hearing will come to order good morning i'd like to welcome everyone to the subcommittees hearing metrology the measurement needs to support the development of biologics and  biosimilars while i'm very very aware that other policy issues related to biologics and biosimilars are being considered by congress today we are focused on the role that we can play in helping develop the underlying science needed to support the growing biologics industry in general as i have studied the challenges of developing biological drugs i realize that some of the issues facing  products do not exist for biologics today i have learned as a member of this subcommittee and i have frequently said that if you can't measure it it doesn't really exist for technological or economic purposes it is an important could be an important item of faith but it is not an item of economics or technology i do believe that this is the crux of the inconclusive nature of the biologics debate this difficulty in characterization and measurement which is why this subcommittee has convened this hearing and this is at least at this point i view this is the beginning of a series of hearings that we will hold on this and related biologics topics this is not a new area of inquiry for the science and technology committee eddie was the first in congress to hold hearings on the science and potential other growing scientific fields such as recombinant d n a cloning genome mapping and genetic testing the committee sampras's has always been focused on meeting the metrology needs that allow these new technologies to move forward i would like to think that the science and technology committee was successful in realizing that goal in a number of other  arenas in that line today's hearing will focus on the metrology needs of the biologics industry and this will be the first in a series of hearings surrounding potentially personalized medicine and genetic  diagnostics one additional issue that i want to address today is the interaction between the industry and the federal government to date i welcome the suggestions of our industry witnesses on how the relationship between nest and industry might be enhanced to ensure that nist can fully anticipate the industry's metrology needs the thrust of these questions will not be to criticize but to learn how better working relationship might be created i want to thank our witnesses for appearing before the subcommittee and i look forward to your comments and suggestions and now i would like to recognize my colleague representative smith for his opening statement thank you mr chairman for calling this hearing today on the very important emerging issue of biologic drugs and the associated standards and measurement science necessary to facilitate their continued safe and effective this committee we regularly review and consider the impact science and technology related policies have on our lives arguably in no other area has this impact been so direct and profound as in medical science where dramatic technological answers have lengthened improved countless lives here in america and throughout the world at the heart of these advances are the continuous revolutionary innovations of the pharmaceutical industry we have almost come to take new lifesaving drugs for granted expecting the arrival of new medications to continue quickly without full appreciation of the complicated and sensitive development system central to this system of course are strong intellectual property protections without which there would not be incentives to enable the risk taking and investment of capital necessary to foster new drugs  throughout the long scientific development and regulatory approval process this is especially important with respect to biologics where the enormous and unique potential to combat major diseases is hindered by the lack of a regulatory pathway for managing intellectual property to this and i am pleased to be a sponsor along with chairman lew of the pathway for biosimilars act which would provide the intellectual property protections and regulatory clarity necessary for ensuring and accelerating continued advances in biologics however we are here this morning to focus on a separate potentially limiting factor to biologic drug development the need for measurement science and standards and development to enable and leverage further advances in biologics the f d a and industry stakeholders have identified significant measurement science  needs to support the regulatory approval and manufacturing processes associated with bio pharmaceuticals and we and we know nist has world class measurement science capabilities well suited to this task while there appears to be a good opportunity to leverage this capabilities to meet these needs the details of what exactly needs to be done and what the appropriate roles and responsibilities of nist f d a industry and other stakeholders should be must be carefully considered these are complicated questions surrounding an incredibly complex issue that is of course of why we are here today and i certainly hope and expect this hearing provides us a better understanding to this and i want to welcome the witnesses here today thank you for your time out of your busy schedules and i look forward to a productive thank you very much if there are any other members who wish to submit opening statements your statements will be added to the record at this point i would like to introduce our witnesses dr anthony myers sluice did i get that right very good is the executive director of global product quality and quality compliance at amgen dr patrick vinck is the senior vice president and global head of who is the director of the chemical science and technology laboratory at the national institute of standards and technology you will each have five minutes for your spoken testimony your written testimony will be included in the record  in their entirety and when you complete all of your testimony we will begin with questions and each member will have five minutes to question the panel dr myers loose please beg ranking member and members of the subcommittee i'd like to thank you for the opportunity to testify to today i have devoted much of my career as a scientific research and regulate to the question of how best to standardize and improve methods by technology medicinal products so i am particularly grateful for the chance to weigh in on this topic there is a clear and pressing need need for standards and methods to better understand evolves and finally while having the best standards possible is necessary it is not sufficient to assure safety and efficacy randomized clinical trials will be needed in order to understand biotechnology medicines the best that we can first let us look at the impact of standards on patient safety one place where it is very critical to have the best and most modern standards is when detecting and measuring whether and how a patient's immune system is reacting to a biological product that is immunogenicity testing immunity unicity happens when your body attacks the medicine that it has been given consequences can be that the drug does not language second let us look at the impact the standards could have on testing bought knology products themselves it is essential that we understand the structure of our biological product and its impact on and having the very best standard methods and reference materials available will help us to achieve this they could also lead to reduce costs by minimizing waste of time and effort and could facilitate gray to refute efficienc a but measurement stand alone cannot ensure the continued health of the bottom pipeline it is essential that we preserve the incentives that drive innovative research and development and that we have a strong science based a companies must invest on average one and a quarter billion dollars to develop and test a biological product and only seven percent of biotech medicines that enter development ever reach the market that is sign stripping regulatory agency is essential to public health and safety only vigilant government oversight can sustain confidence in the safety and effectiveness of biotechnology products taken by millions of patient a have increased in recent years however more needs to be done to the pole the agency's ability to recruit and retain the best and brightest scientists the medical review and modernize the agency's information technology policymakers to continue to foster botton ology as our best hope against the devastating disease of the face off today so thank you for inviting me to testify today and i'll be pleased to answer any questions you may have thank you very much  manufacturer with one out of every thirteen prescriptions dispensed in the u s brand name or generic being a mile and product today mr chairman on the twenty fifth anniversary of his waxman we face a situation comparable to that  eighty four when perpetual mono police and joined by biologics regulators over the p h s act like europe the us lex biosimilars possibly a viable bio similar path way does not require a competitor to the established didn't over the safety and efficacy of a legacy molecule instead of biosimilars possibly recognizes how much is already known about legacy biologics and enables bulls regulators and competing biologic manufacturers to appropriately he light up on the prior knowledge and regulatory conclusion flowing from that data specifically this information is the safety and efficacy of the underlying molecule itself demonstration of compatibility mr chairman where for all biologics and yet every time a brand biologic manufacturer has implemented a manufacturing change the change has resulted in a change in its biologic the evolutionary process of the school bikeability creep lineage of a brand biologic there is therefore a continuum of substitutability determinations that have maintained the market acceptance and enhance the abundant market success of so many high priced biologics in the us market today it is time to straightforward manner to existing a future incentives benefiting brand biologics so as to provide a return to american taxpayers the us health care system and patients you need or the biologics specifically believe reference standard should be linked if there needs to be and this can be accomplished by simply conditioning brands biotech companies receipt of exclusivity all the brands for them terry provision over reference monograph and reference standard materials calls easting of supplies of active ingredient and the which would become quite problematic at the regulatory interface with f d a authorizing nations to implement such a system could do us back in the leadership position and enable the us to begin catching up with europe and other countries that are now many years ahead in terms evaluation and research in the f d a thank you for this opportunity to discuss how the development of measurement science standards and related technologies might make it easier to understand the composition of f d a regulated biological products and the benefits that could be gained from these advances the term biological product or biologic includes products that have been manufactured using a biological process such as a cell line with walter d n a to produce there are different types of biologics presently on the market but i will focus on one type today therapeutic proteins as part of the f d a has responsibility of ensuring the safety and effectiveness of drugs and biologic sold in the united states it is important that we be able to understand or to characterize the composition of these products we want to know what materials they are made up of and how the materials are arranged at a molecular level that is what is the molecular structure i will begin with a general description of biologics with a focus of therapeutic proteins and explain why they are so difficult to characterize i will then discuss potential benefits that could follow from improve the analytical methods and measurement standards please take a look at the slide on the displays this is a graphic representation to scale of a single molecule of the drug aspirin and a single molecule of the protein product a human growth hormone you can see the molecular size of human growth hormone but then the aspirin would have been rather difficult to even see i would like to point out three specific limitations of our current analytical methods first there are additional components not shown on this graphic that we call post translational modifications for monoclonal antibodies and many other proteins these modifications include sugar chains of various sizes and our current analytical methods are not sufficient to fully assess these additions second we are unable to fully characterize the three dimensional structure of biologics and third we currently lack methods to measure and quantify the aggregation or the clumping together or protein molecules i will now turn to three specific benefits we might see from improve the analytical methods and measurement standards improved analytical methods would enable quicker and more confident assessments of the potential effects of manufacturing changes in process equipment or raw materials this could reduce the requirements for animal or human studies for evaluating these manufacturing changes in addition for products that have abbreviated pathways for approval improved analytical methods could facilitate comparison of products and detection of differences between different manufacturers number two the development of analytical methods would evaluate the quality of a biologic throughout the manufacturing process and that could provide a superior system for ensuring product quality in the manufacture of all biologics improve the analytical mind this would increase general knowledge in the field of bio pharmaceuticals the f d a can use this knowledge from improved on a global analytical me to inform our regulatory decisions and industry can use this knowledge to design even better products with the development of new analytical methods comes the need for new standards to evaluate them the term standard can apply to measurements or prophecies and although process standards are valuable in ensuring effective manufacturing process operation invalidation today i will focus on measurement standards a measurement standard can be a standardized test  standardized materials used to evaluate the performance of a measurement method standardized test materials can be used to evaluate the precision and accuracy of many different types of analytical technologies and thus are more likely to foster competition and development of new and improved analytical methods by industry and academia the development of such measurement standards would also be extremely valuable for ensuring both current and future methods are working properly and provide consistent results from ask and from laboratory to laboratory in conclusion the field of bio pharmaceuticals is advancing rapidly in many ways more rapidly than analytical technologies we have identified three specific properties of biologics that we cannot measure that are very important to medicinal activity post translational modifications three dimensional structure and protein aggregation furthermore reliable and discriminating material standards would enhance use of c technologies and encourage new technologies to fill current grant gaps thank you for the opportunity to testify today i am happy to address any questions you may have thank you dr cause lasky dr may please p good morning chairman ranking member smith and members of subcommittee thank you for the invitation to testify today i am william a director of the chemical science and technology laboratory at the national institute of standards and technology additionally for the past several years have led a strategic planning effort for this program growth in the bio sciences the previous speakers have discussed the need for additional measurement science and measurement standards to improve the quality an in the development manufacture and regulatory approval about logic drugs therefore i will focus my comments on past experiences and successfully responding to other health related measurement problems and our over the years capabilities and our programs have expanded and evolved and evolved in accordance with both societal and industry needs the primary focus of our current program and health care is on the provision of reference methods and human serum base standards for clinical diagnostics and on standards for medical imaging and both these areas and this traceable measurement standards in calibrations are reducing misdiagnoses wasteful repeat testing and treatment decisions based on an accurate measurement results and this can also be critical contributions to underpin the development of the development and the regulatory approval process for biologic drugs this range of the table unique comfort combination of expertise in the physical chemical and biological measurement sciences these along with expertise in statistics and information sas provide us with the tools required to efficiency and reliability and manufacturing processes based on extensive discussions with our colleagues at f d a and the pharmaceutical industry we've identified five critical areas where improved measurement methods and standards would benefit both a and companies that produce innovative as well as generic biologic drugs first assessment of structural samus and this area this expertise in the determination of protein structure and function and protein measurement science could be used to develop quality assurance assurance standards for the measurement methods used to compare pros translational modifications and three dimensional structure in predicting adverse immune response in patients in addition to developing reference methods and standards for protein aggregation it's richie's and protein measurement science and cell system science can be expanded and applied to support a better understanding of first the protein aggregation process and secondly its induction of  verse human responses to biologic drugs developing a comprehensive understanding of the inner complex workings of production sales in this area this expertise can enable a better understanding of the genetics and complex biochemical networks of sales used in power reactors this would support industry efforts to optimize the production of droughts with desirable features namely low immunity ginna city and the appropriate as a portal more accurate characterizations of the human cell types most often use in toxicity essays this would in terms of development of more accurate measurement systems and modeling to predicting therapeutic function and at v human reactions to candida drugs and finally contamination from the manufacturing process and packaging in this area and this expertise in our local chemistry and protein chemistry can provide the reference matheson quality assurance standards for measurement used to detect and quantify potential cabinet contaminants such as unwanted proteins from production cells viruses metals and various organic compounds and this is already that there is much more to be done witness we'll continue our out outreach to stakeholders and determine and refine our best path forward for addressing the critical measurement standards challenges associated with biologic drugs so in summary measurement science of measurement standards for biologic drugs would facilitate scientifically sound and fact based decision making in research and development manufacturing and the river regulatory approval process for biologics mr chairman thank you for this opportunity to testify today this completes my statement and i too will be happy to answer questions i thank the panel each and every witness we are now going to start questions from the  panel and each member will have five minutes to ask questions and i will begin with with myself it's been a while since i've been exposed to biochemistry so please bear with me when you all couple of areas where we need work and i think that that was implicit or explicit and you're testing are you saying that right now that we can well that what we have is the translation process but that post being able to characterize molecules and we do know a lot about post translational modifications with cutting ad technologies but we don't know everything there are areas where we're lacking the capabilities some of these capabilities are more in academic labs and not necessarily translatable as well to industry routine use so i think we're much better at knowing the very primary structure of the list of  o acids in sequence in a protein but our ability to account for all the different ways they're modified is whacking but that's not to say we can't do it at all and i think that you know in terms of the molecules that i showed in my slide human growth hormone was approved through an abbreviated pathway both in the u s and europe through the five zero five pathway and so we felt we knew enough from the characterization of that molecule to make some judgment about an abbreviated pathway so i think we have a lot of capabilities now the question is how to make them better because they're still a lot of uncertainty and gaps in those areas so we're a lot better at the translational and and improvements will be helpful in the other arenas yes ok thank you for that purely a curiosity question i guess although hopefully will be helpful to my attempts to engage the biotech industry what's been done well what can be improved so i can speak from my personal experience and i'm gins experience of working with nesta on this program  through the work that i have done and i b s e in the world health organization i'm very well versed in the mechanisms for producing standard methods and reference standards i've collaborated very closely with nesta on this effort providing advice from an industry perspective as to our priorities obviously there are multiple different areas that we could explore from a scientific perspective and it's naive to think that we can do them  those possible potential side effects i think aids ability priest relevant i would also say that from a perspective of having looked specifically for institutes whose role is to improve methods and standards directly related to personal health i think transparency is a big requirement for any institute working in that manner these methods and style cannot be provided in a vacuum that has to be the highest scientific rigor associated with his methods as described not testimony making a bad standard does not do anybody any good and therefore sharing industry and research expertise i think is vital so i feel that outreach opportunity of laying down standards and making objective compatibility tools available so that everybody's helps to the same stand ups can play a very big role in a invited the other witnesses to comment about how nice what things can do when it comes back to my turn i plan to ask you about your views of how congress can enable you to do your job better what the research really focuses on so i'm not really prepared to provide the funding for what happens with biologics at the f d a i can tell you that there are laboratories in the office  biotechnology product which look at the manufacturing of biologics including characterization and we are in discussion in fact with nest moving forward on some of those projects together we're also look at biological acetates that measure the activity of molecules which is another way of characterizing them and there are other labs within the center for drugs evaluation and research which characterize proteins using current methods and may actually look at some samples that are provided for them so we have capabilities again you know could we do more with more capabilities that's always true could you speak to or share with us if you're comfortable that there's not a lot of overlap between nest and f d a but yet capabilities in an organization simply so that they can communicate and work together and show some level of overlap in technology is good and i think you know you need to be communicating and that's the way to to leverage that the least overlap in big ways and to get the most benefit and for instance the f d a had a meeting a number of years ago on the issue of characterizing proteins that they co sponsored and vite it industry and i think that was a great opportunity for dialogue and further meetings like this that involve both f d a and industry to gather may be good ways of figuring out what our overlaps are how to how to work best together and how to do things in a way that as as a combined group makes the most progress you know this has absolutely no regulatory authority we are not lead agency on anything except measurements and we focus on mission science technology and standards that have impact across other areas  where other agents and in the federal government do have lead agents a response of responsibility so the only way for us to be successful is to collaborate with both industry and other federal agencies in areas where they have interest and lead agency responsibility and we do the things that we do and do well that is the management side the underpinning measurement science technology and the provision of standards thank you and dr vink in your testimony you propose a repositor nest federal government basically that would then sell some of the information to other companies for testing and research and given the nature of biologic drugs do you think that such an arrangement might undermine the intellectual property you know the facets of intellectual property and certainly the incentives to move forward in the future no not we believe that tool to get an ts for the for public health that there is a standard for every product and that everybody who wants to compare itself to that standard can be measured in an objective transparent way and up everyone who wants to make a similar product available and be measured to that standard we don't believe that there is a ip issue around it ok thank you thank you mr chairman and thank all of you for being here i'd like to just follow up on what mr smith was talking about and and find out what the other members of the panel think about that and before that i just want to ask one question   concerned about the standards and the conclusion of the case where the f d a allowed a a new drug to to go on the market which was never really tested but it was a test of another similar drug that allowed that so i'd like to know you know as far as intellectual property from the other members but also is that the way our regulations work that a drug really doesn't have to go through  and novel drugs to benefit our patients do you think that we are losing the innovation creativity i know dr vaisse testimony talked about the fact that we are behind the european countries and so many other countries in our development of  has in considering these products so again i think that there are technological issues for everybody in terms of better methods to facilitate you know how much clinical information is necessary but i don't think there's actually a scientific advantage i think it's a question of what pathways are available for what types of products dr think maybe comment since you're the one that ra you we have two votes called and there are approximately six minutes that's n b a time six minutes before the clock runs out it's my intention to try to get to everyone's questions so other than sending nest more money what are some legislative improvements that would help nest do its job better certainly providing legislation that need to be a lot of work on measurement science to understand the underlying mechanisms and phenomena that i also see deal with things like aggregation and many of the phenomena that we've all s critical to the regulatory approval of biologic drugs obviously we would certainly be happy to see you support any budget and issues that come from the executive branch in this area thank you dr may frank milan you try to do or you do biosimilars since a pathway exists in europe and currently either does not exist or is a very narrow pathway here in the united states is your biosimilars activity primarily in europe and then what you're looking at the pipeline in the united states just trying to understand your milans business model and has recently a standards should are the same or very much aligned between the different continents so we aim a global product files and a global strategy and we do believe that the u s will also offer a tremendous opportunity for patients healthcare and companies to enter the biosimilars so of course currently the market for us is open in europe and it has recently opened in japan we have a strong belief that this will be also in the u s so we do not make any difference for regions back to our strategy but your activity is a little bit higher in those other areas right now and part of it is a biosimilars pathway but for the research and reference materials would would would assist in those efforts absolutely well we have a number of other questions this is the nature of this institution that you make a plan and then you adjust upon contact with reality i think that witnesses we would like coming here to testify and we will adjourn this hearing thank you very much