生似葯的監管科學基礎尚在發展中 - FDA在參議院的證詞

9月17日，FDA藥品審評與研究中心主任Janet Woodcock，出席參議院健康、教育、勞工與養老金委員會（HELP）聽證會，報告生物類似藥方面的進展。她在聽證會上強調，開闢穩健的美國生物類似葯市場並建立法規支持體系，最重要的部分之一是確保科學框架「刀槍不入」。在聽證會上，她談到了一系列與生物類似葯相關的尚未解決的問題，包括期待已久的可替換性指南，以及在新產品研發、命名和標籤方面的困難。

《平價醫療法案》（ACA）授予FDA批准生物類似葯的權利。然而，自從2010該法案簽署以來，FDA僅批准一例生物類似葯 – Novartis公司的Zarxio，它是Amgen公司抗癌藥Neupogen的生物類似葯。有關該生似葯批准的相關報道請見識林往期資訊。Zarxio並未批准為可替換產品，可替換性意味著需要符合更嚴格的標準。Woodcock表示，「我們認為可替換性是可行的，我們將會實現這一目標」。人體免疫系統能夠檢測生物類似葯中的微小變異，FDA必須確保生物類似葯不會因意料之外的免疫應答造成額外傷害。

一些參議員質疑FDA在指南發布方面的拖延，尤其是可替換性和標籤指南。Woodcock指出，傳統仿製葯的成功不是一朝一夕之事，雖然首個生物類似葯已經獲批，但前路上仍布有法律和政策的挑戰。她還表示，現在有57個生物類似葯在研，FDA正與這些產品的持有人會談，並且已經發布3份有關生物類似藥科學性和監管考慮的定稿指南。尚未發布的指南大多關乎政策問題，而不是科學問題。但在參議員Elizabeth Warren批評FDA批准生物類似葯的速度緩慢時，Woodcock博士承認，尚有科學問題未解決：「We have to get the science right. We can"t have problems with the first biosimilars out of the block。我們 必須在科學上搞清楚，不能讓最先獲批的生物類似葯存在科學上的問題。」本文作者認為，此處所談科學可能就是常說的監管科學，即評估藥品安全、有效、質量可控和效用的方法學，而不是基礎科學問題。她表示，由於複雜的授權過程，FDA無法就這些指南何日發布或何日定稿提供任何具體日期。

但Woodcock指出《用統計方法評估分析類似性數據以支持生物類似性證明》指南可期待在6個月之內發布，這是繼可替換性和標籤指南之後第三重要的指南文件。她提到，生物製品和生物類似葯「批與批」之間可能存在變異，因此需要一種方法通過分析化學和統計測量變異的影響。她還表示，FDA已經諮詢歐洲藥品管理局，「他們認為我們的做法是合理的。」

至於生物類似葯的命名，這是最近很大的一個問題。Woodcock強調，發生問題時能夠將適當的生物類似葯撤出市場的重要性。Woodcock還指出需要權衡多方標籤方案，FDA需要一個能維持醫生信任的標籤約定。

Janet Woodcock博士在聽證會上的答辯原文摘錄如下（根據視頻整理，可能存在個別遺漏或錯誤）

Thank you very much, good morning, I really thank all of you for holding this hearing today. It is very important topic. FDA and I personally have long supported the availability of a biosimilar pathway. I』ve been work on this since the late 1990s. So this is important to me. I』ve been involved in biologic therapeutic about thirty years. As a Rheumatologist which is authorised docotor, I』ve seen a transformation in the treatment of Rheumatoid arthritis by these medicine. Due in large part to biologics therapeutics, chinics full of wheelchairs are now a thing of the past in a Rheumatologist clinics, . and Instead of talking about joint replacement for these patients ongoing care, We talk about treating them to eliminate disease ,try to make their disease go away. But these transformative medicine are still inaccessible to some Americans, because of their cost.

Since Biosimilar pathways created by congress in 2010, A lot of progress has been made, chairman said the first biosimilar was recently approved in the United States, But people are anxious to see more progress. Our generic program, the small molecules that Senator Cassidy refered to is now hugely successful with over 85% of dispense prescriptions in the United States being generic drugs. This saves hundreds of billions of dollars to healthcare system. But this success I have to stress ,did not happen over night. It has been the work of many decades. Developing both maturity in the industry and gaining confidence of the health care community to use generics, this broadly.

Although the first biosimilar is now marketed, there are many legal, technical, and policy challenges ahead. And I look forward to discussing them, as the subject of today』s hearing. Nevertheless, I believe there is a bright future ahead for our biosimilar program. It will produce same access to important medicines that are our currentl generic program is doing, I am happy to answer questions.

Well firstly answer your second question, We believe that getting them scientific practically. we are going to get there.

However, Let me tell this statute what the congress have passed said Interchangeability, first of all, it is expected to produce the same clinical result as the reference product in any given patient; and second of all, when a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biosimilar here phrasing and the reference product is not greater than the risk of using the reference product alone.

So we have to make interpretation of that statute standard. But the statute standard set a high bar. The reason for this, the basic reason is, the human』s immune response. Because when we approve a biosimilar as biosimilar, we are going to find that it is highly similar to the reference product, meaning it is expected to produce the same clinical effect for both safety and efficacy.

However, that raises a question, if what happen in our current system with generic, your patient, and you get your medicine, switch over and over again, between one generic or another, sometimes you make the reference drug. The question is, would that cause additional harm because unexpected immune response? Because unlike most our small molecular drugs, the body recognize this large protein molecular that are Biosimilars, often in some people will make an immune response. The concern has been ,is that continue switching could raise that immunity, provide a reductive effects.

We certainly do, in the degree to which something is highly similar as finger print level would be a very strong point level, people』s immune system is capable of detecting tiny variability.

Perhaps, not ususally, as you said, but the problems I was talking about were from RLD, they were between different versions of RLD not biosimilar.

Well this have very small manufacturing changes that we believe is broad upon these problems.

We are working very hard to get them out, but I cannot, I never give a date to guidances, because it is some sort out of my hand. it is Complex. We are working very hard on these.

CMS codes are often used by us, as well as other purposes, as for tracking purpose, So we can determine who got what drug. CMS has a proposed rule, still in the rule making process, But CMS,if they were to , would finalize this proposal, FDA and CMS are developing approach to use sub-code, we would call it coding-modifier, already exist in the CMS world. That would help us distinguish who got what. That would distinguish amongst the variaties.

Yes I think, to great scientists, it has fallen on FDA』s shoulder. they say this over and over again, We did go through this, we still going this with generics, with some specialty groups. As we』ve been doing trials to equivalence of generics. We have laid out a plan of campaigns of education, we also doing focus groups , and other activities to determine what is the current level of understanding, and what people need to know. But my experience, if I may, is that we are going to target the subspecially groups one by one. with people who want to educate them about things. And we are going to offer CME type of course, most clinicians are overwhelmed we can go subspecially by subteam, as we approve biosimilars used by subteam. This is a very complicated issue, We have a menu of activities planned out for the next several years.

We have not really make a change. We did not put anything in the final guidance, because it was not really about labeling. We plan to issue a labeling guidance. We also have a citizen petition before us, From Abbvie on variabilities of these issues, that is in the docket. We are going to evaluate it, we are going to put into guidance.

I can answer the when, because it still under consideration. I cannot answer the what. As soon as possible, We understand the criticality of this issue, it is really important for us to gain and maintain the trust of health care community in these products. Why now the biosimilar we approve is not interchangeable, and clinician would have to write for patients to get, just as they would for any other drug, they can write with the brand name, they can write with the proprietary name of biosimilar product.

Well, There are trade-offs involved in the various labeling decision. We have had a citizen petition go through, focus on either side of this issue. We need to have a labeling convention maintain the trust of clinician, I understand they want to know what the patients are getting. but right now, you have to write a prescription for the new biosimilar for patients. And they will want to know if patients want to get a biosimilar medicine. As expected right now, to deliver the same clinical effects as the reference product.

They are not interchangeable, because they are not determined the immune issues.

We have issued three final guidances, and one of them is the foundational guidance for how you develop biosimilar, just scientific consideration, put forward what company need to do, to start. Because the statute said comparison has to be, to use with US listed drug. Many company have to restart by comparing to US drug, which might be different than with the EU drug. We give a scientific structure, the foundation is the analytical similarity, other type of studies would on top of that, the mount of clinical data needed depend on how much the uncertainty remain about similarity about doing that program. These 57 are engaged in the scientific program.

First of all, we have to get the science right. We can"t have problems with the first biosimilars out of the block. The guidances you are talking about are about policy issues, not about scientific standard. We have issued 8 guidances, 3 final and 5 draft guidances.

Well, for your first question, we have the resources use of this program, the resource is available in the testimony, appropriate dollars 21 million dollars. We are talking about savings of millions of dollars here. The program did not come and claim, founding for large education campaign to the outside world, We are really highly fully occupied on the 57 development programs, and another 27 coming to us about developing individual products. Plus developing the guidances, and the legal, regulatory scientific, and policy frame work, for how we are going to do this. That will stand up to legal challenge, and also the scrutiny scientific community. So I agree with the committee, most important next guidance would be the Interchangeability and labeling, finalizing the naming guidance, Although that is the issue for the outside world, it is not a scientific issue per se. Most important thing we have to do, we set scientific frame work, is bulletproof. OK. We earn the trust of community, actual work to provide biosimilar that are safe, and effective, and have the same properties, as innovator. This is most important No.1. But Clearly, We have to conduct the education, we need to get out all of the frame work, not just the fundamental building blocks.

How do you prove the interchangeability, of course we talk about the 57 sponsors about how they will show interchangeability, right? We are learning from what they are learning, we are learning that each of these 57 product is a little bit different. And so, we will learn a lot from this experience. There is no doubt that these are very important we get out. we will try to get them out expialidociously.

The guidance is mainly going to be directed to the industry, other than the labeling, naming, convention will be of great interest to the health care community. But the scientific frame work is directed to the industry, What do you have to do, to show your product is first biosimilar, which we have already put out a guidance on, and interchangeable.

Well, I will say, Some products the EU approved have been approved in US for some time, We did not approve it as biologics, we approve it as drugs, so we will able to put, basically similar versions on the market, because the drug laws and regulation has been for a long time, those provisions are not present in EU.

I have to get back on a good example, the Growth hormone, we do not know the exact time we approve it. But it is on the market already. There are other examples Insulin. Interfeon is biologic, is the one I approve when I was at CBER.

There are a lot of trade-offs in the naming Convention, We want to know what people got. So if there are severe problem out there, we want to pull the single one from the market. We can deal with the one that cause the problem, So we want to, need to identify them. But there is concern about the uniquely identify them may inhibit switching when interchangeability becomes reality.

So with these trade-offs, there are a lot of opinions about what should be done, and so in the guidance, we have put out, we ask, should we have the company contraction as the suffix? or should we have four letters random suffix? We are asking about that. The first biosimilar has the contraction of the company, now that one is easier to remember, obviously, but also, it is tight to that company, if the product is sold, transferred. you know the different trade-off involved, if you start thinking through how you do the suffix. We do not know the right answer. So in the guidance, we are asking, also asking about interchangeability. Should they have the same suffix as the reference drug, or should they have unique suffix. There are trade-off there too.

Apparently ,No, A lot of these warnings come from the hospital, In the hospital, they do not have the NDC code, that we can track. So we need a different way to track them when they are in imminent settings, which are built a different way. And we must figure out what is causing the problem.

We believe that will be some cost for the innovators to put suffix on to their drugs. That is the policy, that is right at the end based on the proposed rule.

Certainly, we work with the INN committee on naming at WHO, We are part of that. We are aware of the convention they are considering now. Certainly, we exchange views with them, we talk to them about that. If you look around the world, you will see people have been switching over time to different conventions. Right now in EU, prescribers are required to identify the product by brand name, that would not be a good solution in US. So the WHO convention discuss is very similar to the proposal in our guidance.

This is part of the foundtional work in determining Biosimilarity. And it is the third important guidance, after interchangeability , naming. We need to get out as soon as possible.

Why do we need it? As you said, The innovator drug can vary from lot to lot，that is Statistical matter, how much variability there is In the reference drug. Biosimilar can vary, we have to decide how much is confidence may need to overlap to claim them biosimilar, this is matter of biochemistry and Statistical. So we have really world class scientists working on this, they have consulted with the EU, They think our approach sound. We hope to get out that guidance quickly, We do not believe that we need legend limit, such as in the generic world for BE. This is going to be a flexible standard, but we need to tell people, how to run the Statistics. I would hope In next six months.

There are two tiers to this. One is have to find interchangeability first, but if we find sth interchangeable, then state law will govern pharmacist substitution.

That is right, that is the use of the purple book. Generics, we use the orange book, because it has the interchangeability readings. Look at there, can determine the interchangeability. We are going to have a purple book for the biosimilar.

Well currently, some biological products filled in the India, we do not know whether they are produced, sent for US market. Or just making them for itself. The laws around biologicals are very stringent, as far as there are many factory, because of the long checked history of problems actually.

Any biosimilar, whoever produce, we go out to inspect the facilities, we sent someone from labs, usually another person from OPQ, to go out and participate in the inspection. The manufactory is very carefully regulated.

We have more people whose job is to go out and inspect foreign facilities. A lot of them have to do generic Program. The requirement for parenterals inspection mechanism between US and ex-US is welcome developed. We also have office in India. The biological are difficult, but they are inspected very carefully.

These are patch work, some of them may facilitatory, some actually may cause barrier. We know as to generic age, there are many different state laws passed, we have got over that. It does take earning the trust, maintaining the trust. the clinical community above this program, there is scientific sound their patients will not suffer at all, they will have same clinical effects.

We have been asked to explanation for what the program are. But we do have the under government affairs office that interact with these states.

Yes , We have seen the patch work in EU, every country has statutory frame work. In EU, Interchangeability means different by the countries, quite different across the EU.

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