A comprehensive review addressing the factors influencing generic drug substitution

Abstract

Generic drug substitution is a common practice in healthcare systems worldwide to promote cost-saving treatments while maintaining therapeutic effectiveness. Several factors influence this substitution, including regulatory policies, safety and efficacy considerations, patient and physician preferences, and market dynamics. This review comprehensively analyzes how these factors interact and influence generic drug substitution in healthcare settings and across various therapeutic classes and highlight the importance of balancing cost-saving measures with maintaining patient safety and therapeutic efficacy. Policies and guidelines established by health authorities in each country influence the approval, interchangeability, and substitution of generic drugs. Bioequivalence and therapeutic equivalence are critical factors, particularly in drugs with narrow therapeutic indexes. Moreover, physicians’ acceptance and willingness to prescribe generic drugs, as well as patient acceptance and compliance with generic drug use, play a vital role in promoting generic substitution.

Introduction

Generic drugs are medications equivalent to brand-name drugs in terms of their active ingredients, dosage, strength, quality, and intended use. ¹ Nevertheless, they may contain different inactive ingredients than brand-name drugs. These inactive ingredients, such as fillers or colorants, do not affect the drug’s therapeutic effect but may cause an allergic reaction in some people. ² Generic drugs are typically less expensive than their brand-name counterparts and can be a more affordable option for people who need to take prescription medications regularly. Pharmaceutical companies can introduce generic drugs after the patent for a brand-name drug has expired.^1,3 The generic manufacturer must demonstrate to the regulatory agency that the generic drug is bioequivalent to the brand-name drug, meaning it has the same therapeutic effect in the body. ³ Once the generic drug is approved, it can be marketed and sold to consumers.

Overall, using generic drugs is safe and effective and can provide cost savings for consumers. ⁴ Generic drug substitution describes replacing a brand-name medication with an equivalent generic one. This can occur when a healthcare provider prescribes a medication, the pharmacist dispenses a generic version, or when a patient requests a generic version instead of the brand. ⁵ Generally, generic drug substitution is safe and effective since generics must meet the same safety and efficacy standards as their brand-name counterparts. However, there are some situations where generic drug substitution may be inappropriate. For example, some drugs have a narrow therapeutic index, which means that small dose or concentration changes can significantly impact the drug’s effectiveness or safety. ⁶ In these cases, a healthcare provider may prefer to use the brand-name medication to ensure precise dosing. ⁷

Most recently, the coronavirus disease pandemic and the corresponding economic impact induced a lack of access to essential drugs, which encouraged the cost-effective prescription of substitutes. ⁸ Many policies were developed and implemented to encourage doctors to prescribe generics,^9,10 increase their acceptance among patients, ¹¹ and promote their substitution by pharmacists when possible. ⁹ Specific requirements and regulations for interchangeability exist and differ between countries. ¹² Moreover, several factors can affect generic drug substitution, and many misconceptions may prevent it.^5,13 To allow a better understanding of factors affecting generic drug use and substitution, this short review aims to assess the norms for interchangeability and the efficacy and safety of generic drug substitution by addressing the role of different manufacturing countries.

Methods

Two authors independently performed a literature review for 2 months (November-December 2022). The keywords ‘Generic drug’ or ‘Generic medicine,’ substitution’ or ‘interchangeability,’ ‘factor’ or ‘mediator,’ and ‘safety’ or ‘efficacy’ were searched on Google Scholar and PubMed Central. The search results included reports, qualitative reviews, and observational studies after 2000. Conflicts were discussed and resolved at each step of the evaluation. The PICO format was considered for framing a foreground research question. This question was formulated considering the four components: Population: healthcare stakeholders (pharmacists, doctors, nurses, and health authorities), Intervention: generic drug substitution, Comparison: norms for interchangeability, efficacy, and safety of the substitution; and the role of excipients and manufacturing country; and Outcome: factors impacting generic drug substitution.

Results

Overview of generic drug substitution

Many governments have considered using generic drugs to cope with increasing healthcare costs and medical expenses.^14,15 Such efforts required multi-faceted global policies, defining the norms, stakeholders, and rights for drug substitution. Substitution to generic drugs aims to stimulate lower prices through competition and access to cheaper options. ¹⁶ Nevertheless, this involves substituting the same chemical or biological entity at the exact dosage and pharmaceutical form with another product, presenting the same quality, efficacy, and safety profiles.^1,6

Once the marketing authorization file of a generic drug has been accepted, the national regulatory authority can register it, which allows doctors to prescribe it and pharmacists to consider it for substitution.^17,18 The bioequivalence studies guarantee the efficacy of a generic drug identical to that of the originator, but its tolerance may be different due to the disparity of excipients with known effects.^19,20 These studies must guarantee the quality and efficacy of the new generic drug, comparable to those of the corresponding brand drug. Furthermore, manufacturing quality should be fulfilled by assuring adequate compliance with manufacturing conditions and controls by regulatory agencies. ²¹ Previous research found high similarities between a generic drug and its originator regarding efficacy and safety. Nevertheless, many misconceptions and misbeliefs can lead to rejection or lower effectiveness.^10,22,23 However, despite its promotion, substitution to generic drugs is indicative in most countries since community pharmacists are allowed to dispense generics but are not obliged to do so and require patient consent before generic substitution. ²⁴ Among others, generic drug substitution is mandatory in six European countries (Sweden, Germany, Norway, France, Finland, and Spain) and permissive in others (Portugal, Denmark, Italy, Poland, Czech Republic, Netherlands, Hungary, Poland, and Latvia).^24–26 In most cases, Substitution should consider patients’ and doctors’ preferences, the price difference, and the availability of treatment options.

Interchangeability between generic drugs

Market authorization requires that generic drugs be bioequivalent to their originators with an acceptance interval of 80%–125%. ²⁰ This shows that a generic drug may overestimate the pharmacokinetic parameters of the original, whereas another may underestimate them. ²⁷ As a result, while these two generics have demonstrated bioequivalence to the brand to obtain regulatory approval, they are not bioequivalent between themselves. ²⁸ In clinical settings, the outcome could be a loss of efficacy in case of a relative underdosing or the development of drug-related adverse events or toxicity in case of a relative overdosing, especially in drugs with narrow therapeutic indexes. ⁶ A study comparing generic formulations of nine different drugs found that in most cases (87.0% for maximum concentration (Cmax), 90.1% for the area under the curve (AUC), and 80.5% for both) generic drugs are bioequivalent to each other. ²⁹ Only 1% and 3% for AUC and Cmax, respectively, the limits of the interchangeability were exceeded. ²⁹ While these findings were reassuring, changing a prescribed drug (whether original or generic) is reasonable only if there is a valid justification. This is also because bioequivalent drugs may vary in excipient content, affecting their safety profiles. ³⁰

Impact of different manufacturing origins

The manufacturing country of a drug can impact its efficacy and quality due to differences in manufacturing standards, regulations, quality control processes, and the use of different raw materials. ³¹ Different countries have varying regulatory agencies responsible for overseeing drug manufacturing. ³² Some countries have strict and well-established regulatory bodies, such as the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA), which enforce stringent quality control measures. ³³ Other countries may have less stringent regulations, leading to variations in manufacturing practices. Moreover, the implementation and adherence to Good Manufacturing Practices can vary across countries, which as a result, can influence the quality and safety of pharmaceutical products during manufacturing.^33,34 The methods and technologies employed during drug production can impact the drug’s stability, bioavailability, and efficacy. Furthermore, the level of quality control implemented during manufacturing can vary. Well-controlled processes ensure consistency in drug composition and effectiveness. ³⁵ Depending on manufacturing practices, drugs produced in different countries or even by different manufacturers within the same country might exhibit slight variations in efficacy between batches. ³⁶ The high cost of these inspections, particularly in local or small firms, can substantially increase the manufacturing cost and introduce more expensive generic drugs. ³⁷

Conclusion

To ensure the sustainability of healthcare systems, generic drugs are commonly adopted, and firms are encouraged to manufacture and market new generics to increase competitiveness and reduce costs. Despite the economic benefit of having many manufacturing firms, sometimes in the same country, for the same drug, quality assurance and control systems are crucial to ensure the interchangeability and effectiveness of different generic drugs to improve trust in them and their prescription. In contrast, a lack of efficient quality assessment can lead to reduced efficacy and, as a result, decreased use due to doubts among physicians, pharmacists, and patients.