The Center for Biosimilars® interviewed Anurag S. Rathore, PhD, whose team of investigators evaluated why applications for biosimilar approvals do not succeed. Large companies as well as small find the approval process challenging, but there is a learning curve that may be followed by more consistent approvals, he explains.
I’m Tony Hagen, senior editor for the Center for Biosimilars® (CfB). Today we’re talking with Dr Anurag Rathore, coordinator of the Center of Excellence for Biopharmaceutical Technology in Delhi, India. In this interview, Dr Rathore discusses his recent study on failed applications for biosimilar approval. He explains common reasons why applications are rejected, lessons to be learned, and the evolution of biosimilar regulatory approval.
CfB: What made you decide to do this study?
Rathore: Biosimilars are gradually increasing in number. When this started 10 years ago, I think people were quite doubtful how biosimilars would be. And they had a pretty rough time for 5 years or so, because even if drugs got approved, it took basically a long time for them to get a decent market share; but now it’s everywhere, including in the United States. Even in the US market now, biosimilars are becoming more acceptable. Providers and patients both feel that this is OK and if it reduces my health care bill, then, yes, this is fine. So, we wanted to take a look at the reasons why some of these things have happened. Because if I were to do this 5 years ago, I wouldn’t have that many examples. It would have been difficult to write an article.
CfB: What’s significant about some of the reasons for the rejected applications and for withdrawals of applications?
Rathore: The first one was issues with comparability, which was not surprising because comparability is a major regulatory expectation for a biosimilar drug. It’s not surprising that that also becomes a major hurdle, and that’s one reason why an application would be rejected. But then I was a bit surprised by things like process validation and GMP [Good Manufacturing Practices], and some of these rejections are happening to pretty large companies, even companies like Amgen and Mylan. These are companies that have gone through many, many projects and many approvals. They know what is required. It seems to me that in general most of the rejections are for smaller companies. I think that’s because in general biosimilar manufacturers tend to have more limited resources compared with larger companies. I would say it’s lack of experience, probably, and what are the expectations in terms of proper process control, following GMP, how to do validation, stuff like that. I think that’s what it was, but I was surprised by how many rejections there were.
CfB: What can biosimilar developers learn from the failed applications that might help them be more successful?
Rathore: Of course, this is my gut feeling, from the regulators’ perspective, the expectations of a biosimilar manufacture are no less than for some of the major manufacturers, and in some ways they’re more, because regulators are worried about approving something that already is going through a limited clinical examination. The last thing they want is a shoddy product which ultimately ends up hurting the patients. They basically look at these quality aspects in some ways harder than they would in a normal molecule. For a manufacturer, you do need to invest in having your process understanding, your product understanding, and then your GMPs, the way you’re manufacturing, so all these things are done as an Amgen or a Roche would do. So, don’t misfire on some of these things, because that’s ultimately what will get your application rejected.
CfB: Are there areas where companies repeatedly fail in applications that they could be more careful about or more aware of?
Rathore: If you look at all the issues, you can kind of classify them into 2 parts. One is the scientific part of it, which is whether you have a molecule that is actually similar to the innovator molecule. That’s a very fundamental question. And of course, if you don’t have it, then you’re not going to be approved, because it’s not going to show up in your comparability studies, it’s not going to show up in your clinical comparability studies, and at the end of the day it’s going to get rejected; but there is a sizeable number of rejections where the molecules were actually comparable but the problem was that the manufacturer had not, the way they had developed the processes, the way they had done the manufacturing, was not up to the regulatory expectations of today. To me, that’s more a system issue. You have the right molecule but you have flaws in your quality system, basically, and that has been shown in many cases that that can be a problem. The regulator is not only worrying about the molecule, it’s worrying about your ability to make the same product with the same purity and the same quality in the future. That’s rightfully so. There’s no point in them giving the approval today if you can’t make the same product in the same way tomorrow. I think a lot of these companies that are doing biosimilar production have not really had any experience with a particular approval process or manufacturing process. It’s a natural cycle where over time, I’m sure, they will learn. And I think you’ll see that in most of these cases where people had rejections, they actually ended up getting approvals, so they figured out what is to be done, they did it, and so I think that over time, manufacturing of biotherapeutics will become as commonplace as manufacturing of pharmaceuticals. It won’t be such a big deal or such a niche market.
CfB: Do you think that these companies are getting enough information from the originator companies to handle the manufacturing side of it?
Rathore: The companies obviously are getting no information at all from the originator companies. No innovator company will give you anything at all. I’ve been in this industry for almost 35 years now, and I remember that when I started in this business, the whole concept of the manufacturing of the biologic was considered very novel. There were very few companies in the world who actually had biologic products approved, who had a manufacturing facility that could make these products. Then around 2000 or so the [monoclonal antibodies] mAbs came to market, and they were considered very complex molecules, extremely complex, very difficult to make. It was quite an art. I think even in early 2000, Amgen—all of these big companies—struggled to do large-scale manufacturing, because contamination was a major, major issue. Eventually of course, people have figured it out. Today, if you were to do a count, more than 1000 manufacturers around the world are capable of making mAb products. So, I think it is gradually getting commoditized. I wouldn’t call it a commodity today, but I think that 10 years from now these will be considered fairly easy to make products that many people will be making. There will just be a learning curve for all of us to get there.
It’s often said that the patents covering a product have to do with a manufacturing process rather than the formulation, so if you’re a company that wants to do biosimilars sometimes you have to work around the process that the originator company is using, right? Do you feel that that’s an impediment that’s also part of this picture?
Rathore: The manufacturing process over time has become simpler. In the early 2000s you had few people who had this kind of experience. Now, almost 20 years later, you have many, many people who have extensive experience in manufacturing these types of products. The biosimilar companies also have benefited from this, because they now have access to resources like that. Of course, many of these companies are relying on contract manufacturers. There are contract manufacturers who are quite capable of making these products safely. It is interesting that, because you are aiming for biosimilarity and you are planning to get approval from a regulatory agency, your molecule is similar to another molecule. Actually, companies are imitating exactly what the originator companies are doing, so they aim to copy exactly the same process performed that the manufacturers do, and in some ways that actually increases the cost of these products. You’ll notice that biosimilars [globally] are 30% to 40% cheaper than innovator drugs. But it’s not like that with [generic] products, which can go to 5% or 10% of the original price. You don’t see that kind of savings [with biosimilars], and I think if you look at the accessibility of these products around the world, it’s very, very poor, and I would say that the prices are too high for the majority of the world, right? So, there is a need to dramatically reduce the prices of these products, which is unfortunate because, again, everybody’s copying the same process platforms, the same expression systems. We are not able to get there. I’m hoping that over time, this too will change.
CfB: Do you feel that guidelines are clear, or do these need refinement in Europe and the United States to reduce the failure rate in the application and manufacturing process?
Rathore: That argument I’m not sure has anything to do with biosimilars. You’re right, there is an effort from regulatory agencies to reduce failure rate in manufacturing, to improve quality of the product, but that kind of applies to all biotherapeutics, including biosimilars, right? In terms of guidance, specifically for biosimilars, I would say that the main benefit of having them is that for a manufacturer they kind of tell you what is expected, right? They normally do not tell you how to get there, but at least they tell you what is expected. I think that is obviously quite helpful. The EMA documents are quite informative. Especially the EMA has done a lot for making biosimilars accessible, otherwise we would be 10 years behind where we are, so they actually get the credit for bringing biosimilar systems to where we are. And I’m glad that the FDA is opening up. The mindset is gradually changing.
CfB: I got from your report that the manufacturers might be rushing the process a bit to get their applications in, but would a much more paced and careful process, in the long run, be the shortest and most efficient for them.
Rathore: I think what I meant was because biotech products are manufactured from living systems, there is an inherent variability in the product. People have done studies on even products that are manufactured by innovator companies, and if you look at that product over a 10- or 15-year period, you’ll see that there is a considerable change in quality over that time, and the reason for that is that with time processes get updated. There are a whole lot of reasons why the process is changing. As a biosimilar manufacturer, you have a problem. As a biosimilar company, you would not have that kind of information that an innovator company would have. Innovator companies invest a lot of money and time in a lot of studies before they get approval, right? So, they have a huge database of information. Biosimiar manufacturers by design will never have that. That’s the whole point. If they accrue the same database, then biosimilars will become as expensive as innovator drugs. But as a downside to that, what happens is, because you don’t have that information, your aim is to replicate the process that will create a biosimilar drug as close to the innovator drug as possible, and when regulators are looking at a product, they are so much harder on you to make sure not just that you have the right product, but also the ability to manufacture the same product over and over again. That’s why it’s important for a biosimilar manufacturer also to invest in your process and ensure that the process is capable of producing a product that is consistent.
CfB: Please could you discuss the Quality by Design initiative and its significance.
Rathore: Quality by Design is a concept that the FDA kind of pushed in 2000, toward the end of 2000 timeframe, and basically it’s answering 2 questions. How well do you understand your product? What are the attributes of your product, and how do those attributes affect quality and safety? The second is how does your process affect your product? It basically means knowing what each step in your process is doing, how are you controlling that step, how are you making sure that your product at the end of that process is consistent? What it means is that as a manufacturer you need to understand your product and you need to understand your process, and I think that in the case of a biosimilar manufacturer, the same argument applies. You need to match the innovator product as closely as you can. And you need to know your process, because only then you will figure out how to control your process so that your product is consistent in quality.
CfB: Ultimately, would you say regulatory intervention is a very positive process? Are the number and type of rejections that are happening quite valid reasons for rejecting these processes or products as they move along?
Rathore: There are 2 ways to look at it. If you look at rejections, you’re right. Most of the rejections are valid and for the right reasons. Most of the manufacturers should have done what they did not do, but in this business a good way to put a hurdle in a manufacturer’s path is to keep asking for more and more information. That won’t show up in the rejection, but if you keep asking for more and more comparative trials, or larger and larger trials, then the whole thing becomes less and less attractive to a manufacturer, because then the biosimilar manufacture ends up spending the same amount of money as the innovator. That is something I think particularly the US FDA has to watch out for, because even the clinical program that they ask for is more than most, and this becomes a hurdle, because not many companies can afford to give that kind of data. Over time, as regulators become more at ease with biosimilars, hopefully they will gradually lower the bar.
CfB: Please compare the European regulatory environment and the FDA regulatory process with what’s happening elsewhere in the world with biosimilars. Do you feel that standards are gradually moving up or that other countries are basically relaying on the FDA, the WHO, the EMA to do this job for them?
Rathore: That I would say has less to do with biosimilars and is more of a biotherapeutic question. You’re right, the EMA and FDA are by far the leaders in deciding how to regulate these products, and a lot of countries depend on them. I think the level of expertise the amount of experience, all these things, are in an order of magnitude higher in these agencies than in the next agencies. Part of it is if you look at the size of the market, more than half of the global market is the US and then Europe is another 1/3 of the global market, so that is a big reason why these regulators play a very big role. I think over time as other economies pick up. China has come a long way, India is gradually rising. As they become bigger, I think more regulatory agencies would play a bigger role.
CfB: How would you summarize some of the conclusions from the report and some of your findings and explain what you think would be good advice for biosimilars companies to follow or be aware of as we go forward?
Rathore: Things to be concluded from the study, obvious things, you need to have a good comparability package. The biosimilar molecule has to match the innovator molecule in the analytical comparability package, and your [pharmacokinetic/pharmacodynamic] strategies, your clinical comparability strategies. That’s kind of obvious. I think everybody knows. But I think I said that that the thing that people probably don’t realise is that besides having the right molecule, it’s equally important to have a good process of design, of control, that can deliver the same product quality consistently over long period of time, and [you have to] invest those resources so that a regulator knows you have a well-controlled process. I think that’s something that a lot of biosimilar manufacturers kind of miss out on, and that’s something they need to know. Otherwise, people are too focused on product.
CfB: Other thoughts, Mr Rathore?
Rathore: In general, I would want to see more biosimilars approved in the United States. That’s happening gradually. If you look at price of all biotherapeutic products all around the world, the United States is paying 5 to 10 times more for any given product than anybody else in the world, which to me is quite surprising. I just hope that US policy ultimately lowers the prices of these products. Even in the United States, not everybody has access to these products. If the prices come down, more people can have access to them.
To read the article about the study described by Dr. Rathore, please click here.