Essential medicines (2017)

Equitable and economical access to effective therapies is certainly a desirable goal. In this presentation, I am going to explain how this is can be achieved. Healthcare systems need to rest on reliable foundations of evidence-based medical practice and respect the evolving needs of their respective populations. A defined list of essential medicines is an integral part of any solution. The dataset used for the initial evaluation comes from the Czech State Institute for Drug Control. The circulated report is based on information from December 2016, and the data lock point for this presentation is end of May 2017. Information on population turbulence comes from statistics of the Ministry of Interior. 

The Essential Medicines List compiled by the World Health Organization represents the most efficacious, safe and cost-effective treatment options available for a variety of conditions that affect significant portion of the population. The list is reviewed every two years by a team of experts and using a rigorous methodology for inclusion and exclusion to reflect the available evidence, efficacy and safety profile, and cost. The medications included should be available to the population at all times. Many countries adopted the WHO list as is or adjusted it for national usage. 

The main challenges public health systems encounter include the definition of Standard of Care, level of access and prioritization of the most cost-effective options, and international interoperability. International travel increases the probability of exposure to pathogens. Moreover, the most cost-effective options for health systems are often those less profitable for business. 

Standard of Care is also called best practice, standard medical care, or standard therapy. Standard of care is defined as A diagnostic and treatment process that a clinician should follow for a certain type of patient, illness, or clinical circumstance. 

Standard medical care has to be based on Evidence-based practice and implemented with fidelity. Standards of Care need to reflect any changes due to development in medical science. Implementation of Standards of Care for specific conditions requires minimum competence that is achieved through continuing professional education that respects these Standards of Care. The objective is to limit improvisation and  human error. 

Standards of Care ensure the Cost of Care is predictable and manageable without creating pockets of high spending and lack of appropriate care or neglect. Equitable access to effective therapies is the best way to ensure good health of the population and lower the overall burden of disability, expressed as Quality-adjusted Life Years (QALY) and Quality-Adjusted Disability Years (QADY). Survival should not be the only metrics used. Adopted Standard of Care also allows individuals to pursue cases of medical negligence. 

“Evidence-based practice is the conscientious and judicious use of current best evidence in conjunction with clinical expertise and patient values to guide health care decisions.” (10 sec)

Transfer of new knowledge into clinical practice requires a functioning process to be timely and effective. Knowledge in medicine is created through formal clinical research conducted as interventional and observational studies. The findings from clinical research have to be distilled into products that reflect the quality, amount of evidence in the context of other available information, and translate these findings into practice recommendations. Professional societies and other bodies, such as the Institute of Medicine or the National Quality Forum, disseminate the evidence through rigorously compiled publications that can be used as a foundation for implementation in clinical practice. Adoption of knowledge has to include an update of training curricula and organizational policies and guidelines by medical schools, healthcare providers, insurers, and regulators. 

Standards of Care, and clinical practice guidelines based on evidence-based practice, do not need to be reinvented and created from scratch. The recommendations already exist, significant effort has been invested into their creation, and they are available for free or through academic libraries. Examples of adoptable guidelines include the standards the National Institute for Health and Care Excellence (NICE) or even the Doctors Without Borders that may be relevant for many tropical diseases uncommon in the developed world. 

To purpose of their implementation is to ensure consistency in care delivery, to ensure equitable access to safe and effective therapies based on rigorous evaluation of their cost-effectiveness, and the ability to predict and plan the costs of care in relation to the evolving population needs. 

Professional education rooted in evidence-based practice then enables international interoperability with foreign partners.  

In medical negligence cases, the plaintiff, through the opinion of an expert, has to establish the appropriate standard of care relevant to the circumstances, and prove that the standard has been breached, and that the breach caused the harm. (60 sec)

Standards of Care need to reflect the burden of disease, including probability of its occurrence due to open borders. Resulting practice guidelines have to respect national circumstances and the division of responsibilities between primary and specialized care. For example, in countries with high prevalence of malaria, these cases are handled in local hospitals, whilst in developed countries they are typically referred to specialized care, although the treatment itself is very similar. 

Essential medicines lists are designed to meet the needs of most health systems. The medicines are included based on their safety and efficacy profile and cost-effectiveness, using a rigorous review process. When used within public health systems, they are designed to deliver adequate therapy that reflects the population’s needs. System needs and the defined standard have to be periodically reviewed  (45 sec)

In order to achieve international operability of local health systems, standards need to exist for both diagnosis and treatment. Collaborative exchange of information is essential to facilitate a shared understanding of the underlying science and its implementation in practice. 

Shared knowledge base and procedural implementation are necessary for participation in medical support mission during peacekeeping, disaster relief and humanitarian and transnational operations. 

Health care delivered in multinational setting such as within multinational facilities and as part of international partnerships need to conform to the same standards in care, procedures, operations, and training to be effective. In the current globalized world, medicine is becoming an industry that attracts significant investment due to medical tourism. 

The Czech Republic is a member of the European Union and the Schengen Agreement. Border checks within the Schengen area have been largely abolished. The map on the right shows countries that are part of the Schengen Agreement compared to EU membership. The map on the left shows the population of people illegally present in this area (20 sec). 

The total population of refugees is distributed unevenly across the member states. Restrictive immigration policy, in combination with failure to properly process and take care of the people physically present in the area, increases the probability they will find a way how to stay within the area illegally. 

The majority successfully granted refugee applications were for people from Syria, Eritrea, Iraq, Afghanistan, and Iran. People coming from failing states with dysfunctional healthcare infrastructure are more likely to suffer from conditions that will require treatment. The risk is higher for those who remain outside the system and unable to pay for their own healthcare. (35 sec) 

However, the highest volume of travel comes from legitimate tourism and international business. The estimates are compiled from a variety of sources that include border surveys, recorded spending and declared hotel stays. 

About two thirds of the total inbound traffic comes from the EU, mostly from Germany, Slovakia and the United Kingdom. The total number of non-EU visitors is around 2.3 million a year. 

The most popular European destinations for Czechs are Croatia, Slovakia, Austria, Italy, Greece, Spain and France. Due to the income gap, Czechs are likely to stay in low-cost accommodation where they are more likely to be exposed to potential sources of harm, including pathogens and their vectors. 

Popular non-EU holiday destinations include Tunisia, Egypt, Turkey, UAE and Morocco, but increasingly also exotic destinations in sub-Saharan Africa, India and South-East Asia. (45 sec) 

The Czech Republic is part of the EU and cannot isolate itself from its influences, without sacrificing economic competitiveness. The total number of illegal border crossings into Europe in 2016 was about 0.5 million people, down from 1.8 million in 2015. The most used routes are the Western Balkans route, the Black Sea route and the Central Mediterranean route. 

The most relevant migration-related medical risks in the Czech Republic is protracted, indirect exposure through EU-wide contact, aggravated by high share of low-cost individual and business travel where the probability of exposure is higher. Country specific risks include the introduction of competent vectors from the Balkans and migration from Russia and post-Soviet republics where the main problem is multi-drug resistant tuberculosis. 

The geopolitical earthquake caused by the dissolution of the Soviet Union and a series of reforms throughout the Eastern Bloc displaced large number of people. Not all of them managed to get through the economic transition that followed unscathed.  

The Czech Republic direct exposure to the refugee population is minimal due to its restrictive immigration policies. 

The evaluation of the situation in the Czech Republic is based on the comparison of the World Health Organization list of essential medicines and the availability of these medicines to local population. (10 sec)  

Of the 427 medications included in the WHO essential medicines lists, 311 are available in the Czech Republic due to either registration or a special access program. The formulations available include all medications that have SUKL ID, not necessarily available through formal registration process.

The worst affected classes of drugs are parenteral nutrition components, antibacterials, immune sera, second line antituberculars, combined formulations of antiretrovirals, antiparasitics and some antidotes. 

The availability gap overlaps significantly with drugs that areperiodicallyor chronically in shortage on global markets. 

Essential drugs are difficult or impossible to replace, and workaround solutions are usually less effective, more toxic, and/or more costly.  

Detailed breakdown by system organ class and analysis how local availability gap relates to global shortages of certain generic drugs can be found in Arete-Zoe report on essential medicines in the Czech Republic.  (45 sec)

Significant gaps in availability of essential medicines affect nearly all system organ classes. Detailed breakdown is available in appendix and can be downloaded from Arete-Zoe website. 

The unavailable medications include parenteral nutrition components, stool softener docusate sodium that is used in palliative care, rectal formulation of hydrocortisone, and topical intestinal antibiotic paromomycin that is used to tackle Clostridium difficile infections. 

In the group of agents for the treatment blood and cardiovascular disorders, the availability gap includes plasmaexpander dextran, heparin dalteparin, magnesium sulfate and antihypertensives nitroprusside and hydralazine. 

Among dermatologicals, the most important gaps include antimicrobials miconazole and griseofulvin. 

Whilst the choice of contraceptives and other sex hormones greatly increased after the fall of communism, some important fixed combinations are still unavailable. 

The most important gap, however, is in the group of antimicrobials. In the beta-lactam group, the gap includes cloxacilin, cefalexim and cefixim. Other antimicrobials unavailable include kanamycin streptomycin and spectinomycin, some second-line antituberculars, fixed combinations of antituberculars and fixed combination antiretrovirals. Moreover, many are only available through special treatment programs. Immune sera such as rabies and diphtheria antitoxin are also in chronic shortage globally. 

Among antineoplastics, the gaps include dactinomycin, daunorubicin and tretinoin. 

The highest number of unavailable essential drugs can be found in the groups of antiparasitics, both antiprotozoals for the treatment of malaria and leishmaniosis and anthelmintics.  

Among drugs for the treatment of sensory system, the most problematic are ophthalmologicals.  

And last, in the ATC group “various”, the gap most affects antidotes such as edetates, acetylcysteine, fomepizole and thiosulfate.  

Detailed breakdown by organ class including comments and context can be found in the Arete-Zoe report on essential medicines in the Czech Republic.  

The Czech Republic is still a low-risk country in regards to tuberculosis. The probability of occurrence of multidrug-resistant tuberculosis increases with migration from the former Soviet Union. The core of first-line treatment of tuberculosis is isoniazid, rifampin, ethambutol, and pyrazinamide. All except ethambutol are only available through special access program. Antituberculars, along with antimalarials and antiretrovirals are drugs most affected by counterfeiting and illegal trade. The table on the right shows antituberculars available in the Czech Republic. The green tick means that the drug was marketed in the past quarter. The green star marks first-line antituberculars, including fixed combinations.

Malaria, although rare in the Czech Republic, can still be introduced through international travel and long-term stay, and cannot be dismissed as irrelevant in the region. The existing treatment options are extremely limited and would have to be solved by other means, including individual import. The green tick means that the drug was marketed in the past quarter. The green star marks antimalarials listed on the WHO list of essential medicines. 

Helminthiases such as flukes, tapeworms, roundworms, filarial worms are rarely diagnosed in Europe despite their zoonotic potential and likely present in the region. Many are transmitted between pets and insect vectors such as mosquitos and fleas. 

Echinococcosis is a zoonosis. The definitive hosts are mainly dogs, foxes and wolves. The adult tapeworm lives in their intestines. Intermediate hosts are usually sheep, cattle, pigs, wild ruminants and rodents. Humans are dead-end hosts, because these days they are rarely eaten by wild animal predators. The egg hatches in the intestines from where it migrates through the intestinal wall to any organ in the body, usually the liver, spleen, lungs or brain. 

Antiparasitic drugs are poorly represented in the Czech Republic.  

At present, the alternative sourcing options include 

Compassionate use, that is drugs that are already submitted for registration and newly authorized drugs that are available elsewhere in the EU, Most essential drugs are generics and compassionate use programs rarely applies. 

Special Treatment Programs are published every quarter by the Ministry of Health. Drugs available through these programs are included in the SUKL database of available products. The programs are intended for all patients who meet specific conditions of the program and can be used by specific treatment centers. Drugs available through these programs are not reimbursed, however. In the graphs that follow, a blue star marks drugs available through special treatment programs. 

Individual Import requires physician’s application for an individual patient. Such import needs to be preapproved by the Agency. A special application is required for reimbursement. 

However, these options may be difficult to find since physicians, who primarily expected to identify appropriate treatment options for their patients, have to rely on public databases such as EudraPharm. EudraPharm was designed to contain all information on medicinal products available across the European Union as an important information-sharing platform. 

Unfortunately, the database is not populated with data, as so far only Portugal and the European Commission uploaded their databases. 

The development of solutions depends on rigorous analysis of burden of disease, risks relating to globalization, meaning both spread of infection and the availability of medicines, and national policy. 

Any solution needs to include the definition of treatment standards applicable locally, the definition of national essential medicines list, the definition of a national stockpile, and regular review of all defined components. 

Treatment standards, rooted in evidence-based medicine, and translated into clinical treatment guidelines; create a shared understanding of best practice. Clinical practice needs to mirror the developments in medicine and be closely tied to medical training at all levels, from nurse and physician education to continuing the professional education of qualified professionals. A shared understanding of underlying science is essential for making the right treatment decisions for individual patients. 

Standards of care are essential for plaintiffs to be able to be able to address any instances of medical malpractice or error. Medical malpractice generally requires the existence of a standard of care, its violation, and the existence of harm caused by this violation. Without a standard of care, it is virtually impossible to pursue cases of medical malpractice. The existence of standards facilitates cooperation with international partners. 

A national essential medicines list may or may not follow exactly the one compiled by the WHO. However, a detailed discussion is necessary about the public health system’s needs. Such defined need shall then be formalized in the form of a regularly reviewed document. National list of essential medicines needs to be tied to defined standards of care to be effective. Essential medicines lists define treatment options that are the most efficient, safe, and cost-effective. It is reasonable to assume that these drugs will be used first as a default treatment of choice. Moreover, essential medicines need to be accessible throughout the system, either through primary or specialized care and shall not be treated as something that requires an exception. 

Pharmaceutical companies have indeed no obligation to register drugs locally; however, national registration is not the only access option. In addition, private business responds well to a well-defined need presented in a public tender. 

Because of the low prevalence of certain diseases, it may not be practicable leaving the responsibility with hospitals. Examples include diphtheria antitoxin, rabies antiserum, or certain antidotes. The creation of a national stockpile would remove the responsibility for defined medications from the hospitals and transfer it to the Ministry of Health. Administration of such stockpile shall allow forward deployment of emergency care medications to hospitals. National stockpile also needs to consider drugs that are in chronic or periodic shortage on global markets and those that are only needed in limited amounts under normal conditions but may be in demand suddenly due to diseases with epidemic or zoonotic potential. Medical countermeasures need to be stocked to allow effective response during disasters, industrial accidents, and the release of biological and chemical warfare agents. 

Periodic review of any plans needs to reflect the burden of disease, including future projections, the effects of globalization on the accessibility of drugs, periodic and chronic shortages of specific medications, and the availability of counterfeits. Any plans need to be kept current and operational to be effective. 

The following section is the overview of the availability of essential medicines in the Czech Republic presented by system organ class 

The highest share of approved and marketed drugs was found for glucose lowering agent metformin, gastric ulcer medication omeprazole, fast-acting insulin and oral hypoglycemic agent gliclazide. Unavailable medications include motion sickness drug hyoscine, or scopolamine hydrobromide, docusate sodium – drug for the treatment of constipation important especially in palliatuiva care regimes, intestinal anti-infective paromomycin, ready to use formulations of oral rehydration therapy salts, hydrocortisone for topical rectal use, vitamins nicotinamide and riboflavin, zinc sulfate and sodium fluoride. Most of these products are subject to continuing or periodically emerging global shortages that affect many off-patent drugs and especially sterile injectables and parenteral nutrition components.  

Unavailable medications include low-molecular-weight heparin dalteparin, streptokinase, hydroxycobalmin, dextran and magnesium sulfate. Magnesium sulfate, hydroxycobalamin and dextran are in chronic or periodic shortage globally. Heparins are another group of products subject to periodic global shortages. Heparin is produced almost exclusively in China and any disruptions are likely to result in a global shortage. Import bans imposed by the FDA and other regulators create a window of opportunity to transfer rejected supplies to less regulated markets and jurisdictions with gaps in the detection of adulterated products and inconsistent enforcement. Unavailability of packed red blood cells and fresh frozen plasma is likely related to local incentives for blood donors. Utilization of the same donor pool by commercial producers compounds the problem. 

The availability gap includes injectable vasodilatator hydrazaline, medication for hypertensive crises nitroprusside and potassium-conserving diuretic amiloride. 

The main issues in this therapeutic group are problems relating to other old, off-patent sterile injectable drugs. In addition, some older off-patent drugs such as nitroprusside have become hard to reach due to sudden sharp increase in price. In the U.S., nitroprusside is considered the standard of care, which means that the drug must be available in limited situations when needed. The drug’s price increased significantly upon acquisition by Valeant. 

Many dermatologicals are available as compounded products although they may not be available as registered products. Internationally significant shortages of dermatologicals due occasionally occur, mainly due to manufacturing delays and low demand. Examples of such shortages are chlorhexidine and muciprocin. Shortage of isopropanol (rubbing alcohol) in Europe is a long-term problem caused by major increase in price and relatively low demand.  

Unavailable medications include ergometrine, mainly used as uterotonic for prevention of bleeding after childbirth, contraceptives norethisterone, etonorgestrel, combination of norethisterone and ethinylestradiol, medication for the treatment of menopausal symptoms medroxyprogesterone and estrogen, and emergency contraceptive levonorgestrel. Of these medications, current shortage of norethisterone has been reported from Australia. In addition, shortage of oxytocine and ergometrine has been a chronic problem in Pakistan. 

Prednisolone is available through centralized registration as Okrido (European Commission). 

Unavailable anti-bacterials include beta-lactams cloxacillin and cefalexin, sulfonamide sulfadiazine, macrolide erythromycin, aminoglycosides streptomycin and kanamycin, and spectinomycin. 

Of the three essential antimycotics, flucytosine is not available in the Czech Republic. 

The WHO lists 18 drugs for the treatment of tuberculosis and 2 for the treatment of leprosy. As you can see, the blue stars mark drugs available through special access programs. Green stars mark first-line antituberculars. Combination products are important because of patient compliance with treatment and the prevention of resistance. 

Antivirals are a numerous group scarcely represented in the Czech Republic. In addition to valganciclovir, the unavailable antivirals include standard combinations for the treatment of HIV/AIDS. 

Imunoglobulins are generally well-represented on the Czech market, both for intravascular and extravascular use. Snake venom antisera and rabies antiserum are available through special access programs. Diphtheria antitoxin is not available. Lack of availability of immune sera against rabies and diphtheria antitoxin, as well as snake antivenom against most species are a global problem. Global shortages were also reported for numerous vaccines, namely diphtheria toxoid and tetanus toxoid, as well as Bacille Calmette–Guérin (BCG). 

The highest number of products is available for combined bacterial and viral vaccines, hepatitis B, tick-borne encephalitis, varicella zoster and meningococcal vaccines. Most vaccines are available in combinations, so the only vaccine that is truly unavailable is live attenuated tuberculosis. 

Tretinoin, miltefosine, procarbazine, daunorubicin and dactinomycin are unavailable in the Czech Republic. Shortages and limited availability of generic injectable oncology products have been an ongoing problem for more than a decade. Additional concern relates to counterfeit and falsified cancer products in legitimate supply chain. Drugs in shortage are particularly likely to become the target of counterfeiters due to attempts of hospitals to obtain them from less familiar sources. Efforts to push the costs as much down as possible and procurement and sourcing policies compound the problem. 

As you can see, there is no problem with endocrine system products and immunomodulants. 

In the musculoskeletal system group, only vecuronium, is unavailable. In the U.S., vecuronium is currently in short supply due to manufacturing delays experienced by Pfizer. In December 2013, Pfizer sold Vecuronium injection to Mylan, and in 2014, Ben Venue has stopped production in Ohio. Teva and Sagent are not actively marketing the drug. 

In the group of anesthetics and analgesics, the availability gap includes halothane and combinations of lidocaine. Halothane has been in short supply around the world. 

Other nervous system drugs that cannot be currently obtained in the Czech Republic include lorazepam and methadone. Methadone is registered but not marketed. Lorazepam has been in short supply globally. 

Antiparasitics are the worst affected drug class in the Czech Republic. Of the 36 essential antiparasitic drugs, only 9 are registered and 6 are marketed. Availability of antiparasitic medications is a serious global concern. Especially antimalarial medications are periodically in short supply due to reliance on plant Artemisia that needs to be grown, harvested and processed. Demand increased greatly after in 2004-5 following WHO recommendation to switch to artemisin-based products as first-line treatment. Antimalarials are also among the most commonly found counterfeit drugs. 

In the U.S. Turing’s Daraprim (pyrimethamine) for the treatment of toxoplasmosis recently became the most recognizable antiparasitic medication of all times due to a massive price hike. Acquisition and rebranding of old generic products became another concern that limits availability of certain drugs in developed markets.  

The availability of anthelmintics was discussed earlier as a major concern due to the fact that many parasitic infestations are zoonoses transferred by insect vectors. In the Czech Republic, the lack of availability of antiparasitics is combined with an aggressive internet disinformation campaign that promotes the use of hydrogen peroxide and other folk remedies to tackle parasites. 

Cyclizine is used to prevent nausea and vertigo. It is the only essential respiratory system drug unavailable in the Czech Republic  

In the sensory organs group, the most problematic medications include ophthalmologicals tetracycline, epinephrine, pilocarpine, and tetracaine. Shortages of ophthalmic formulations of generic drugs occur occasionally elsewhere in the world, too. 

In category Various, 11 drugs are unavailable, including antidotes such as edetates, sodium nitrite, dimercaprol, acetylcystein, and fomepizol. Shortage of tuberculin is a global concern, not limited to the Czech Republic. 

ARETE-ZOE, LLC

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