Efficacy Of Biosimilars Research Articles

Quality characteristics and nonclinical/clinical profiles of Etanercept BS SC [MA]

Etanercept is a dimeric genetic recombinant glycoprotein consisting of Fc domain of human Immunoglobulin G1 and the extracellular domain of human tumor necrosis factor (TNF) receptor type II. Etanercept exerts therapeutic effects on inflammatory diseases such as rheumatoid arthritis and juvenile idiopathic arthritis by neutralizing biological activities of TNFα/Lymphotoxin (LT) α. Mochida Pharmaceutical and LG Chem have developed syringe, pen, and vial products of Etanercept BS (biosimilar) as the first biosimilar of Enbrel in Japan. The active ingredient of those products "Etanercept biosimilar 1" has the identical primary structure to that of Enbrel. The development of the Etanercept BS, including evaluations of quality attributes, nonclinical and clinical studies was performed in accordance with "Policies on Assurance of Quality, Safety and Efficacy of Biosimilars". The quality attributes of Etanercept BS were similar to those of Enbrel, and the binding affinities to TNFα/LTα, TNFα neutralizing activity, nonclinical pharmacokinetics and toxicological profiles of Etanercept BS were comparable to Enbrel. Additionally, the pharmacokinetic profile and efficacy of Etanercept BS were equivalent to those of Enbrel and there was no clinically significant difference in safety profiles between them in Phase I and Phase III clinical studies. The marketing approval application of the Etanercept BS with the same indications as Enbrel filed by Mochida Pharmaceutical was approved in January 2018 and the products will be launched by Ayumi Pharmaceutical in the near future. The Etanercept BS, which is as highly effective as Enbrel is expected to make beneficial therapies more easily accessible to patients.

Biosimilar medicines and patient registries – expectations, limitations, and opportunities

Abstract Introduction: Biology therapies in a various medical specializations and for a broad spectrum of indications were launched during last two decades. As a new in class the therapies were obliged to provide additional data re gar ding efficacy and safety after their real medical practice integration. Patient registries, databases collecting various patient data, were introduced to grant data on the treatment effectiveness, safety, and long-term on treatment survival. Satisfactory treatment effect and acceptable safety profile were confirmed after couple of years of careful observation. However, the benefits were usually offered at much higher treatment costs compared to the standard therapies. Biologically similar drugs, so-called biosimilars (B.S), are being launched after original molecule patent protection expiry during recent years. They were expected as an ideal solution to avoid distinct impact on the medical budget: comparable effect for less money. The unsubstantiated doubts about biosimilar efficacy and safety were the reason of the late launch in many markets. Since biosimilars are considered as new therapy entities, the cautiousness to certain extent should be required. Information gained from post-marketing observations and patient registries over several years, confirmed the biosimilar product comparable quality. Healthcare budget savings could secure easier therapy access for more new patients.

Patient Perceptions Regarding the Use of Biosimilars in Inflammatory Bowel Disease

Introduction: Inflammatory bowel disease (IBD) often requires treatment with immune modulating medications (biologics). Although biologic agents have been shown to have excellent efficacy in treating IBD patients, the substantial cost has become a barrier to treatment for many patients. Recently, biosimilar drugs have been developed. Many clinical trials have demonstrated similar efficacy of biosimilars compared to originator biologics in IBD patients. Patients' perception and knowledge regarding these drugs is not known. We surveyed IBD patients to assess perceptions and knowledge regarding biosimilar medications and willingness to switch from biologics to biosimilars.Table: Table. Characteristic DataMethods: 121 consecutive adult patients in a single outpatient gastroenterology clinic with a pre-existing diagnosis of IBD were surveyed between March and May 2017. Data was then compiled and analyzed. Patients were excluded if they were not able to read English. Results: The mean age of the survey participants was 37.8 ± 15.5 years. Sixty-three percent of the participants were male. Fifty-three patients (43.8%) carried a diagnosis of UC. Sixty-seven patients (55.3%) had Crohn's disease (CD). One patient was not sure of his/her diagnosis. Significantly more CD patients than UC were currently on infliximab or adalimumab (35 vs 16, p=0.014). Only 33 participants (27%) have heard of “biosimilar medications” prior to this study. Seventy-six percent of all participants were uncomfortable using a biosimilar medication that had not been tested in clinical trials specifically for UC or CD. 57% participants were uncomfortable exchanging their current medication for a biosimilar. 92% of all participants wanted to be informed prior to switching to a biosimilar medication. There was a statistically significant correlation between the number of years since diagnosis and the patient's comfort with switching to a biosimilar medication (r=0.203, p=0.027). Conclusion: By investigating patient perceptions and knowledge regarding biosimilars, we hope to better understand patients' level of comfort, preferences, and potential barriers to implementation. Most IBD patients were uncomfortable using a biosimilar that has not been evaluate in a clinical trial in IBD. Of interest, a longer time since diagnosis of CD was associated with increased comfort of switching from biologic to biosimilar. This information will help physicians form their approach to introducing and discussing these biosimilars with patients.Table: Table. Patient Pereceptions Regarding Biosimilar Medications

Biosimilars in psoriasis: Clinical practice and regulatory perspectives in Latin America.

Latin American countries view biosimilar agents as an effective approach to curtail health-care expenditures while maintaining the safety and efficacy profile of their branded innovator comparators. To understand the complexities of the regulatory landscape and key therapeutic issues for use of biosimilars to treat moderate to severe psoriasis in Latin America, the International Psoriasis Council convened dermatology experts from Argentina, Brazil, Chile, Colombia and Mexico in October 2015 to review the definition, approval, marketing and future of biosimilars in each country and develop a consensus statement. The regulatory framework for marketing approval of biosimilars in Latin America is currently a mosaic of disparate, country-specific, regulatory review processes, rules and standards, with considerable heterogeneity in clarity and specificity. Regulations in Argentina, Brazil, Chile and Mexico have undergone multiple refinements whereas Colombia is finalizing draft guidelines. Verification of the similarity in quality, safety and efficacy of biosimilars to the innovator biologic remains a key challenge for policy makers and regulatory authorities. Other key regulatory challenges include: naming of agents and traceability, pharmacovigilance, extrapolation of indications, and interchangeability and substitution. An urgent need exists for more Latin American countries to establish national psoriasis registries and to integrate their common components into a multinational psoriasis network, thereby enhancing their interpretative power and impact. A Latin American psoriasis network similar to PSONET in Europe would assist health-care providers, pharmaceutical companies, regulators and patients to fully comprehend specific products being prescribed and dispensed and to identify potential regional trends or differences in safety or outcomes.

Biosimilars: potential implications for clinicians

With the expiration of patent protection for several biologics looming, the production of highly similar therapeutic agents has begun to emerge on the pharmaceutical market. These alternative drugs are referred to as biosimilars. Many anticipate that the introduction of these agents will result in a reduction in health care costs, which may create a more affordable biopharmaceutical market and also improve patient access. In contrast to generics, which are exact copies of their original products, biosimilars are not identical to their reference products. Due to concern about the safety and efficacy of biosimilars, separate regulatory approval pathways have been developed and implemented by several countries, including the US and Europe. Europe has led the way in acceptance of biosimilars into mainstream clinical practice. Biosimilars are not generic products and require extensive clinical and nonclinical bioequivalence studies before receiving marketing approval. Not only is there a lengthy developmental process, but also they will likely be required to have postmarketing surveillance and ongoing safety monitoring to keep track of issues that may arise, such as immunogenicity. Although US Food and Drug Administration approved the first biosimilar product in March 2015, physicians remain unfamiliar about their indications.

Interchangeability among reference insulin analogues and their biosimilars: regulatory framework, study design and clinical implications.

Biosimilars are regulated differently from small-molecule generic, chemically derived medicines. The complexity of biological products means that small changes in manufacturing or formulation may result in changes in efficacy and safety of the final product. In the face of this complexity, the regulatory landscape for biosimilars continues to evolve, and global harmonization regarding requirements is currently lacking. It is essential that clinicians and patients are reassured that biosimilars are equally safe and effective as their reference product, and this is particularly important when interchangeability, defined as 'changing one medicine for another one which is expected to achieve the same clinical effect in a given clinical setting in any one patient', is considered. Although the automatic substitution (i.e. substitution without input from the prescribing healthcare provider) of biosimilars for reference products is currently not permitted by the majority of countries, this may change in the future. In order to demonstrate interchangeability between reference products and a biosimilar, more stringent and specific studies of the safety and efficacy of biosimilars are likely to be needed; however, guidance on the design of and the need for any such studies is currently limited. The present article provides an overview of the current regulatory framework around the demonstration of interchangeability with biosimilars, with a specific focus on biosimilar insulin analogues, and details experiences with other biosimilar products. In addition, designs for studies to evaluate interchangeability with a biosimilar insulin analogue product are proposed and a discussion about the implications of interchangeability in clinical practice is included.

Tu1351 Crohn's Disease Patients Currently or Previously on Natalizumab Can Be Safely and Effectively Switched to Vedolizumab

G A A b st ra ct s multicentre, observational cohort was designed to examine the safety and efficacy of CTP13 infliximab biosimilar in induction and maintenance of remission in Crohn's disease (CD, 108 weeks follow-up) and ulcerative colitis (UC, 54 weeks follow-up). Demographic data were prospectively collected at inclusion. A harmonized, tight monitoring strategy is applied in terms of clinical scores (CDAI, PDAI, pMAYO at each visit), biochemical markers (including CRP, at least every 3 months) and endoscopic/imaging (at least every 12 months) as requested by the National Health Fund. Sera are collected for drug through and antibody measurement at 0, 12, 24 and 52 weeks. Safety data are meticulously registered during follow-up. Results: 90 consecutive IBD patients were included in the present cohort (57 CD patients (27 males) and 33 UC patients (16 males)). Age at disease onset was 26.0 (SD:10.9) years in CD and 30.5 (SD:14.1) years in UC. In CD ileocolonic and perianal disease was present in 40.4% and 37.5% of patients, respectively. 55.2% of UC patients had extensive colitis. 21.4% of CD patients had previous surgery. In CD and UC, 60.4%/ 50% and 55.2%/74.2% of patients received concomitant immunosuppressives and steroids, while 30.4% of CD and 16.1% of UC patients received previous anti-TNFs. At induction, mean CDAI was 289 (SD:107), while MAYO/pMAYO scores were 8.8 (SD 3.1) and 6.4 (SD 2.6) in UC. There was a significant decrease in CDAI after 2 and 6 weeks of treatment compared to baseline (p<0.001, ANOVA-Scheffe). In addition there was a numeric decrease in the mean CRP level (from 23.5mg/L to W2:11.3mg/L and W6:15.3mg/L). There was a significant decrease also in the mean pMAYO score (from 6.4 to (n=16) W2: 3.7 and W6: 3.6) with a numeric decrease in CRP level during induction therapy in UC . 4 allergic reactions occurred, all in patients who had received previous anti-TNF medication. Conclusions: This is the first prospective nationwide cohort examining the safety and efficacy of the biosimilar infliximab in IBD. A significant decrease of disease activity (CDAI and pMAYO) was observed coupled with a decrease in CRP levels during induction with the infliximab biosimilar. A complete analysis of the induction data will be available at the time of congress.

Tu1350 Vedolizumab in the Treatment of IBD: The University of Chicago Experience

G A A b st ra ct s multicentre, observational cohort was designed to examine the safety and efficacy of CTP13 infliximab biosimilar in induction and maintenance of remission in Crohn's disease (CD, 108 weeks follow-up) and ulcerative colitis (UC, 54 weeks follow-up). Demographic data were prospectively collected at inclusion. A harmonized, tight monitoring strategy is applied in terms of clinical scores (CDAI, PDAI, pMAYO at each visit), biochemical markers (including CRP, at least every 3 months) and endoscopic/imaging (at least every 12 months) as requested by the National Health Fund. Sera are collected for drug through and antibody measurement at 0, 12, 24 and 52 weeks. Safety data are meticulously registered during follow-up. Results: 90 consecutive IBD patients were included in the present cohort (57 CD patients (27 males) and 33 UC patients (16 males)). Age at disease onset was 26.0 (SD:10.9) years in CD and 30.5 (SD:14.1) years in UC. In CD ileocolonic and perianal disease was present in 40.4% and 37.5% of patients, respectively. 55.2% of UC patients had extensive colitis. 21.4% of CD patients had previous surgery. In CD and UC, 60.4%/ 50% and 55.2%/74.2% of patients received concomitant immunosuppressives and steroids, while 30.4% of CD and 16.1% of UC patients received previous anti-TNFs. At induction, mean CDAI was 289 (SD:107), while MAYO/pMAYO scores were 8.8 (SD 3.1) and 6.4 (SD 2.6) in UC. There was a significant decrease in CDAI after 2 and 6 weeks of treatment compared to baseline (p<0.001, ANOVA-Scheffe). In addition there was a numeric decrease in the mean CRP level (from 23.5mg/L to W2:11.3mg/L and W6:15.3mg/L). There was a significant decrease also in the mean pMAYO score (from 6.4 to (n=16) W2: 3.7 and W6: 3.6) with a numeric decrease in CRP level during induction therapy in UC . 4 allergic reactions occurred, all in patients who had received previous anti-TNF medication. Conclusions: This is the first prospective nationwide cohort examining the safety and efficacy of the biosimilar infliximab in IBD. A significant decrease of disease activity (CDAI and pMAYO) was observed coupled with a decrease in CRP levels during induction with the infliximab biosimilar. A complete analysis of the induction data will be available at the time of congress.

Tu1349 The Efficacy and Safety of Calcineurin Inhibitors in Inducing and Maintaining Clinical Remission in IBD Patients Commencing Vedolizumab

G A A b st ra ct s multicentre, observational cohort was designed to examine the safety and efficacy of CTP13 infliximab biosimilar in induction and maintenance of remission in Crohn's disease (CD, 108 weeks follow-up) and ulcerative colitis (UC, 54 weeks follow-up). Demographic data were prospectively collected at inclusion. A harmonized, tight monitoring strategy is applied in terms of clinical scores (CDAI, PDAI, pMAYO at each visit), biochemical markers (including CRP, at least every 3 months) and endoscopic/imaging (at least every 12 months) as requested by the National Health Fund. Sera are collected for drug through and antibody measurement at 0, 12, 24 and 52 weeks. Safety data are meticulously registered during follow-up. Results: 90 consecutive IBD patients were included in the present cohort (57 CD patients (27 males) and 33 UC patients (16 males)). Age at disease onset was 26.0 (SD:10.9) years in CD and 30.5 (SD:14.1) years in UC. In CD ileocolonic and perianal disease was present in 40.4% and 37.5% of patients, respectively. 55.2% of UC patients had extensive colitis. 21.4% of CD patients had previous surgery. In CD and UC, 60.4%/ 50% and 55.2%/74.2% of patients received concomitant immunosuppressives and steroids, while 30.4% of CD and 16.1% of UC patients received previous anti-TNFs. At induction, mean CDAI was 289 (SD:107), while MAYO/pMAYO scores were 8.8 (SD 3.1) and 6.4 (SD 2.6) in UC. There was a significant decrease in CDAI after 2 and 6 weeks of treatment compared to baseline (p<0.001, ANOVA-Scheffe). In addition there was a numeric decrease in the mean CRP level (from 23.5mg/L to W2:11.3mg/L and W6:15.3mg/L). There was a significant decrease also in the mean pMAYO score (from 6.4 to (n=16) W2: 3.7 and W6: 3.6) with a numeric decrease in CRP level during induction therapy in UC . 4 allergic reactions occurred, all in patients who had received previous anti-TNF medication. Conclusions: This is the first prospective nationwide cohort examining the safety and efficacy of the biosimilar infliximab in IBD. A significant decrease of disease activity (CDAI and pMAYO) was observed coupled with a decrease in CRP levels during induction with the infliximab biosimilar. A complete analysis of the induction data will be available at the time of congress.

Biosimilars Versus Brands for Rheumatoid Arthritis: Eu5 Payers and Prescribers Place their Bets.

The entrenched positioning of biologics to treat moderate-to-severe rheumatoid arthritis (RA) has generated a lucrative market. However, amid ongoing economic constraints, the EU5 (France, Germany, Italy, Spain, and the UK) must tighten their health care belts. As biosimilars versions of key brands appear on the horizon, this study explored the expected impact of these cheaper options on reimbursement and prescribing for RA in each country. Across the EU5, 254 rheumatologists were surveyed regarding their views on biosimilars for RA and on current and expected prescribing patterns. In addition, 15 payers who influence reimbursement at national or regional level were interviewed. Considering 54-week Phase III data, ≥80% of surveyed rheumatologists in each country believe CT-P13 (biosimilar infliximab) has similar efficacy to branded Remicade; however, respondents are less confident in the biosimilar’s safety. Furthermore, >80% of respondents in most countries are willing to prescribe biosimilars of infliximab, and of etanercept and rituximab, though largely not before branded biologics. Unsurprisingly, given likely price discounts, interviewed payers will somewhat encourage biosimilar uptake. However, excluding those in Germany, consensus is that discounts offered on biosimilars will not significantly impact their budgets. German payers, however, report that additional rebates to statutory insurers are expected; they admit to financial incentives for physicians to prescribe rebated drugs, thus manufacturers may consider robust uptake will compensate for hefty discounts. Available data have inspired prescriber confidence in biosimilar efficacy, although safety concerns, likely stemming from complex biosimilar manufacturing and lack of long-term safety data, will ensure continued brand uptake, at least initially. Furthermore, the expected modesty of biosimilar discounts in most countries will somewhat curb payer policy promoting use of such agents. However, as prescribers become more familiar with biosimilars, and, as the full extent of cost savings are revealed, increasing uptake of biosimilars is probable.

PMS86 - Anti-Tnf Biosimilars Indicated for Rheumatoid Arthritis are Increasingly Available in Europe: How Do Payers and Key Stakeholders Perceive Them?

The process of bringing a biosimilar to market in Europe is quicker, easier and cheaper than developing a new biologic. As a class, rheumatoid arthritis (RA) has the greatest number of anti-TNF biosimilar molecules in development, with more expected to follow. This research was focussed on the key issues reported by payers and Key Opinion Leaders (KOLs) in France, Germany and Italy. MethodsSupported by secondary research our study entailed conducting one hour telephone interviews with influential senior payers involved in budgetary decision making at the national and regional level in addition to KOLs. These structured interviews explored how stakeholders perceived the introduction of anti-TNFs biosimilars. Payers see anti-TNF biosimilars as an opportunity to reduce the biologic budget but KOLs want to treat more patients within the same budget. Payers in Germany and France reported a greater perception of the efficacy of biosimilars than their counterparts in Italy. Treatment naïve patients are considered most suitable for anti-TNF biosimilars while automatic substitution was not favoured by any respondents. Nonetheless, price played a role and some KOLs stated they may attempt to switch existing patients who have a low risk of acute complications with very close monitoring. Biosimilars may be perceived unequally across markets. Manufacturers are likely to require the use of differentiated value stories when presenting their biosimilar products to payers and KOLs, with the latter more inclined to perceive them as an opportunity to treat more patients with the same expenditure instead of reducing budgets. Manufacturers will likely struggle to encourage the switching of existing patients onto biosimilars without offering a significant discount. In France and Germany, anti-TNF RA biosimilars are currently generating demand that closely matches their increasing prevalence.

Biosimilars: Current perspectives and future implications

Biosimilars are biological products that are the replicas of their innovator biopharmaceuticals. These are developed after patent expiration of innovator biopharmaceuticals and are submitted for separate marketing approval. In view of the structural and manufacturing complexities of biopharmaceuticals, biosimilars should not be considered as “biological generics”. These are rather unique molecules with limited data at time of approval, so there are concerns about the safety and efficacy of biosimilars. This article will address the differences between biosimilars and chemical generics, issues of concern with the use of biosimilars and need of appropriate regulations for their approval.

Effective pharmaceutical regulation needs alignment with doctors

Concerns emanating from the medical community about the safety and efficacy of biosimilars indicate an increasing distrust of the outcome of the drug regulatory process. To illustrate this, we analysed the creation of the European biosimilar regulatory framework, specifically focussing on the guidelines outlining approval criteria for biosimilar erythropoietins, which have been recently adopted. We observed an absence of the organised medical community in the public process of creating and updating the guidelines. In this article we argue that, to ensure that innovative medicines continue to find their way to the patients who might benefit from them, a closer collaboration between the organised medical community and regulators is needed.

Similarity of biotechnology‐derived medicinal products: specific problems and new regulatory framework

Biotechnology is used to produce medicinal products for complex therapeutic purposes (recombinant human insulin, erythropoietin, granulocyte colony-stimulating factor, etc.) when they cannot be synthesized chemically or produced in sufficient amounts from biological material by simple extraction. Major therapeutic advances have been made using biotechnological methods, prominent among which is recombinant DNA technology, by which sequences of natural or intentionally modified genes are inserted in a suitable host system, which then expresses the product of interest. The host production system can be a prokaryotic or eukaryotic organism, an animal or a transgenic plant. Biotechnology-derived medicinal products have reached a crossroads in their short history. The expiry of patents protecting innovative recombinant products introduced over the last two decades means that manufacturers with the required know-how and technology can develop and market substitutes. Against this backdrop, a recently published EMEA Directive stipulates what is required to demonstrate that a biotechnological medicinal product, or ‘biosimilar’, is equivalent to the original drug. The new European text marks a significant change with respect to previous EMEA Directives concerning ‘replicas’ of innovative products. Directive 2004/27/EC1 states that a biosimilar is first and foremost a medicinal product which has similar physicochemical and biological properties to the reference product, and the same pharmaceutical form. But the most remarkable measure stipulates that new preclinical and clinical trials must prove a biosimilar to be bioequivalent to the innovator's original drug. If a biosimilar has more than one indication, its safety and efficacy must, where necessary, be demonstrated for each of the claimed indications. This obligation to demonstrate identical safety and efficacy is not necessarily applied to conventional generic drugs, whose equivalence is taken as given if the copy has the same bioavailability as the original. It is therefore clear that the legislators wished to put biosimilar medicinal products in a different category from generic drugs. This distinct status is linked to the very nature of the therapeutic product, and to the risk of modification due to minor, difficult-to-detect alterations in the numerous steps of the production process. Biotechnology-derived therapeutic products are generally proteins with a complex structure. In comparison, chemically synthesized products are far simpler molecules. Biotech products may also contain additional hydrocarbon chains, which may be required for their pharmacological activity. The production of a given protein by two types of cells, which are necessarily different genetically and enzymatically, can lead to quantitative and qualitative variations in glycosylation. The industrial production of biotechnology-derived medicinal products involves many steps that are susceptible to variations: culture of cell line in bioreactors, extraction of crude protein, purification and formulation for delivery as medicinal products. Biosimilars and the original product may both contain impurities, but not necessarily the same ones. All this explains why variations in a protein are seen following a change in production site or method, even when this protein is produced by the same manufacturer using clones of the same cell bank. Potential variations are even greater when the protein is produced by another manufacturer, especially as product innovators quite legitimately protect their industrial secrets. Even minor variations can alter the activity, pharmacokinetics, or pharmacodynamics of the products. This is why the regulations demand proof of the efficacy and safety of biosimilars before they are granted a marketing authorization.

Règles d'utilisation des biosimilaires: Propositions consensuelles de la Société de néphrologie, de la Société francophone de dialyse et de la Société de néphrologie pédiatrique

Concerns emanating from the medical community about the safety and efficacy of biosimilars indicate an increasing distrust of the outcome of the drug regulatory process. To illustrate this, we analysed the creation of the European biosimilar regulatory framework, specifically focussing on the guidelines outlining approval criteria for biosimilar erythropoietins, which have been recently adopted. We observed an absence of the organised medical community in the public process of creating and updating the guidelines. In this article we argue that, to ensure that innovative medicines continue to find their way to the patients who might benefit from them, a closer collaboration between the organised medical community and regulators is needed.

Biosimilars: How similar or dissimilar are they? (Review Article)

The imminent expiry of patents on biological medicinal products, such as epoetin alfa in 2006, has significant implications for nephrology in Australia. The purpose of this review is to examine the differences between biosimilars (similar biological medicinal products) and generic low molecular weight (chemical) drugs. The approach that regulatory agencies, including the European Medicines Agency (EMEA) and the Therapeutic Goods Administration (TGA), are taking towards biosimilars is also discussed. Biosimilars differ from generic chemical drugs in many important ways, including the size and complexity of the active substance, the nature of the starting materials (cell banks, tissues and other biological products), and the complexity of the manufacturing processes. Therefore, it has been acknowledged by the EMEA that established legal and regulatory principles of 'essential similarity' that are applied to standard chemical generics cannot be readily applied to biosimilars. One of the key areas of concern with the introduction of biosimilars into the field of nephrology will be guaranteeing the safety and efficacy of biosimilars. New manufacturers will need to ensure that their biopharmaceutical has a similar efficacy and safety profile to the innovator product through more extensive clinical trials than the limited testing done for generic versions of low molecular weight chemical medicines.