Transitioning Long-Acting Products to a Generic Marketplace: What's Missing?

Abstract

Development of and increased access to generic oral medications to treat high-burden diseases including human immunodeficiency virus (HIV), tuberculosis, viral hepatitis, and malaria have had a major impact on reducing global morbidity and mortality. However, access and adherence to these life-saving treatments remains limited for some of the most vulnerable and underserved populations, for whom stigma, control, and discretion are critical to decisions around care. Current efforts to develop long-acting formulations to treat and prevent these conditions could overcome many of these barriers. However, generic manufacturing of these innovative products will be required to ensure affordable access to the communities and patients in greatest need. Strategic investments in new infrastructure will be required even before markets and manufacturing costs are clear, to ensure that access to these new products is not delayed, particularly for patients in low- and middle-income countries. Unlike conventional oral medications, long-acting products require greater investment for formulation, packaging, and delivery. The requirement for long-term bioequivalence studies will introduce additional delays in regulatory approval of generic long-acting products, and expedited approval pathways must be developed. Lessons learned from the development of long-acting hormonal contraceptives and long-acting antiretroviral products may provide a way forward.

Long-acting (LA) drugs and formulations for infectious diseases need to be available in low- and middle-income countries in less expensive generic formats. Although the manufacture of LA products is more expensive than oral alternatives, there is precedent to allow their inexpensive production in a generic marketplace.

Massive gains in health have been achieved in the past 2 decades in the prevention and treatment of human immunodeficiency virus (HIV), tuberculosis (TB), malaria, and viral hepatitis infections due to large scale availability of high-quality, low-cost diagnostics and therapeutics. Critical to the therapeutics market has been the role of generic drug manufacturers’ ability to supply low- and middle-income (LMIC) markets with off-patent and licensed products at a high volume and relatively low cost (Table 1). Recent innovation in developing long-acting (LA) products for a variety of conditions promises the potential for single dose cures and infrequent dosing for prevention and treatment of chronic conditions such as HIV. LA products offer the potential to substantially improve adherence and offer additional benefits to the most vulnerable and underserved populations, for whom stigma, control, and discretion are critical to decisions around care. These groups include women, children, adolescents, members of minority, Indigenous, or discriminated classes, sex-workers, migrants, intravenous drugs users, members of the lesbian gay bisexual transgender queer (LGBTQ) community, and others.

Table 1.

Generic Products With Global Health Impact

Condition	Product	Cost	Reference
HIV treatment	Tenofovir disoproxil/lamivudine/dolutegravir	$52 PPPY	GHSC-PSM eCatalog, April 2022 [1]
HIV PrEP	Tenofovir disoproxil/emtricitabine	$48 PPPY	GHSC-PSM eCatalog, April 2022 [1]
HCV	Direct-acting antiviral therapies	<$60 per cure	CHAI, 2019 [2]
Family planning	Medroxyprogesterone acetate	$0.74/vial	UNFPA Contraceptives Price Indicator 2020 [3]
Family planning	Levonorgestrel 75 mg × 2 rods	$7.94	UNFPA Contraceptives Price Indicator 2020 [3]

Abbreviations: HCV, hepatitis C virus; GHSC-PSM, Global Health Supply Chain-Procurement and Supply Management; HIV, human immunodeficiency virus; PrEP, pre-exposure prophylaxis; UNFPA, United Nations Population Fund.

In order for these products to reach their full potential and transform care for patients on a massive scale, they will have to be cost-competitive with shorter acting alternatives. Premium pricing for LA products, even if they deliver a higher positive outcome rate, will lead to fewer patients accessing treatment because healthcare budgets are often fixed. This raises 2 critical questions: (1) Is it possible for LA products to be cost-competitive with shorter acting products? (2) Is there a route to generic development, approval, and supply that will make LA products accessible to LMICs?

These questions have been asked and answered in the family planning space for the delivery of contraceptives, where we have seen the entry of highly affordable LA products, and where generic versions of these products have been developed, approved, sold, and delivered on large scale while offering cost advantages over shorter acting products.

There remain substantial additional barriers to these products realizing their potential. A particularly large one is programmatic ability to deliver chronic treatment with LA products without interruption, with good retention in care, and with minimal tail-period resistance issues emerging in patients who are not re-dosed in a timely manner. Though substantial, these questions can be addressed as evidenced by the delivery of 3-monthly injectables and LA implants to millions of users in LMICs.

OVERCOMING CHALLENGES TO DEVELOPING COST-COMPETITIVE GENERIC LA DRUGS

There is often the temptation, when new products are introduced, to delay generic manufacture until the size of the potential market can be properly assessed. In the case of LA formulations for HIV and other infectious diseases, however, the large positive impact on global health needs to be weighed against any risk-taking on the part of manufacturers. It is especially important that investment in the cost-effective manufacture of products using new technologies not be delayed in the short-term due to assumptions about high introductory costs. Limiting investment in manufacturing until costs are low (the so-called chicken-and-egg standoff) delays the arrival of high-volume, low-margin markets. This has led to unnecessarily delayed access for countless patients to countless products in LMICs. As an example, despite first receiving US FDA approval in 2006, it took approximately 15 years for an affordably priced generic version of the optimal protease inhibitor darunavir (DRV) to come to market for use in LMICs. It was finally brought to market as an affordable generic suitable for use as a second line treatment option as part of a CHAI-Unitaid pricing agreement [4, 5].

Donors and investors have market shaping tools, such as development incentives, advanced market commitments, volume guarantees, and other financial vehicles that can de-risk investment and ensure volumes such that products can be introduced into the market at anticipated scale-efficient costs. An example is the highly successful introduction of oral tenofovir/lamivudine/dolutegravir (TLD) into LMICs at a lower price than the existing preferred product (tenofovir/lamivudine/efavirenz [TLE]) using a volume guarantee mechanism [6, 7]. Within 4 years, over 18 million patients have switched over to the superior regimen [8].

With a plethora of drugs and delivery technologies in development, it is important that we not construct artificial barriers to making investments in those that are most successful—for example, holding back on investing in 1 technology lest another in the pipeline come along and surpass it. If we consider the history of HIV treatment scale-up, no one would go back in time and skip investing in the delivery of stavudine-based treatments because at some point in the future tenofovir would come along and surpass it. Too many patients would have died waiting. Likewise, we could not have skipped investing in hot-melt extrusion manufacturing capacity to deliver protease inhibitors for second line patients because at some point in the future cobicistat or dolutegravir would come along [9].

The Conferences on Antiretroviral Drug Optimization (CADO) 1–4 [10] have laid the groundwork for new products to be developed and incorporated into treatment guidelines partly by overlooking current perceptions on product cost, prioritizing the best therapeutic candidates and then prioritizing activities to make them affordable. It is important we do the same when investing in LA products; we cannot let our current understanding of costs drive decision making but instead must focus instead on technology investments to make the most effective products affordable now.

Consider genetic sequencing as an analogy. Today we can have a complete genome sequenced for well under $1000, given the necessary level of expertise required to collect a sample, get it to a lab, and run current equipment in almost any setting to get a result quickly. Twenty years ago, the first human genome to be sequenced in its entirety cost $3 billion and took 13 years, an effort requiring hundreds if not thousands of scientists and technicians. Of course, there was a long path between then and now, with a number of critical innovations. An unanswered question is whether investments made early, in parallel with the development of the products themselves, could reduce the time required to move from point A to point B on a cost curve. In this case, this means moving for affordable access to novel products in LMICs at the same time they are becoming available in high-income countries.

COMPARING THE GENERIC MANUFACTURING COSTS OF LA AND SHORTER ACTING PRODUCTS

Short-acting oral product cost drivers include the cost of the Active Pharmaceutical Ingredient (API), the cost of the excipients used to provide the bulk of the tablet and to ensure bioavailability, and the cost of tableting these ingredients into the final product. Of these 3 inputs, the API cost in an oral product is a much larger component of the cost than the others. The reason behind this is that most excipients are commoditized products available in large quantities from multiple manufacturers. The manufacturing costs for making a tablet or capsule are very low, a matter of pennies, due to the large quantities that can be made and the relatively simple and repetitious processing involved. For a typical oral antiretroviral drug, roughly 70–85% of generic product cost is driven by the API, with the remainder being formulation and packaging.

Long-acting products, by design, need to deliver a smaller amount of active ingredient in a more complex formulation designed to release drug over time. In the absence of a more potent active ingredient, the amount of API that would have to be delivered by injection or other means would be way too large and incompatible with a long-acting formulation. We can expect 2 cost impacts from this—first, the percentage of product cost attributable to API will be lower, and second, as less API is needed, less scale-efficiency will be achieved in manufacturing the API. This is a paradox of LA formulations that does not, generally apply to oral ones. As a trend, the longer the duration of action for an LA product, the less the cost of the active ingredient will be relative to shorter acting products.

CASE STUDY: LONG ACTING CABOTEGRAVIR (CAB-LA) COST OF GOODS ANALYSIS

For most small molecule injectable products, whether long-acting or immediate-release, the main driver of manufacturing costs is the cost of the formulation, rather than the cost of the API as is the case with oral products. This is due to the much larger cost for formulation of an injectable product rather than a tablet [11, 12]. The manufacturing process for an injectable formulation is complex relative to making a tablet or capsule, mainly driven by the cost of effecting, proving, and maintaining the sterility of the product. For CAB-LA, the primary drivers for its cost of goods (COGs) are the formulation costs, in this case driven both by the sterility requirements and the milling requirements to get the small particle size necessary for the long half-life of the product, followed by the cost of the API [13].

In the case of cabotegravir, due to its close similarity in structure to dolutegravir (DTG), the API price for DTG can be used as the basis for CAB API pricing (Table 2). Based on chemical knowledge and a visual review of their structures, it is likely that only one alternative starting material required to prepare CAB, and the synthetic process used to make the 2 APIs should be similar [13]. In 2016, when it first came to market, 20 kg of DTG API was imported from China to India at a cost of $3232/kg, reflecting the early, low-scale commercial cost of the API. It is reasonable to assume that CAB API will initially be priced comparably to the DTG initial sales price. At roughly $3000/kg, 600 mg of CAB will cost $1.80 (600/1000/1000 × $3000 = $1.80), or $10.80 ($1.80 × 6 = $10.80) per-patient-per-year (PPPY) for 6 vials if the drug is given every 2 months. By 2019, approximately 3 metric tons (MT) of DTG API was imported from China to India at an average price of $774/kg. The cost of CAB API is therefore expected to decrease over time as volumes increase, comparable to DTG API pricing. At $1000/kg, 600 mg of CAB API will cost $0.60 (600/1000/1000 × $1000 = $0.60) or $3.60 PPPY for 6 vials [13].

Table 2.

Cost of Goods: Oral DTG vs CAB LA

	Oral DTG	CAB LA (Projected)
API (weight PPPY)	18.25 g	3.60 g
API (cost PPPY)a	$14.12	$10.80–$3.60
Product costb	$24.00 PPPY	$23.00–$16.00 PPPY
% contribution of API	59%	47–22%

Comparison of manufacturing costs only.

Abbreviations: API, active pharmaceutical ingredient; CAB, cabotegravir; CAB LA, long acting cabotegravir; DTG, dolutegravir; GHSC-PSM, Global Health Supply Chain-Procurement and Supply Management; PPPY, per patient per year.

^aCAB range of $3000/kg to $1000/kg, DTG $774/kg.

^bDTG (50 mg) GHSC-PSM eCatalog, April 2022 [1], CAB (600 mg) vide infra.

Of course, the formulation costs for a sterile, vial-filled injectable need to be added to these API costs. However, these can be as low as $0.50 for a product manufactured in high volumes [11]. In the case of CAB LA, to be highly conservative, let us assume that this cost will be at $2 per sterile vial ($12 PPPY, assumption based on more expensive sterile, vial filled catalog products in the Global Health Supply Chain-Procurement and Supply Management eCatalog, April 2022 [14]); this is the largest cost driver for the product (explained below). CAB LA is formulated through a nanomilling process which is used less often with pharmaceutical products, and its initial volumes will be relatively low. A wet-bead mill is the tool used to nanomill CAB. Mills of various sizes and throughputs are estimated to cost $1 M to $1.5 M USD. The costs of installing the mill can and should be amortized over a relatively small volume and short period of time, or possibly through a donor-supplier incentive process (as has been used for 3HP for TB Preventative Treatment [15], and for pediatric DTG [16]). The capital investment costs for a CAB manufacturing line could be substantial and could range from $1.5M to $25 M depending on what capacity already exists at a given supplier, with the largest driver being the cost of a large-scale sterile fill-and-finish line. These costs are not factored into the cost estimates that follow. In addition to cost, due to the longer timeframe for bioequivalence studies and the time required to procure and install any new manufacturing tools such as wet-bead mills, it is important to understand that generic LA product development timelines will be substantially longer than for daily oral products.

CAB LA is sterilized both at the API stage and after the product has been formulated, utilizing gamma-irradiation. This is a commoditized service, and an estimate of the cost of irradiation is $0.70/kg based on the overall weight of material loaded into the unit and based on a confidential quote from a gamma-irradiation contractor [17]. This cost for CAB LA is equivalent to approximately $0.04 PPPY.

Adding the above costs together, the cost of the CAB LA product could be as low as $23 PPPY and eventually decrease to $15 as volumes increase and as manufacturers gain experience making the product. As stated, these costs don’t include the cost building a new manufacturing line, purchase of the nanomill and irradiator, the regulatory costs of developing the product, or the cost of the bioequivalence studies, which are projected based on prior experience and discussions with manufacturers, to be approximately $8 M, excluding the cost of a new fill-and-finish line if needed.

The $8 M cost of development includes the cost of the mill and installation, and a conservative (high) estimate for the cost of bioequivalence studies due to the substantially longer time required for a dosing interval of 2 months and an expectation of a high number of participants required due to patient-to-patient variability. For comparison, a bioequivalence (BE) program for a daily oral product is typically about $200 000; we estimate $1 M for CAB-LA. We add a buffer of $5 M in additional development costs to cover the long development timeline, potentially longer clinical studies, additional mill procurement, or other unexpected costs.

OVERCOMING CHALLENGES TO REGULATORY APPROVAL OF LA GENERIC PRODUCTS

Although LA products intended for either treatment or prevention of HIV are highly desirable, the regulatory pathway is not as straightforward as for oral products. Generic oral products for HIV, TB, and other conditions have well-established quality assurance and regulatory processes. Antiretroviral drugs intended for treatment of HIV may utilize the US Food and Drug Administration's (FDA’s) program for reviewing products eligible for procurement by the President's Emergency Plan for AIDS Relief (PEPFAR), that is, “tentative approval” status [18]. However, drugs intended for other indications, including prevention of HIV, and treatment of TB and hepatitis C, are not currently eligible for this regulatory pathway. The recent expansion of the tentative approval process for coronavirus disease (COVID) therapeutics is a demonstration that legislative action is not required to add HIV prevention products to the PEPFAR program [19].

In many instances, drugs deemed by the World Health Organization (WHO) to be essential medicines for global use, including ARVs, can be reviewed by the WHO's Prequalification (PQ) Team. In a relatively few cases, the European Medicines Agency's EU-M4All program (also called the Article 58 program) can be used to provide regulatory opinions on medicines and vaccines intended for use in markets outside of the European Union [20]. To date, none of these reviewing agencies have provided clear general guidance on how to develop generic LA products. When asked for advice, the FDA currently refers to their guidance on Scale-up and Post-approval Changes: Modified Release Solid Oral Dosage Forms (SUPAC-MR), a document that does not address the unique issues of LA injectable formulations [21]. However, improving advice on review of complex products including LA injectables and nanoformulations has been an area of FDA focus as part of their Drug Competition Action Plan [22], which has improving the efficiency of generic drug development as one of its core aims. In recent years, FDA has published new guidance on product development, pre-submission, and other formal FDA meetings, and new policies and procedures for classifying complex products [14, 23].

In addition, both the FDA and WHO PQ routinely publish product-specific guidance for generic drug development, including some LA products, and there are lessons to be learned from the success of LA products developed for other conditions. Product-specific guidance is available for generic depot medroxyprogesterone acetate (DMPA), an off-patent LA injectable hormonal contraceptive [24], and multiple FDA-approved generic products are now available. Similarly, guidance is available for development of paliperidone palmitate, an LA injectable anti-psychotic drug for which a generic company has successfully received approval [25]. These LA generic products were approved on the basis of demonstrating bioequivalence to the reference listed (innovator) drug over the planned dosing interval. LA injectable drugs may have substantial variability in absorption and systemic pharmacokinetics, and bioequivalence studies must take into account not only that variability, but also the planned dosing interval and how many participants might not complete the study, in order to enroll enough participants to meet the statistical endpoints. Clearly, bioequivalence studies for LA products are more complex than for immediate-release oral products, but they can be done. For example, one recent single-injection DMPA-IM bioequivalence study enrolled 124 healthy participants requiring repeated blood draws up to 140 days after the injection [24]. FDA's Office of Generic Drugs recently expressed their intention to provide product-specific guidance for both CAB-LA and CAB-LA/RPV-LA, which they consider complex drug products, in their planned 2022 guidance schedule [26].

CONCLUSIONS

As discussed, the technical challenges to developing an LA product are entirely surmountable, though investment in product specific technologies and longer and larger bioequivalence studies will make them more expensive for generic manufacturers to develop. For products that will ultimately benefit millions of patients, these development costs can be quickly recovered with only marginal cost added to products, or via donor-supported market-shaping activities such as development incentives, advanced purchase commitments, or other mechanisms. It is critical to the ongoing investment in new LA product development that we not let the novel aspects and elevated costs deter investment to make new products accessible in LMICs. Due to the longer anticipated timelines to develop these products, this raises the importance of preapproval voluntary licensing agreements coming several years before anticipated approval dates in high-income countries. The success of long-acting hormonal contraceptive implants is a powerful example demonstrating that LA generic anti-infectives can become reality.

Notes

Financial support. C. F. and R. C. B. received related support during the preparation of this manuscript from National Institutes of Health (NIH) grant number NIAID R24 AI118397, Long-Acting/Extended Release Antiretroviral Resource Program (LEAP), www.longactinghiv.org, awarded to Johns Hopkins University. D. H. B. R, K. C., L. L., D. R., and C. A. received related support during the preparation of this article from the UK Government (FCDO), and CIFF (Children's Investment Fund Foundation).

Supplement sponsorship. This article appears as part of the supplement “Long-Acting and Extended-Release Formulations for the Treatment and Prevention of Infectious Diseases,” sponsored by the Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP).