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Two studies of the antihypertensive amlodipine’s quality in south Nigeria found problems: one study reported 30 percent of samples failed pharmacopeial tests for content uniformity (Eichie et al generic 15 mg mentax overnight delivery antifungal wipes. The management of diseases such as type 2 diabetes and hypertension depend on maintenance medication and monitoring discount mentax 15 mg online xylitol fungus sinus. The sheer amount of products used to treat these conditions raises the patients’ lifetime risk of encountering a bad product buy cheap mentax 15 mg on-line fungus gnats bonsai, even in countries with strin- gent regulatory authorities (see Box 2-1) cheap 15mg mentax mastercard antifungal youtube. The need for reliable medicines in low- and middle-income countries will become more pronounced as the burden of chronic disease increases in these countries. Already cardiovascu- lar disease is the main killer of adults in low- and middle-income countries, Copyright © National Academy of Sciences. OneTouch Ultra brand blood glucose moni- tors after LifeScan notifed the agency that it had received a number of customer complaints. The strips produced inaccurate blood glucose level readings, the results of which are used by diabetics to monitor their condi- tion and determine medication dosing (Bloomberg News, 2007). Diabetics rely on their blood glucose monitors to manage their self-treatment, and incorrect readings can lead patients to administer the wrong dosage of in- sulin or induce unnecessary panic. The manufacturer sold approximately one million substandard test strips to importers, and from there the strips went through the sup- ply chain to reach U. Over the course of the next year, the test strips made their way to 8 countries and 35 U. The Chinese authorities eventually arrested and imprisoned Henry Fu, owner of Halson Pharmaceuticals (Bloomberg News, 2007). The LifeScan recall is a reminder that substandard medical products can fnd their way into countries with strong regulatory systems. The United States and Canada have systems in place for prompt recalls, al- lowing them to mitigate the threat the product poses to public health. Within 2 years the fake test strips were fully recalled in the United States, but between 2009 and 2011 customers and investigators still found them in other countries, including Egypt, India, and Pakistan (Loftus, 2011). As the prevalence of diabetes increases rapidly in the developing world, new, loosely regulated markets attract potential counterfeiters. India is home to more than 50 million diabetics, more than any other country, and the number is expected to increase dramatically over the coming years (World Diabetes Foundation, 2013). In 2007, not long after the frst bad test strips appeared in the United States, there were ap- proximately 40. As the chronic disease burden in- creases in developing countries, falsifed and substandard versions of the expensive products used to treat them pose new risks. Maintenance medication for cardiovascular disease is a vulnerable target for fraud, but the need for these drugs is still unmet in much of the world (Gaziano, 2007). In developing countries, there has been a greater emphasis on controlling infectious disease, especially the infectious diseases of childhood. Considerable research indicates that the anti-infective drugs used to do this are often compromised in poor countries. A more recent survey in Egypt, Jordan, Lebanon, and Saudi Arabia found more than half of antibiotics sampled to be substandard (Kyriacos et al. A similar survey in Burma uncovered substandard drugs in 16 per- cent of amoxicillin and 13 percent of ampicillin samples (Wondemagegnehu, 1999). More recently, a survey of amoxicillin in the capital of Papua New Guinea found all samples outside of pharmacopeial specifcations; 14 per- cent had undetectable levels of active ingredient (Nair et al. In most low- and middle-income countries β-lactam antibiotics, an inexpensive and widely available class of drugs that includes penicillin and amoxicillin, are the frst-line treatment for dozens of bacterial infections, including scarlet fever, pneumonia, and respiratory and urinary tract infec- tions (Byarugaba, 2004). Alone it ac- counts for as much as 12 percent of all child deaths worldwide (O’Brien et al. This will remain the best strategy un- til the pneumococcal conjugate vaccine becomes more widely available. The treatment of pneumonia and other devastating bacterial infections depends on effective antibiotic supply. No research to date has attempted to quan- tify the proportion of child deaths attributable to falsifed and substandard medicines, but Table 2-1 presents the most common causes of child death and links them to verifed reports of substandard medicines. Chapter 5 describes the medicines supply chain in developing countries; in Copyright © National Academy of Sciences. If antibiotics are some of the oldest and most widely used medicines in the world, antiretrovirals are their opposites: new medicines, prescribed in complicated regimes, to a relatively small segment of the population. In 1995, during a meningitis epidemic, about 60,000 Nigeriens were injected with water disguised as meningitis vac- cine (Cockburn, 2005). More recently, in China, substandard hepatitis B and rabies vaccines killed or sickened about 100 babies (Jia and Carey, 2011). Precise infor- mation regarding the event is scarce due to the Chinese government’s denial of a connection between the vaccines and the incidents as well as its control over the Chinese media. According to the Associated Press, the original article in the China Economic Times that exposed the scan- dal stated that four children who died never had a precise diagnosis, but sufered from fevers and convulsions before their deaths; others who became ill were later diagnosed with encephalitis, among other conditions, and some sufered permanent damage (Associated Press, 2010a). About 200,000 doses of substandard rabies vaccine circulated in Jiangsu province in 2010 before a manufacturer recall (Associated Press, 2010b). These vaccines, like the falsifed meningitis vaccine used in Niger, convey no immunity to the patient. When herd immunity is an important result of vaccination, there is no such beneft to society. Assuming the patients survive injection with nonsterile, unidentifed liquids, they are still at risk for death from the disease they were not inoculated against. In September 2011, falsifed and substandard versions of the triple combination therapy Zidolam-N surfaced in Kenya, many samples molding and crumbling in the packages (Taylor, 2011). A year later, in Tanzania, the regulatory authority uncovered falsifed anti- retrovirals at a district hospital (Athumani, 2012). As their viral loads increase, these patients are also more likely to transmit the infection, impeding efforts to control the virus. Although data suggesting compromised antiretroviral drug quality are mixed, there is substantial evidence, presented in Chapter 3, that antima- larials are often of poor quality. Substandard and falsifed malaria drugs are especially common in malaria-endemic parts of Africa and Asia. In 2003, substandard sulfadoxine-pyrimethamine was used to treat a malaria epidemic in northwest Pakistan refugee camps (Leslie et al. Health workers diagnosed the parasite with microscopy, monitored drug resistance, and checked drug quality using procedures described in the U. Good care during initial infection and treatment with an effective second- line drug prevented any deaths, and the onset of cooler weather stopped transmission (Leslie et al. The prognosis for most people treated with poor-quality antimalarial drugs is worse. Not only will their malaria be untreated, but inadequate treatment favors the selection of resistant parasites, which threaten their entire communities. Treatment Failure Individual patients have much to lose from substandard and falsifed medicines.

For example generic mentax 15mg with mastercard fungus packaging, these drugs decrease the clearance of lithium generic mentax 15 mg visa fungi quiz, which can result in lithi- um toxicity cheap mentax 15 mg on line fungus identification. Phenazopyridine hydrochloride Phenazopyridine hydrochloride buy mentax 15 mg visa antifungal for lips, an azo dye used in commercial coloring, produces a local analgesic effect on the urinary tract. The remainder is excreted unchanged in the urine, causing the pa- tient’s urine to turn an orange or red color. Adverse Pharmacodynamics reactions Phenazopyridine is taken orally and produces an analgesic effect to phenazo- on the urinary tract usually within 24 to 48 hours after therapy be- pyridine gins. The word opioid refers to derivatives of the opium plant or to syn- thetic drugs that imitate natural narcotics. Opioid agonists (also called narcotic agonists) include opium derivatives and synthetic drugs with similar properties. They’re used to relieve or decrease Opioid refers to pain without causing the person to lose consciousness. Unfortunately, by reversing the analgesic effect, they also cause the patient’s pain to recur. Having it both ways Some opioid analgesics, called mixed opioid agonist-antago- nists, have agonist and antagonist properties. The agonist compo- nent relieves pain, while the antagonist component decreases the risk of toxicity and drug dependence. These mixed opioid agonist- antagonists reduce the risk of respiratory depression and drug abuse. Gold standard Morphine sulfate is the standard against which the effectiveness and adverse reactions of other pain medications are measured. Using opioid Distribution Opioid agonists are distributed widely throughout body tissues. For ex- avoid confusing the ample, meperidine is metabolized to normeperidine, a toxic drugs, never use abbre- metabolite with a longer half-life than meperidine. When these drugs stimulate the opiate receptors, they mimic the effects of endorphins (naturally occurring opiates that are part of the body’s own pain relief sys- tem). This receptor-site binding produces the therapeutic effects of analgesia and cough suppression. It also produces adverse re- actions, such as respiratory depression and constipation. It also slows intestinal peristalsis (rhythmic contractions that move food along the digestive tract), resulting in constipa- tion, a common adverse effect of opiates. Too much of a good thing These drugs also cause blood vessels to dilate, especially in the face, head, and neck. In addition, they suppress the cough center in the brain, producing antitussive effects and causing constric- tion of the bronchial muscles. For example, if the blood vessels dilate too breathe easier much, hypotension can occur. Pharmacotherapeutics Opioid agonists are prescribed to relieve severe pain in acute, chronic, and terminal illnesses. They also reduce anxiety before a patient receives anesthesia and are some- times prescribed to control diarrhea and suppress cough- ing. Other opioids and remifentanil are used for the induction and maintenance of general anesthesia. How opioid agonists control pain Opioid agonists, such as meperidine, inhibit pain transmission by mimicking the body’s natural pain control mechanisms. This peripheral pain neuron to inhibit release sciousness of pain, but how this mecha- agent helps transfer pain impulses to the of substance P and to retard the trans- nism works remains unknown. It does this by dilating peripheral blood vessels, keeping more blood in the periphery, and decreasing cardiac preload. Adverse reactions to opioid agonists One of the most common adverse reactions to • orthostatic hypotension opioid agonists is decreased rate and depth of • pupil constriction. This may cause periodic, irregular • tremors breathing or trigger asthmatic attacks in sus- • palpitations ceptible patients. Drug interactions • The use of opioid agonists with other drugs that also decrease respirations, such as alcohol, sedatives, hypnotics, and anesthet- ics, increases the patient’s risk of severe respiratory depression. The mixed opioid agonist- antagonists include: • buprenorphine • butorphanol • nalbuphine • pentazocine hydrochloride (combined with pentazocine lactate, naloxone, aspirin, or acetaminophen). No free ride Originally, mixed opioid agonist-antagonists appeared to have less abuse potential than the pure opioid agonists. Pharmacokinetics Absorption of mixed opioid agonist-antagonists occurs rapidly from parenteral sites. These drugs are distributed to most body tissues and also cross the placental barrier. They’re metabolized in the liver and excreted primarily by the kidneys, although more than 10% of a butorphanol dose and a small amount of a penta- zocine dose are excreted in stool. Pharmacodynamics The exact mechanism of action of the mixed opioid agonist- antagonists isn’t known. However, researchers believe that these drugs weakly antagonize the effects of morphine, meperidine, and other opiates at one of the opioid receptor sites, while exerting ag- onistic effects at other opioid receptor sites. It seems to release slowly from binding sites, produc- ing a longer duration of action than the other drugs in this class. Don’t get emotional The site of action of butorphanol may be opiate receptors in the limbic system (the part of the brain involved in emotion). Patients with a Like pentazocine, butorphanol also acts on pulmonary circula- history of opioid tion, increasing pulmonary vascular resistance (the resistance in abuse shouldn’t the blood vessels of the lungs that the right ventricle must pump receive mixed opioid agonist- against). Pharmacotherapeutics Mixed opioid agonist-antagonists are used as analgesia during childbirth and are also administered postoperatively. Independence day Mixed opioid agonist-antagonists are sometimes prescribed in place of opioid agonists because they have a lower risk of drug de- pendence. The most common ad- Patients who abuse opioids shouldn’t receive mixed opioid verse reactions to opioid agonist-antagonists because these drugs can cause symptoms of agonist-antagonists in- withdrawal. Opioid antagonists Opioid antagonists have a greater attraction for opiate receptors than opioids do; however, they don’t stimulate those receptors. As a result, opioid antagonists block the effects of opioid drugs, enkephalins, and endorphins. Pharmacodynamics Opioid antagonists act by occupying opiate receptor sites, displac- ing opioids attached to opiate receptors, and preventing opioids from binding at these sites. This process, known as competitive inhibition, effectively blocks the effects of opioids. Pharmacotherapeutics Naloxone is the drug of choice for managing an opioid overdose. It reverses respiratory depression and sedation and helps stabilize the patient’s vital signs within seconds after administration. To prevent acute withdrawal during treatment for opioid addiction, plan to use naltrexone as part of a comprehensive rehabilitation program. Keep in mind the following guidelines: Adverse • Don’t give naltrexone until a negative naloxone challenge test is obtained. Naloxone and naltrex- • For a patient who’s addicted to a longer-acting opioid, such as methadone, wait at least 10 days one produce different after the last opioid dose before starting naltrexone.

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In fact 15 mg mentax with mastercard fungus gnats kitchen sink, the Deponit device exerts considerable control over the input rate of nitroglycerin (nearly 90% patch control) mentax 15mg low price antifungal drops for ears, whereas Nitrodur lets the natural barrier function of the skin determine drug absorption into the systemic circulation (approximately 90% skin control) cheap 15mg mentax overnight delivery urine antifungal. For Transderm-Nitro purchase mentax 15mg fast delivery spray for fungus gnats, despite the presence of the so-called “rate-controlling” membrane, the responsibility for metering the delivery is, on average, shared between patch and skin. The maximum rate that nitroglycerin can diffuse across intact human skin is on the order of 20 µg/cm /hr. On the other hand, if a larger surface area is used (say 40 cm ),2 then ratecontrol can be an integral part of the patch such that nitroglycerin is presented to the skin at only 10 µg/cm /hr. In conclusion, it is evident that transdermal delivery is very much determined by the area of contact between patch and skin. Indeed, dose titration with transdermal delivery is achieved not by altering the formulation but rather by adjusting the size of the system (Figure 8. It is also apparent that delivery is not particularly sensitive to the loading of the patch, especially when the input rate is controlled by the skin. The loading does need to be sufficient, however, to ensure that delivery is maintained for the desired period, and to sustain a diffusional driving force. Next, it must be emphasized that the design of the patch does not necessarily guarantee that it will control the overall delivery (for example, the presence of a membrane in a reservoir system does not ensure 100% control by the patch). Thus, drug loading and the mechanism of drug release from a transdermal delivery system are inappropriate measures for bioequivalence assessment. Finally, it is worth noting that the discussion of rate-control as presented is most applicable during the period of what might be termed “steady-state” delivery. In other words, as the patch is applied there are drug molecules waiting at the external surface of the adhesive that become instantaneously available for transport. At the opposite extreme, if a patch remains in contact with the skin for sufficient time that the drug loading is almost completely depleted then, at this point, delivery control is 204 Figure 8. Of course, with almost all the systems presently used, this situation does not arise as the designated application is such that significant amounts of the “payload” remain in the device when it is replaced with a fresh system. However, it is not inconceivable that such depleting systems may become more common in the future, especially for drug substances which are exquisitely potent or expensive or potentially subject to abuse. Scopolamine Scopolamine was the first drug to be marketed as a transdermal delivery system (Transderm-Scop) to alleviate the discomfort of motion sickness. After oral administration, scopolamine has a short duration of action because of a high first-pass effect. In addition, several side-effects are associated with the peak plasma levels obtained. Transderm-Scop is a reservoir system that incorporates two types of release mechanims: a rapid, short-term release of drug from the adhesive layer, superimposed on an essentially zero-order input profile metered by the microporous membrane separating the reservoir from the skin surface. The scopolamine patch is able to maintain plasma levels in the therapeutic window for extended periods of time, delivering 0. Nitroglycerin This drug has been used to treat angina pectoris for over 100 years. It is a potent compound with a high clearance (266 L/hr), short half-life (1–4 minutes) and extremely low oral bioavailability (<1%). Percutaneous transport of mtroglycerin is relatively efficient, and conventional ointment formulations were the first modern-day transdermal formulations available. In the early 1980s, however, three patches appeared more or less simultaneously (Transderm-Nitro NitroDisc, and NitroDur), and transdermal delivery became widely recognized as an alternative route of administration for appropriate drugs. Since that time, numerous new and modified patches have been approved which differ considerably in design, composition, drug loading and release mechanism. Nevertheless, it is possible to demonstrate a bioequivalence between these patches, in terms of the resulting plasma concentration versus time profiles (Figure 8. When nitroglycerin is delivered via the skin, a sustained concentration can be achieved over an extended period of time. This profile contrasts sharply with those obtained following administration of sublingual and ointment 205 Figure 8. Despite this apparently clear pharmacokinetic advantage, however, it turns out that zero- order delivery of nitroglycerin for 24 hours, on a chronic basis, poses a pharmacodynamic problem: namely, tolerance. That is, even though the delivered amount of drug per unit time remains constant, the pharmacological effect of the drug decreases progressively, to the point that there is essentially no benefit to the patient. The problem is resolved by imposing a drug-free period during each dosing interval of 24 hours. Thus, presently, the patches are applied in the morning, after showering, and worn for 12–16 hours, with a “resting” or wash-out period overnight when patients are less susceptible (although not immune) to angina attacks. The drug has a relatively long half-life (6–20 h) and a modest clearance (13 L h−1). The rationale for the development of transdermal clonidine was to reduce side-effects and to improve patient compliance. The control of drug delivery over 7 days is impressive, and avoids the “peaks and valleys” of2 conventional (twice-a-day) oral administration (Figure 8. However, this system has not achieved as wide a success as first seemed likely because of skin sensitization. Clonidine itself, when administered transdermally on a chronic, repetitive basis, induces in a significant fraction of patients a classic immunologic skin reaction, and this has severely attenuated its use. Estmdiol Transdermal estradiol is indicated for postmenopausal hormone replacement therapy. Estradiol is a potent, high clearance (600– 800 L/hr) and short half-life (1 hr) drug. Due to the very high hepatic first-pass effect, conventional oral hormone replacement therapy results in an artificially elevated and, in the long 206 Figure 8. Transdermal delivery of estradiol, however, results in sustained plasma concentrations over several days (Figure 8. Pharmacologically, beneficial effects on the frequency of hot flushes, sleep disturbance, irritability and mental accuity have been documented. More recently, other simpler, and more elegant, monolithic systems have reached the market, and perform as well as, if not better than, the original system. Because the postmenopausal woman is usually treated concomitantly with an oral progestin (i. One of the first of these systems containing estradiol and levonorgestrel has recently been approved for marketing. Fentanyl This very powerful analgesic had been limited to parenteral use during and after surgery. Accurate dose titration is necessary because of the drug’s very narrow therapeutic window (1–2 ng mL−1). The potential of fentanyl, however, to significantly improve the treatment of acute post-operative pain and chronic cancer pain provoked the development of the now-approved Duragesic transdermal system. This reservoir system can be used for up to 3 days and is available in four “doses” (10, 20, 30 and 40 cm delivering, respectively, 25,2 50, 75 and 100 µg hr−1). Nicotine 207 Nicotine is generally believed to be the principal addictive component in tobacco. Patches containing nicotine are targeted at smoking cessation and compete with other nicotine-based systems, including chewing gum, lozenges and a nasal spray.

Usually only the national regulatory authority could have the information needed to make this distinction buy 15 mg mentax free shipping fungus gnats uc davis. In many countries generic mentax 15mg without prescription fungus gnats rollitup, even the regulatory authority would not have that information or the political will to act on it (Christian et al cheap mentax 15 mg with amex antifungal used to treat thrush. Pinpointing cases of deliberate tiered manufacturing is diffcult to do buy mentax 15 mg with visa fungi characteristics, though it is easier to see practices that allow it happen. Companies provide contract manufacturers with the materials, includ- ing packaging, to make their products. As Dilip Shah, Secretary General of the Indian Pharmaceutical Alliance, explained to a committee delegation in India, “Very few companies, foreign or domestic, monitor the [contract manufacturer’s] process loss of raw materials, active ingredients, and pack- aging materials. I have known of cases of 15 to 20 percent packaging mate- rial losses and companies are not bothered. Because the contract manufacturers have the processes and materials needed to produce a proper drug, they will sometimes sell perfectly made drugs outside of the licit distribution system. Pharmaceutical exporting countries can also unintentionally facilitate tiered manufacturing by not requiring the same evaluations for exported drugs as for those sold domestically (Caudron et al. In general, regulatory agencies are responsible for protecting their country’s domestic medicine supply; ensuring quality for exported products is often beyond their mandate and budget. It is more diffcult for low- and middle-income countries to ensure checks on drug quality during manufacture, a problem discussed later in this chapter. Procurement and Substandard Medicines When regulatory checks on production are inconsistent, procurement practices can help ensure that quality medicines get the largest market share. The Global Fund explains the goal of good procurement as supplying medicine “meeting agreed quality standards at the lowest possible price and in accordance with national and international laws” (Global Fund, 2009, p. Government agencies procuring medicines have to reconcile a tension between quality and price (Torstensson and Pugatch, 2012). The frms that offer the cheapest prices may do so by buying impure ingredients or cutting corners in formulation. Good procurement dictates that the cheapest tenders are not accepted Copyright © National Academy of Sciences. Chinese provincial procurement, for example, is known for “pressuring manufacturers to produce the lowest cost possible while preserving their profts” (Burkitt, 2012). These agencies face pressure to supply medicines for entire populations on tight budgets; sometimes there is added demand to support local manufacturers (Dickens, 2011; Torstensson and Pugatch, 2012). Openness in procurement can bal- ance these pressures by exposing unnecessarily high costs or bad quality, but transparency, which also includes vetting procurement offcers for con- ficts of interest, auditing suppliers, documenting decisions, and scrutinizing procurement agents, adds costs to the process (Torstensson and Pugatch, 2012). In Argen- tina, for example, a health transparency program brought down the pro- curement costs of medicines (Lewis, 2006). Reducing costs of procurement would be especially helpful in the poorest countries, which tend to spend a higher proportion of their health budget on drugs and where medicines are often expensive (Torstensson and Pugatch, 2012). In a study of 36 low- and middle-income countries, Cameron and colleagues found that public procurement agencies in the western Pacifc, Africa, and the former Soviet bloc pay an average of 34 to 44 percent above the international reference prices (Cameron et al. Donors may attempt to cover unmet demand for drugs, though donor procurement also has problems. Many European donors ask their recipients to assure quality of medicines procured with donated funds (Moore et al. Proper precaution in the medicines procurement process can prevent poor-quality products from infltrating the market. Good procurement involves separating the various steps of procurement process identifed in Table 4-2. Good procurement also puts a strong emphasis on controlling corruption and promoting transparency. Recommendation 4-2: Procurement agencies should develop a plan, within the next 3 to 5 years, to comply with the World Health Orga- nization’s Model Quality Assurance System for procurement agencies and work to remove any barriers to compliance. The model draws on the accumulated experience of these agencies’ procure- ment experts and combines advice on the procurement of medicines, vac- cines, diagnostic kits, and devices. The model focuses on four key activities: prequalifcation of pharmaceutical products and manufacturers and drug purchase, storage, and distribution. At its launch in 2006, the model had an aspirational element; it de- scribed standards that few if any of the international procurement agencies were able to maintain at that time. In the past 6 years, large procurement agencies have made great progress toward meeting the standards laid out in the model (van Zyl et al. The committee sees the model quality assurance system as a useful independent standard to assess procurement agencies. The system is a practical tool that can be used by national and international procurement agencies. Pharmaceutical procurement almost always means working with foreign suppliers; a practice that exceeds capacity of national regulators, who cannot hope to inspect foreign manufacturers as they would domestic ones. Good procurement also means that only organi- zations that follow the model system should import medicines. Small-scale importation and procurement by small actors threaten the medicines supply chain. Countering the Problem of Falsified and Substandard Drugs 149 Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 150 Copyright © National Academy of Sciences. Countering the Problem of Falsified and Substandard Drugs 151 Copyright © National Academy of Sciences. District hospitals and health posts in poor countries will not likely meet the model standards for premises, equipment, or staffng any time in the near future (Dickens, 2011). In the meantime, if full preselection of quality suppliers is not possible, interim solutions such as a two-envelope system can help reduce bias to- ward the cheapest frms. In this system, used by the Delhi hospital system, bidders submit their technical statement of work and their costs in sepa- rate, sealed envelopes (Chaudhury et al. Only if the quality controls are suffcient do they open the second envelope, containing the project budget. Ultimately, medicine procurement is complicated and requires consid- erable investment in staff and procedures. Cutting corners in procurement creates opportunities for substandard products to infltrate the supply chain. Therefore, smaller organizations such as district health offces should be free to choose the products and amounts they need from licensed, national wholesalers or importers, but they should not procure directly from manufacturers. The committee recognizes that licensing wholesalers and importers requires political will. It might take time to build momentum for this step, as discussed further in Chapter 5. Therefore, the committee recommends that national and international procurement agencies take 3 to 5 years to develop and implement their compliance plans. These agencies can develop their quality- assurance system within the next 5 years. The regulatory authority can then license national procurement agencies to buy medicines directly from manu- facturers. Instead, these organizations will be able to order their medicines from licensed procurement agencies, thereby making more effcient use of their staff and budgets and avoiding the dangers of primary procurement.