Dr Kim: Biosimilars are very different from brand drugs， because the brand drug is a chemical that is produced by combining other chemicals to create reactions to produce an identical compound. For biosimilars， the biological agent is coming from living cells. We have to know how to make the monoclonal antibody that cells are making. The problem is that cells don’t always behave the same way – sometimes they are adding some glycosylation that can result in variations in the chemical structure. For example， the most successful monoclonal antibody， rituximab， made last year was a little different from the rituximab made this year. In trials， we have compared rituximab from US and European sources， and because the cells behave a little differently， the monoclonal antibody is not the same from each location. Living cells will behave differently. The brand drug is the same chemical compound as the biosimilar， but it is not exactly the same. That is the reason why we are using the name ‘biosimilar’， due to its similarity.

 

A generic drug is a compound produced after the original drug patent has ended. We can say that a biosimilar is a type of generic， but generally， the generic drug is a chemical compound， same as the brand drug.

 

 

Dr Kim: The big advantage of biosimilar compounds in daily practice is that we can reduce the cost of healthcare. Right now， there is a big financial burden globally as more biological agents are used. They are very expensive. Many patients who need a biological agent cannot access drugs and are losing the chance to receive the best healthcare. We have to think about the use of biosimilar compounds in the future to reduce the cost so more patients can access them. But， as I have said， the development of biological agents and biosimilars is not very easy. The biochemical properties should be the same， the 

 

Dr Kim: The brand drug is the exact same chemical compound with the same pharmacokinetic (PK) and pharmacodynamic (PD) data， so there is no need to confirm efficacy because the chemical is exactly the same. In the case of biosimilars， the drugs are not exactly the same， so we have to conduct more steps to confirm the similarity. The first step is the sequence of amino acids – the amino acids should be the same. The next step is to confirm the chemical and physical properties and these should be the same – molecular weight， affinity and so on. We then need to confirm the PK and PD data. Those are the basic steps in the development of biosimilar drugs. The most important part should be the efficacy part， because as the biosimilars are not exactly the same chemical compound， sometimes the efficacy can be different， even though the PK and PD data are the same. That is the reason why we need a phase III trial every time to compare the reference drug to the biosimilar. That costs a lot of money and takes more time to confirm efficacy， and that is the biggest difference in the development of generic drugs and biosimilar drugs.

 

Dr Kim: The reason we did a trial comparing R-CVP in advanced stage follicular lymphoma was because rituximab was approved first in hematological malignancies for follicular lymphoma. The regulatory authorities， especially the EMA， asked for the same indications that rituximab was approved for the first time. So we had to do the trial with R-CVP. For the second question， the dosing schedule for rheumatoid arthritis is totally different from that for follicular lymphoma， so we had to confirm that the same efficacy was maintained at a different dosing schedule in a different disease. At the same time， CD20 expression is different between the hematological malignancies and rheumatoid arthritis. Extrapolation means getting evidence and approval for one disease entity so we can determine the efficacy in other disease entities. This can be difficult， and in the case of rheumatoid arthritis and follicular lymphoma， because the CD20 expression is different， that extrapolation was very hard for these two indications. That is why we did another confirmatory phase III trial in follicular lymphoma after obtaining the data for rheumatoid arthritis. The question is whether we need to do further phase III trials for other hematological malignancies. For curable diseases like DLBCL， MCL， physicians and patients need to have the confidence to use drugs like these， so outcomes should be confirmed in trials for these indications. Another issue is interchangeability. If a patient is receiving one biosimilar like the original rituximab and then after several cycles need to change， can that be done using a similar drug or some other biosimilar? There will be more and more biosimilars available to use. Within a couple of years， we may have four or five biosimilar rituximabs， so we will need to know if it is safe to use more than one of these with similar efficacy. We don’t have data on this yet， but in the next trials with low tumor burden follicular lymphomas， we will be assessing drug interchangeability. Some patients will receive the original rituximab and then moved to a biosimilar. This data will determine whether interchangeability is possible， but right now， we don’t have that data.

 

 

Dr Kim: Because there is not enough data on their interchangeability. If we are using the same name， we will not know which compound is given to a patient. There will be more and more biosimilar compounds over the coming years， so if using the same name as the first compound then the whole course of treatment will get confused if several biosimilars are used. Until we have interchangeability data， I think we should be separating the compound names.

 

 

Dr Kim: Absolutely. Sometimes the biological agent can induce immune reactions. Most of them are proteins， which means they themselves can be immunogenic. After a period of time， patients who received a biological agent can develop a neutralizing antibody that reduces the efficacy and can also produce other immune reactions. So we definitely need long-term follow-up data. But we don’t have that data yet.