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Quality of low-cost drugs: the frailty of costs savings

Alcocer, Luisa,b

doi: 10.1097/HJH.0000000000001579
EDITORIAL COMMENTARIES
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aMexican Institute of Cardiovascular Health (General Director)

bInteramerican Society of Hypertension (President), Mexico City, Mexico

Correspondence to Prof Luis Alcocer, MD, MPH, General Director, Instituto Mexicano de Salud Cardiovascular, Tuxpan 16, Colonia Roma Sur, Cuauhtemoc, Mexico City 06760, Cd Mx, Mexico. Tel: +52 15554040801; fax: +52 5555741490; e-mail: alcocerdb@gmail.com

The work of Macquart de Terline et al.[1], published in this issue of the Journal of Hypertension, calls attention to a major, alarming problem: the model of access to low-price generic antihypertensive drugs, a possible solution to unequal and inequitable access to treatment in low-income to middle-income countries has weaknesses as patients may receive suboptimal-quality drugs from the market. The authors by using a single quality control method found that the quantity of the active ingredient in the pill available to patients is very often significantly different from the quantity declared on the label. In fact, this occurred at least 25% of the times in the countries of sub-Saharan Africa. This study reveals the tip of an iceberg as it only refers to some aspects of the availability of quality drugs, aspects which are of great importance, but that must be understood within the whole context of the process.

The final goal of the treatment of the patient suffering from arterial hypertension is restoration of the lifetime lost when hypertension is not treated in a timely, adequately, and sustained way throughout life. To achieve this end, sustained and lifelong use of medicines is required. For the correct analysis of the problem, this process should be understood as a quality chain that culminates with therapeutic success and is integrated by the following mandatory steps:

  1. The availability of drugs of sufficient quality, within each pharmacological class and their fixed combinations recommended by applicable guidelines.
  2. Equitable and efficient access for all patients to the medications required for the control of blood pressure, the other cardiovascular risk factors, and the complications and comorbidities present.
  3. The correct and responsible prescription of the necessary and personalized integral treatment for each patient.
  4. The patient's continuing adherence to the prescription.

In brief, first, total and equitable access to drugs by the patient with arterial hypertension would be of little real utility if drugs are not of a quality such as to ensure maximum efficacy, efficiency, and safety; second, access to quality medicines would not be useful if they are not prescribed correctly, and finally, easy access and correct prescription of quality medicines would not be useful if the patient does not adhere to treatment for the rest of his/her life.

The economic aspects of antihypertensive treatment as significant components of health expenditures have the following characteristics:

  1. Inflation of the price of medicine has traditionally been greater than the general inflation index and has grown faster than any other component of health spending [2].
  2. The economic, social, and commercial magnitude of the global drug market is huge and is expected to be $1.12 trillion in 2022 [3].
  3. Spending for health care is highly inequitable as low-income to middle-income countries represent 84% of the world's population [4], but spend only 14.6% of the total amount spent on health worldwide [5].
  4. Healthcare spending is concentrated on a group of elderly people in poor health who make up a very small portion of the population, although a significant portion of the population spends very little on health care. For example, in the United States of America in 2009, 22.7% of all personal healthcare spending benefitted only 1% of the population, and nearly half of all medical expenses regarded 5% of the population. Hypertension is the most frequent chronic medical condition among this group of high spenders and is present in more than 35 and 65% of all nonelderly and elderly people, respectively. The high cost of medical conditions for 5% of all people normally persists over several years [6].
  5. Asymmetric regulation: although name-brand innovative products are subject to strict and universal requirements prior to authorization of their sale, the methods of controlling generic medications vary widely in different countries. High-income countries apply clear rules for generic registration; in contrast, low-income to middle-income countries have regulations ranging from very strict to practically nonexistent.

The high global burden of diseases caused by hypertension makes it a priority public health problem. Treating high blood pressure has very important social and economic implications, and has an impact on macroeconomics. The annual cost of treating hypertension with drugs represents between 0.03 and 0.17% of gross domestic product and between 0.54 and 3.20% of the total health spending of countries in the world, among which Chile and India are those of the highest proportions of spending, and Pakistan, South Africa, and China those with the lowest [7].

Between 2000 and 2013, the use of antihypertensive, antidiabetic, and antidepressant drugs almost doubled, although the use of lipid-lowering drugs tripled. These trends reflect a growing demand for pharmaceuticals due to an increasing prevalence of chronic diseases, aging populations, changes in clinical practice, and expansions in insurance coverage, as well as new treatment opportunities. Guidelines for clinical practice currently have a very important influence on the increasing consumption of pharmaceuticals.

One strategy for containing the cost of treatment involves savings available during the purchase of medications. This method is especially popular among health policymakers and is considered something like a blanket policy as there is a general perception that the direct cost of medications is the main item that can be regulated and can affect the total cost of health care. Nevertheless, this perception requires some clarifications. Although high drug prices are a major barrier to accessing medications for most patients, the cost of medications (pharmaceutical spending) as part of total health expenditures varies from country to country even in the middle-high-income to high-income countries and at different times. For example, for member nations of the Organization for Economic Cooperation and Development in 2013, expenditures on medications consumed outside the hospital was 800 billion dollars, which represents more than 500 USD per person. This is equivalent to about one-sixth (17%) of total health expenditures. If pharmaceuticals consumed in hospitals and other healthcare facilities are added, total spending on pharmaceuticals rises to about 20% of total health expenditures. About 43% of these out-of-hospital drug expenditures are paid from private sources (patient pocket or health insurance), compared with 21% for those purchased for in-patient hospital care. Most private drug spending (37%) comes directly from households [8]. In contrast, in 2016, the WHO [9] indicated that in lower scale middle-income countries, between 20 and 60% of total health expenditures go to medications. In addition, 80–90% of these drugs are purchased as out-of-pocket expenses with 50% of the cost covered by families directly from personal income. This same report indicated that the proportion of generic drugs acquired by these countries was 42% in the public sector and 72% in the private sector. Generics account for more than 90% of China's total pharmaceutical market [10]. In the United States, generic medications account for approximately 75% of prescriptions, but represent only 13% of the cost of newer, name-brand, and more expensive medications.

Importantly, as more than 50% of drug spending comes directly from personal income in most low-income to middle-income countries, purchasing medications can lead a family toward poverty; one study estimated that 10–17% of the population would be pushed under the $1.25/day poverty line because of purchasing individual name-brand medications [11]. Moreover, switching from name brands to the lowest priced generic equivalents could result in an average cost savings of 60% in the private sector in 17 developing countries [12].

The acquisition of low-cost generic drugs is very important. The WHO defines generic medicine as ‘a pharmaceutical product’ usually intended to be interchangeable with a name-brand product that is manufactured without the license from the original manufacturer and is marketed after the expiration date of the original patent [13]. This provides an attractive solution to the problem of rising drug costs in medium-income to low-income countries. However, in the context of socioeconomic conditions and state participation, generic policies in these populations require a different strategy from those used in developed countries. Individuals with high blood pressure in populations in these relatively low-income countries are largely undiagnosed and if diagnosed, are often poorly treated. Providing adequate medication is hampered by strong constraints in terms of purchasing power, government reimbursement, and the quality of medicine available, as well as by access to health care and accurate diagnosis. In these settings, what matters most to the authorities and patients is the availability of a good-quality medicine at a reasonable price.

The purchase of medications at a relatively low price has several scenarios that must be considered.

  1. A name-brand, lower-priced drug obtained through negotiation based on purchase volumes, generally based on consolidated purchasing.
  2. A generic labeled with the name of the salt or branded generic, which may be interchangeable (bioequivalent, manufactured under Good Manufacturing Practice standards with the same effectiveness of the original medication).
  3. A suboptimal copy of a drugSalt with the same name, but of low qualityInadequate excipientImproper manufacturingIncorrect packagingInappropriate storageCombinations of the above
  4. Fraudulent drugsDeciduousStolenCounterfeit

On 29 May 2017 at the 70th World Health Assembly, the WHO adopted rules related to substandard/spurious/falsely labeled/falsified/counterfeit drugs, defined as follows: The word ‘substandard’ was also called ‘out of specification;’ these include authorized medical products that fail to meet either their standards or specifications, or both.

Unregistered/unlicensed: medical products that have not undergone evaluation and/or approval by the National or Regional Regulatory Authority for the market in which they are marketed, distributed, and/or used, subject to permitted conditions under national or regional regulation and legislation.

Falsified: medical products that deliberately and/or fraudulently misrepresent their identity, composition, or source [13].

It is important to insist that the purchase of inexpensive generic drugs is an attractive solution to the problem of rising drug costs; however, a fundamental requirement is that the quality of generic drugs is not inferior to that of brand-name medications. This seems like an obvious concept; however, it is not easy to evaluate medications in daily practice. The main techniques related to quality assurance include as follows:

  1. Stability and bioequivalence
  2. Bioequivalence studies are a surrogate marker for clinical effectiveness and safety data.
    Definition: ‘Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioability (rate and extent of availability) after administration in the same molar dose are like to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same. Pharmaceutical equivalence implies the same amount of the same active substance(s), in the same dosage form, for the same route of administration and meeting the same or comparable standards’ [14].
    The main limitations of this definition are that the drug is tested in conditions very different from those occurring when the drug is consumed in real life. These tests are performed on healthy patients, in very small samples, with a very short time of exposure to the drug, and are performed with a single dose. The actual differences between generic and name-brand medications to determine that two medications are bioequivalent is accepted to be a ±20% difference between the statistical ‘area under the curve’ and Cmax.
    Another important problem with these type of tests is in using a technique assuring the quality of the finished product, when in fact it is desirable to control the quality of the process and not only the final product. In other words, it is preferable not to allow low-quality products to be manufactured and not to allow such products to be sold when they have already been manufactured.
  3. One way to ensure interchangeability would be to conduct comparative studies of noninferiority, safety, and efficacy between the generic and the brand-name products. These types of evaluation are rarely practiced, even though they would be the most similar to those studies that are required to license a name-brand drug.
  4. Standardization, certification, and monitoring of good drug manufacturing practices.

Good Manufacturing Practice is the part of quality management which ensures that products are consistently produced and their quality is controlled according to standards appropriate to their intended use. Ideally, marketing authorization for pharmaceutical products, included generics, should only be granted to those pharmaceuticals produced by licensed manufacturers (holders of a manufacturing authorization) whose activities are regularly inspected by competent national authorities [15].

In 2014, a group of experts from seven Latin American countries met in the Balbuena neighborhood of Mexico City and issued the Statement of Balbuena [16], providing a position on the use of quality generic medications; this statement is summarized as follows:

Access to quality medications is a fundamental human right as having this right is necessary for the rights to life, health, and well being.

To ensure the best possible accomplishment of his or her mission, a physician needs to know that a patient has full access to the best quality medications, as prescribed.

Generic drugs are an appropriate substitution which can be used to improve the efficiency and equity of access to medications, provided that their therapeutic equivalence is assured. Having this equivalence requires the demonstration of bioequivalence by the manufacture under the strict monitoring of ‘Good practices of manufacturing,’ by a laboratory with current process certification, with certified quality of the finished product, and preferably with clinical studies of noninferiority.

Strict compliance with these standards is the criterion that must be adopted by health authorities prior to granting marketing authorization and dispensation of any medication.

Pharmacovigilance should be mandatory for the testing of all medications and should be done not only to test for side effects but tests of therapeutic failure should also be conducted.

The patient should be fully informed about the characteristics of a drug that replaces an original innovative medication and this information should not be based solely on the difference in price, whether paid by a third-party payer or received from an institution with which the patient is affiliated.

The responsibility for ensuring that the drug prescribed under a generic name is interchangeable rests with the government health authorities and responsibility for therapeutic failure or adverse side effects attributable to the preparation is by no means the responsibility of the patient or the physician who prescribed it.

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ACKNOWLEDGEMENTS

Conflicts of interest

There are no conflicts of interest.

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REFERENCES

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