Deana Ferreri, PhD

The story of biologics and biologic copy products in India is very much a story about a work in progress. Although some companies are producing genuine biosimilars on par with international standards, many products fall into categories that are not comparable to biosimilar quality in the West. Recently, Indian regulators have endeavored to provide a pathway toward biosimilar development that meets international standards.

Newer, more comprehensive guidelines issued by Indian authorities in 2016 were intended as an upgrade to standards from 2012 that governed 

, India’s term for biosimilars. “A similar biologic product [in India] is that which is similar in terms of quality, safety, and efficacy to an approved reference biological product based on comparability,” the authors of a recent paper explained.

The authors noted India’s success in providing access to biologics, stating that approximately 60 biologics have been approved in India, almost half of which are similar biologics. In India, the cost of similar biologics “is approximately half the cost of innovator products,” and patient assistance programs address affordability and improve access.

However, there is also the potential for compromise: almost 20 similar biologics to infliximab, etanercept, adalimumab and rituximab were approved based on the less-stringent 2012 guidelines and were supported by limited clinical data.

The authors discuss the difficulty of producing biologics and true copies of originator products in a country that does not have the resources that the West does. “It remains a big challenge for a biosimilar manufacturing company to develop a similar product, as detailed information on the process of manufacturing of the original drug is patent protected and also because the same cell line is not available to the biosimilar manufacturer. Any changes in the manufacturing process such as use of different cell lines, growth medium, and protein purification processes can also result in variations in the final product,” the authors wrote.

Further, doubts about the quality of biologics persist and small patient population sizes during trials conducted to demonstrate bioequivalence to reference products may not produce the volume of data necessary to satisfy the need for statistical clarity, the authors wrote.

“In controlled clinical studies of biologics, particularly biosimilars, safety concerns may occur beyond the study completion. Long-term evaluations, such as postmarketing studies of biological agents, are required as there are only limited patient experiences available during approval in terms of safety and immunogenicity. Side effects related to the long-term use, off-label use, drug-drug interactions, or use in comorbid conditions can only be identified on exposure to the drug after its approval,” they said.

, need to be distinguished from similar biologics to prevent physician and patient confusion. They cite significant differences in the approval process for these products. Unlike similar biologics, intended copies do not undergo comparative clinical studies or analytical studies to demonstrate similarity to the reference product and have not been equated with similar biologics under the 2016 regulatory guidelines. With so little data, patients “face a greater risk of therapeutic failure and side effects” from these products, the authors reasoned.

Similar biologic products were evaluated on a case-by-case basis prior to the first approval guidelines for similar biologics released by India’s Central Drugs Standard Control Organization (CDSCO) in 2012. The 2016 guidelines were developed with some input from the World Health Organization (WHO) and “expert consensus opinion.” The goal of the 2016 rules was “to provide a well-defined pathway at par with international regulations,” although there is lingering controversy over whether India’s current guidelines achieve international standards.

The authors compared CDSCO’s 2016 guidelines with those of the FDA, the European Medicines Agency (EMA), and the WHO. Like the guidelines from the FDA, the EMA, and the WHO, India’s require demonstration of similarity to the originator product in nonclinical studies, a comparative pharmacokinetic and pharmacodynamic study in humans, a comparative clinical efficacy and safety trial in a relevant medical condition (India’s guidelines specify the trial should include more than 100 patients), and postmarketing safety monitoring.

The authors also highlighted “key considerations” regarding the current guidelines, which they say should be addressed in future iterations.

Interchangeability is not addressed in India’s biosimilar guidelines, and the authors noted that reference products are often switched for similar products “randomly by the prescriber or pharmacist based on the product cost and assumed patient affordability.” In 

, interchangeability is determined by individual member states. The United States has a process for biosimilar products to demonstrate 

, but no biosimilar has yet met this standard.

Nomenclature is also not addressed in CDSCO’s 2016 guidelines. The authors commented that accurate safety monitoring of biologics and biosimilars depends on identifiability “with easily distinguishable product names.” The WHO recommends a 4-letter suffix with the international nonproprietary name to distinguish a biosimilar from its reference product and other biosimilars to that reference product. However, 

 have been controversial, as they are thought to cause patient hesitance or confusion.

The authors also expressed concern about transparency in labeling, saying the package insert for a similar biologic should clearly disclose the extent of similarity to the reference product with respect to safety, immunogenicity, and efficacy.

Overall, the researchers view the 2016 regulations as successful in improving “stringency” in the approval process and more closely matching the safety requirements of international guidelines. However, some experts consider the 2016 requirements less stringent than EU and US standards.

Jois R, Mukherjee S, Rajeswari S, Rath PD, Goyal V, Gupta D. Similar biologics in India: a story of access or potential for compromise? 

. 2020;152(5):456-467. doi:10.4103/ijmr.IJMR_43_18

Articles

India has tightened up guidelines for biosimilar development in a quest to achieve standards equivalent to those in Europe and the United States. 

Indian Biosimilar Standards: A Work in Progress

In vivo animal studies of biosimilars “have added little evidence to provide clinically relevant information for biosimilar development,” concluded investigators in an 

 of the company’s findings from nonclinical animal studies during the development of 8 biosimilar candidates.

Demonstrating biosimilarity uses a “totality of evidence” approach. This starts with assessing structural and functional characteristics in analytical studies, possibly followed by 

 comparing the reference product and candidate biosimilar in animal models. Human clinical studies follow in the form of a clinical study to evaluate comparative pharmacokinetic and pharmacodynamic parameters and, potentially, a comparative clinical efficacy and safety study.

The authors shared their experiences and perspectives on the value of nonclinical toxicology studies, concluding animal studies “have provided little information to meaningfully inform clinical efficacy, safety, or immunogenicity.” They said that comparative clinical studies are the best way to confirm similarity in pharmacokinetics and pharmacodynamics, efficacy, safety, and immunogenicity between a biosimilar candidate and a reference product.

Different Approaches to Nonclinical Toxicology Studies

The authors noted the requirement for nonclinical toxicology studies differs by regulatory agency. In the United States, evidence from animal studies supporting biosimilarity is sought when the FDA considers that “uncertainties remain regarding the safety of the proposed product that need to be addressed” after analytical similarity has been demonstrated.

In contrast, the European Medicines Agency (EMA) requires animal toxicological studies only in some situations, such as “when the proposed biosimilar is produced in a different type of cell or organism, or when the formulation includes new [nondrug substances] not previously used.”

In Japan, the Pharmaceuticals and Medical Devices Agency determines if animal studies are required depending on the extent of biosimilarity demonstrated by analytical studies and the “degree of residual uncertainty” regarding similarity between the originator and biosimilar. World Health Organization guidelines are similar.

According to the authors, anticipation of a request from a regulatory agency in a specific country or region is the top reason biosimilar manufacturers conduct in vivo animal studies. They noted “conducting in vivo studies may take less time than waiting for feedback from regulatory authorities in some countries that may then request such data be included for evaluation of similarity.”

The paper summarized in vivo studies conducted for 6 of 8 Amgen candidate biosimilars (neither the FDA nor EMA required in vivo studies for the other 2). All 6 candidate biosimilars and their reference products were tolerated by animals. There were no unexpected safety or toxicity findings, and toxicokinetics were similar between biosimilars and reference products. The authors noted similar findings were reported in a review of in vivo studies conducted by Covance and of in vivo data from European Public Assessment Reports.

The investigators concluded, “Nonclinical studies to support biosimilar development should be reserved for the rare cases in which a targeted toxicology study could address specific questions around residual uncertainty that are unanswered by analytical and in vitro assessments.” For example, in Amgen’s development of an aflibercept biosimilar (ABP 938), “a toxicity study was considered justifiable based on the novelty of the formulation used and injection into the eye, a very sensitive compartment.”

Apart from that example, the investigators wrote, “In vivo studies usually do not have the power to resolve residual uncertainties following analytical and in vitro studies or changes in formulation,” whereas clinical studies can provide that statistical power.

They recommended, “In general, clinical trials should be conducted to determine whether residual uncertainties, after analytical and functional in vitro assessments, confer clinically meaningful differences between a proposed biosimilar and its reference product.”

Mihalcik L, Chow V, Ramchandani M, Hinkle B, McBride HJ, Lebbrec H. Use of nonclinical toxicity studies to support biosimilar antibody development. 

. Published online March 1, 2021. doi:10.1016/j.yrtph.2021.104912

Animal toxicology studies contribute little to demonstrations of biosimilarity and yet these studies frequently must be done to satisfy international regulatory requirements, investigators conclude. 

Investigators Question Use of Animal Toxicology Studies for Biosimilar Development

Government policies for generics and biosimilars drive down prices too far and fail to incentivize the use of these lower cost medicines, the Association for Accessible Medicines (AAM), a manufacturers’ trade group, argues in a new 

that calls for multiple revisions in public payer policy.

Top among challenges faced by generics and biosimilars are rapid price deflation, anticompetitive practices, and government policies that contribute to both shortages of older generics and slow adoption of new generics and biosimilars, the AAM argues. Among the report’s key recommendations is that policymakers update Medicare to better incentivize the use and production of generics and biosimilars.

The Association for Accessible Medicines argues that “imprudent or out-of-date government policies” undermine the market for less expensive generics and biosimilars and recommended a list of changes, including:

Place generic drugs in Medicare Part D on generic formulary tiers with lower cost-sharing than brand name drugs

Ensure Medicare beneficiaries have access to new generics

Update Medicare Part D to include a dedicated specialty tier for generics and biosimilars

Reward Medicare health plans for encouraging use of lower-cost generics or biosimilars and eliminating barriers to access

End brand “rebate traps” that prevent use of generics and biosimilars

Increase the Medicare Part B add-on payment to providers who use biosimilars

Encourage adoption of biosimilars with a shared savings program

Repeal or amend the Medicaid drug price inflation penalty for generics

The report also made recommendations for emergency preparedness: to support the expansion of the Strategic National Stockpile; to include domestically produced medicines that will be necessary during public health emergencies; and to support local manufacturers of essential medicines “by ensuring the economic conditions exist to justify the use of currently existing local manufacturing capacity.”

The AAM also calls for beefing up domestic production of medicines so that the United States is better equipped to ride out supply disruptions, such as those that occurred during the early stages of the COVID-19 pandemic; however, a yet-unpublished IQVIA study cited by AAM reveals that the US pharmaceutical sector quickly increased supply in response to a demand spike shortly after the pandemic arrived.

Penalties for drug price inflation may apply to generics but not brand name drugs, the group argues, contending this is one reason manufacturers may not launch new generic products and, actually, may discontinue production of generic products, further contributing to supply shortages. Also, the AAM argues, a handful of large wholesaler purchasers in the United States dominate the marketplace and make business conditions even rougher by effectively blocking some drugs from market.

Noting brand specialty drugs and biologics make up approximately 2% of prescriptions but almost 50% of spending on prescription drugs in the United States, the AAM argued that competition from generics and biosimilars is “critical to the long-term affordability of these medicines.” The AAM noted biosimilars “lower the price of the brand-name biologic as a result of competition” and “are directly responsible for increasing patient access to therapy by as much as 5%.” They cited research estimating biosimilars and specialty generics saved patients and taxpayers more than $67 billion in 2019, with projected savings amounting to $100 billion between 2021 and 2025.

Prices for older, commoditized generics have fallen steadily, creating what the report termed “financial pressure” on their producers. The AAM blamed this price decline in part on government policies intended to control the costs of prescription drugs.

One example is a Medicaid inflationary rebate penalty that imposes financial penalties on manufacturers when generic prices under Medicaid increase faster than the average. The AAM contends generics manufacturers are often wrongly penalized because the formula for calculating price increases doesn’t take into account simple price variability caused by “changes in customer mix, not price increases.”

The AAM also blames heavy competitive pressure in markets crowded with producers. Often, newly approved generics simply fail to launch, or might be launched a year or more after they are FDA approved, it said 

Medicare Part D formulary placement is another challenge to a sustainable market for generics, according to the report 

. Patients may pay more at the pharmacy even if the price of their generic drug has fallen, the AAM said, “because Medicare plan formularies now place more generics on brand formulary tiers with higher cost-sharing requirements.”

According to AAM, Medicare Advantage and Part D formularies may prefer brand name drugs over generics and biosimilars. An AAM examination of launches of newly approved generics “found that only about half were included on formularies of Medicare Part D plans.” They found that even when these medicines are added to formularies, they are routinely placed on expensive brand drug tiers with higher patient copays, and that it typically takes nearly 3 years after introduction to the market before first generics are covered on 50% of Medicare Part D formularies.

AAM says that biosimilars, despite being “on average 30% less expensive” than their reference biologics, “have yet to realize the full potential of savings through broad adoption.” The report noted new biosimilars face adoption barriers that “stem largely from payment policies that do not encourage biosimilar adoption or that actively reward use of higher-priced brand drugs.”

Despite their competitive cost, biosimilars in some cases have been slow to win significant market share, which the report attributed largely to rebate traps and other Medicare payment policies. The report singled out Medicare Part B for paying providers the same administration fee regardless if they prescribed more expensive treatment.

“While this ensures providers are not penalized for using a lower-cost biosimilar, it also means providers have no incentive to use the lower-cost option,” the report noted.

Unsustainably low prices for generics are preventing some manufacturers from producing them, while biosimilars are blocked by policies that favor originator drugs, the Association for Accessible Medicines (AAM) argues. 

AAM Seeks Changes to CMS Policy on Generics, Biosimilars

Trastuzumab biosimilars are available in intravenous (IV) but not subcutaneous (SC) form, and although the SC form of originator trastuzumab is often preferred, IV biosimilars may offer the better deal from the standpoints of cost and convenience, investigators concluded in a recent review of trastuzumab options.

“It is therefore important for health care providers to consider the potential benefits of IV trastuzumab biosimilars (eg, lack of need for additional injections) and whether they outweigh the benefits associated with SC administration, as well as to consider patient preferences,” the authors wrote. The review outlined the current options available for trastuzumab therapy to aid decision-making by health care providers.

Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), is used to treat HER2-positive breast cancer and metastatic gastric cancer. According to the authors, combined with chemotherapy, biologics including trastuzumab “have emerged as paradigm-shifting treatments for patients with HER2-positive breast cancer, significantly improving patient outcomes and survival rates.”

The IV formulation of trastuzumab was approved by the FDA in 1998. An SC formulation was approved (for HER2-positive breast cancer only) by the European Medicines Agency in 2013 and FDA in 2019.

The reviewers noted a drawback of trastuzumab, as with other biologics, is its high cost. Since patent expirations in the European Union and United States, multiple trastuzumab biosimilars have been approved in these 2 regions, all formulated for IV use only. The patent on the SC formulation is set to expire in 2030 in the United States, precluding the availability of biosimilars using the SC route of administration for almost a decade.

Comparable pharmacological and clinical parameters

The authors noted that several studies have investigated the dose of SC trastuzumab required to produce similar pharmacokinetic parameters and serum trough concentrations to the IV formulation and that several studies have compared the efficacy and safety of IV vs SC trastuzumab. Collectively, according to the authors, these studies demonstrate that the IV and SC formulations have “generally comparable pharmacological and clinical profiles” in patients with HER2-positive breast cancer.

However, they acknowledged some questions do remain. The authors said the effect of body weight on the efficacy of each of the 2 formulations might “require additional evaluation.” Additionally, they noted that one study found twice as many patients taking the SC formulation compared with the IV form (6.8% vs 3.4%) developed antidrug antibodies. They also cited 2 trials that evaluated switching between the formulations. In one trial, adverse events (AEs) were similar in patients switched from SC to IV or IV to SC adjuvant therapy for HER2-positive early breast cancer. In a similar study of patients with metastatic breast cancer, there were more AEs in patients during the SC treatment compared with the IV treatment (67.6% vs 44.1%).

Each formulation may offer “unique advantages to patients depending on their individual needs,” the reviewers wrote. They noted the potential for pain at the injection site associated with the SC formulation, due to the large (5 mL) injection volume, and recommended health care providers discuss this with their patients.

The authors suggested that for patients receiving trastuzumab as monotherapy, SC administration could be a time-saving option in that it requires only 2 to 5 minutes vs 30 to 90 minutes for IV administration.

They concluded that as an adjuvant therapy, the SC formulation probably does not present an advantage in time or convenience to the patient, because trastuzumab would likely be combined with another IV therapy, and in many cases, the patient would have a central venous port in place. Therefore, IV administration could be more convenient for these patients, avoiding an additional injection. Contrary to this practicality, the patients in the 2 formulation-switching studies the authors cited overwhelmingly preferred SC administration (88.9% and 85.9%) over IV administration.

The authors cited 2 time-and-motion studies, 1 in the United Kingdom and 1 in Belgium. Both found higher costs associated with IV treatment compared with SC treatment. Based on the United Kingdom study, the authors estimated that over a full treatment course (18 cycles), SC trastuzumab would cost approximately $2826 less per patient. The authors noted limitations in both studies; in particular, they did not consider the cost of insertion, maintenance, and potential complications associated with IV catheters.

The authors argued that the discussion of cost savings associated with the SC administration route compared with the IV route “have predominantly overlooked the possible cost benefits of IV trastuzumab biosimilars.” However, patent expirations for the trastuzumab reference product were recent (European Union, 2014; United States, 2019), and therefore, they wrote, this limits “a comprehensive assessment of economic benefits.”

A budget impact analysis the authors cited estimated potential cost savings associated with trastuzumab biosimilars in 28 European countries, estimating cost savings between $1.1 billion and $2.74 billion during the first 5 years, and an additional 55,000 to 116,000 patients able to access trastuzumab therapy.

Trastuzumab biosimilars could improve access by giving physicians a lower-cost option to prescribe. According to the authors’ review of the literature, health care providers may be hesitant to prescribe biologics, despite their efficacy, because of their high cost. They cited a 2014 survey that found “nearly half of oncologists would increase the prescription of anti-HER2 biologics across multiple settings if a lower-cost biosimilar was available.”

The reviewers viewed IV trastuzumab biosimilars as having more potential for cost savings compared with the SC formulation of the reference product. “Given the general reduction in cost associated with the introduction of a biosimilar to the market, it is unlikely that the reduced administration costs associated with the SC formulation of trastuzumab will outweigh the lower cost of IV biosimilars,” they wrote.

Waller CF, Möbius J, Fuentes-Alburo A. Intravenous and subcutaneous formulations of trastuzumab, and trastuzumab biosimilars: implications for clinical practice. 

. Published online February 16, 2021. doi:10.1038/s41416-020-01255-z

In a review of trastuzumab treatment options, reviewers concluded subcutaneous (SC) vs intravenous (IV) options may be more costly and sometimes less practical. 

Deana Ferreri, PhD

Indian Biosimilar Standards: A Work in Progress

Investigators Question Use of Animal Toxicology Studies for Biosimilar Development

AAM Seeks Changes to CMS Policy on Generics, Biosimilars

Study: Trastuzumab Biosimilar IV Offers Better Value Than Reference SC