Absorption Systems: complex generics offer obstacles, opportunities

Generic drugs comprise a significant chunk of pharmaceutical business—more than 80% of all drugs prescribed to US patients currently are generic products. However, getting such therapies in the hands of users can be challenging, especially for complex products.

Outsourcing-Pharma (OSP) recently talked with Vatsala Naageshwaran (VN), chief business officer for Absorption Systems, about the vital role generic drugs play on the pharmaceutical landscape, and how to overcome the various challenges associated with bringing such drugs to market.

OSP: Could you please talk about generic drugs, and their role in the market?​

VN: A generic medicine works in the same way as its branded equivalent, providing the same clinical benefit. To ensure generics can be effectively substituted for the branded drug, the FDA requires pharmaceutical companies to demonstrate that they are the same in terms of dosage, effectiveness, strength, durability, and quality, as well as in the way they are administered.

Generic drugs cost less to develop than the branded equivalent as there is less burden in terms of the clinical studies that need to be performed. After the patents and exclusivity that protect the branded product have expired, it’s not unusual for multiple generic versions to be created, causing good market competition that drives down prices. In fact, generic drugs typically cost 85% less than the branded product.

According to IMS Health Institute, generic drugs saved the US healthcare system $1.6t between 2007 and 2016. And if we compare the percent of prescriptions to the percent of cost, branded products account for only about 11% of all prescriptions, yet they constitute 74% of the pass-through cost to the Medicare system, which is about $334 billion.

On the other hand, generics account for about 89% of all prescriptions but comprise just 26% of the cost, so you can see there is a significant financial benefit to patients as well as the medical system.

OSP: What is meant by a complex generic drug product?​

VN: A complex generic product could have a complex active ingredient, formulation, route of delivery, or be a drug-device combination. Since the market has become saturated with simple generic products, many companies are turning their focus to complex generic drugs, which deliver more value to patients by addressing additional unmet needs by promoting drug competition and patient access.

By focusing on complex generics, companies can also achieve market differentiation and take advantage of opportunities for a higher margin. However, the added complexity associated with the drugs can result in substantial uncertainty about how to approach the development of these products.

OSP: Could you please talk about some of the obstacles and challenges in bringing complex generics to market?​

Ensuring equivalence to an approved branded product is the primary goal and challenge when developing a complex generic. First it is necessary to make assumptions about some aspects of pharmaceutical equivalence (qualitative Q1 and quantitative Q2); this translates to the same active ingredients, inactive excipients, dosage form, route of administration, strength, and so on.

Beyond that, you have to demonstrate bioequivalence, meaning there is a very similar rate and amount of the active ingredient at the site of action. Once generic products have demonstrated pharmaceutical equivalence and bioequivalence to the reference branded product, you rely on the safety and efficacy of the branded product to establish therapeutic equivalence; only once therapeutic equivalence has been demonstrated can your product be substituted for the branded product.

The most common method for evaluating bioequivalence of two formulations of a simple, orally administered drug is to do a competitive blood level trial—the assumption is that the drug has to enter the systemic circulation to reach the site of action. The resulting blood level vs. time profile following administration also reflects the product’s solubility, permeability, and the effect of the formulation on the rate and extent of drug release and drug absorption.

But when it comes to complex products, these have either a complex formulation or a complex route of administration. Additionally, a number of these products act locally rather than systemically, and therefore it’s not possible to use the systemic compartment to compare concentration levels.

Therefore, the only option for these complex generics is to use a clinical endpoint study to establish bioequivalence. However, the design of a clinical endpoint study requires the enrollment of hundreds of patients, often over a long duration, making these studies very expensive to conduct.

Clinical endpoint studies can also present some safety concerns because of unknown inter-subject variability within the reference population, and this variability can make it very difficult to achieve consistency between studies, resulting in a high likelihood of such studies failing. This is a big obstacle in bringing complex generics to market and can result in the loss of significant resource and financial investment.

OSP: You mentioned that applying alternative in vitro methods can help. Could you please explain and discuss the importance and benefit in this?​

VN: Developing a complex generic product is challenging because pharmaceutical equivalence may not translate to a therapeutically equivalent formulation. As a result, a generic formulation that is qualitatively (Q1) and quantitatively (Q2) the same as a reference formulation can still have different physicochemical properties, due to the complexity of manufacturing processes; this can impact particle size, interfacial tension between the phases, product rheology, etc. of a complex formulation, which in turn can affect critical in vivo parameters, and ultimately the rate and extent of drug delivery at the target site.

Investigations have shown that even when you have formulations that are similar in terms of these physicochemical parameters, you may still see differences in pharmacokinetics and efficacy. There are critical gaps that remain in the testing recommended for these products because there is a lack of understanding of the biological complexity; ultimately, this is what perpetuates the barrier for the successful development of complex generics.

So, when we talk about alternative in vitro methods, there are several testing methodologies used, called Q3 tests, which evaluate the physicochemical characteristics of a product. In fact, the FDA has published several guidance documents for complex topical and ophthalmic products that include this option.

However, the adequacy of these tests to establish bioequivalence is still in question and, importantly, there are no set criteria for the comparative assessment of the generic products versus the branded, making the outcomes methodology dependent. The impact of physicochemical factors on in vivo parameters is not established and these tests typically lack physiologic relevance.

Bioassays are necessary to complement these Q3 tests and provide ’totality of evidence’ for confirmation of therapeutic equivalence between a generic and reference product.

OSP: Could you please also talk about taking an integrative bioequivalence approach, and what benefits/advantages come from that?​

VN: The benefit of an integrated bioequivalence approach is that we can evaluate complex, multifaceted formulations while looking at the entire behavior of the formulation in a biological setting, instead of measuring a single formulation property at a time, which is what a Q3 test does.

Understanding the behavior of the formulation is very important in terms of developing a performance matrix for the complex drug product. In this context, bioassays are very useful as they help us look at the differences in pharmaceutics-based formulations and functional characteristics between a test and a reference product. We can then use these insights to develop a more bio-relevant system or assay.

Additionally, a bioassay can overcome residual uncertainty in product equivalence as it integrates all the discrete formulation characteristics within a single assay. Finally, when bioassay data are combined with other evidence of excipient effects, you can establish the bio-impact of any quantitative (Q2) differences that may exist between the generic formulation and a brand product.

OSP: Could you talk about how in vitro bioassays can be harnessed effectively, and how they can reduce reliance or burden on human trials ongoing?​

We’re seeing that the COVID-19 pandemic is having a significant impact on clinical trials in terms of patient enrollment and care, and data collection and analysis, irrespective of indication. During these times, in vitro bioassays are extremely beneficial as they enable a waiver of clinical endpoint studies.

By precluding the need to perform these clinical trials, bioassays reduce the barriers for complex generic products. Instead, a comprehensive approach, which integrates data across multiple physicochemical and biological parameters, minimizes the requirement for clinical trials and enables the development of these needed complex generic products.

OSP: How is the FDA working with the industry and companies like Absorption Systems to enable patient access to affordable complex generics?​

VN: Historically it has been difficult to gain approval of complex generic products due to their complex formulation or mode of delivery. As a result, many complex drugs lack generic competition, even though there is no exclusivity to block their approval.

In response, the FDA has taken several steps in conjunction with the industry to identify and develop in vitro assays. They have prioritized research to establish reliable and reproducible scientific tools that measure bioequivalence. The development of these marks a major step forward in helping accelerate the progress or approval of complex generics.

In fact, this year, the FDA approved the first generic of albuterol sulfate, an inhalation aerosol for the treatment or prevention of bronchospasm in patients who have reversible obstructive airway disease. This is a key milestone for patients and healthcare providers who now have access to a generic for one of the most commonly used rescue inhalers in the US.

At Absorption Systems, we’ve been fortunate to be the recipient of multiple FDA awards for developing the in vitro evaluation of locally acting products, such as ophthalmic or dermal products as well as BCS Class 3 oral products. Based on our extensive experience and expertise, our validated and proprietary biological models support the efforts of the FDA and the companies who are developing complex generic therapeutics; ultimately, this will enable complex generics to come to market quicker and into the hands of the patients who need them most.