Differences of Present Recommendations and Guidelines for Generic Low-Molecular-Weight Heparins: Is There Room for Harmonization

Abstract

Based on the results of large clinical trials, several low-molecular-weight heparins (LMWHs) have been approved for prophylaxis and the treatment of venous and arterial thromboembolism. As a result of expiration or pending expiration of patent protection of the originator LMWHs, the first generic LMWH enoxaparin has been approved by the Food and Drug Administration for clinical use in all medical indications. The European Medicines Agency has set up guidelines for the production of generic LMWHs. The International Society of Thrombosis, the North American Thrombosis Forum and other scientific organizations raised concerns regarding the safety of generic LMWHs due to economic reasons. These organizations have published statements for the production of generic LMWHs to ensure the quality of the products and the safety for patients. Ideally, the differences between the actual recommendations and guidelines for the production of generic version of LMWHs should be harmonized.

Introduction

Low-molecular-weight heparins (LMWHs) have received regulatory approval as individual biological medicines for many indications. The patents for LMWHs have expired or will expire in the near future. Therefore, generic LMWHs have been produced in the past years and they are marketed in China, India, Argentina, and Brazil. The Food and Drug Administration (FDA) has approved the first biosimilar LMWH enoxaparin for clinical use in any indication where the branded product has achieved approval. ¹ The original LMWHs are used for prophylaxis and treatment of venous and arterial thromboembolism. Their efficacy for preventing fatal pulmonary embolism (PE) and progression of thrombosis has been demonstrated in large randomized clinical trials.

The widespread availability of biosimilar LMWHs may reduce the treatment costs associated with LMWHs. As a consequence, LMWHs may become more readily available to patients. However, biosimilar LMWHs may also raise some new concerns related to the presence of inactive, uncharacterized, less and/or more active moieties not found in the originator products.

The FDA has now established guidelines after having approved the first generic/biosimilar LMWH.^1,2 The statements of the European Medicinal Agency (EMA), ³ the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH), ⁴ the International Union of Angiology (IUA), ⁵ the North American Thrombosis Forum (NATF), ⁶ and the South Asian Society of Atherosclerosis and Thrombosis (SASAT) ⁷ differed substantially from those of the FDA for the approval of a generic version of an LMWH. ⁸ First, the differences between the recommendations are discussed. Second, a concerted action is outlined after the approval of the generic enoxaparin to minimize the patients safety concerns.

Guidelines of the FDA

In the United States, innovator LMWHs are classified as drugs under the New Drug Application (NDA) process. The 505(j) pathway, which is commonly referred to as the abbreviated NDA (ANDA), requires the demonstration of bioequivalence through pharmacokinetic (PK) studies. The approval of the first generic LMWH enoxaparin followed this pathway.

The approval of ANDAs for enoxaparin raises complicated scientific and regulatory issues, which the FDA carefully considered. The FDA concluded that an ANDA applicant for enoxaparin can demonstrate active ingredient sameness by meeting 5 criteria, each of which captures different aspects of the active ingredient’s “sameness.”

The 5 criteria involve (1) the physical and chemical characteristics of enoxaparin, (2) the nature of the source material and the method used to break up the polysaccharide chains into smaller fragments, (3) the nature and arrangement of components that constitute enoxaparin, (4) certain laboratory measurements of anticoagulant activity, and (5) certain aspects of the drug’s effect in humans. The equivalence evaluation demonstrates that the molecular diversity of the generic drug product’s enoxaparin and branded enoxaparin is equivalent, including with respect to the 1,6 anhydro ring structure at the reducing ends between 15% and 25% of its saccharide units. Equivalent molecular diversity demonstrated sameness for the generic version of enoxaparin.

The term “same as” means “identical in active ingredient/ingredients.” In the preamble to the final rule of the Hatch-Waxman Amendments, FDA specifically rejected the suggestion that active ingredients exhibit the same physical and chemical characteristics, that no additional residues or impurities can result from the different manufacture or synthesis process, and that the stereochemistry characteristics and solid state forms of the drug have not been altered. Instead, FDA adopted a more flexible approach considering an active ingredient (in a generic drug product) to be the same as that of the reference listed drug (RLD) if it meets the same standards for identity. The standards for identity are described in the United States Pharmacopeia (USP), although FDA might prescribe additional standards that are material to the ingredient’s sameness. In the case of enoxaparin, there is an USP monograph and there are additional standards that are material to enoxaparin’s sameness.

The first criterion for demonstrating sameness of enoxaparin is equivalence of physicochemical properties, such as molecular weight distribution using size exclusion chromatography, chain mapping by cetyltrimethylammonium-coated strong anion exchange chromatography, matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS), gel permeation chromatograph—electro spray ionization mass spectroscopy (GPC-ESI-MS), or reverse phase ion pair—electro spray ionization mass spectroscopy (RPIP-ESI-MS).

The second criterion for demonstrating the sameness of enoxaparin is equivalence of heparin source material (ie, heparin that is derived from porcine intestinal mucosa and that meets USP monograph standards for heparin sodium USP) and mode of depolymerization (ie, cleavage by alkaline β-elimination of the benzyl ester derivative of heparin). The equivalent heparin source material should have at least a similar distribution of natural disaccharide building block sequences (within the context of its variability). If an equivalent mode of depolymerization is used, the generic drug products should be at least similar.

The third criterion for demonstrating the sameness of enoxaparin is equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species. This can be achieved by exhaustive digestion of enoxaparin with purified heparin digesting enzymes (heparinases I, II, and III) and nitrous acid, among other means, to yield the constituent disaccharide building blocks comprising enoxaparin. These individual disaccharide building blocks can be quantified by capillary electrophoresis (CE), reverse phase high-performance liquid chromatography (RP-HPLC), strong anion exchange HPLC (SAX-HPLC), mass spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. Chemical approaches such as analysis with modifying reagents (eg, sodium borohydride, nitrous acid) or modifying enzymes (eg, 2-0-sulfatase, 6-0-sulfatase, and 5-glucuronidase) can be included.

The fourth criterion for establishing sameness of enoxaparin is equivalence of in vitro biological and biochemical assay results using activated partial thromboplastin time (aPTT) and Heptest prolongation time. The equivalence in anti-Xa activity, anti-IIa activity, and anti-Xa/anti-IIa ratio between the generic LMWHs should be provided.

The fifth criterion for establishing sameness of enoxaparin is equivalence of ex vivo pharmacodynamic (PD) profile in human volunteers. The comparison of in vivo PD profiles is based on measurements of in vivo anti-Xa and anti-IIa profiles.

The FDA made some additional statements on several topics raised by the scientific communities. They concluded that the rigorous chemical analyses will detect the antithrombin binding site of the generic LMWH, impurities leading to severe anaphylactoid reactions, and immunogenicity leading to heparin-induced thrombocytopenia type II (HIT-II). The FDA stated that it is not necessary to completely characterize all of the different polysaccharide sequences, nor is it necessary to use the same manufacturing process as that used for the RLD or to conduct clinical trials to demonstrate equivalent safety or effectiveness. The FDA regulations do not require that an ANDA applicant uses the same methods used in, or the facilities and controls used for, the manufacture, processing, and packing of the RLD to assure and preserve the identity, strength, quality, and purity of the generic drug. The FDA concludes that ANDA applicants are not required to submit clinical trials to establish the safety and effectiveness of a generic LMWH if the 5 criteria—see above—are fulfilled.

Guidelines of the EMA

The guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance—nonclinical and clinical issues (EMEA/CPMP/42832/05/)—lays down the general requirements for demonstration of the similar nature of 2 biological products in terms of safety and efficacy. This product-specific guidance complements the above guideline and presents the current view of the Committee for Medicinal Products for Human Use (CHMP) on the application of the guideline for demonstration of biosimilarity of 2 LMWH-containing medicinal products.

Biochemical characterization: The guideline does not address the quality requirements. For quality aspects the principles as laid out in the comparability guidelines including the “guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: Quality issues” (EMEA/CHMP/ 49348/05) apply.

Pharmacodynamic studies: In order to compare alterations in activity between the similar and the reference LMWH, data from a number of in vitro comparative bioassays (based on state-of-the-art knowledge about clinically relevant PD effects of LMWH and including, at least, evaluations of anti-FXa and anti-FIIa activity) should be provided. If available, standardized assays (eg, in accordance with the European Pharmacopoeia) should be used to measure activity.

The in vivo PD activity of the similar and the reference LMWH should be quantitatively compared in an appropriate in vivo PD model, which takes into account state-of-the-art knowledge about clinically relevant PD effects of LMWH and includes, at least, an evaluation of anti-FXa and anti-FIIa activity and of release of tissue factor pathway inhibitor (TFPI). If feasible, these evaluations should be performed as part of the described repeated dose toxicity study. The studies should be in accordance with the intended clinical indication/indications, either a suitable animal venous or an arterial thrombosis model.

Data from at least 1 repeated dose toxicity study in a relevant species (eg, the rat) should be provided. Study duration should be chosen in accordance with the intended duration of clinical application, however, should be at least 4 weeks. The study should be performed in accordance with the requirements of the “Note for guidance on repeated dose toxicity” (CPMP/SWP/1042/99). Special emphasis should be laid on the determination of effects on blood coagulation and hemostasis.

Due to difficulties in physical detection of LMWHs, conventional toxicokinetic studies cannot be performed; measuring appropriate PD markers should monitor exposure of study animals. Data on local tolerance in at least 1 species should be provided in accordance with the “Note for guidance on nonclinical local tolerance testing of medicinal products” (CPMP/SWP/2145/00). If feasible, local tolerance testing can be performed as part of the described repeated dose toxicity study.

Safety pharmacology, reproduction toxicology, mutagenicity, and carcinogenicity studies are not routine requirements for nonclinical testing of a similar biological medicinal product containing LMWH.

Phase I studies: The absorption and elimination characteristics of biosimilar LMWHs should be compared with the branded LMWH by determining PD activities (including anti-FXa and anti-FIIa), as surrogate markers for their circulating concentrations. In addition to other PD tests such as TFPI activity, the ratio of anti-FXa and anti-FIIa activity should be compared. Assessment of these PD parameters will provide a fingerprint of the polysaccharidic profile.

These PK/PD properties of the similar biological medicinal product and the reference product should be compared in a randomized, single-dose 2-way crossover study in healthy volunteers using subcutaneous administration. In case the originator product is also licensed for the intravenous or intra-arterial route, an additional comparative study should be performed via the intravenous route.

The selected doses should be in the sensitive part of the dose−response curve and within the recommended dose ranges for the different indications.

Equivalence margins should be prespecified and appropriately justified.

Since a clear correlation between surrogate PD parameters (anti-FXa or anti-FIIa) and clinical outcome has not been established, a similar biological medicinal product containing LMWH should show equivalent efficacy and safety to a reference product approved in the European Union (EU). This therapeutic equivalence should be demonstrated in at least 1 adequately powered, randomized, double-blind, parallel group clinical trial. In theory, this could be done either in the setting of prevention of venous or arterial thromboembolism, or in the setting of treatment of venous thromboembolism (VTE). However, the most sensitive model to detect potential differences in efficacy between the new LMWH and the reference product should be selected.

Surgical patients have the highest prevalence of VTE. Furthermore, the vast majority of published trials have been performed in surgical patients with high VTE risk, especially in patients with hip and knee surgery, and thus the knowledge about influence of types of surgery, duration of trials, and risks of bleeding is the most accurate for this patient population.

Therefore, it is recommended to demonstrate efficacy in the prevention of VTE in patients undergoing surgery with high VTE risk. Preferably, the trial should be conducted in major orthopedic surgery such as hip surgery. In this clinical setting, patients with hip fracture should be well represented in the study as they have both high thrombotic risk and high perioperative bleeding risk. In the VTE-prevention setting, the clinically most relevant end point consists of proximal deep vein thrombosis (DVT), PE, and VTE-related death. However, the comparative efficacy and safety of the 2 products may also be assessed using the “surrogate” composite end point, consisting of total number of thromboembolic events (total DVTs, PE, and VTE-related death). A central independent and blinded committee of experts should perform adjudication of VTE events.

The study should follow a strict equivalence design where equivalence margins have to be defined a priori and appropriately justified, primarily on clinical grounds. The study should be powered to show therapeutic equivalence on 1 of the 2 recommended end points mentioned above.

State-of-art imaging technique should be used for the end point assessment. While proximal DVTs could be diagnosed with high specificity and sensitivity using ultrasonography, a clear assessment of distal DVT is only possible using bilateral venography.

The most relevant components of the primary end point (in particular in the number of proximal DVTs, PE, and deaths) should favorably support the biosimilarity of the 2 products.

Assessment of the primary end point should be performed at the time of occurrence of symptoms suggestive of VTE or, in asymptomatic patients, at the end of treatment. The overall follow-up should be at least 60 days to detect late thrombotic events.

Even if the efficacy is shown to be comparable, the similar biological medicinal product may exhibit a difference in the safety profile. Prelicencing safety data should be obtained in a number of patients sufficient to determine the adverse effect profiles of the test medicinal product.

Usually, comparative safety data from the efficacy trial will be sufficient to provide an adequate premarketing safety database. Major bleeding events and clinically relevant nonmajor bleeding events should be carefully assessed and documented. A consistent and clinically relevant classification of bleedings should be used. Similar to the efficacy evaluation, the adjudication of bleeding events by a central independent and blinded committee of experts, using prespecified limits should be performed.

For the detection of the immune-mediated type of HIT-II, monitoring of platelet count and an adequate diagnostic procedure in patients developing thrombocytopenia and/or thromboembolism (HITT) during the trial has to be performed. Liver function testing is recommended.

Demonstration of comparable efficacy and safety in surgical patients at high risk of VTE as recommended may allow extrapolation to other indications of the reference medicinal product if appropriately justified by the applicant.

Within the authorization procedure, the applicant should present a risk management program plan in accordance with the current EU legislation and pharmacovigilance guidelines. The risk management plan should particularly focus on rare serious adverse events known to be associated with LMWHs, such as HIT-II, HITT, as well as anaphylactoid and anaphylactic reactions.

Recommendations by the ISTH

The SSC of the ISTH summarized the recommendations for the development of a generic version of a branded LMWH. The lack of significant differences between the biosimilar and originator LMWH should be demonstrated using an adequate study design. All results obtained in vitro, ex vivo, and in clinical settings should adequately demonstrate the similarity or noninferiority of the biosimilar LMWH relative to the originator LMWH, and the confidence intervals should be defined using adequate statistical methods. The number of in vitro experiments can be lower and the size of the preclinical and clinical study designs can be smaller for head-to-head comparison of the biosimilar to the originator LMWH than those for the development of the originator patented LMWHs.

The origin of the starting material (animal tissue and country of origin) of the originator and the biosimilar LMWH should be known.

The characteristics of a biosimilar LMWH should be described exactly as in the monograph of the originator product and it should be produced exactly in the same way. Appropriate experiments comparing a biosimilar LMWH with the originator product should be required. Tests establishing lot-to-lot variations should be performed to show that these variations are not larger than in the originator. Point estimate and statistical dispersion should be shown for all data. Similarity testing should be performed on all experimental settings for the biosimilar compared to the originator LMWH.

Quantification of a biosimilar LMWH should include an analysis of the internal disaccharide sequences and the terminal groups both at the “reducing end” and at the “nonreducing end,” the average molecular weight, and the dispersion of molecular weight. The internal and end groups of the biosimilar LMWHs should correspond to those of the originator LMWHs, as determined by established methods. The 1, 6, and 2,5-anhydromannose residues (nitrous acid degradation method) and the 6-anhydroglucose or unmodified N-sulfated glucosamine end groups (heparinase treatment method) are the most frequent end groups occurring in LMWHs prepared from unfractionated heparins (UFHs).

The sulfate and carboxyl groups content should be described for the originator and the biosimilar LMWHs by measuring their charge density as expressed by molar ratios of >2 for sulfate/carboxyl groups using conductimetric or potentiometric titration.

LMWHs contain 12% to 20% of antithrombin binding chains. This should be compared for the biosimilar LMWHs with the originator LMWH using antithrombin affinity chromatography technique. Heparin cofactor II activity should be comparable for the biosimilar and originator LMWH.

With the exception below for dermatan sulfate, other glycosaminoglycans or impurities detected by NMR and other techniques should not be allowed. Up to 3% of the naturally accompanying dermatan sulfate could be tolerated. No significant differences between biosimilar and originator LMWHs should be found by repeated analysis of one lot of the LMWHs as well as for different lots of both LMWHs.

The ability (biological activities) of a biosimilar LMWH to catalyze inhibition of factor Xa and thrombin and to prolong the aPTT of pooled human plasma should be in the same range as the originator LMWH. Lot-to-lot variations should not be different for the 2 products. Appropriate statistical analysis of the data should be performed.

The protamine neutralization or titration and platelet factor-4 (PF4) binding should be assessed with different lots of the biosimilar and originator LMWH. No differences should be allowed for the 2 LMWHs as demonstrated by appropriate statistical analysis.

1. Studies assessing acute and chronic toxicity should be performed in appropriate settings comparing the biosimilar with the originator LMWH. Acute and repeated toxicity studies in accordance with the good laboratory practice (GLP) guidelines should be available in 2 animal species using different dosages comparing the biosimilar and the originator product.

The effects of the biosimilar and originator LMWH should be compared in animal thrombosis models of the venous and the arterial system and in a bleeding model. The lack of difference between the 2 compounds should be demonstrated.

1. Phase I clinical trials should be performed in human volunteers using the typical doses for prophylaxis and treatment of thromboembolism over 5 to 7 days. The effect on anti-FXa activity, anti-FIIa activity, aPTT, release of TFPI, and on the interaction with PF4 should be investigated. The anti-FXa/anti-FIIa ratio of the area under the activity−time curve is calculated from these experiments. The lack of statistically significant differences should be demonstrated for all parameters between the biosimilar and the originator LMWH.

2. Patients with renal impairment should be investigated using the dose for prophylaxis of VTE comparing the originator and biosimilar LMWH once daily subcutaneously for 5 to 7 days. Parameters are the same as in the phase I study in healthy volunteers. The lack of differences between the biosimilar and the originator LMWH should be demonstrated.

3. Due to differences in the pathophysiology and treatment regimes of venous and arterial thromboembolism, the efficacy and safety of a biosimilar LMWH preparation has to be demonstrated in these different indications. The complexity of the structure of LMWH includes non-anticoagulant activities resulting in investigating the antitumor and antimetastatic effect in various cancer diseases.

The efficacy and safety of a biosimilar LMWH should be demonstrated in comparison to the originator LMWH in clinical trials for every indication for which regulatory approval is sought. This contrasts to the development of new LMWH preparations, which are compared to UFH for efficacy and safety in clinical trials. However, if biosimilar LMWHs claim to be as effective and safe as the originator products, a head-to-head comparison of the 2 LMWH preparations should also be performed in clinical trials. Thus, prospective, randomized, double-blind trial should be performed to show the noninferiority of a biosimilar LMWH compared to the originator LMWH. The most relevant indications are prophylaxis of postoperative VTE, prophylaxis of VTE in hospitalized patients with acute medical illness, treatment of acute DVT and PE, prevention of acute coronary events in patients with unstable or stable angina, prevention of acute coronary syndrome during and after percutaneous coronary intervention, extracorporeal circulation, and chronic hemodialysis.

1. Based on the heterogeneity of LMWHs, biosimilar compounds have to demonstrate their noninferiority compared to the originator products in preclinical and clinical investigations. Simplified pharmacological, PKs, and clinical studies may be required for biosimilar LMWHs whose compositional profiles and physicochemical properties are similar to those of the originator.

Statement from the NATF

The regulatory approval process for biosimilar LMWHs should be as rigorous and comprehensive as it was for the branded LMWH to ensure safety and efficacy and to define structure and function.

The biological activity of the follow-on LMWH must use the same unit of biologic activity as the reference product.

Potency or activity units of the follow-on LMWH and the reference must be equivalent so that they will exhibit comparable PD properties in vivo.

Interchangeability should not be “preordained” for a biosimilar; it is a designation which must be earned not presumed.

The NATF suggests that

• the FDA approval process must be flexible enough to accommodate scientific progress and clinical realities and

• the FDA must have the discretion to implement different regulatory guidelines for different types of biologics.

Statement From the Scientific Committee of the IUA

The IUA recognizes the difficult issues related to the development and approval of generic versions of LMWH.

The IUA has reviewed several reports on the introduction of substandard versions of biosimilar LMWH in South America and South East Asia. ⁵

The IUA identified the need to develop revised guidelines specific for the development of biosimilar equivalents of LMWH.

It also identified the need for peer review and additional input to further improve these recommendations to address the safety and efficacy issues.

Therapeutic interchange among these products is not appropriate. The choice of LMWH should reflect the level of clinical evidence and the approval of the regulatory authorities for each indication. ¹

Statements From SASAT

Low-molecular-weight heparins represent a critical group of drugs which are more complex than most of the other drugs. They are hybrids of natural origin and chemical processes.

Unlike UFHs, LMWHs are made by different processes, with significant product specifications and represent distinct entities.

SASAT agrees the newer guidelines should include the updated technology to characterize these agents and demonstrate their chemical equivalence.

SASAT recommends the development of international monographs on each LMWH by the United States, the European, Japanese and other pharmacopoeiae.

Other Statements

The American College of Chest Physicians, the Society of Hospital Medicine, the American Pharmacists Association (APhA) position, the American College of Cardiology (ACC), and the American Heart Association (AHA) have published their position that “although LMWHs share many pharmacological similarities, they also vary in important respects, and it is important to consider each drug individually rather than as members of interchangeable compounds.” A position paper on biosimilars by the Austrian Society of Hematology and Oncology ⁹ concludes that “a final assessment of the safety of biosimilars has to take into account indication, dosage, route of application and duration of treatment and can only be made after comprehensive post-marketing studies.”

Room for Harmonization?

All recommendations and guidelines have week and strong points. Accordingly, the strong points of every publication are brought together in the following suggestions. Differences of the wordings biosimilar, generic, or biogeneric are not analyzed and the wording generic is used. The difference between sameness and similarity are not analyzed due to the differences in the origin of these 2 words. LMWH's are complex biological compounds/drugs, their heterogeneity being still not fully characterized. Therefore, detailed comparisons are required for generic with the originator LMWH to ensure patients safety. Even if it does not look likely that after the release of the statement of the FDA there is any place for harmonization of the different published opinions on generic LMWHs, the following proposals are made:

The traceability of the origin of a generic LMWH has to be documented. The production has to follow the description in the monograph of the branded LMWH as stated by the ISTH, NATF and others.

The analytical methods to characterize the chemical composition of a generic LMWH should be those described by the FDA.

Impurities with proteins, prions, other glycosaminoglycans, and any other chemical substance with influence of the coagulation system have to be excluded using highly sensitive standard methods as stated by the scientific organizations.

Adequately powered statistical methods have to be used to demonstrate the noninferiority of the generic product compared by head-to-head comparison in all investigations as stated by the ISTH.

Lot-to-lot variations have to be the same for the generic and branded LMWH demonstrated by statistical analysis as indicated by the ISTH.

A generic LMWH distributed to different countries by the same company have to be the batches.

A second generation of generic LMWHs may be produced under less rigorous production controls. The material of producers of such second-generation generic LMWHs has to be reviewed as rigorously by the FDA and EMEA as the first-generation generic LMWHs.

The generalizability of the data of one clinical study, as requested by the EMEA, to all other indications is not in accordance with the complexity of LMWHs chemical structure. A compromise has to be found between EMEAs position and the position of the scientific societies requesting one clinical trial for almost every indication.

The safety of a generic LMWH has to be documented in rigorous phase IV trials with special regard to bleeding, HIT-II, and anaphylactoic reactions. This is very close to the requested pharmacovigilance plan requested by the EMEA.

At present, health care professionals should ask for an adequate number of safety data of a generic LMWH before administration to patients in order to ensure the patients safety. Health care professionals may also inform the patients of the lack of safety data of a generic LMWH in order to avoid legal consequences if severe side effects occur following the administration a generic LMWH.