Intensifying competition and pricing pressures in the pharmaceutical industry are placing demand on developers and manufacturers to explore innovative pathways to differentiate their products and create value, particularly in the generic drug market. As a result, many pharma companies are turning their focus to value-added medicines (VAMs) to achieve differentiation. VAMs stand at the forefront of pharmaceutical innovation, offering enhanced therapeutic options that distinguish themselves from traditional generics. This article examines the different approaches to VAM development and explore the complexities involved in bringing VAMs to market, including formulation hurdles and clinical considerations. 

Exploring the Innovation Behind VAMs

VAMs represent a distinct category of therapies within the pharmaceutical landscape, going beyond the scope of traditional generic drugs. While generics primarily focus on replicating the active ingredient and therapeutic effect of an original drug, VAMs are created through incremental innovation of well-established medicines, introducing enhancements that create tangible benefits for patients, healthcare providers and payers. These improvements commonly focus on providing better therapeutic outcomes, promoting adherence and personalizing medicines to specific patient groups, such as children or the elderly.

The development of VAMs is primarily facilitated through three distinct approaches, each offering unique opportunities for innovation and therapeutic advancement:

1. Drug repositioning/repurposing

This approach involves the identification and exploration of new therapeutic applications for existing, approved drugs. A prime example is the repurposing of sildenafil (Viagra), originally developed for hypertension, to treat erectile dysfunction.^1,2 Similarly, dexamethasone, a widely used corticosteroid, was successfully repositioned for the treatment of COVID-19.³

2. Drug reformulation

This strategy focuses on the development of new and improved formulations of existing drugs. Reformulations can optimize drug delivery, enhance patient compliance or address specific patient populations. The development of Pheburane oral pellets is one example of drug reformulation. The taste-masked formulation of sodium phenylbutyrate (NaPB) was developed to address the bitter taste of traditional NaPB treatments for pediatric patients with urea cycle disorders.^4,5

3. Drug combinations

This approach involves the combination of two or more active ingredients into a single dosage form. Fixed-dose combinations can offer advantages such as simplified treatment regimens, reduced pill burden and synergistic therapeutic effects. Vimovo, a combination of naproxen, a non-steroidal anti-inflammatory drug (NSAID) that provides pain relief and reduces inflammation, and esomeprazole, a proton pump inhibitor that decreases stomach acid production, is a prime example of applying this approach. The combination of these two active ingredients enables Vimovo to provide pain relief while mitigating the risk of gastric irritation and NSAID-associated gastric ulcers that can be caused by naproxen.^6,7

Formulation Considerations for VAMs

The journey of a VAM from concept to patient involves a series of carefully orchestrated steps, with formulation and clinical development playing pivotal roles. Formulation transforms the VAM concept into a tangible product, addressing key challenges and optimizing its therapeutic value and patient experience. Throughout formulation, VAM developers and manufacturers will need to carefully consider the steps they will take to enhance already known molecules, these strategies could include:

Tailoring dosage forms and strengths

Adapting dosage forms and strengths is a fundamental strategy in VAM development to enhance patient experience and optimize treatment outcomes. This can involve:

• Transforming solid dosage forms into liquids, improving ease of administration for pediatric or geriatric populations.

• Developing age-appropriate formulations like mini-tablets or orally disintegrating strips to address specific patient needs.

• Modifying dosage strengths to enable personalized treatment regimens, ensuring optimal efficacy and safety for individual patients.

These adaptations often necessitate overcoming formulation challenges such as solubility and stability. For instance, when developing liquid formulations, maintaining stability and ensuring adequate drug solubility can be critical hurdles. Developers will need to employ techniques like solubilization agents, pH adjustment and stability-enhancing excipients to overcome these challenges.

Improving stability

Stability is a critical factor in drug product development, especially for liquid formulations susceptible to degradation. Chemical instability, such as hydrolysis or oxidation, and physical instability, like polymorphic transitions or crystal growth, can compromise a VAM’s efficacy and safety. 

To improve stability, VAM developers can leverage a range of strategies, including:

• Careful selection of excipients compatible with the active pharmaceutical ingredient (API) and formulation.

• Optimization of packaging materials to protect the product from environmental factors.

• Implementation of specialized techniques like lyophilization or the addition of stabilizers.

By prioritizing stability, developers can ensure that their VAMs remain potent and safe for patients, reinforcing their value proposition and contributing to better therapeutic outcomes.

Enhancing the sensory experience

The sensory attributes of a medicine, encompassing its taste, smell and texture, significantly impact patient acceptance and adherence, particularly for pediatric and geriatric patients. VAM developers must carefully consider the therapy’s palatability to ensure it is palatable for the intended patient population. 

Taste-masking technologies, such as coatings, flavoring agents and complexation, play a key role in transforming unpalatable active ingredients into more agreeable forms. Additionally, optimizing texture and mouthfeel can further enhance the patient experience and promote compliance.

Optimizing release profiles and dosage regimens

Modifying release profiles is a key strategy to achieve tailored drug delivery, offering benefits like faster onset of action, sustained release for prolonged therapeutic effect or reduced dosing frequency for improved patient convenience. These modifications necessitate overcoming formulation challenges related to controlling drug release kinetics and ensuring consistent drug levels in the body. Innovative formulation techniques, such as modified-release polymers, matrix systems or targeted drug delivery technologies, can be employed to achieve these desired release profiles.

However, achieving such precise control over drug release kinetics presents significant formulation challenges. Developers must carefully select and balance the proportions of immediate-release and modified-release components, ensuring consistent drug levels in the body while avoiding fluctuations that could compromise efficacy or safety. This necessitates a deep understanding of drug dissolution, diffusion and absorption processes.

Compatibility in product combinations

Combining multiple active ingredients into a single dosage form, such as fixed-dose combinations, simplifies treatment regimens, reduces pill burden and can even achieve synergistic therapeutic effects. However, formulation challenges can arise in ensuring compatibility between the different APIs, maintaining stability of the combined product, and achieving the desired release profiles for each active ingredient.

Rethinking administration route

Changing the route of administration, such as from intravenous to subcutaneous injection or from oral to transdermal delivery, can significantly enhance patient convenience, improve adherence, and reduce healthcare resource utilization. This approach, however, often requires reformulation to ensure optimal drug delivery and bioavailability via the new route. Addressing challenges related to drug permeation, stability in the new dosage form and patient acceptability are crucial in successfully implementing route of administration changes.

Ensuring Safety & Efficacy in VAMs with Appropriate Clinical Studies

Drug developers must also navigate the crucial phase of clinical development. This stage serves to establish the safety and efficacy of the VAM, ensuring it meets rigorous standards before reaching patients. Understanding the specific scenarios where clinical development programs are necessary is vital for sponsors seeking to bring their VAMs to market successfully. 

Clinical studies may be required for VAMs in several scenarios, for example, If a VAM makes novel claims regarding its safety or efficacy compared to the reference product, clinical data from controlled studies are typically required to substantiate these claims. This could involve demonstrating superior efficacy in a specific patient population, a reduced incidence of side effects, or an improved therapeutic outcome.

When a VAM introduces a novel combination of active substances not previously used together, clinical studies may also be required to evaluate the safety and efficacy of the combination, particularly if there is a lack of supporting literature or data. Drug-drug interaction studies may also be necessary to assess potential interactions between the combined active ingredients.

Additionally, if a VAM is intended for use in the pediatric population, clinical studies may be needed to establish its safety and efficacy in children, as extrapolation from adult data may not always be sufficient.

Clinical studies may also be required if modifications to the drug’s formulation, strength, release profile or route of administration are likely to alter its blood concentration profile. In such cases, bioequivalence studies are often necessary to demonstrate that the VAM exhibits comparable pharmacokinetic properties to the reference product, ensuring a consistent therapeutic effect.

As part of clinical development, bioequivalence studies play a key role, especially when modifications in formulation, dosage strength, release profile or route of administration are introduced. These studies serve to demonstrate that the VAM exhibits comparable pharmacokinetic properties to its reference product, ensuring that the active ingredient is absorbed, distributed, metabolized and excreted in a similar manner.

However, in some cases, bioequivalence may not be fully achievable due to inherent differences in formulation or release profile. In such scenarios, sponsors can explore various strategies to address bioinequivalence, such as:

• Providing clinical justification: Demonstrating through clinical data that the observed differences in pharmacokinetic parameters do not translate into clinically significant differences in safety or efficacy.

• Dose adjustments: Proposing a dose adjustment for the VAM based on the observed differences in bioequivalence studies, ensuring comparable therapeutic effect.

• Formulation optimization: Revisiting the formulation to minimize differences in pharmacokinetic parameters and achieve bioequivalence.

The Future of VAMs & the Power of Strategic Partnerships

VAMs represent a dynamic and promising frontier in the pharmaceutical landscape. They offer a strategic pathway to address unmet patient needs, enhance therapeutic outcomes, and navigate the challenges of an increasingly competitive market. By building on existing knowledge and leveraging innovative formulation approaches, VAMs have the potential to revolutionize patient care and deliver significant value to the healthcare system. As the demand for innovative and patient-centric medicines continues to grow, VAMs are poised to play a pivotal role in shaping the future of healthcare.

However, the successful development and commercialization of VAMs require specialized expertise and a deep understanding of the formulation and clinical complexities involved. Partnering with an experienced contract development and manufacturing organization (CDMO) can be a strategic imperative for companies seeking to capitalize on the potential of VAMs. A CDMO with a proven track record in formulation development and clinical expertise can provide invaluable support throughout the VAM lifecycle, from concept to commercialization. By leveraging the capabilities of a trusted CDMO partner, pharmaceutical companies can accelerate their VAM development timelines, mitigate risks and optimize their chances of success in this rapidly evolving market.

References

1. Hatzimouratidis K. Sildenafil in the treatment of erectile dysfunction: an overview of the clinical evidence. Clin Interv Aging. 2006;1(4):403-14. doi: 10.2147/ciia.2006.1.4.403. PMID: 18046917; PMCID: PMC2699643.

2. https://www.accessdata.fda.gov/drugsatfda_docs/NDA/98/viagra/viagra_toc.cfm

3. RECOVERY Collaborative Group, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.

4. Kibleur Y, Dobbelaere D, Barth M, Brassier A, Guffon N. Results from a Nationwide Cohort Temporary Utilization Authorization (ATU) survey of patients in france treated with Pheburane(®) (Sodium Phenylbutyrate) taste-masked granules. Paediatr Drugs. 2014 Oct;16(5):407-15. doi: 10.1007/s40272-014-0081-5. PMID: 24962711; PMCID: PMC4168023.

5. https://www.biospace.com/pheburane-sodium-phenylbutyrate-coverage-rapidly-expands-to-the-benefit-of-americans-with-certain-urea-cycle-disorders-ucds

6. https://www.drugs.com/pro/vimovo.html

7. https://www.medicines.org.uk/emc/product/5743/pil

John Kytariolos is head of clinical and scientific affairs, and Konstantinos Apostolou, is senior manager for R&D, at Adragos Pharma.