Biosimilars-a prologue
The dawn of the 21st century earmarked the revolution in the field of medical sciences & healthcare sector. The world saw the advent of the big pharma giants which gave blockbuster molecules to the suffering patient population. Off late macromolecules based on protein and peptide chemistry has been trying to occupy the healthcare centrestage. Unlike pharmaceuticals, biopharmaceuticals pose a challenge in term of product lifecycle management by innovator companies due to the complex structure of these molecules and the variation in the available genetic pool and resources.
The term "Biosimilars" (generic version of a biopharmaceutical product) with widely accepted analogy "biogenerics, follow-on biologics, follow-on protein, biocomparables, biopharmaceuticals, biologics, biological products, subsequent-entry biologicals and similar biological medicinal products" has off-late become one of the most debatable and controversial issues in the biopharma environment. In line with the chemical substances, biosimilars belong to the most pivotal group of the molecules that contribute to both the nation's and world's economy and the health and welfare of its citizens. The analogous "Follow-on protein" products generally refers to protein and peptide products that are intended to be sufficiently similar to a product already approved or licensed to permit the applicant to rely for approval on certain existing scientific knowledge about the safety and effectiveness of the approved protein product. These complex molecules are discrete as compared to synthetic molecules which occur due to distinct structure, active agent sources, manufacturing procedures, composition, stability, associated intellectual asset, regulatory procedures and marketing guidelines. Biosimilars are made up of huge molecular masses comprising of strands of polymeric chains with diverse chemical structures. These huge masses may include proteins, sugars, DNA or RNA such as Erythropoietin with a molecular weight of 34,000 and Enbrel with a molecular weight of 1,50,000. This property results in diversifying each and every individual biopharmaceutical with different efficacy and safety profiles which are again similar to corresponding well established medicinal products. First biologic product-Eli-Lily's Humulin made by recombinant DNA genetic engineering process was approved by the FDA way back in 1982 and since then by manipulating the complex structures, myriad biotechnological products have gained approval. Off-late 165 biopharmaceutical products have gained approval and in 2006 about 400 biotechnological medicines were in clinical trials. It has been estimated that by the year 2010, expenses to biologics would be around $105 billion with projected market capture equivalent to half of the chemical counterparts. Distinct property and edge over its chemical counterparts has propelled the genesis of new regulatory frameworks in various parts of the world. However, a lot of speculation is still going on within the regulatory agencies as a small change in the complex molecular structure could result in a completely different immune response as a result of which these bodies are focusing their approach on highly purified products such as recombinant proteins as the active pharmaceutical ingredient excluding blood or plasma-derived products and immunologicals. Further changes in biologic manufacturing processes can occur through alteration of cell lines, different variants of vectors, extraction or purification conditions. For example, the efficacy of the well known drug erythropoietin was affected due to the changes in glycosylation which also was the reason for loss in the efficacy as well as the immunogenicity of granulocyte-macrophage colony stimulating factor and interferon ß1b9. Changes so observed must be brought to the notice of the regulatory bodies by the biological product manufacturers done by carrying out extensive laboratory studies without affecting the physicochemical properties of the product.
The task of manufacturing the duplicate copy of biopharmaceuticals is tedious as it requires expertise to demonstrate and convince the regulatory bodies that the manufacturing conditions followed are sufficient enough to form a reliable biogeneric product. Moreover, to add on to this, it becomes a hindrance to the biosimilar manufacturers as they are devoid of access to the manufacturing processes of innovator products due to strong IP barricades. Thus, it becomes almost impossible for biosimilar manufacturers to generate a duplicate copy of any protein product. The original biopharmaceutical products which had been under patent protection since 1980's are either expired or about to expire. The complex molecular structure, heterogeneity and challenging manufacturing procedure with advantageous effects have further attracted and prompted the study and development of alternative versions of biologic products.
Biosimilars: Nomenclature
The International Non-proprietary Name (INN) established by the WHO in 1953 serves to designate each pharmaceutical substance with a unique name to be known globally which helps in indexing, worldwide exchange of information and identification of the pharmaceutical substance by the clinicians and health care professionals. The INN also serves as an essential part in the regulatory process of many countries wherein a non-proprietary name is required for licensing. Comparative to pharmaceutical products, it is highly an arduous and complicated task to assign useful nomenclature to biopharmaceutical products.
Since 1953, biologics have been included in the WHO INN system, and off late a lot of controversies have rooted up with regards to revision of the current INN system to assign a distinct name to a biological product. The probable reason might be due to ever-expanding growth of these new breed of innovative biopharmaceutical products not only in developed countries but also in developing parts of the world. The Governing bodies are facing a lot of hurdles to assign a unique product name and further complication of the situations which arise due to mere compilation of different names which are rather unjustified. Sometimes the roadblocks are so intense that naming that applies well to chemical molecules is not so successful in case of biogenerics. In this aspect nomenclature is a very argumentative issue as it affects companies' image as well as market capital.
The complex nature of biogenerics requires clear and utmost definition of each and every aspect with respect to assignment of distinctive names. Ambiguous nomenclature creates chaos by making situation worse to identify the actual biogeneric product. Proleukin (Aldesleukin for injection) a recombinant des-alanyl-1, serine-125 human interleukin-2 with modified amino acid sequence developed by Novartis is referred to simply as IL-2 which is not the actual active agent. Taking into consideration the complex format of its structure, if it is given a suitable name, assigning the same is not an easy task as it would require myriad data to arrive at a particular distinct name.
Numerous nomenclature systems such as IUPAC and CAS; sequence database identifiers; ATCC and other culture collection accession numbers; nonproprietary names (e.g., USAN and INN) are used to identify distinct biopharmaceutical products. It has been proposed that nonproprietary names such as USANs and INNs be modified to construct unique names for products and/or active agents; use of generic names with unique suffixes could be the source of providing distinct names.
Comparison of biosimilars and small molecules
Biopharmaceuticals are pharmaceutical products made up of glycoproteins. Complex structure is responsible for their activity which cannot be fully defined with conventional analytical techniques and approaches for potency testing. This creates a major roadblock as during safety testing and clinical test programmes, numbers of factors arise regarding response to varied patient population, different dosing schedules, route of administration, and the possible occurrence of immunogenicity. Optimal therapeutic effect and minimal adverse reaction are highly dependent on the complex conformational structure of a protein as well as preparation of a formulation.
Low molecular weight compounds also differ a lot as compared to biogenerics in terms of molecular weight which are tremendously different in size. A biologic with thousands to millions of atoms forms a highly interconnected group of hundreds to thousands of amino acids. For example aspirin's molecular weight is approximately 180.32 and a single amino acid has a molecular weight roughly between 75 and 20433. Since there are a large number of amino acids connected together to form a protein, common biologic drugs have resultant weights of a much greater order of magnitude than aspirin. For example, insulin, a small biologic, has an approximate molecular weight of 5,800; while growth hormone has a molecular weight of approximately 22,000; erythropoietin, which stimulates red blood cell production, has a molecular weight of approximately 30,000; and daclizumab, which suppresses the immune system for transplant patients, has a molecular weight of approximately 142,600.
Further, small molecules on the contrary can be fully described in terms of their molecular structure and different analytical assays have been described in details in various pharmacopoeias for the sole purpose of identification of these molecules. Low molecular weight compounds yield metabolites which might be active or inactive whereas biopharmaceuticals rarely yield metabolites that are pharmacologically or toxicologically active instead these biopharmaceuticals are simply degraded to non-active products. Further, because of the differences in production and size as well as the unique cellular source of biologics, true copies of a particular cell line's product using other cells is in fact impossible.
The FDA has commented upon the 'interchangeable' nature of biologic drugs from different manufacturers which is reproduced herein: With small molecule [chemical] products, there is a long history to support the use of various scientific approaches to establishing "bioequivalence" between products with the same active ingredient(s) product by different manufacturers. … [T]hese "bioequivalent" [chemical] products can indeed be expected to behave in a pharmacologically interchangeable manner when used in patient care. With protein products, as of today, the FDA has not determined how interchangeability can be established for complex proteins. Different large protein products, with similar molecular composition may behave differently in people and substitution of one for another may result in serious health outcomes, e.g., generation of a pathologic immune response. When scientific data establishing pharmacologic interchangeability do not exist, especially with more complicated protein molecules with potential critical immunologic safety issues, it is important that patients and physicians be aware that protein products with similar molecular composition may indeed not be interchangeable.
Owing to the complex nature of biologics, the potential to induce adverse immunologic reactions in patients taking biologics cannot be forgotten as the body sees the drug as an intruder/immunogen as a virus or bacteria. The immunogenicity reactions thus raised by the said biologics poses a serious threat and are absolutely essential for safety and clinical monitoring purposes. Moreover, any unknown reactions can be severe and have serious negative outcomes. The classic example is erythropoietin which is a naturally occurring substance in the body as well as a biologic drug that promotes red blood cell growth sold in US as Epogen and in Europe as Eprex. Johnson & Johnson under a licensing agreement with Amgen to sell erythropoietin in Europe used the methodology followed by Amgen. However, Johnson & Johnson made several manufacturing changes to its production of Eprex, which according to them were minor. Patients in Europe that took erythropoietin for two years developed a rejection reaction to the drug resulting in pure red cell aplasia (a severe and life-threatening condition where the bone marrow ceases to produce red blood cells). Such an effect was not observed in patients taking Epogen in the US.
An alarm was raised in Europe and it was revealed that modified erythropoietin (Johnson & Johnson's Eprex) had a different immunogenicity profile than the original drug (Amgen's erythropoietin) which developed antibodies in the patients. This created a situation wherein patients' own immune system started attacking their own body's erythropoietin as well as a cross-reactivity response to other medicinal forms of the biologic beyond Eprex. As a result patients could not produce red blood cells using their own or other biologic forms of the drug. Several patients died and others became permanently transfusion-dependent. Those saved were provided a combination of high dose immunosuppressive therapy and renal transplantation, but at the end the results of seemingly minor changes in the biologic had a tremendous clinical impact on these patients. Although, we are very much dependent on chemical counterparts for their less associated side effects, the benefits linked to biologics cannot be disregarded. This could be done by ensuring that safety is emphasized while access is ensured for all. Proper regulatory guidelines shall be followed so as to provide a safe and efficacious biologic drug to the public.
Regulatory aspects
Specific regulatory pathways are still a point of debate in USFDA for biosimilars due to the associated safety issues. Further, a conflict of responsibility and regulatory processes is point of agenda within the FDA since drugs are assessed by the Center for Drug Evaluation and Research (CDER) after submission of a New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) whereas biologicals are assessed by the Center for Biologics Evaluation and Research (CBER) under the Public Health Service Act (PHSA) after submission of a Biologic License Application (BLA). Bills such as Access to Life-Saving Medicine Act (Feb. 14, 2007) and Patent Protection and Innovative Biologic Medicines Act (Apr. 19, 2007) Biologics Price Competition and Innovation Act (Sept 26, 2007), HR 1427 by Henry Waxman and H.R.1548 (Co-sponsored by Anna Eshoo, Jay Inslee, and Joseph Barton), the Pathway for Biosimilars Act have been proposed in the Congress, but still a final decision is awaited.
The bills proposed above were a result of numerous arguments regarding the issue of safety due to immunogenicity parameters in the USA. Further, it was a challenging task to demonstrate comparability between generic biologics and innovator products. FDA put forth that ANDA route would not be sufficient to approve a generic biopharmaceutical. However, FDA compromised by allowing a 505 (b)(2) route wherein the applicant could refer to innovator data and provide additional data. This could be considered as an intermediate between the regular NDA and the ANDA. But this hybrid regulation is not specifically intended for generic biologics and only addresses those products regulated by CDER. The biotech industry had strict reservations against the said regulations as this was providing an easy access to generic biologic companies and emphasized that the FDA should not reveal or rely on any proprietary information submitted by an innovator to review or approve a biologic. The innovator companies had strong resentments that the tests done to ascertain the safety as well as effectiveness of the bioproducts were unique to a particular bioproduct and it would not be favorable to allow the generic companies to use the said information and get approval of their biogeneric.
The other issue that is raised in US relates to interchangeability aspect wherein the FDA is of the view that interchangeability is linked to their opinion on granting of INNs. FDA comments that interchangeability demonstrates that two products can be safely substituted for one another. But still it is a debate that how interchangeability can be established for complex biologics in the FDA as robust data has to be supported with comparative clinical data so as to justify claims of interchangeability or substitutability. A key feature of the budget that has to be proposed in the financial year ending September 30, 2009 is the introduction of a new regulatory pathway that will prescribe the type of data required for the FDA to review applications for follow-on-biologics.
The European Union has a more advanced framework for biological products than the US. The biologics applications in USA are analyzed on a case-by-case basis and depend on product characterization whereas EU forbids reference to the innovator's file for the approval of follow-on-protein. The EU mandates that biotechnology products including biosimilars follow the centralized procedure which falls within the scope of Regulation EC 726/2004. A single Market Authorization Application (MAA) has to be submitted to the EMEA resulting in one single application which shall be valid throughout the EU as per the centralized procedure. The legal basis for a biosimilar approval is article 10 (4) of Directive 2001/83/EC as amended and Section 4, Part II of Annex I to this Directive. The Directive 2003/63/EC as Annex I of Directive 2001/83/EC as amended define the approval requirements for biological medicinal products including biosimilars wherein the usual generic approach is not sufficient in the case of biological medicinal products. Clinical and safety studies have to be provided so as to demonstrate similarity between two biological medicinal products which would further depend on a case-by-case basis in accordance with CHMP guidelines. Batch-to-batch inconsistencies are possible amongst biologic products and the impact on the clinical outcome needs to be documented. Possibilities might occur wherein many biological actions and clinical characteristics could not be detected which may influence the product profile. Thus, batch-to-batch consistency should be taken care of. Database generation for the inconsistencies and changes that might occur need to be maintained. Thus, the applicant should justify the approach taken during the development and contact the EMEA before starting the development for scientific and regulatory advice.
The Hatch- Waxman Act
The sale of Follow On Proteins (FOPs) is expected to grow by $60 billion by 2010. The growth is escalating over the prescription drugs at twice the rate which has thus focused its interests to the regulatory agencies and the interests of the patients to continuous access to beneficial therapies. The patents for a number of blockbuster biologics are near expiry as a result of which the FDA is under pressure to enable the expedited approval of follow-on biologics. Further, this would have a significant impact on the economic front as the increased product approvals would lead to competition amongst different companies which would be based upon price; better access to biologics dues to cheaper counterparts available in biologics and incentives to innovation. But the question that would still bother would be the differences in the market status of follow-on biologics as compared to generic drugs.
The Drug Price Competition and Patent Term Restoration Act of 1984 (often referred to as the Hatch-Waxman Act) established the Abbreviated New Drug Application (ANDA) process for generic drug approval. For approval of the ANDA product (generic equivalent to NDA), the FDA reviews the reference to prior finding of safety and efficacy for a referenced listed drug (RLD) wherein the generic applicant has to demonstrate bioequivalence between its product and the RLD. The Hatch-Waxman proved to be a boon to the low cost generics but its impact on biologics could not be well defined as it did not apply to biologics. Biologics are regulated by Public Health Service Act (PHS Act) which has no equivalent provision to the ANDA. However, legislation has been attempting to apply the Hatch-Waxman Act to biologics. Two options that could have been possible for getting approval of the biogenerics was either through section 505(j) of the Hatch-Waxman Act and the other via section 505(b)(2) of the Food, Drug, and Cosmetic Act (FDCA). First route is not the most sought-after methodology and the other one being the most common methodology. Recombinant follitropin beta (Follistim), recombinant human glucogon (GlucaGen), and human growth hormone (Omnitrope) are some of the examples which have got approval via filing 505(b)(2) application. The 505(b)(2) application provides cost effectiveness, less time consumption and freedom of relying on the experimentation conducted by a third party including the innovator's data to show the safety of their own products. But pursuant to complex biological therapies involved with the biologics, FDA is hesitant to approve further molecules under 505(b)(2). However, FDA comments that "there is no abbreviated approval pathway… for produce products licensed under section 351 of the PHSA". Thus, this has further limited the use 505(b)(2) pathway within the Hatch-Waxman Act.
Questions regarding the validity of Hatch-Waxman Act have then and now been put in the Congress and raised by the FDA regarding its benefit to apply it to biosimilars for process of approval and generic manufacture. As discussed earlier, various bills have been introduced in order to streamline the regulatory process approval in the US. However, it's still a matter of debate between the US Congress and the FDA as a stringent action with regards to the regulatory issues surrounding follow-on biologics is still yet to be finalized.
Associated challenges
Approval of a corresponding biogeneric is not an easy task. Challenges come as a complementary task. It is well known that a biosimilar has a different active ingredient as compared to the innovator product. Moreover, being complex in nature, they require varied manufacturing processes as compared to generic counterparts which result in heterogeneity of the resulting biopharmaceuticals. Innovator companies do not divulge the proprietary knowledge of their biological products as a result of which it becomes quite impossible for biogeneric companies to replicate or make copy cat versions of the biologicals. This results in substantial differences between biopharmaceutical products and consequently the approval process differs according to the product.
Approval process of biosimilars requires demonstration of comparable efficacy and safety to an innovator reference product alongwith immunogenicity testing and pharmacovigilance programs. These programmes would monitor the efficacy and safety of biosimilar products post-approval. For e.g. Omnitrope [somatropin (rDNA) for injection] during its development was transferred from one facility to another. It was observed that the end product due to shifting resulted in difference in immunogenicity which was subsequently resolved by the manufacturer prior to approval. This is highly required as potential risks with regards to immunogenicity are associated with biosimilars (including innovator products and biosimilars). This can be monitored by various pharmacovigilance programmes to monitor all biopharmaceuticals for safety and efficacy issues during the post-approval period. Pharmacovigilance programmes involve report generation by healthcare professionals that contains information regarding the type of adverse event (known and unknown) and information on the drug.
Another factor that poses a significant challenge with biosimilars is the cost as compared to innovator products. It is still a controversial matter as nothing is clear with respect to the cost pressures biosimilars would pose on the innovative products as the innovator companies tend to alter price of their innovative products prior to patent expiration so as to help them recoup investment costs. Furthermore it is be taken care of that the biogeneric manufacturers cannot bet of the cost savings from their corresponding biosimilar products as compared to generic counterparts due to high development costs involved and the costs of bringing the products to market. However, it could still be projected that in near future the cost savings with biosimilars may increase access to therapeutic FOPs and stimulate innovative research.
Omnitrope - a controversial biosimilar
Omnitrope (somatropin [rDNA origin]), is a recombinant human growth hormone product indicated for long-term treatment of pediatric patients who have growth failure due to an inadequate secretion of endogenous growth hormone, and for long-term replacement therapy in adults with GHD of either childhood- or adult onset. Omnitrope was approved by FDA in May 30, 2006 and is administered Omnitrope Cartridge 5 mg/1.5 mL and Cartridge 10 mg/1.5 mL and Omnitrope for injection 1.5 mg/vial and 5.8 mg/vial in US. Omnitrope was approved by EMEA April 12, 2006 and is available as a powder and solvent, which are made up into a solution for injection (1.3 or 5 mg/ml), or as a ready-to-use solution in a cartridge (3.3 or 6.7 mg/ml) in Europe.
The approval of Omnitrope in the US had raised a lot of controversies with regards to its safety as well as effectiveness as compared to innovator's product. Omnitrope is a biosimilar product of Sandoz which is the first "follow-on" Pfizer's Genotropin for which Sandoz filed its application for Omnitrope in 2003. However, as per FDA Omnitrope did not prove to be a biogeneric due to lack of therapeutic equivalence to any of the other approved human growth hormone products. FDA stated that the approval of Omnitrope did not create a new pathway for biogenerics. It stated that "There is no abbreviated approval pathway analogous to 505(b)(2) or 505(j) of the [Food, Drug, and Cosmetic] Act for protein products." FDA commented that for approval of the said biogeneric, a new legislation had to be introduced. Further, after filing the request for approval by Sandoz, citizen petitions were filed by Pfizer, Genentech, and the Biotechnology Industrial Organization (BIO) in 2003 and 2004.
The companies via their citizen petitions primarily objected to the safety and efficacy studies that were provided by Sandoz which relied on the data of Pfizer's rhGH (Genotropin) which was approved for the same indications that Sandoz sought for Omnitrope (pediatric and adult growth hormone deficiencies). BIO further in its petition requested the FDA to refuse any application for a therapeutic protein product that relies on information contained in another approved application. Sandoz filed its application for Omnitrope approval under section 505(b)(2) of the FFDCA, for which the 505(b)(2) applicant can rely on the data from NDA's full reports of safety and effectiveness and wherein at least some of the information required for approval comes from non-applicant studies and for which the applicant has not obtained a right of reference.
The objections further in the citizen petition stated that it was not satisfactorily justified that Omnitrope and Genotropin were similar with regards to their safety and efficacy data requirements under section 505(b)(2). The only way wherein the two could be 'compared' to prove 'similarity' would be done by using Pfizer's proprietary information submitted in the Genotropin NDA to assess manufacturing differences between the two rhGH's.
FDA denied the petition by commenting that Sandoz had provided adequate data, including Sandoz's own clinical trial data which established that Sandoz's Omnitrope fulfilled safety and effectiveness criteria as compared to Genotropin without the need to access any proprietary Pfizer information. This could be justified as the end products in both the cases (Pfizer and Sandoz) had so called 'similar' nature. The matter took three years to conclude whereby in April 10, 2006 FDA gave a green signal to finally approve Omnitrope which was a result of a decision by the US District Court for the District of Columbia requiring the FDA to make a decision on Sandoz's Omnitrope application, which had been held up for three years post 2003.
Conclusion
With the number of biosimilars already approved or pending approval, it could be concluded that these agents would prove a boon to the ailing mankind. Introduction of the biosimilars in appropriate manner via rigorous pharmacovigilance programmes shall help to overcome the challenges associated with these complex proteins and would thus help to decrease the potential concerns/threats regarding the use of biosimilars.
The authors Gautam Bakshi, manager & Inderjit S Bansal, sr. executive, IPR department and Sukhjeet Singh, VP, pharmaceutical R&D ,Panacea Biotec Ltd, Punjab.
Disclaimer
The views expressed in the said article are those of the authors alone. They do not represent the views or opinions of their employer organization (Panacea Biotec Ltd) or its staff. Hence Panacea Biotec assumes no legal responsibility for the views/ information expressed in the article.