CPD: Is generic substitution in NTIDs ethical?

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Is generic substitution in NTIDs ethical?

Generic substitution is advocated worldwide to reduce healthcare-related costs.1 In South Africa, medicine substitution is promulgated by the South African Medicines and Related Substances Act (Act 101 of 1965).2 In addition, the Consumer Protection Act (Act 68 of 2008) affords consumers the right to choose.3

Some experts, however, argue that substitution is not always in the best interest of the patient and can in fact have a negative impact on outcomes – especially in those treated with narrow therapeutic index drugs (NTIDs) also referred to as critical dose drugs.1

The aim of this article is not to question the value of generic substitution, but rather to provide healthcare professionals with some guidance on generic substitution of NTIDs, because of these drugs’ narrow margin between safe and lethal dosages.

Legal and ethical considerations in generic substitution

The South African Medicines and Related Substances Act makes provision for substitution of an innovator or branded drug by an interchangeable multi-source drug. The only time a pharmacist may not dispense a substitute is when the patient expressly forbids it, if the prescriber has added in his/her own handwriting ‘no substitution’ next to the drug prescribed, if the retail price of the interchangeable multi-source medicine is higher than that of the prescribed medicine, or if the drug has been declared not substitutable.2

According to the Consumer Protection Act, patients are ‘consumers’ from a legal perspective. Therefore, patients have the right to equality in terms of marketing, privacy, choice, disclosure of information, fair and responsible marketing, fair and honest dealing, fair, just, and reasonable terms and conditions, fair value, good quality and safety, and to hold the supplier accountable.3

The Health Professions Council of South Africa’s (HPCSA) ethical guidelines state that ‘healthcare practitioners should honour the right of patients to self-determination or to make their own informed choices, and to live their lives by their own beliefs, values and preferences’.4

The guidelines also state that healthcare practitioners should always have their patients’ best interests or well-being as their primary professional focus, respond appropriately to protect patients from any risk or harm and explain to the patients the benefits, costs and consequences associated with each service option offered.4

A practitioner may prescribe or supply medicine or a medical device to a patient, provided that the diagnosis of the patient has been confirmed through a personal examination or by virtue of a report by another practitioner under whose treatment the patient is or has been, and such medicine or medical device is clinically indicated.4

Furthermore, the patient should be offered the best possible care at a cost-effective rate compared to other available medicines or medical devices, and the patient is informed of such other available medicines or medical devices. However, in the case of a patient with a chronic disease, the above-mentioned does not apply.4

Medicine and therapeutic substitution

Substitution infers switching to another drug because it is cheaper. Substitution can be generic or therapeutic. Generic substitution means switching between a branded product and a generic version of the same drug. Therapeutic substitution refers to switching between drugs either within the same class or from different classes, with the same clinical effect. This article focuses on generic substitution.1

Generic drugs are produced without a licence from the innovator company when the patent or other market exclusivity rights on the innovator product has expired.5

According to the World Health Organization approval of a generic is based on the demonstration of interchangeability or therapeutic equivalence to the innovator through bioequivalence studies.5

Because the active ingredient in the generic drug has already been shown in testing of the brand-name drug to be safe and effective, bioequivalence studies only have to show that the generic produces virtually the same levels of the drug in the blood over time.7

Bioequivalence studies must demonstrate a 90% confidence interval for the generic/ innovator ratios of the area under the drug curve (AUC), and that the maximum concentration (Cmax) is within the range of 80%-125%. This acceptance range of 80%125% can be widened based on a scaled approach for Cmax up to 69.84%-143.19% for highly variable drugs or can be tightened to 90%-111.11% for NTIDs.6

Generics can contain different nontherapeutic components such as colourants, preservatives, lubricants and diluents, which may lead to differences between the two drugs. The American College of Cardiology Foundation (AACF)/American Heart Association’s (AHA) most Health Policy Statement on Therapeutic Interchange and Substitution guideline, warns that some additives traditionally thought to be inert, such as alcohol sugars, cyclodextrins, and polysorbate-80, may alter a drug’s dissolution, thereby impacting its bioavailability. 7,11

Bioequivalence studies require testing in only a small number (eg 24 to 36) of healthy volunteers.6p1 Tamargo et al argue that studies in healthy volunteers, who do not take any concurrent medication, assume that bioequivalence in this homogeneous population will equate to all patient populations.7

The authors explain for example, that patients with tachyarrhythmias are older, present structural heart diseases, are treated with several drugs and present rapid changes in heart rate over time, leading to intraindividual variability in drug pharmacodynamics (PD) and -kinetics (PK) due to a decrease in cardiac output, volume of distribution and organ perfusion. This population is quite different from that in whom the average bioequivalence testing is performed, they state.7

In addition, writes Reiffel, bioequivalent studies do not test the reproducibility of the measurements, which, for patients whose values are at the extremes of the 80% to 125% range, may cause periodic fluctuations out of the range. For antiarrhythmic inefficacy or proarrhythmia, a momentary, brief excursion out of a therapeutic range may be all it takes for a clinical event to occur.8

For regulatory agencies, narrow bioequivalence values may be adequate, but for practitioners, potential inefficacy or toxicity becomes an issue, even though therapeutic equivalence will hold true for most patients, adds Reiffel.8

Although studies demonstrate generic–innovator bioequivalence, some reports suggest that bioinequivalence may exist for several drugs

Concerns about NTI drug substitution

NTIDs have the following characteristics:7

» Steep drug dose-response relationship for both safety and efficacy within the usual dosing range or narrow span between effective drug concentrations and concentrations associated with serious adverse drug reactions

» Serious adverse reactions are defined as those which may be persistent, irreversible, slowly reversible, or life-threatening, which could result in in-patient hospitalisation or prolongation of existing hospitalisation, persistent or significant disability or incapacity, or death

» They are subject to therapeutic drug monitoring based on PK or PD measures to ensure safe and effective use of the drug

» Small within-subject variability. Otherwise, patients will routinely experience toxicity and lack of efficacy.

Therapeutic index is calculated using two indicators: the effective dose (ED) to 50% of laboratory animals (dose that causes the clinical effect to half of the laboratory animals), and lethal dose (LD) 50% (the dose that kills half the laboratory animals). The therapeutic index is the ratio between LD50 and ED50. The therapeutic index is considered small when the ratio between LD50 and DE50 is <20%. NTID dosages require careful titration and have to be individualised. Therefore, by definition, generic substitution is not applicable to NTIDs, postulate Paveliu et al.9

Black stresses that substitution should be done with caution, if:3

» A patient is stabilised on a particular medicine, the pharmacist should be cautious when switching him or her to another product. There are individual reactions to particular medicines

» Extra caution should be applied in the case of elderly patients. Elderly people often resist change, and even small changes, such as the colour, size, or shape of a tablet, may lead to non-adherence

» Although the old non-substitutable list published by the former Medicines Control Council now no longer applies, it may serve as a useful reminder or reference source for some medicines which should be substituted with caution, for example, drugs with an NTI.

Although studies demonstrate generic–innovator bioequivalence, some reports suggest that bioinequivalence may exist for several drugs.8

Reiffel cautions that the generic equivalence of NTIDs, is of particular concern – especially those used in the treatment of neurological, immunosuppressive, haematological (anticoagulants), and cardiovascular (antiarrhythmics, hypertension) conditions.8

The AACF/AHA guideline recommends:11

1. Therapeutic substitution should not be accepted.

2. Each healthcare facility should have a formally chartered interdisciplinary pharmacy and therapeutics committee charged with ensuring medication safety and developing an evidence-based formulary. The committee’s charge should include the development of policy for therapeutic interchange/substitution. Decisions and recommendations should be reviewed at least annually to address new evidence as it becomes available.

3. All formulary decisions should be made based primarily on the recommendations of the healthcare team after considering the scientific evidence in the specific patient or patient groups to be treated and the ratio of risk/balance in that setting. These decisions should be widely and proactively promulgated to prescribing physicians and include provisions for appeals both at the policy level and for individual patient exceptions. Economic considerations, although of substantial importance, should only be addressed after those other considerations have been fully evaluated.

4. Applicable policies concerning metrics of equivalence, manufacturing, packaging, and purity need to be monitored annually, at minimum. These policies should be followed by the pharmacy and therapeutics committee with the appearance of new formulations or generics on the market and when issues surrounding product manufacturing, packaging, and purity are reported by specific manufacturers. It is very important for healthcare teams to have full and timely access to measures of bioequivalence in generic drugs.

5. Contemporary pharmacy practice requires confirmation that a substituted generic drug is bioequivalent to the prescribed product. At the state level, policymakers overseeing generic substitution should encourage consistency in regulations. When dispensing medications for chronic conditions, a pharmacist should communicate to the patient both verbally and in writing (eg on the label of the prescription bottle) when a medication’s manufacturer has changed. This is of particular importance when dispensing NTIDs.

6. Pharmacogenomics may have a substantial impact on the field in the future. As scientific data and evidence continue to emerge and technologies improve, policies should be adapted as needed. This may enhance the ability to personalise medical care for the individual patient.

7. Special groups of patients with unique requirements, such as immunocompromised patients, paediatric patients, women – particularly those who are pregnant – or the elderly who require multiple medications in the setting of acute or chronic illness, should be given special consideration before therapeutic substitution is implemented. This is of significant importance when drugs with an NTI/toxicity ratio are administered or considered.

Primum non nocere

Medicine’s guiding principle is ‘first do no harm’. According to Reiffel, if generics of innovator drugs are similar, but not absolutely identical to the originator drug, then their reduced cost may come at some risk to the patient, such as an altered efficacy, safety, or tolerance profile.8

According to Paveliu et al the decision to substitute should be based on exclusively on the medical indication, therapeutic equivalence information, financial factors, and consideration of how the substitution will impact the patient. Generic substitution of NTDIs should be avoided.9

Alameri et al argue that when substitutions involve a cheaper drug that is known to have different effects and side effects, or even a drug whose effects and side effects are unknown, they are potentially deleterious to the patient, and that no competent and wellinformed patient would ever consent to them. Such substitutions are thus unethical in their very own terms.1

Sweeping, indiscriminate, and empirically poor substitutions clearly give financial savings exclusive priority over any other considerations. Moreover, they cannot even presume to be cost-effectiveness because additional monitoring may offset any the potential cost savings, they add.1

“Switching patients to alternative drugs may require additional clinician time in providing reassurance to patients. This may result in compromising patients’ adherence and may also result in further switches back to the original branded drugs. As long as we adhere to a patient-centred medicine, we should not support substitutions that lack sufficient data asserting clinical equivalence,” conclude Alameri et al.1

References

1. Alameri NM, Epstein M and Johnson A. Generic and therapeutic substitutions: Are they always ethical in their own terms? International Journal of Clinical Pharmacy, 2010.

2. Medicines and Related Substances Act, 1965 (Act 101 Of 1965).

3. Black G. Generic substitution and the Consumer Protection Act: a pharmacist’s perspective. SAPJ, 2013.

4. HPCSA. Ethical guidelines for good practice in the health care professions. https://www.hpcsa.co.za/ Uploads/Professional_Practice/Ethics_Booklet.pdf.

5. WHO. Generic medicines: Interchangeability of WHOprequalified generics. WHO Drug Information, 2016.

6. Yu Y, Teerenstra S, Need C, et al. Investigation into the interchangeability of generic formulations using immunosuppressants and a broad selection of medicines. European Journal Pharmacology, 2015.

7. Tamargo J, Le Heuzey J-Y and Mabo P. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. European Journal Pharmacology, 2015.

8. Reiffel JA. Issues in the use of generic antiarrhythmic drugs. Current Opinion in Cardiology, 2001.

9. Paveliu MS, Bengea S, Paveliu F, et al. Generic Substitution Issues: Brand-generic Substitution, Generic-generic Substitution, and Generic Substitution of Narrow Therapeutic Index (NTI)/ Critical Dose Drugs. Medica, 2011.

10. Singh A, Maisch NM and Saad M. A Closer Look at Generic Interchangeability in Narrow Therapeutic Index Drugs. US Pharmacists, 2014.

11. Holmes DR, Becker JA, Granger CB, et al. ACCF/ AHA 2011 Health Policy Statement on Therapeutic Interchange and Substitution. Circulation, 2011. SF

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