A similar biological - or ‘biosimilar’ medicine - is a biological medicine that is similar to another biological medicine that has already been authorised for use. Biological medicines are drugs that are made by or derived from a biological source, such as a bacterium or yeast. They may consist of relatively small molecules such as human insulin or erythropoietin, or complex molecules such as monoclonal antibodies
Biosimilars can only be authorised for use once the period of data exclusivity of the original ‘reference’ biological medicine has expired.
In general, this means that the biological reference drug must have been authorised for at least 10 years before a similar biological medicine can be made available by another company(1).
Biosimilars in Romania
In Romania, National Agency for Medicines and Medical Devices guides the using of biosimilars, according to the rules adopted by the European Medicines Agency (EMA).
Biosimilars issues pose a challenge in medical science world. Great personalities in medical oncology in Europe look with confidence on the biosimilars’ development, which will result in cheaper treatments that will be easier to be supported by the health systems.
Of course, the safety of using these products is very important, thus EMA has developed guidelines for the approval of these drugs. These guides provide an analysis of the pharmacokinetics, pharmacodynamics and toxicity for biosimilars proposed to enter the pharmaceutical market. For complex substances such as monoclonal antibodies, head-to-head clinical studies with reference drugs are needed.
Therefore, Romanian National Society of Medical Oncology (SNOMR) can only join the EMA position on biosimilars, hoping that they will be priced at least 20-30% lower than generics.
I present below some aspects about biosimilars revealed by two key figures in medical oncology in Europe: David J. Kerr, professor of cancer medicine and oncology at the University of Oxford, and Håkan S.T. Mellstedt, professor of oncology at the Karolinska Institute and professor of oncologic biotherapy at Cancer Center Karolinska in Stockholm.
Looking at sustainable healthcare and at the way we could get better value out of it, these important figures reveal the importance of biosimilars in the field of medical oncology. They consider that biosimilars could contribute to this.
Håkan S.T. Mellstedt thinks that these new drugs will have an important role, especially in oncology, because most of the drugs we talk about are blockbusters, and we could save money using these new drugs. Håkan Mellstedt stated: “There is much confusion about biosimilars. Biosimilars were introduced in 2006 in Europe when the first patent of erythropoietin ran out. Then came G-CSF (granulocyte colony stimulating factor). Now, we see a lot of biosimilars - monoclonal antibodies - that are much more complex drugs than the simple hematopoietic growth factors. And here comes the problem”. Håkan Mellstedt explained that erythropoietin and G-CSF are small molecules compared with monoclonal antibodies, which are large molecules, also hematopoietic growth factors, that are in use now, are nonglycosylated.
Håkan Mellstedt added that “we are used to talk about small chemical molecules for generic drugs and for which we accept that (the original and variant) as exactly the same. You only have to do some bioavailability studies, no clinical studies. But when it comes to these complex biosimilars, monoclonal antibodies, do they have the same efficacy and safety profiles as the original drug?”
The answer in “No”, said Håkan Mellstedt. “What is exactly the same is the protein backbone structure, but the folding and the posttranslational modifications are not exactly the same. However, with improvements in technology, the differences are smaller and smaller. It’s these small differences - if there are any differences of clinical significance - that’s what the question is about”.
Håkan Mellstedt concluded that you can accept minor differences between reference products and biosimilar, but the regulatory authority and the company decide from the beginning what kinds of margins you can accept. “We have a much more robust characterization of the protein drugs today than we had 10 years ago because of the advancement in technology”.
The conclusion is that clinical studies will be required for the authorization of these biosimilars. “However, those studies are not to prove the efficacy, because efficacy has already been proven by the original. It should only prove that there is no difference in regard to clinical efficacy and safety”.
For the efficacy requirement, an equivalence study must be carried out. Håkan Mellstedt explains that if we need to do a trial of thousands of patients, “then the biosimilar drug will be much more expensive because you have to do all of these clinical trials”(2).
Clinical trials for approval of biosimilars asco 2016
To understand the process of accreditation of a biosimilar, the example of trastuzumab biosimilar trial seems to be relevant. The product Myl-1401O (Mylan NV) has efficacy and safety comparable to the branded product, according to new findings presented here at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting.
“The results from a large randomized phase 3 trial, known as HERITAGE, show that response rates in breast cancer patients treated with trastuzumab were comparable to those in patients treated with Myl-1401O. At 24 weeks, objective response rates were 69.6% with Myl-1401O and 64% with trastuzumab.
“This is one of the first trials with biosimilars in oncology to demonstrate similar efficacy, safety, and immunogenicity as the reference product”, said the lead study author, Hope S. Rugo, MD, professor of medicine at the University of California, San Francisco.
“Myl-1401O has the potential to meet the need for an affordable treatment option for patients with HER2-positive cancers”, added dr Rugo, who presented the findings during a press briefing.
“Many biologics are losing patent protection soon, and biosimilars have the potential to significantly improve access to expensive agents”, she explained.
No oncologic biosimilars have yet received regulatory approval in the United States or Europe, although ongoing clinical trials are investigating biosimilars of other cancer agents, including rituximab (Rituxan) and bevacizumab (Avastin)(3).
Position of EMA regarding biosimilars
Finally, to better understand how to look at the issue of biosimilars, we will present the EMA position.
The definition of biological medicine is the following: “A biological medicine is a medicine that contains one or more active substances made by or derived from a biological source”. (Some of them may be already present in the human body and examples include proteins such as insulin, growth hormone and erythropoietins).
“A biosimilar medicine is a biological medicine that is developed to be similar to an existing biological medicine (the ‘reference medicine’)”.
“Biosimilars are not the same as generics, which have simpler chemical structures and are considered to be identical to their reference medicines. The active substance of a biosimilar and its reference medicine is essentially the same biological substance, though there may be minor differences due to their complex nature and production methods. Like the reference medicine, the biosimilar has a degree of natural variability. When approved, its variability and any differences between it and its reference medicine will have been shown not to affect safety or effectiveness”.
A list of all biosimilar medicines authorised centrally in the EU can be found on the EMA website. Information on whether a medicine is a biosimilar medicine can be found in the medicine’s summary of product characteristics (SmPC).
How are biosimilar medicines evaluated in the EU?
Because the reference medicine has been authorised in the EU for several years and its clinical benefit is established, some studies carried out with the reference medicine may not need to be reproduced.
“The studies on quality include comprehensive comparisons of the structure and biological activity of their active substances, while the studies on safety and effectiveness should show that there are no significant differences in their benefits and risks, including the risk of immune reactions”.
“Biosimilar medicines are manufactured following the same standards as for other medicines, and regulatory authorities perform periodic inspections of the manufacturing sites.”
How is the safety of biosimilar medicines monitored?
“As for all medicines, the safety of biosimilar medicines is continuously monitored after authorization.”
Interchangeably of reference medicine with biosimilars
“The EMA evaluates biosimilar medicines for authorisation purposes. The Agency’s evaluations do not include recommendations on whether a biosimilar should be used interchangeably with its reference medicine. For questions related to switching from one biological medicine to another, patients should speak to their doctor and pharmacist”(4).
The legislation of EMA regarding biosimilars
CPMP/BWP/328/99 Development Pharmaceutics for Biotechnological and Biological Products - Annex to Note for Guidance on Development Pharmaceutics.
CHMP/EWP/89249/2004 Clinical Investigation of the PK of Therapeutic Proteins.
CHMP/437/04 Similar Biological Medicinal Products.
EMA/CHMP/BWP/534898/2008 Requirements for quality documentation concerning biological investigational medicinal products in clinical trials.
EMA/940451/2011 EMA Procedural advice for users of the centralised procedure for similar biological medicinal products applications.
EMA/CHMP/BWP/247713/2012 Guideline on similar biological medicinal products containing biotechnology - derived proteins as active substance: quality issues (revision 1).
EMEA/CHMP/BWP/49348/2005 Biosimilars containing Biotechnology - Derived Proteins as Active Substance: Quality Issues.
EMEA/CHMP/BMWP/42832/2005 Similar biological medicinal products containing biotechnology derived proteins as active substance: non-clinical and clinical issues.
EMEA/CHMP/BMWP/101695/2006 Comparability of Biotechnology - Derived Medicinal Products after a change in the Manufacturing Process(5). n