, which serve to profile the mode of action more precisely or for long-term observation.

Submission of the application for approval

After successfully completing phases I to III, a comprehensive approval dossier, a Common Technical Document (CTD, usually in electronic form, see eCTD ) is created, in which all data on pharmaceutical quality (manufacture, testing, shelf life), preclinical testing and be presented, summarized and assessed for the three clinical examination phases. This dossier serves as the basis for the competent drug authority to decide whether the drug will be approved.

Phase IV

Finally, phase IV describes the entirety of the clinical studies carried out after the market launch. This can include extensive studies on large patient populations to record possible rare but relevant side effects, but also smaller studies, primarily for publication purposes in specialist journals. For the extension of the approval of a drug to additional indications or for other forms of administration of the same active substance, however, new studies of at least phase III (possibly also phases I and II) must be carried out.

On average, of around 10,000 active ingredients evaluated in preclinical research in the USA, around five reach clinical research. One of these finally receives approval from the responsible drug authority, the Food and Drug Administration (FDA). It takes an average of 14.2 years from the synthesis of a new active ingredient to market approval of the drug, of which the clinical phases I – III take around 8.6 years and the approval process 1.8 years. The remaining time of around 3.8 years can be estimated for preclinical research including the search for and optimization of active ingredients (data for the USA).

Legal

Drug testing and approval guidelines

The drug laws only provide a framework for the requirements for research into and approval of novel drugs. Under this legal basis, a complex set of rules has therefore been created that must be taken into account in pharmaceutical research. A distinction must be made between legally binding guidelines and recommending guidelines. However, guidelines must also be observed, as they contribute to the state of scientific knowledge , which must always be taken into account.

In Germany there are binding drug testing guidelines based on Section 26 AMG , which essentially take over the detailed annex of Directive 2001/83 / EC . The GCP Ordinance and the 3rd Announcement on the Clinical Testing of Medicinal Products on Humans from the Paul Ehrlich Institute and the Federal Institute for Drugs and Medical Devices are binding for clinical trials .

At the global level, the most important pharmaceutical authorities - the US FDA , the European Medicines Agency and the Japanese MHLW - have set uniform guidelines together with the researching industry as part of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) ( English: Guidelines ) for admission criteria. This enables the submission of largely identical approval applications for the leading markets.

ICH guidelines are guidelines for testing quality (Q1-Q11), effectiveness (E1-E16) and safety (S1-S10) as well as for multidisciplinary questions (M1-M8). The guidelines are harmonized for the three large markets of the EU, USA and Japan.

EMA guidelines partly correspond to the ICH guidelines, but a large number of special guidelines are published only for the EU. Guidelines drawn up spontaneously by the committees of the European Medicines Agency are recommended; Guidelines, on the other hand, that were drawn up on formal request from EU law ( e.g. the Note for Guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products ) are to be regarded as legally binding.

FDA guidelines are extensive, detailed, sometimes standards-setting guidelines. The FDA also adopts ICH guidelines and publishes special regulations only for the USA.

National guidelines are also available and play a role in special approval procedures. Example: approval of a production.

Approval of drugs

Finished medicinal products require approval by the drug authorities before they can be placed on the market. The approval procedures for a drug are regulated in drug law. These have also been introduced or tightened in recent decades with a view to catastrophes such as the Contergan scandal .

For the approval of a new drug, the manufacturer must prove the tolerability and harmlessness of his drug on the basis of animal experiments and present the results of the efficacy tests on humans as part of clinical development. In addition, the approval documents must contain information on the composition of the medicinal product in terms of type and amount of ingredients, information on the manufacture of the starting materials, the semi-finished goods and the production product and on the quality assurance measures as well as test results on shelf life.

Uniform procedural rules for approval are now in force for the states of the European Union . The pharmaceutical company can choose between the centralized and the decentralized approval procedure and the mutual recognition procedure. In the central authorization procedure, which is mandatory for certain drugs, including those produced by genetic engineering, the dossier is submitted directly to the European Medicines Agency. After successful testing and consultation with the member states, the European Commission grants Europe-wide approval. In the mutual recognition procedure, the application for approval is submitted in a single reference state. Once approved in this country, this national approval can be extended to other member states in a process coordinated between the national pharmaceutical authorities. The decentralized procedure is similar, only here the application for approval is submitted simultaneously in all the desired member states; a reference state prepares an assessment report that is recognized by the other member states.

Sometimes, in the course of clinical development, the situation arises that patients who have participated in clinical studies cannot regularly receive a potentially life-saving drug after these studies have been completed until approval has been granted. In such situations it is often possible in individual cases to dispense the drug as part of compassionate use .

Economic aspects

Drug development costs

The development of a new innovative drug is costly and takes about 10 to 12 years. It is a high economic risk for companies, as very few substances that are tested in research make it onto the market. The most cited study of drug development costs found a cost of $ 802 million to develop a new, innovative drug in 2000 from confidential industry information. However, this information relates to full costs , including the high opportunity costs due to the long development time , money that the developing company misses because it cannot invest it in the capital market - these make up 50% of the $ 800 million. It also includes the substantial costs of the large number of failed development projects. Nevertheless, it can be stated that the costs of getting a potential drug to the end of a phase III study increased by around 2.5 times between 1991 and 2001. Despite the significantly increased spending on the development of new drugs, the rate of newly launched drugs, with an average of only three active ingredients in new drug classes per year, has remained relatively constant over the past 30 years.

According to DiMasi, the average cash expenditure (out-of-pocket) for a newly developed drug in the various stages of development in 2000 was as follows:

  • preclinical development: US $ 121 million
  • Phase I trials: US $ 15.2 million
  • Phase II trials: US $ 23.5 million
  • Phase III trials: US $ 86.3 million
  • long-term animal experiments: US $ 5.2 million

A study by Adams and Brantner published in 2006 subjected the above-cited study by DiMasi and colleagues to a critical examination: instead of the development costs determined there of $ 802 million, these authors estimated the cost at $ 500 million to $ 2 billion, depending on the targeted therapy and the developing pharmaceutical company.

In contrast, a study by Light and Warburton from 2011 found significantly lower average costs of 43.4 million US dollars for the development of a drug. This deviation by a factor of 18 arises from significant design errors and massively exaggerated figures when calculating the costs of clinical trials in the DiMasi study.

Innovative drugs are comparatively seldom on the market.In 2006 the FDA approved 22 drugs with new active ingredients, of which only ten were classified in the Priority Review category ( Priority Review means that the FDA assumes that the drug will make a significant improvement in the Compared to existing medicinal products). The further development of existing pharmaceuticals causes far lower research and development costs , but there are few concrete figures on this.

Drug development in Europe and North America

In the last few decades, the pharmaceutical industry in Europe and North America has concentrated more and more on the development of so-called blockbusters , drugs that generate annual sales of more than one billion US dollars. Accordingly, research focused on developing new remedies for common diseases , while other, less lucrative areas were abandoned. In 2005, 94 blockbusters generated more than a third of global drug sales. However, it is uncertain whether this trend will continue. A major problem in industry is the falling productivity of pharmaceutical research. The number of newly introduced drugs has stagnated for years despite a massive increase in research expenditure; Various takeovers and mergers of large pharmaceutical companies have not changed this either.

As a corrective to the focus on blockbusters, various legal regulations have been introduced so that drugs required for other areas can also be developed. In both the EU and the USA , for example, there are simplifications for the approval of orphan drugs , which should enable drugs to be developed profitably for rare diseases . These were also accepted; around 40 orphan drugs have now been approved in the EU, many of which were developed by smaller biotechnology companies. The criteria for such drugs are very restrictive.

A different approach has been taken in the EU for medicinal products for children. Here, the companies are now obliged to test drugs with new active ingredients in children and to strive for approval as pediatric drugs; if this is not done, the medicinal product is only approved in justified exceptions. As compensation, the companies receive patent protection extended by six months.

Research on the use of drugs (for example, on the dosage or the duration of the use of drugs) is not handled uniformly in the EU. While z. B. in Germany this research is carried out almost exclusively by pharmaceutical companies, z. In Italy, for example, pharmaceutical companies pay part of their marketing expenses into a fund. This fund then finances independent studies on drug use.

Drug development for third world diseases

This article or the following section is not adequately provided with supporting documents ( e.g. individual evidence ). Information without sufficient evidence could be removed soon. Please help Wikipedia by researching the information and including good evidence.

Pharmaceutical research for diseases that affect the people of the Third World is lagging behind the diseases of civilization in industrialized countries, as no financially strong health insurance companies can cover the costs of profit-oriented pharmaceutical research in these countries - hence the term " neglected diseases ". The situation is particularly precarious for diseases that are triggered by worms and protozoa : These pathogens hardly play a role in industrialized countries, but they do play a role in developing countries. In addition, the number of drugs available is small. The African sleeping sickness is an example : Today two drugs are used - Melarsoprol , which often causes severe side effects; and eflornithine , the production of which has been resumed because it has found buyers in industrialized countries as a facial hair remedy.

There are various strategies to remedy this deficit:

  • Increased demand (so-called pull incentives ): The state or aid organizations subsidize the buyers so that the patients are able to pay for the drug. The state can also buy a contracted amount of the drug to remove some of the business risk.
  • Improvement of offers (so-called push incentives ): The state participates in research costs or offers pharmaceutical companies other incentives, for example lower taxes. The state helps companies to get new active ingredients approved.

Both of the above options tend to favor large, established pharmaceutical companies. They don't take into account the fact that for-profit companies fail to develop products for poor patients and financially weak third world countries.

  • Public-private partnerships (PPPs), of which dozen now exist. If a drug to be developed can at least partially be used in the industrialized world (i.e. there are wealthy customers in developed countries), a pharmaceutical company's investment in a private-public partnership is worthwhile. Foundations and philanthropists donate the money, experts from university research, for example, test active ingredients that were developed in private-sector research for other diseases. Even small but specialized companies get an opportunity in PPPs to contribute their skills. The know-how is exchanged and does not remain within private companies. Contracts regulate who ultimately manufactures and markets the active ingredient.
  • The open source approach is a relatively new idea : Anyone involved in the development of an active ingredient must disclose new findings to the community. Every laboratory technician, researcher, authority and company can donate their time or money; and since the developed active ingredient cannot be patented as an open source product, anyone can manufacture, sell or even further develop it. The pursuit of profit is therefore not possible, which is likely to be a strong ideological incentive for donors. Open source also corresponds to the spirit of Jonas Salks (inventor of the polio vaccination): “Who does my vaccine belong to? To the people! Could you patent the sun? "

criticism

Pharmaceutical companies can try, or have already done so, to influence research, scientific publications and continuing medical education about their products in their favor. Researchers, in particular opinion leaders, who conduct the clinical studies and draw up the clinical guidelines are supported. The support is not always provided with money, but can also be provided by helping with the writing of scientific publications. The researchers can get into conflicts of interest ( bias ) between the general welfare and the personal (e.g. financial) interest. In order to increase transparency, conflicts of interest must be indicated in biomedical scientific publications.

literature

Individual evidence

  1. ↑ Hans-Joachim Böhm, Gerhard Klebe, Hugo Kubinyi: Active substance design . 2002, ISBN 3-8274-1353-2 .
  2. ^ P. Greaves, A. Williams, M. Eve: First dose of potential new medicines to humans: how animals help. In: Nat Rev Drug Discov . Volume 3, 2004, pp. 226-236. PMID 15031736 .
  3. ^ H. Kubinyi: Drug research: myths, hype and reality. In: Nature Rev Drug Disc. Volume 2, 2003, pp. 665-669. PMID 12904816 .
  4. ^ Vfa on animal experiments in pharmaceutical research ( Memento from December 14, 2007 in the Internet Archive ).
  5. ^ ICH M3: Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals ( Memento of October 16, 2010 in the web archive archive.today ).
  6. ↑ FDA guideline on starting dose in clinical studies ( memo of January 18, 2009 in the Internet Archive ).
  7. ↑ ICH E8: General considerations for clinical trials ( Memento from March 23, 2006 in the Internet Archive )
  8. ↑ European Public Assessment Report (European assessment report on Glivec) ( Memento of July 17, 2006 in the Internet Archive )
  9. ↑ BP Zambrowicz, AT Sands: Knockouts model the 100 best-selling drugs - wants They model the next 100? In: Nat Rev Drug Discov. Volume 2 (1), 2003, pp. 38-51. PMID 12509758 .
  10. ^ A b c J. K. Willmann et al.: Molecular imaging in drug development. In: Nat Rev Drug Discov. Volume 7 (7), 2008, pp. 591-607. PMID 18591980 .
  11. ↑ YES Dimasi: New drug development in the United States from 1963 to 1999. In: Clin Pharmacol Ther . Volume 69 (5), 2001, pp. 286-296. PMID 11371996 .
  12. ↑ ICH Guidelines .
  13. ↑ EMA guidelines .
  14. ↑ FDA Guidance ( Memento from May 19, 2009 in the web archive archive.today ).
  15. ↑ JA DiMasi et al: The price of innovation: new estimates of drug development costs. In: J Health Econ. Volume 22, 2003, pp. 151-185. PMID 12606142 .
  16. ↑ JA DiMasi et al.: Cost of innovation in the pharmaceutical industry. In: J Health Econ. Volume 10, 1991, pp. 107-142. PMID 10113009 .
  17. ^ CP Adams, VV Brantner: Estimating the cost of new drug development: is it really 802 million dollars? In: Health Aff (Millwood). Volume 25 (2), 2006, pp. 420-428. PMID 16522582 .
  18. ^ DW Light, R. Warburton: Demythologizing the high costs of pharmaceutical research. In: BioSocieties (Millwood). Volume 5, 2011, pp. 1-17.
  19. ↑ Pharmabrief ( Memento of the original from 23 September 2015 in the Internet Archive ) Info: The @1@ 2Template: Webachiv / IABot / www.bukopharma.de archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. . No. 2–3, March / April 2011, pp. 3–4, accessed on December 25, 2015.
  20. ↑ FDA approval of novel active ingredients 2006 .
  21. ↑ DM Cutler: The demise of the blockbuster? In: N Engl J Med . Volume 356 (13), 2007, pp. 1292-1293. PMID 17392299 .
  22. ^ RF Service: Surviving the blockbuster syndrome. In: Science . Volume 303, 2004, pp. 1796-1799. PMID 15031490 .
  23. ↑ Regulation (EC) No. 1901/2006 on medicinal products for children
  24. ↑ Risk to patients - No independent pharmaceutical studies in Germany. ( Memento from August 22, 2010 on WebCite ) In: Magazin Kontraste. Broadcasting Berlin-Brandenburg , May 28, 2009.
  25. ↑ Stephen M. Maurer, Arti Rai, Andrej Sali: Finding Cures for Tropical Diseases: Is Open Source an Answer? ( Memento from April 15, 2013 in the web archive archive.today ) In: PLoS Medicine. 1, 2004, p. 56.
  26. ^ GA Jelinek, SL Neate: The influence of the pharmaceutical industry in medicine . In: Journal of Law and Medicine . tape 17 , no. 2 , October 2009, p. 216-223 , PMID 19998591 ( taking control of multiplesclerosis.org [PDF]).
  27. ^ The influence of the pharmaceutical industry. (PDF) (No longer available online.) House of Commons Health Committee, Fourth Report of Session 2004–05, Volume I, March 22, 2005, archived from the original on August 29, 2011 ; Retrieved March 20, 2010 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.parliament.the-stationery-office.co.uk
  28. ↑ JR Lacasse, J. Leo: Ghostwriting at elite academic medical centers in the United States . In: PLoS Med . tape 7 , no. 2 , 2010, p. e1000230 , doi : 10.1371 / journal.pmed.1000230 , PMID 20126384 , PMC 2814828 (free full text).
  29. ↑ B. Lo: Serving two masters - conflicts of interest in academic medicine . In: N. Engl. J. Med. Band 362 , no. 8 , February 2010, p. 669-671 , doi : 10.1056 / NEJMp1000213 , PMID 20181969 .
  30. ↑ SN Young: Bias in the research literature and conflict of interest: an issue for publishers, editors, reviewers and authors, and it is not just about the money . In: J Psychiatry Neurosci . tape 34 , no. 6 , November 2009, p. 412-417 , PMID 19949717 , PMC 2783432 (free full text) - ( cma.ca [PDF]).
  31. ^ Uniform Format for Disclosure of Competing Interests in ICMJE Journals. ( Memento from May 16, 2012 in the Internet Archive ) icmje.org
  32. ↑ ICMJE Form for Disclosure of Potential Conflicts of Interest. icmje.org
  33. ^ Conflict of Interest in Peer-Reviewed Medical Journals. ( Memento of December 8, 2013 in the web archive archive.today ) wame.org

Web links