Biotech Values

[DewDiligence]

Following is the FoB presentation (including Q&A) by MNTA’s CMO,
James Roach to the FDA’s public hearing on 11/3/10. (A link to the
entire hearing was posted by ‘rwdm’ in #msg-57454316, which is
referenced in the MNTA ReadMeFirst in the section on FoB’s.)

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PREPARED REMARKS

Dr. Roach: Momenta is a biotechnology company that belongs to both GPhA and BIO and we develop analytical tools and methods that advance the science of thorough product and process characterization and knowledge.

We apply these methods to develop generic versions of complex products such as enoxaparin and glatiramer acetate [Copaxone] and also to develop biosimilar and potentially interchangeable products.

We seek to further define product structure and use this enhanced product knowledge to lead to an increased understanding of structure function and process-product relationships, tighter control of process development and greater assurance of purity, potency, and sameness.

We believe that innovation in the analytical methods and tools offers the biologics industry the opportunity to improve the quality of all biologics whether branded or biosimilar.

The industry has historically taken the approach to characterizing proteins by evaluating identity, size, charge, and glycosylation profile into various methods. We believe generally this is limited and perhaps doesn't capture the complexity of most glycoprotein products.

Though it is beyond the scope of this forum to delve into a detailed technical presentation or spend too much time on slides like this, we believe that the ability does exist to much more thoroughly characterize the entire structural space of the biologic by applying a variety of additional and orthogonal high-resolution analytical methods and data integration techniques.

As an example of how this technology may be applied, I would refer you to a paper being published in the next week or two in Nature Biotechnology entitled, “Chinese Hamster Ovary Cells Can Produce Galactose-Alpha-1,3-Galactose Antigens on Proteins,” by Carlos Bosques, Brian Collins, James Meador, et al.

Patient access to biologics is increasingly limited by high cost and growing demand. Many emphasize the potential risks to patients if we rush too quickly to bring biosimilars to the market. However, equal emphasis should be placed on the potential benefit to patients by implementing the pathway in a way that ensures the introduction of safe and effective biosimilars into the marketplace.

The BPCI Act offers the opportunity to extend the significant benefits that the Hatch-Waxman legislation provided to patients in need of biologics by permitting appropriate reliance on what is already known about an existing biologic. Unnecessary duplication of human or animal testing can be avoided and access to these potentially life altering or lifesaving medications will be significantly increased.

With this in mind, I would like to emphasize the following points. If the rules establish burdensome limitations on the application of new scientific approaches, the goals of this legislation will be undermined and investment will be further directed away from the development of technologies intended to enhance product understanding and safety.

The Agency's statutory scientific discretion was presumably enacted for precisely this purpose: To accept applications that may offer new solutions and scientific approaches to the traditional drug-development paradigm.

It is critically important to allow the Agency the broad scientific discretion needed to make determinations on data required for approval on a case-by-case basis, and not to implement unnecessary obstacles to use of the pathway such as issuing guidances which perhaps mandate certain requirements for approval.

To offer the most potential benefit to patients, the Agency's implementation of the BPCI Act must allow for the practical and feasible development of both biosimilars and potentially interchangeable biologics. It will only make sense for companies to pursue approval via the 351(k) pathway if requirements for pre-clinical and clinical studies are reduced relative to a traditional BLA pathway. The degree of analytical data and knowledge of product-quality attributes will help to inform the Agency in deciding the nature and scope of pre-clinical and clinical trials required to support approval.

The state of the science with respect to the enhancement of product understanding has evolved considerably in the last decade and will continue to do so. We need to set policy that is flexible enough to allow the Agency to consider scientific advancements on an ongoing and real-time basis.

Pre-clinical and clinical trials clearly have an essential role in assuring the safety and efficacy of novel products. It is certainly appropriate for both pre-clinical and clinical trials to potentially play a role in determination of similarity. However, this data requirement should be implemented in the context of the existing product knowledge data set. Clinical trials could be positioned as supportive and designed to provide adequate safety and efficacy information to establish comparability to the reference product. [I.e., the focus of the FDA’s review of FoB applications should be on analytics, not clinical trials.]

These trials must also be feasible to conduct. Establishing statistical non- inferiority or equivalence of a biosimilar relative to a branded product in clinical studies may be impractical for many products and indications. Additionally, switching studies to assess the potential immunogenicity, efficacy and/or safety of a biosimilar relative to a branded product may neither be feasible nor particularly informative in certain circumstances.

Immunogenic responses and other safety-related issues may not manifest themselves until well after initial exposure making it difficult to determine the product that may be causing a biological response and similarly biological efficacy may be the result of a long-term cumulative affect with exposure, again making it difficult to envision the concept of switching. For example, in oncology studies designed to demonstrate an effect on survival. There are certainly lessons to be learned from novel biologics as to how similarity and comparability may be defined.

It is important to recognize that existing products may exhibit a considerable amount of lot-to-lot variability for a number of product-quality attributes. However, as long as each lot falls within certain predefined specifications for these variables, they are considered the same or sufficiently similar to be interchangeable and treated as the same.

We believe that the principles articulated in the ICH Q5E Guidance on Comparability of Biologic Products are very relevant to determining the type of data that may be required case-by-case to support approval of a biosimilar product. To quote the guidance, "Determinations of product comparability can be based solely on quality considerations if the manufacturer can provide assurance of comparability through analytical studies and additional evidence from non-clinical or clinical studies as appropriate when quality data are insufficient to establish comparability."

We support this approach, as the comparison of a very thoroughly characterized biosimilar to a reference product can be thought of in many instances as analogous to the comparison between a pre-change and post-change product. The burden, of course, will be on the sponsor to demonstrate that the variability of the biosimilar or potentially interchangeable product falls within a comprehensive set of prospectively defined product quality attributes so that one can reasonably expect that the product will have the same clinical activity as the brand product.

Biotechnology companies that have successfully commercialized products are often referred to as innovators. Many of these companies state the process is the product and replicating biologics is impossible and appear to be advocating for policy requirements that if implemented could effectively render the 351(k) pathway unusable. Many people stated that replicating enoxaparin was impossible as well [indeed they did].

I find it interesting that an industry which has always prided itself on innovation and the ability to solve complex problems is to quick to emphatically conclude that something is impossible and can't be done [e.g. Teva’s propaganda about replicating Copaxone].

I submit that the technology platforms that we and other biotechnology companies have developed in the interest of advancing product knowledge are every bit as innovative as more traditional drug-development platforms and if appropriately applied and supported have the potential to translate into very substantial benefit to patients.

So, in summary, there's no arguing with the concept that patient safety is of paramount concern. However, this phrase is often positioned to support the foregone conclusion that comprehensive non-clinical and clinical trials must, therefore, be conducted to ensure patient safety. I submit that the patient is of paramount concern and we may not be benefitting patients by conducting redundant and arguably unethical trials should criteria for similarity and/or sameness be otherwise met.

I sincerely hope that as the debate moves forward that sound bites and rhetoric will be replaced with fact, objectivity and solid science that enable the use of this pathway in a responsible way. Although the pathway presents challenges to both sponsors and regulators, it also presents a tremendous opportunity for all involved. Most importantly, patients.

In conclusion, I would like to borrow a quote from a presentation given by Dr. Daniela Verthelyi, Chief of Laboratory of Immunology in the Division of Therapeutic Proteins and OBP at FDA. "The regulatory process must render a balance between the desire for rapidly available novel therapeutics and the need the carefully evaluate potential safety risks and clinical efficacy."

We agree, and hope the Agency finds these comments useful as you move forward to implement the BPCI pathway.


Q&A

Dr. Kozlowski: Dr. Roach, one should use a standard of within-manufacturer comparability for doing a biosimilar evaluation and the previous speaker mentioned in his presentation some issues that are different like access to intermediates. So, could you comment a little on the actual differences or lack of differences in your view within manufacturer change and a biosimilarity evaluation?

Dr. Roach: Sure. It's a great question and I think we would have to evaluate certainly on a product-by-product basis the differences that we're observing.

But, I think the main point is if you can apply analytical technologies at various points in time in process development with your own biosimilar, you learn certain things about how the process may affect the product. Such that by the time you get to drug product, you can see certain structural fingerprints that you think perhaps were influenced by the process. So that, by the time you get to drug product through these learnings, you may, in fact, have a drug product that may be more similar to the reference product that the differences you observed between lot-to-lot in the reference product.

Obviously, this is an evolving science, but that's kind of how I would approach it.

Dr. Kozlowski: So, to follow up, that assumes that you can characterize anything of importance.

Dr. Roach: I don't know that I want to be so bold as to make that statement here today, but what I will say is that our technology platform, and I'm sure other people that are working on this, bring a whole other degree of resolution to these compounds.

Dr. Kozlowski: And to follow up on another note, in your first slide, you had sort of Dr. Nasr's wheel of quality by design. And I think the concept of more advanced pharmaceutical manufacturing that can deliver targeted sets of attributes very consistently I think is something the Agency would like everybody to do. You know, innovators and biosimilar industries.

And I guess if manufacturing can really advance to be much more targeted, how do you think that relates to the question of drift? Because that's something which has come up, I guess yesterday and today.

Dr. Roach: No, absolutely and I think I made the point early on that I think these technologies that we and others are working on can be applied certainly both to development of biosimilars and to ensure a higher degree of quality for branded products.

So, to me the product drift question, I think if I'm the manufacturer, I would embrace these kind of technologies to ensure that your product is not drifting very much rather than to try and position it as what happens if you get a biosimilar on the market and the reference product drifts. To me, the problem or the potential situation could be that there are more issues with product drift than there is from the biosimilar being comparable to the reference product that's approved.

Dr. Jenkins: I'd like to follow up on some of your comments about the role of clinical data. You said that clinical trials in this context should be positioned as supportive to the existing data set and designed to provide adequate safety and efficacy information to establish comparability to the referenced product. We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product. So, how do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there's no clinically meaningful difference as the statute requires between the biosimilar and the reference product?

Dr. Roach: Well, I do think again it would be on a case-by-case basis. But, I also think that as you develop more product knowledge through various analytical and biocharacterization techniques, we can't underestimate the benefit to patients by getting the products on the market without having to replicate trials conducted by the sponsor or, in some instances depending on how you set this, you could envision a scenario where if you're requiring establishment of non-inferiority or equivalence, you might end up having to run a trial that's 4X or 5X greater in size than what the innovator needed to do to get the product approved in the first place. So, I would emphasize that the burden is clearly on the sponsor to make the arguments as to why it is that their collective package including certainly all the analytical and biocharacterization data, in vivo data animal studies support a more limited clinical data set. But, I do think it's possible to provide a limited clinical-data set in conjunction with the entire existing data package to get a product approved.

Dr. Jenkins: There is a model that's used in the Office of Generic Drugs in certain situations where you can't determine bioequivalents for small molecules based on either pharmacokinetics, which is their preferred approach, or pharmacodynamics. They do use clinical trials in some settings such as for topical products. Are you familiar with that model, and if you are, do you have any thoughts how that should apply to biosimilars?

Dr. Roach: I'm only vaguely familiar with that model. I understand the model in concept, but I think the concept still applies that the sponsor will propose a study that they think makes sense in conjunction with their package to support approval. Above and beyond that, I guess I'm not that familiar with the specifics of the model. But, it is limited -- it's not necessarily the same kind of study that de novo you would be obviously putting forth for an NCE.

Dr. Kozlowski: One more follow-up on that. So, you mention that there should be supportive clinical trials, but you suggest a non-inferiority trial or a two-sided equivalence trial or a switching trial may be inappropriate. So, I guess I'm wondering what would you envision the design of a supportive trial other than those looking like?

Dr. Roach: I'm not suggesting that non-inferiority or equivalence are necessarily not appropriate for products like this, but it may be, as an example, how you define the non-inferiority or equivalence margin for a product like this relative to an NCE. You might allow a wider margin as an example to provide evidence of comparability.

Dr. Behrman: Just a quick question on your slide eight. It seems to imply that you believe that interchangeability can be established without any clinical data. Is that your position?

Dr. Roach: I guess my position is I would like to believe that over time as the science evolves that it's certainly possible at some point in time and maybe for some products very soon, and maybe for others not so soon, that possibility exists. So, my main point was more to allow the policy to be flexible enough to able to respond to that kind of data package.

Dr. Behrman: That's very helpful.‹