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Thus buy cheap levitra oral jelly 20 mg line, the question remains open as to whether the French legislation provided a satisfactory system cheap levitra oral jelly 20mg free shipping, or whether the system just appeared to be satisfactory generic levitra oral jelly 20 mg mastercard. At the other extreme, I have no ideal optimal (whether in terms of market economics or public health) model of legislation to offer as a benchmark against which to measure this French approach. Why did they need an ‘independent’ institute to check the quality of all the serum that was produced? Was it because of the tuberculine scandal associated with Robert Koch and the failure of the state to assume its responsibilities in this case? We can also consider an explanation in terms of different cultures of legislation and administration? Of course, looking in more detail at the economics of production may also provide some clues about the national interest of ‘satisfcing’ in regulating a proftable drug marketplace versus introducing stronger strictures that give the state more leverage in encouraging competition or shoring up ‘cartels’ that are seen to be functioning in everyone’s interest. Whatever the answers to these questions, it seems improbable that the differences between France and Germany can be reduced to ‘rational’ economic calculations. Marks Cured yesterday of my disease I died last night of my physician Matthew Prior (1664-1721)1 A popular statin used to lower cholesterol is associated with an unusual breakdown of muscle tissue. The scenarios involved in the recent cases of Baycol and Vioxx should be familiar. Investigative journalists then trumpet the drug’s fall from grace, revealing a “back story” in which the warning signs of harm were ignored or suppressed. The drug’s makers defend their product and their integrity while medical reformers and social scientists condemn corporate cupidity. Members of a bewildered public wonder about drug safety while injured patients and outraged politicians call for remedial action. Psychically gratifying as such “histoires morales” are, they are of limited analytical value. The problem of identifying and regulating “adverse” drug effects is chronic, not acute, long- standing rather than recent. First, that the handling of adverse drug reactions ultimately derives from a regulatory system which at all costs preserves medical autonomy. Harvard University PhD thesis 2005; J Abraham, Science, politics and the pharmaceutical industry. The resulting regulatory system allows for maximum physician autonomy in drug prescribing. Second: Within such a regulatory system, “making risks visible” poses both technical and political diffculties. When the prospect looms of adding new warnings to a drug’s labeling, drug companies enter a war of position, seeking – up to a point – to defend the market for their product. While the adversarial character of these negotiations will vary with changes in the political and ideological climate, the result is invariably delay Abraham 1995. I follow with a discussion of two paradigmatic cases: chloramphenicol and diethylstilbestrol, drawing on the work of Thomas Maeder and Susan Bell. I then analyze the contested history of administrative and technical efforts in the 1960s, 1970s and 1980s to make drug hazards visible. The new law required drug frms to demonstrate that drugs were “safe for use under the conditions prescribed, recommended or suggested in the proposed labeling thereof [my emphasis]. The reader is referred to these publications for additional detail and documentation. This clause sets the standards for new 106 Making Risks Visible language incorporated the twin premises of contemporary drug regulation: 1) that drug safety must be defned in risk-beneft terms. A drug that was unsafe for treating colds might be safe for treating pneumonia or infuenza; ) that drug regulation was largely informational in character, intended to instruct but never to command physicians’ actions. This informational approach was characteristic of much New Deal regulation, which sought to improve markets by improving information. Sulfapyridine was the newest of the sulfonamides, anti-infective drugs that had been introduced into medical practice only a few years before. Approving sulfapyridine was a matter of assessing its risks in relation to its clinical beneft. As Durrett put it: drugs; sec 502 (j) authorized the secretary to treat as misbranded any drug that was dangerous to health when used in the dosage and conditions recommended in the labeling. There are elements of a similar approach even in more interventionist economic legislation, such as the National Recovery Administration, so dependent on industry-specifc „codes“ for regulating industrial competition. Marks If the drug that killed one person in 10,000 was of only minor use therapeutically it might still be judged to be unsafe, whereas the drug which killed one in a thousand persons if it had marked and undisputed therapeutic value, such as the drug under question [sulfapyridine], it would still be a safe and valuable drug. Those contacted constituted a virtual who’s who of prominent clinical investigators and infectious disease specialists. Clearly, “the drug was not killing many people” but at the same time, there was “no uniformity of opinion with respect to the harm which the drug might be capable of doing from one investigator to another. While diffcult to use in community settings, serum therapy was standard treatment in major hospitals. Blankenhorn (University of Cincinnati), David Rutstein (New York State Health Department) and O. Richards [Columbia University], December 1, 1938; in Durrett’s view, “there was no way to dispute the value of this drug. Five additional manufacturers had submitted applications for sulfapyridine since the original Merck fling. Along with its medical allies, industry has invoked physician autonomy, medical need and freedom from governmental ukases as inviolable principles. The registration system was put into place only after repeated failures of efforts to warn physicians through labeling and medical alerts. For thalidomide, see S Timmermans; Leiter, V, “The redemption of thalidomide: Standardizing the risk of birth defects,” Social Studies Science 30 (2000): 41-71. Calver to the Pure Food and Drug Administration, July 1, 1948, 88-59A- 7 6, Box 58 , folder 51 6. Not surprisingly, such intensifed conficts develop around reports of the adverse effects of previously approved drugs. How directive should revised labeling be in instructing physicians how to use a particular product? Protracted regulatory conficts therefore focus on the justifcation for specifc changes in informational labeling. The moralized histories which accompany the recent episodes of adverse drug reactions (e. These narratives refect a long-enduring confict within the medical profession itself, between reformers who regard commercial infuences as inherently corrupting--”Nearly all abuses arise because someone profts thereby”--and practitioners committed to the conjoined principles of therapeutic innovation and professional autonomy. Both sides invest regulatory language with enormous powers to direct action, yet even reformers seem uncomfortable with more directive regulation which might limit physician autonomy. The Role of Disciplines and Institutions,” Conference on Ethical Issues and Clinical Trials, University of Alabama at Birmingham, February ( 000b): 5- 6). In the oral hypoglycemic case, the challenges to labeling changes ultimately reached the Supreme Court (Marks, 1997: 216-228).

Also included is a summary of studies of interaction effects among factors that increase or decrease conformity behavior 20 mg levitra oral jelly free shipping. Differences in Shifting of Responses Attributable to Stimulus Materials Employed Several studies have evaluated those differences in conformity behavior that are associated with the nature of the stimulus materials -227- and the conditions of their presentation buy 20mg levitra oral jelly. Helson levitra oral jelly 20 mg lowest price, Blake, and Mouton (61) studied the frequency of shifting as a function of the content of the task. Greater shifting of responses from the correct or modal report toward the erroneous responses expressed by others was observed for attitude statements than for materials involving knowledge or ability. Festinger and Thibaut (41) employed two different discussion problems as stimulus materials, and reported results consistent with those by Helson, Blake, and Mouton (61). Crutchfield (34) presented a variety of stimulus materials to a test sample under social pressure conditions. Since he describes results obtained for some but not all the materials, it is impossible to determine if response shifts are a function of the character of the stimulus materials. The materials most subject to conformity effects appear to derive meaning or validity from a social frame of reference, such as attitudes toward war or general social problems. One source of variation is the difficulty experienced by the subject in reacting to the materials presented. The hypothesis tested holds that the more difficult the materials, the more easily the individual is influenced. Blake, Helson, and Mouton (18) had male college students respond to arithmetic items and the metronome click counting problems under simulated conditions. For the arithmetic items, shifting increased toward the erroneous response of the simulated group as the difficulty of the problems increased. Results for the metronome are interpreted as indicating that variations in rate were not sufficiently great -228- for shifts from social pressure related to difficulty to appear in a statistically clear manner. Coleman, Blake, and Mouton (31) have demonstrated a significant relatiorkship between task difficulty and susceptibility to conformity pressures. The results are interpreted as indicating that an individual certain of the correct answer is more able to resist pressures because he is more able to respond in terms of internal cues. Differences between the variable lines and the standard were small for one set of trials, and larger for another set. Fewer errors Nere made by subjects when the discrepancy between lines was greater. These results support the hypothesis that difficult stimulus milterials lead to a greater degree of conformity. Bereada (11) used child subjects for two different tasks, and investigated frequency of shifting as a function of the difficulty of items. The gretatest shifting for both tasks occurred in those trials that produced the highest frequency of errors under private conditions. In a study by Wiener (132), the task consisted of selecting one of two naules for each of ten ambiguous designs, and indicating the degree of certainty of each judgment on a four-point scale ranging from "absolutely certain" to "absolutely uncertain. Pressures have been maintained at a constant level in some studies of the relationship between ambiguity of the materials and conformity. Caylor (26) defined the ambiguity of the stimulus materials as the number of equally probable reactions perceived as appropriate in response to the Stouffer questionnaire approach to conflict in norms. Conformity was found to be positively associated with the more ambiguous stimulus materials. Wiener, Carpenter, and Carpenter (131) failed to confirm the relationship reported by Caylor (26). The general hypothesis tested is that susceptibility is greater the farther removed stimulus materials are from direct examination. The materials for one were present for visual examination at the time the subject made his judgments. Significantly less influence was exerted by other persons when stimulus materials were present. Raven and Rietsema (110) studied conditions of presentation and susceptibility as a function of the clarity of the task and found that the subjects who understood the requirements conformed more to the needs of others even though this placed them at a personal disadvantage. Luchins (87) investigated susceptibility under conditions permitting some subjects to test objectively their experience with the stimulus materials. Child subjects permitted to test the accuracy of their judgments were less influenced by the confederate. These studies generally agree in confirming the prediction that susceptibility is less when subjects have the opportunity to employ an objective frame of reference. Shifting in the direction of endorsement of a petition as a function of the strength of the request has been investigated by Blake, Mouton, and Hain (19). An increase in compliance attributable to increases in strength of the request was found for influence created by the compliant model, and a decrease when the model resisted. These results were confirmed by Rosenbaum (112) using a similar request to solicit volunteers. The frequency of compliance was found to be positively or negatively related to the strength of the prohibition stimulus in the same manner as in the studies just summarized. Reactions are evoked more easily when pressures are exerted on attitudes toward social issues; factual matters and personal preferences seem to be most resistan to change. This generalization is important for its implication that susceptibility is highest in areas dealing with political ideology, social attitudes, and expressions of opinions. A situation where it is difficult for the subject to check on the accuracy of his response results in a decrease of resistance. Greater susceptibility has been shown to occur with increases in request strength when pressures are created by a compliant model as well as the converse. Conformity Behavior and Social Context Conformity pressures may be created when a person is confronted with reactions differing from his own. Individual reactions under private conditions have been compared with reactions to the same problem in a social context. Properties of social contexts singly or in combination have been studied to determine their effects on increases or decreases in susceptibility. Knowledge of group opinion during the third administration of an attitude questionnaire -231- produced frequency of shifting in the direction of agreement with the majority three times greater than that in the control condition, with disagreement reduced to approximately one-half of chance expectancy. Gorden (52) evaluated shifts in responses from an initial individual administration of a twelve-item scale of attitudes toward Russia to responses given in the presence of other members. Over half of the subjects shifted toward group opinion, and approximately a third shifted away from it, with no change in the total shift score for approximately an eighth. Helson, Blake, Mouton, and Olmstead (63) reported that naive subjects expressed significantly different degrees of agreement or disagreement with statements matched for degree of militarism as a function and in the direction of prearranged responses by other subjects. Duncker (38) reports that children, responding after one, two, or three other subjects expressed their food preferences, had a selection rate of 81 per cent for foods chosen only 26 per cent of the time earlier in private. Grosser, Polansky, and Lippitt (53) found that a significantly larger number of naive child subjects engaged in unauthorized activities under the influence of perceiving violations by a model in the experimental rather than in the control conditions. Freed, Chandler, Mouton, and Blake (45) have reported similar results in a prohibition situation (see foregoing), as have Barch, Trumbo, and Nagle (5) who observed the behavior of motorists in turning lanes to determine conformance with or violation of a state law requiring turn signals. The behavior of a person following a lead car was significantly related to that of the lead car driver. Blake, Mouton, and Hain (19) obtained similar results for endorsement of a petition (see the foregoing).

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Observational studies are initially rated as low-quality evidence but may be upgraded if the magnitude of the treatment effect is very large purchase levitra oral jelly 20 mg on-line, if multiple studies show the same effect buy 20 mg levitra oral jelly free shipping, if evidence indicates a dose–response relationship or if all plausible biases would underestimate the effect (10) levitra oral jelly 20mg visa. The higher the quality of evidence, the more likely a strong recommendation can be made. The strength of a recommendation reflects the extent to which the Guideline Development Group was confident that the desirable effects of following a recommendation outweigh the potential undesirable effects. The strength is influenced by the following factors: the quality of the evidence, the balance of benefits and harms, values and preferences, resource use and the feasibility of the intervention (Table 3. A strong recommendation is one for which the Guideline Development Group was confident that the desirable effects of adhering to the recommendation outweigh the undesirable effects. A conditional recommendation is one for which the Guideline Development Group concluded that the desirable effects of adhering to the recommendation probably outweigh the undesirable effects but the Guideline Development Group is not confident about these trade-offs. The reasons for making a conditional recommendation include the absence of high- quality evidence; imprecision in outcome estimates; variability in the values and preferences of individuals regarding the outcomes of interventions; small benefits; applicability in all settings versus specific settings; and benefits that may not be worth the costs (including the costs of implementing the recommendation). The more that the benefts outweigh the risks, the more likely that a strong recommendation will be made. Values and If the recommendation is likely to be widely accepted or highly valued, a preferences strong recommendation will probably be made. If there are strong reasons (acceptability) that the recommended course of action is unlikely to be accepted, a conditional recommendation is more likely to be made. Costs and fnancial Lower costs (monetary, infrastructure, equipment or human resources) implications or greater cost–effectiveness will more likely result in a strong (resource use) recommendation. Feasibility If an intervention is achievable in a setting where the greatest impact is expected, a strong recommendation is more probable. Recommendations that require updating are noted, and it is clearly stated where updated guidelines are planned. This applies to specific topics in Chapter 9, including retention across the continuum of care, but this did not lead to formal recommendations. A short version will summarize key new and existing recommendations for easy reference. A library of all supporting documentation and evidence will also be made available on the web site. Assistance will be provided to Member States to adapt the guidelines to their national contexts. An evaluation of how users have implemented the guidelines has been developed to assess the uptake of the recommendations and the barriers to effective implementation. Interim technical and programmatic updates may be developed if important new evidence becomes available. These include existing recommendations that have been updated, where a new evidence review was undertaken as part of this guidelines process. They are presented in the following format to reflect the full evidence review and discussion held within the Guideline Development Group for new recommendations. When the recommendation relates to a specific population, the key issues for that population may be briefly summarized. The new evidence on which the recommendation is based and other key operational and programmatic considerations that informed the development of the recommendation are summarized. In some cases, key clinical implementation issues specific to the recommendation are listed. For several key recommendations, discussion of implementation considerations relevant to programme managers is presented in Chapter 10. In some cases, critical issues requiring further research are briefly described or listed, where these are integral to the recommendations. The references relating to each section are listed at the end of the guidelines by chapter number. In general, these are presented in the following format: Background; Source(s) for recommendation(s); Additional guidance (where appropriate); and Existing recommendation(s). The population relevant to each recommendation is clearly specifed and also marked by an appropriate symbol for quick reference. The tables highlight selected topics that are particularly relevant to the respective populations. However, the topics listed are not exhaustive and many of the recommendations and other guidance are relevant across different populations. Algorithms for the 2013 recommendations for pregnant and breastfeeding women Annex 6. Adolescents may access care in a variety of settings, including paediatric and antenatal care clinics, as well as adult clinics. Since few health systems provide adolescent-specific services it can be challenging for adolescents to access health care and maintain adherence to treatment regimens. In general, in these guidelines, clinical and general care recommendations for adults apply to adolescents. Where guidance for adolescents is addressed in recommendations for children, this is clearly indicated. There are four specific recommendations on testing and counselling taken from additional recent adolescent-specific guidance. Most-at-risk populations include men who have sex with men, transgender people, people who inject drugs and sex workers. The location of the most important guidance and recommendations specific to key populations is summarized in Table 4. The topics Guidance for listed here are indicative of some of the specifc issues programme managers Socioeconomic, policy and legal context Section 10. The people tested who are not infected should be linked to appropriate prevention services, such as voluntary male medical circumcision in the priority countries in sub-Saharan Africa, or harm reduction services for those who use drugs, and encouraged to retest at a later time. Strategies should be able to reach the people who are most vulnerable, most-at-risk and marginalized (Box 5. Quality assurance systems should be put in place to minimize false-positive and false-negative results. Failure to do this will lead to people being given incorrect test results, with potential serious adverse long-term consequences. Mandatory or coerced testing is never appropriate, whether that coercion comes from a health care provider or from a partner or family member. Although confdentiality should be respected, it should not be allowed to reinforce secrecy, stigma or shame. Counsellors should raise, among other issues, whom else the person may wish to inform and how they would like this to be done. Shared confdentiality with a partner or family members and trusted others and with health care providers is often highly benefcial. Quality assurance mechanisms and supportive supervision and mentoring systems should be in place to ensure the provision of high-quality counselling. Quality assurance may include both internal and external measures and should include support from the national reference laboratory as needed. Connections to prevention, care and treatment services should include the provision of effective referral to appropriate follow-up services as indicated, including long- term prevention and treatment support.

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Although originally developed for testing often copied malaria drugs cheap levitra oral jelly 20 mg on-line, PharmaCheck will also be able to test other kinds of medications (Barlow cheap 20 mg levitra oral jelly fast delivery, 2012) discount levitra oral jelly online mastercard. Zaman has said that the device should be undergoing testing in developing countries by early 2013 (Seifert, 2012). The organization recognized PharmaCheck’s potential with a $250,000 grant given to Zaman and his partners over the next 2 years to further develop the device, one of only 15 projects chosen out of the more than 500 applications (Saving Lives at Birth, 2012c; Seifert, 2012). Staub and colleagues developed a capil- lary electrophoresis system paired with time-of-fight mass spectrometry for analyzing protein-based drugs, such as insulin, without sample preparation (Staub et al. Radio wave technologies similar to those used in bomb detection are also being tailored for pharma- ceutical analysis (Sprey, 2010). The information a technique provides, as well as its reliability, cost, required expertise, speed, and portability make it more or less appropriate in any given situation. In order to conclude that a drug is of good quality, an inspector must test a sample for all of the main defciencies of substandard and falsifed drugs: fake packaging, incorrect color, shape, or markings, absent or incor- rect active ingredients, incorrect quantities of ingredients, impurities, and reduced dissolution or disintegration. Table 6-2 outlines which classes of analytical techniques can test for these problems and how well they can be used in the feld. In general, feld use describes a relatively straightforward assay or technique that depends on portable or sturdy equipment. Most feld methods can be used by professionals such as regulators, pharmacists, or health workers, but some, like mobile verifcation, are accessible to a layperson. Figure 6-9 shows how investigators in the network test samples in national drug quality surveys (Fernandez et al. The steps shown in green can be done in the feld, but samples are generally sent to a central laboratory for the steps show in brown (Fernandez et al. Fernandez and colleagues have used this system Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 275 Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 276 Copyright © National Academy of Sciences. Poorly trained chemists and dilapidated infrastructure are common obstacles in performing accurate drug quality testing. Combining Techniques Although any one test may suffce to label a drug substandard or falsi- fed, no single analytical technique provides enough information to con- frm that a drug is genuine. Spectroscopic techniques are useful for identifying active ingredients but cannot rule out the presence of countless possible impurities. Chromatographic techniques may suggest that the drug contains suffcient active ingredient, but they do not provide any information about how much of that active ingredient will reach the patient. Time and budget allowing, the best understanding of drug quality comes from the several complementary experiments. Even combinations of techniques from within a class, such as spec- troscopy, can be helpful. One study illustrated how, due to differences in the ranges of their spectral regions, infrared spectroscopy may at times be better at identifying organic substances in tablet coatings, whereas Raman spectroscopy may better identify the inorganic components (Witkowski, 2005). Experiments that looked at the coating on Cialis tablets found that Copyright © National Academy of Sciences. Raman spectroscopy did not distinguish between the real coating and falsi- fed coating, but infrared spectroscopy did (Lim, 2012). For example, liquid chromatography-mass spec- trometry is a highly reliable separation technique, but does not directly provide quantitative data about the amount of active ingredient present; analysts must compare results to standards to determine content (Kaur et al. Mulligan and colleagues found that automated equilibrium headspace sampling with capillary gas chromatography provides information about volatile impuri- ties, but adding mass spec analysis provides extra qualitative information about the identity of any impurities present (Mulligan et al. When Captagon, a stimulant drug popular in the Middle East, was out- lawed, illegal manufacturers began selling the drug (Alabdalla, 2005). The copies were generally falsifed drugs containing amphetamines and caffeine meant to mimic Captagon’s therapeutic effects. The combined analysis also indicated, with reasonable certainty, which drugs were from the same batches (Alabdalla, 2005). Courts prefer them to other analytical techniques as forensic evidence (Rivier, 2003). Combining analytical techniques is a challenge both in the feld and in the laboratory. It is diffcult to determine which tests can be combined to allow inspectors to use the minimum number of different techniques. It is usually best to work through tests beginning with the easiest or least ex- pensive ones and to only move on to the more expensive or diffcult tests if the sample passes the earlier ones. For example, a drug that fails an identity test does not need to be tested for the amount of incorrect active ingredient. Using Technology in Developing Countries The question remains as to how to use analytical methods in parts of the world with limited laboratory capacity and trained chemists. Reliable reference materials to test samples against are often scarce in poor countries (Fernandez et al. Manufacturers are reluctant to release reference standards when they fear the information could be used to make an illegiti- mate drug. In any case, the most sophisticated analytic technologies were not designed for the feld. Field Technologies Technologies for feld detection of falsifed and substandard drugs in developing countries must be portable, relatively simple to use, sturdy, and inexpensive to buy, use, and maintain. As the previous section explains, these techniques are durable, fast, relatively inexpensive, and fairly easy to use, making them attractive to regulators interested in monitoring drug quality. Package verifcation technologies can also aid in feld detection of falsifed drugs, although these methods are useful more to the patient at the point of use than to the regulator. First used in Henan province in March 2006, mobile labs quickly spread to 29 provinces (Jin, 2007). The mobile lab program also trained 760 technicians to operate the labs, which bring drug screening technology to rural areas (Jin, 2007). The vans also house information on 200,000 manufacturers, including names, addresses, and licensed products, as well as a provincial “Drug Quality Bulletin” with annually updated information on known poor-quality drugs (Jin, 2007). In the frst 6 months of operation, mobile labs screened 110,426 batches of drugs and confrmed 3,122 of them to be substandard (Jin, 2007). The project’s success has inspired the regulatory authority to help other countries develop similar mobile labs and to use them in drug procurement (Jin, 2007). Field tests are no substitute for defnitive laboratory techniques and cannot test all aspects of a product’s quality, including its drug content, impurity profle, and dissolution profle. Noting the cost of laboratory pharmaceutical testing and the dearth of qualifed laboratories in developing countries, the German Pharma Health Fund (now known as the Global Pharma Health Fund) devel- oped the Minilab, a portable quality-analysis laboratory described in Box 6-4 (Jähnke et al. During a November 2012 Minilab training session in Angola, trainees tested an illegal shipment of various pharmaceuticals seized by customs offcials along the African coast (Minilab Saves Lives, 2012; World Customs Organization, 2012).