Biosimilar
A biosimilar (plural: biosimilars ) is an imitation product of a biopharmaceutical , for example a biotechnologically produced protein , which is approved after the patent period of the original active ingredient has expired. The active ingredients of these biotechnology products are, unlike the classic, molecular structure-defined drugs, not completely identical to the original active ingredient and therefore require more complex approval procedures and monitoring measures than the classic generics. The main reasons for these differences are the different organisms in which the target protein is expressed and the other methods used, such as separation and purification. Frequent differences are different glycosylation patterns , which has consequences for the pharmacokinetics in particular . For this reason, the term “biogeneric” (plural “biogeneric” ) used occasionally is an inadequate characterization of this new type of imitation drug. Although there may be differences in the quantity of specific variants, a biosimilar must not have any clinically relevant differences from the original active ingredient and must have equivalent safety and effectiveness to the original active ingredient. After a positive assessment by the Committee for Human Medicinal Products of the European Medicines Agency , a biosimilar is approved for the entire EU by the European Commission . In Switzerland, Swissmedic (Bern) is responsible as the licensing authority.
Definitions of terms
Based on chemically synthesized generics , which are brought onto the market at significantly lower prices after the patent term of an original medicinal product has expired , the term biogeneric has been introduced for recombinant therapeutic proteins that will soon be released from patent protection . From the point of view of the approval authorities ( European Medicines Agency , FDA , Swissmedic ), however, the term chosen is incorrect and the products concerned should be referred to as equivalent biotechnological medicinal products or bio-like products ( biosimilars ). The term Follow-on-Biologicals (FOB), which refers to genuine new developments based on well-known models, has also become common.
Admission requirements
In addition to the non-uniform choice of terms, however, the different interpretation of definitions is in the foreground for industry. There is agreement on three criteria that characterize a biosimilar:
- Marketing after the original patent expires
- Selling at a significantly reduced price compared to the original
- It is very similar to the reference product despite the natural variability of organic products
- There are no significant medical differences in terms of effectiveness, quality, or safety
When approving low-molecular chemical generics, the pharmaceutical company may refer to the pharmacological and clinical studies of the original product that were submitted when the product was first approved . The pharmaceutical company only has to prove bioequivalence and pharmaceutical quality, then the generic can be sold under an international non-proprietary name ( INN ). The situation is different with biosimilars, as they are drugs that differ from the original protein in the way they are produced and the choice of expression system. Not only the quality, but also the identity of a recombinant drug is derived from its manufacturing process. The main differences lie in the protein conformation and the glycosylation pattern , which depend on the producer. Different glycosylations, for example, have consequences for immunogenicity or pharmacokinetics . In summary, it can be said that biosimilars are copies of therapeutic proteins, but due to the chemical differences in the centralized procedure of the European Medicines Agency, they have to be assessed and approved with their own studies on efficacy and safety. A similar procedure is to be used in Switzerland.
Biosimilars approved in the EU
As of April 2019, there are around 60 biosimilars from various pharmaceutical companies in Germany resp. approved in the EU.
- Enoxaparin sodium
- The enoxaparin sodium used to inhibit blood clotting is not produced biotechnologically, but is one of the so-called non-biological complex drugs . As such, it is treated like a biological in the EU. Inhixa (manufacturer: Techdow Pharma Germany GmbH) has been the first enoxaparin biosimilar on the German market since September 2017 ; it received European approval in September 2016. The reference product is Clexane ( Sanofi ).
- Epoetin
- Five biosimilars for erythropoietin (epoetin or EPO), the first recombinantly produced variant of which comes from Amgen research, have been approved in the EU since 2007: Abseamed ( medice ), Epoetin alfa Hexal ( Hexal ), Binocrit (Hexal), Retacrit ( Pfizer Pharma PFE) and Silapo ( Stada ). The reference product is the Erypo (active ingredient: epoetin alfa) approved for the treatment of anemia.
- Etanercept
- Benepali ( Biogen ) received European approval as a biosimilar for Enbrel ( Pfizer ) in January 2016 . Erezil ( Hexal ) followed in September 2017 . Because of its immunosuppressive effect, Etanercept is used in the treatment of rheumatic diseases and psoriasis.
- Filgrastim
- For the recombinant G-CSF (Filgrastim, trade name Neupogen ) originally developed by Amgen , biosimilars were applied for between 2008 and 2014, seven of which are still approved: Filgrastim Hexal ( Hexal ), Zarzio (Sandoz), Ratiograstim ( Ratiopharm / Teva), Tevagrastim ( Teva ), Nivestim ( Pfizer Pharma PFE), Grastofil ( STADApharma ) and Accofil (Accord Healthcare).
- Follitropin alfa (FSH)
- The follicle-stimulating hormone (FSH) is used to stimulate the oocytes as part of a fertility treatment when the desire to have children is unfulfilled. The reference product Gonal-f ( Merck Serono ) includes the two biosimilars Bemfola ( Gedeon Richter Pharma ) and Ovaleap ( Teva ), which were approved in 2013 and 2014.
- Insulin glargine
- In September 2014, Abasaglar (Lilly) received European approval as a biosimilar of the reference product Lantus ( Sanofi ) with the active ingredient insulin glargine . Lilly is cooperating with Boehringer Ingelheim here . This was followed by further biosimilar approvals in Europe in 2017 with Lusduna (MSD) and 2018 with Semglee (Mylan).
- Insulin lispro
- With Insulin lispro Sanofi ( Sanofi ), the first fast-acting biosimilar insulin from Insulin lispro received European approval in October 2017. The reference product is Humalog from Lilly.
- Pegfilgrastim
- For pegylated filgrastim, pegfilgrastim (original drug Neulasta from Amgen), the biosimilar Pelgraz (Accord Healthcare) initially received European approval in September 2018 . In the same year, further approvals for Pelmeg ( Mundipharma ), Ziextenzo ( Hexal ), Fulphila (Mylan) and Udenyca (ERA) followed.
- Somatropin
- The first biosimilar approved in Europe in 2006 was a somatropin preparation from the manufacturer Sandoz : Omnitrope (now from Hexal ).
- Monoclonal antibodies
- Monoclonal antibodies (mAB) for which biosimilars ( biosimilar antibodies ) have been developed and approved are shown in the table.
| mAB | Biosimilars | Reference product | Indication (s) |
| Adalimumab |
Amgevita (Amgen, 2017) |
Humira (AbbVie, 2003) | Juvenile idiopathic arthritis, plaque psoriasis, uveitis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis |
| Bevacizumab |
Mvasi (Amgen, 2018) |
Avastin (Roche, 2005) | Colorectal cancer, breast cancer, non-small cell lung cancer, renal cell carcinoma, ovarian cancer |
| Infliximab |
Inflectra (Pfizer, 2013) |
Remicade (Janssen, 1999) | Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, Ankylosing Spondylitis, Psoriatic Arthritis, Psoriasis |
| Rituximab |
Truxima (Celltrion, 2017) |
Mabthera
(Roche, 1998) |
NHL , rheumatoid arthritis, CLL , granulomatosis with polyangiitis and microscopic polyangiitis, Wegner granulomatosis |
| Trastuzumab |
Ontruzant ( MSD , 2017) |
Herceptin ( Hoffmann-La Roche , 2000) | Gastric cancer, breast cancer |
Biosimilars in medical practice
From the point of view of the Drugs Commission of the German Medical Association (AkdÄ), there is sufficient evidence of effectiveness, quality and harmlessness available due to the regulatory requirements for approval. According to the current state of knowledge, biosimilars are equivalent to the original preparations and can be used just like these at the beginning of treatment. With regard to the biosimilars that are on the market in China, India or South America, however, there are some doubts as to their equivalence, since simpler approval criteria apply there.
The extent to which it is possible to switch from the reference product to the biosimilar is not standardized. The EU stipulates that interchangeability is a matter for the licensing authorities of the countries. In Germany, only the doctor can decide whether to switch to a biosimilar.
The German pharmacist may or must not exchange goods in the case of discount agreements. He may or must exchange for referring imports, even if the name of the import differs from the original. (Original and import are legally identical: "minor differences are to be tolerated").
The AkdÄ recommends that the patient be closely monitored in the period after the switch from a reference product to a biosimilar. The Austrian drug authority AGES also expressed its positive opinion about the interchangeability for the first time in 2016.
Web links
- What I should know about biosimilars - information for patients , information brochure of the EU Commission (2016).
- Biosimilar medicines: Overview on the European Medicines Agency website
- List of biosimilars authorized in the EU on the website of the European Medicines Agency (EMA)
- List of US approved biosimilars on the US Food & Drug Administration (FDA) website
- Industry Association Pro Generics: Biosimilars - A Handbook. (PDF file; 4.9 MB)
Individual evidence
- ^ William C. Lamanna, Johann Holzmann, Hillel P. Cohen, Xinghua Guo, Monika Schweigler: Maintaining consistent quality and clinical performance of biopharmaceuticals . In: Expert Opinion on Biological Therapy . January 10, 2018, ISSN 1744-7682 , p. 1–11 , doi : 10.1080 / 14712598.2018.1421169 , PMID 29285958 .
- ↑ Guideline on Similar Biological Medicinal Products. (PDF) (No longer available online.) European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP), October 30, 2005, archived from the original on June 30, 2007 ; accessed on July 7, 2009 (English, 107KB).
- ↑ Questions and Answers on biosimilar medicines (similar biological medicinal products). (PDF) (No longer available online.) European Medicines Agency, October 22, 2008, archived from the original on January 4, 2009 ; accessed on July 7, 2009 (English, 30KB).
- ↑ Instructions for the approval of similar biological medicinal products (biosimilars). (No longer available online.) Swissmedic, February 1, 2014, archived from the original on December 21, 2015 ; Retrieved December 9, 2015 .
- ↑ Original products and biosimilars (approved in the EU)
- ↑ Techdow Pharma Germany. Retrieved June 26, 2019 .
- ↑ European Commission grants Lilly and Boehringer Ingelheim's insulin glargine product marketing authorization in Europe , PM by Boehringer Ingelheim on September 10, 2014
- ↑ a b Chart of the month January: Biosimilars on the market in Germany. January 24, 2019, accessed on February 6, 2019 (German).
- ↑ No biosimilar exchange by pharmacists . Deutsche Apotheker Zeitung, January 22, 2019.
- ↑ Drugs Commission of the German Medical Association: Statement of the Drugs Commission of the German Medical Association on biosimilars. Berlin, December 9, 2008. (PDF; 124 kB)
- ↑ Blickpunkt-Info: Biosimilars , Volume 28, No. 3 / July 2016
- ^ Baumgärtel, Christoph; Austrian medicines authority positive towards biosimilar interchangeability, Generics and Biosimilars Initiative Journal (GaBI Journal. 2017) 6 (1): 41
