How to Optimise Method and Design in Comparator Studies

Claire Willsher, Manager for Analytical Preformulation at LifeCycle Pharma, joins Pharma IQ to discuss Comparator Studies.

Pharma IQ: Can you describe a typical study design when using comparators? 

C Willsher: It’s very common practice in Phase II and III studies to look for clinical comparisons between the drug you have in development compared to the current market leader, or another well-established product on the market. The aim of your study is obviously to show that your investigational drug product is comparable, or even superior, to the current marketed product. Regulatory agencies require clinical comparisons as part of your proof of efficacy, and the use of a blinded comparator is usually preferred as that leads to a more powerful clinical study design.

There are various ways of achieving a blinded study. You can use blinded comparators where the drug under investigation and comparators are all made to look the same, or a double-dummy design, where the drug under investigation and the placebo look alike. Or you could even do a mixture of the two: double-dummy; double-blind. The overall challenge is how to make the comparator look like the drug under investigation without compromising the integrity of the comparator. In addition to all that, you also have to demonstrate that all that’s been achieved.

Pharma IQ:
What are the key sourcing issues in running globalised comparator studies, Claire?

C Willsher: I think sourcing for globalised comparator trials is a dynamic process, and there are many factors that can influence it. Deciding on a single, global, regional EU/US/rest of the world or a local source is vitally important, as well as taking into consideration things such as pricing, lead time, and available documentation. Also, in today’s market you’ve got other issues such as counterfeiting, and even your innovator company trying to prevent head-to-head trials, and that can also play a big role in making your sourcing decisions. You should also not underestimate some of the challenges around moving different materials around the world. A good example of that is lactose and your TSE Certification.

Pharma IQ: Can you explain a little bit about that challenge?

C Willsher: If you’re moving into Asia or areas that don’t take lactose, if you don’t have a TSE Certification for your drug, then moving them into those countries can be very difficult.

Pharma IQ: What are the main considerations when ascertaining comparator characteristics?

C Willsher: I think some of the main considerations when ascertaining comparator characteristics include things like how established the drug is as a first line therapy in your investigated indication. Is its mechanism and action similar, or at least resemblant of the investigational drug product. Also, is the comparator approved in the countries that you’re looking at for your licence, and are there any considerations or special factors in the investigational group. For example, is the dose response the safest, or the efficacy of your investigated drug and comparator drug similar between different ethnic populations?

Pharma IQ: As much of the information regarding the formulation, methods and related stability of the comparator agent is often limited and inaccessible, what are your views on how to overcome this challenge?

C Willsher: You’re totally correct here. One of the most difficult parts of comparator investigations is the minimum amount of information available. It’s not like your comparators don’t want to make it easy for you. With regards to the formulation and stability, some of that information is available and can be found, for example, in the label, or if the comparator is marketed in the US, there will be some information somewhere in the FDA site, which you can access via the Freedom of Information. Also, sometimes if you buy a significant quantity from your wholesaler, you can request a C of A, but you’d usually have to declare, then, that you’re buying it for clinical trial purposes. But when it comes to method, often that’s a completely different story.

If you’re lucky enough, there might be a monograph, and then this is literally your most practical way of analysing your comparator product. If not, then you have to take the time to research and develop the method yourself. You’re often using a different API to the product that you’re using yourself, which means you obviously have limited information about that, so in order to ease your method development, I think it’s a good idea to spend some time getting to know that API first. One thing also to remember is that once your method is developed for your comparator, it also has to work if you modify your comparator as well.

Pharma IQ: How would you describe the optimal process for formulating a blinding strategy as part of the comparator development process?

C Willsher: From my experience, it’s really important to get a team together as early as possible and ensure that all the affected disciplines are represented. To ensure that you’ve got a smooth as possible strategy, I think you should have representation, not just from your clinical side, which is normally where it lies, but also regulatory CMC, so somebody from analytical, formulation, manufacturing. All these disciplines play a really important part in the blinding strategy, and we often approach it from different angles. If all your disciplines are covered, then your blinding strategy should take all considerations into account, and, of course, you need to identify which are the things you’re trying to blind, such as taste, appearance or touch.

Pharma IQ: There are a lot of considerations. What are your thoughts on the different merits and applicability of some of the variety of strategies available for blinding comparator agents - over encapsulation, de-inking, etc.

C Willsher: There are a large number of different types of blinding employed in the industry, and many of those depend on the dosage form that’s being blinded. If you take solid, or doses for an example, the number of ways from simple over-encapsulation to a manufacture of a near-match generic, and each of them has its own pros and cons, a simple over-encapsulation is probably the most widely used and accepted, and often stability and dissolution are typically good. However, it can also be labour-intensive if you don’t have an automated manufacturing process. It can also lead to poor compliance: some patients don’t like swallowing capsules. Or even on blinding, as a race we are quite curious and we want to know, and we can often open the capsule by patients so you can unblind your study. Also issues with colour and composition. For example, porcine gelatin or lactose tolerability in certain countries.

There are a number of blinding strategies, as you said, such as de-inking, also over-coating, and they’re often used in the same way as over-encapsulation. But you do need to take care, then, not to damage the tablet or its relief mechanism. And if it’s embossed or de-bossed, that blinding technique is not always successfully employed. You can also get solvent penetration, which can lead to chemical stability issues.

Other methods that are also used, such as the mill-and-fill as it’s called, is useful if you’re doing large quantities. And typically stability is good. However, other issues, if it’s a controlled release, or dissolution and content uniformity, can be problematic.

There are other more complex techniques, such as like the near-match generic manufacture, and they’re employed much less frequently, and they often require a significant higher resource input with increased risk of issues with formulation stability and commercial comparison.

Pharma IQ: Can you discuss the impact of various blinding strategies on the stability of comparative agents?

C Willsher: The overall goal is obviously that the modification of the comparator doesn’t adversely affect the stability, and there are a number of things to be aware of when choosing your blinding strategy when it comes to stability of the product. However, more often than not, it is very product-dependent. I’d say, in general, when you’re over-encapsulating, whereas the chemical stability of the modified product may be not so much of a concern, the physical stability with respect mainly to the dissolution can be greatly affected. Also with modification such as the de-inking or over-coating, you’re adding in another variable, ie the code for the solvents, and this can lead to both chemical and physical stability concerns, and the physical stability may also be affected with respect to the release mechanism.

With the more complex techniques, such as the generic manufacture, the comparator has to be viewed in the same light as you would a normal development stability, and all the problems that you have with that. One important thing also here to remember is don’t forget the pack issue. We talk about blinding the actual comparator, but if we change the pack, if the comparator comes in a special pack, whether that be an alu bag or an opaque, in a gas headspace etc, then even if the blinding is simple, such as an over-encapsulation, then the stability impact of the changing pack may not be.

Pharma IQ: These are some really useful points. Claire, we’re delighted to have you as a speaker at our Global Comparator Studies Conference; what’s going to be the key message of your presentation?

C Willsher:In my presentation, I am going to be using some case studies to look at comparator products and modifications, and how this affects methods and stability, and by using case studies I’m actually going to go through some of the experiences and the highs and lows that we’ve experienced here at LifeCycle.