REGULATORY APPLICATIONS OF REAL WORLD EVIDENCE

Transcription

1 REGULATORY APPLICATIONS OF REAL WORLD EVIDENCE by Nei A. Beson R ea-word Evidence (RWE) hods out the promise of reducing time and costs of product approvas, identifying 54 new uses for existing products, increasing our abiity What is Rea Word Evidence? Reguatory approvas of new drugs have traditionay reied on randomized cinica trias (RCT s), conducted in controed to treat rare diseases, and improving cinica practices for using conditions with tria subjects who meet drugs and medica devices. The 21st Century Cures Act, enacted specific eigibiity criteria. RCT s, though, in 2016, requires FDA to evauate the use of RWE in approving new drug indications. FDA in 2017 issued a fina guidance have many imitations and deficiencies. Cinica trias are engthy and expensive, typicay representing about 60% of the cost document regarding RWE in reguatory decisions invoving of new drug products. Furthermore RCT s medica devices. The private sector is aso focusing on RWE: are inefficient: ony about 12% of new drug more than haf the pharmaceutica companies in a recent survey say they are significanty expanding their invovement in RWE. candidates which enter cinica studies utimatey receive marketing approva. Whie RCT s might answer baseine questions of Nonetheess, misunderstandings and uncertainties remain, whether a product is safe and effective under both about what constitutes RWE and its potentia roe in the controed conditions of the study, RCT s reguatory and other aspects of precision medicine. may not refect conditions in rea-ife patient use. The eigibiity criteria for incusion in cinica studies may not refect the actua patient popuation which coud use a product. For exampe, because of the need to minimize variabes, RCT s may not incude patients who suffer from comorbidities (i.e, patients with mutipe, unreated, pathoogic or disease processes). The inherenty imited number of study subjects and the time imits of RCT s mean that infrequent or ong-term side effects may remain undetected at the time of product approva. RCT s may not be practica for deveoping treatments for rare diseases, due to difficuties in recruiting adequate numbers of study subjects.

2 RWE represents both a potentia aternative Used appropriatey, RWE coud advance or risks, of a drug derived from sources other and compement to traditiona RCT s. RWE medica and reguatory science in many than randomized cinica trias. reies on evidence from actua cinica use of respects, both in pre-approva and post- Section 3022 requires the Secretary to: products to evauate new appications of approva contexts. Pre-approva RWE coud products and inform cinica decisions for suppement RCT s, reducing the time and using products. costs of drug and device deveopment. RWE Sources of RWE coud hep to generate research hypotheses Gaps in data coection activities in cinica trias, and hep seect more As an initia matter, it is important to differentiate between RWE and rea word data (RWD). FDA considers RWD to be the kinds of data reating to patient heath status or the deivery of heath care which are routiney coected from various sources. Exampes of RWD incude data from such sources as eectronic heath records (EHR s), hospita or insurance company administrative and caims, data obtained directy from providers or patients during an observationa study, patient-generated data from in-home monitoring devices or fitness trackers, and data obtained from registries which coect or research. RWD may aso incude data on environmenta exposures and socio-economic factors. to support traditiona RCT s. RWE can aso be professiona organizations, representatives of patient advocacy organizations, consumer organizations, and disease research or device coud hep to identify and approve foundations regarding the above-mentioned new indications, and identify factors in safety, framework; effectiveness and cinica treatment practices Within two years of the Act s enactment, cinica trias. Whie it is highy unikey that impement the program for evauating RWE wi competey repace RCT s in the potentia use of rea word evidence in foreseeabe future, RWE can become an accordance with the above-mentioned important compementary source of informa- framework; tion where RCT s are appropriate and a vauabe of RWD are deveoped for non-reguatory of this artice discusses recent U.S. egisative purposes, i.e., to document patient care or and FDA efforts to address use of RWE. It for submission of insurance caims. As such, aso incudes some case studies invoving the not a RWD is suitabe for reguatory purposes use of RWE for reguatory purposes where such as product approvas. FDA has accepted, or indicated it can accept, or risks of a medica product derived from Consut with stakehoders incuding reguated industry, academia, medica Post-approva RWE of patient uses of a drug aternative where they are not. The remainder regarding the usage and potentia benefits ethica considerations precude RCT s. which may not be apparent in traditiona Priority areas, remaining chaenges and potentia piot opportunities used to evauate prospective treatments when As is evident from the ist above, many sources FDA defines RWE as cinica evidence diseases more feasibe, particuary when it is not practica to recruit enough cinica subjects Standards and methodoogies for coecting and anayzing RWE; and RWE. Whie the focus of this artice is on U.S. Prepare a draft guidance for industry within five years of the Act s enactment on the circumstances under which drug sponsors may rey on RWE and the appropriate standards and methodoogies for coecting and anayzing such RWE; and Issue a revised or fina guidance for industry reguation, some of the case studies and other within 18 months foowing the cose of the information may have broader appicabiity. pubic comment period for the draft guidance described above. anaysis of RWD. The Duke-Margois Center The 21st Century Cures Act for Heath Poicy, in a 2017 white paper The 21st Century Cures Act, enacted in 2016, Importanty, section 3022 does not ater the prepared with FDA funding, stated that RWE recognized the growing importance of RWE. standards of evidence for approving new is evidence derived from RWD through the Section 3022 of the Act directed the Secretary drug appications, incuding the substantia appication of research methods. In other of HHS, who wi act through FDA, to deveop evidence standard. Simiary, the Act words, RWE is not merey passivey coected a program to evauate the potentia use of does not ater the Secretary s authority or anecdota data. Rather, RWE resuts from RWE. Section 3022 defines RWE as data to require post-approva studies or carefu study designs to assess the treatment regarding the usage, or the potentia benefits cinica trias. effects on patient outcomes. FDA s recent guidance document, discussed beow, provides information on how the Agency determines what constitutes RWE. 55 COGNOSCIENTI information on various aspects of heath care appropriate cinica tria subjects. RWE coud make deveopment of treatments for rare Estabish a draft framework within two years of the Act s enactment describing:

3 FDA Guidance Document on Rea Word addition of new indications for existing as support for a petition for recassification Evidence and Medica Devices devices. RWE may aso suppement other of a medica device under section 513(e) or Athough the 21st Century Cures Act focused evidence used to support such cearances and (f)(3) of the FD&C Act; on drugs, it was FDA s Center for Devices and approvas. Aggregation of RWD, such as from as evidence for expanding the abeing of Radioogica Heath (Device Center) which medica device registries, may aso be usefu a device to incude additiona indications on August 31, 2017, together with FDA s Center in post-market device safety surveiance. for use or to update the abeing to incude 56 for Bioogics Evauation and Research (CBER), issued a guidance document entited Use of Rea-Word Evidence to Support Reguatory Decision-Making for Medica Devices. The Agency had issued the draft guidance on this subject on Juy 27, FDA stated that Under the right conditions, data derived from rea word sources can be used to support reguatory decisions. The guidance carifies circumstances in which RWD may be used to support FDA decisions. This guidance, ike other Agency guidance documents, is not binding on either FDA or the pubic. It does, though, represent FDA s current thinking on the appicabe topic and shoud be viewed as containing recommendations. Aternative approaches are nonetheess acceptabe if they satisfy the requirements of appicabe statutes or reguations. The Use of RWD for reguatory purposes requires a carefu study design for both RWD aready coected (retrospective studies) or data to be coected in the future (prospective studies). The studies shoud anayze simiar eements as woud be incuded in a traditiona RCT. FDA recommends using the Agency s pre-submission process when deveoping an RWD study, just as when preparing to conduct an RCT. FDA wi consider RWE in making reguatory decisions when it beieves the RWE was generated using data of sufficient quaity to inform reguatory decisions. What constitutes sufficient quaity may depend upon the RWE s intended purpose. For exampe, a particuar registry may be usefu for post-market surveiance but inadequate to support a premarket determination of safety and effectiveness. new information on safety and effectiveness; for pubic heath surveiance efforts, if signas suggest there may be a safety issue with a medica device; to conduct post-approva studies imposed as a condition of device approva or to potentiay precude the need for postmarket surveiance studies ordered under section 522 of the FD&C Act; in certain circumstances, for use in generating summary reports of Medica Device Reports; and to provide postmarket data in ieu of some premarket data. Since RWD is often deveoped for nonreguatory purposes, FDA must assess whether such data is usefu for reguatory purposes. It is therefore important to have a pre-defined Agency notes that its guidance does not ater the evidentiary standards that FDA uses to make reguatory decisions; rather, it describes FDA wi consider use of RWD for a number of purposes, incuding for the foowing: generating hypotheses to be tested in a common set of data eements, a common definitiona framework, and pre-specified time intervas for data eement coection and circumstances in which RWD may be used to support various FDA decisions under the prospective cinica study; as a historica contro, a prior in a Bayesian anaysis. FDA may aso consider the abiity to suppement the RWD with inkages to other existing evidentiary standards. tria, or as one source of data in a data sources such as EHR s or caims data. In estabishing the guidance, FDA noted that at present, there is often no system for systematicay characterizing, aggregating and anayzing data from a uses of a medica device in a manner that informs reguatory decisions. By expressing a wiingness to consider RWE in reguatory decisions, FDA hopes to create incentives for the medica community to obtain greater information from use of devices in routine cinica care. FDA wi consider RWE for both pre-market and post-market reguatory purposes. In a hierarchica mode or a hybrid data synthesis; as a concurrent contro group or as a mechanism for coecting data reated to a cinica study to support device approva or cearance in a setting where a registry or some other systematic data coection mechanism exists; as evidence to identify, demonstrate, or support the cinica vaidity of a biomarker; as evidence to support approva or granting of a Humanitarian Device Exemption, Premarket Approva Appication (PMA), or In evauating the suitabiity of RWD for reguatory purposes, FDA wi evauate its reevance and reiabiity. With regard to reevance, FDA wi examine such factors as (i) whether the data contains adequate detai to evauate use of the device, exposure, and reevant outcomes in the appropriate popuation; (ii) whether the data is amenabe to sound cinica and statistica anaysis; and (iii) whether the data and resuting RWE can be interpreted using informed cinica and scientific judgment. For reiabiity, the primary pre-market context, RWE can support both De Novo request; cearance or approva of a new device, or

4 57 COGNOSCIENTI factors FDA considers incude how the data cinica care on persons with approved or registry data and coection was initiated under was coected and whether the processes and ceared devices, incuding treatment for an approved Investigationa Device Exemption peope used during data coection and anaysis off-abe purposes. RWD from such a registry (IDE) appication. If the RWD proves to be are adequate to minimize errors and to provide coud be used to expand abeing of devices of sufficient quaity to address safety issues, it data of sufficient quaity and integrity. captured in the registry. may support abeing changes for the device. Case Studies of Rea Word Evidence for Reguatory Purposes of registries in a situation in which a device expand the indications of a transcatheter The exampes beow are generaized from which has experienced technoogica advances aortic vave repacement (TAVR), the Sapien 3 situations where FDA has actuay used or since its initia marketing approva is now used produced by Edwards Lifesciences, to incude accepted RWE in reguatory decisions reating in cinica practice outside of its approved vave-in-vave procedures. FDA utiized data to medica devices (the TAVR exampe beow indications. However, data to support the from the Transcatheter Vave Therapy Registry, is a specific instance of using RWE). The ist safety and effectiveness of the new indications which contained records for over 100,000 beow is not exhaustive, but does iustrate is acking, and therefore participating medica TAVR procedures, 600 of which were for some instances where RWE may be appropriate. societies estabish a nationa registry to coect off-abe vave-in-vave procedures. FDA data on patients using the device at participat- reied on this data to evauate the off-abe ing institutions. This registry aso incudes a procedure, incuding the vave function, vaidated agorithm to ink to heathcare improvement of patient symptoms and safety caims as a suppementa dataset. A study of the procedure, to approve the new evauating an off-abe use and using the indication. Use of Registries to Support Expanded Indications. Registries typicay coect information about persons with a specific disease or condition, or persons of varying heath status who agree to participate in research on particuar diseases. Registries may aso coect RWD from routine Aternativey, FDA contempates the use FDA reported in 2017 that it used RWE to

5 FDA representatives noted that the U.S. had retrospective anayses for human subject information as cinica registries, EHR s and been ony the 42nd country to approve the protection purposes). medica biing caims in order to provide origina TAVR device in However, through use of creative reguatory procedures, the U.S. became the first country to approve the new indication. Use as a Contro Group. A medica device manufacturer seeking approva of a next generation device which contained substantia changes from previous versions of improved RWE that providers and patients can use in making treatment decisions. NESTcc is intended to estabish reationships between partners in a neutra, objective Use of RWD to Conduct Post-Market the device was abe to use RWD from a registry manner and seeks to support the sustainabe Surveiance Studies. FDA issued a series which captures data on a uses of medica generation and use of timey, reiabe, and of post-market surveiance orders under devices with a simiar appication as a cinica cost-effective Rea-Word Evidence (RWE). section 522 of the FD&C Act, to investigate study contro group. The manufacturer sti had NESTcc has executed Memoranda of patient safety information regarding mutipe to perform cinica studies on the new device, Understanding with nine organizations, Cass II devices with simiar design and but was abe to use data from the registry for representing approximatey 108 miion intended uses made by different manufacturers. the contro. patients, to act as NESTcc s initia data 58 Many manufacturers, in order to compy with the orders, estabished a patient registry in coaboration with a reevant cinica professiona society and FDA to coect the required data. Post-Approva Device Surveiance as a Suppementary Data. Where RWD has been systematicay coected, FDA has used RWD in combination with other sources of data, when safety issues arise with an approved device which were not detected in pre-approva studies. FDA cited an instance where it partners. NEST is expected to be fuy operationa by In December 2017, NESTcc issued a request for Concepts for Rea-Word Test-Cases. NESTcc was seeking recommendations from medica device manufacturers for test cases Condition of Approva. FDA was abe to had been reviewing a cass III device for a new using RWE which coud be impemented with provide an earier device approva for a indication, in which there was inadequate data NESTcc s data partners. Among the goas of breakthrough Cass III medica device, party as from contro groups. However, a pre-existing the test cases are to expore the feasibiity for the resut of the manufacturer s estabishment registry was coecting and reporting RWD industry to use the RWE sources avaiabe from of a registry which coud meet FDA s require- on contro treatments. FDA was abe to use NESTcc s current partners and to identify areas ments eary in the reguatory review process. this pre-existing registry data to suppement where NESTcc coud pay a roe in reducing Eary construction of the registry permitted and hep interpret the cinica tria data, and transaction costs. coection of data from a patients receiving the device upon approva. FDA granted eary approva of the device conditioned upon continuing robust data coection and reporting foowing approva. FDA noted that the registry went on to be used for (i) coecting surveiance data on future devices with simiar designs and uses; (ii) retrospectivey anayzing data on a uses of the device to support expanded indications; and (iii) supporting prospective embedded cinica studies under IDE s for new devices. (Incidentay, FDA noted that the retrospective data coection activities of the registry which were used to support new indications did not require an IDE because treatment decisions were not infuenced by the expectation of future anayses. However, an Institutiona Review Board (IRB) did review the reach a reguatory decision without requiring additiona cinica tria data. In this case, the avaiabiity of RWE permitted FDA to reach a decision without having to expose additiona study subjects to a device with questionabe benefits. Nationa Evauation System for Heath Technoogy (NEST) In 2016 FDA awarded a grant to the Medica Devices Innovation Consortium, a non-profit pubic-private partnership, to estabish the NEST Coordinating Center (NESTcc). The purpose of NEST is to more efficienty generate better evidence for medica device evauation and reguatory decision-making. FDA envisions NEST as a vountary network of data partners which wi act as a nationa evauation system to ink and synthesize data from different sources of medica device NESTcc isted eeven demonstration projects on its web site as of the submission of this artice. The purpose of these projects is to provide proof of concept for scaabe approaches to evidence generation across device types and across the tota product ife cyce. Future Chaenges RWE as a reguatory too is in its eary stages. Our knowedge of optima uses of RWE, and the best methods for generating it, is sti evoving. The ist beow, whie not intended to be comprehensive, identifies some chaenges in optimizing use of RWE for reguatory purposes: Lack of institutionaized methods of obtaining RWD. Many sources of RWD, particuary those generated by physicians or patients, are not coected for reguatory

6 or research purposes. Some sources of data are generated in formats (such as PDFs) which are not efficient for data anayses. FDA s Device Center web site states that the current fragmented heath care ecosystem does not support the seamess, near rea-time, cost-effective use of heath data to generate high-quaity evidence for medica devices needed for reguatory decision-making in both the pre- and post-market spaces. Lack of Recognized Standards. Another chaenge to broader use of RWE wi be the deveopment of usefu standards for determining what data is usefu or adequate to support reguatory decisions. Gregory Danie, Deputy Director of the Duke-Margois Center for Heath Poicy, which issued a white paper and hosted a workshop on RWE in September 2017 supported by funding and a cooperative agreement with FDA, commented that FDA wi need to consider sources, methods used to generate evidence, reguatory and cinica context, and how the research community can standardize an understanding of usefu RWE. Steve Mier, Chief Medica Officer at Express Scripts, commented that whie pharmacy caims and aboratory resuts are reiabe sources of RWE, subjective provider or patient-entered data are ess so. Data Privacy Concerns. Recurring breaches of data privacy may discourage individuas from aowing their heath data to be used for research purposes. Uncertainties aso remain regarding use of patient data. Uneven Rues for Different Stakehoders. Pharmaceutica and device manufactures are argey prohibited from commenting on uses of their products that have not been approved by FDA. However third party payers and heath care providers do not face such restrictions. It is hard to know how this uneven abiity to use RWE and RWD wi affect the deveopment of RWE as a reguatory too. Concusion Use of RWE for reguatory purposes is in its eary stage. Both the reguations and the technoogy affecting RWE are sti evoving. Significant chaenges exist regarding the proactive and systemic coection of RWD. Many questions remain regarding what constitutes adequate and appropriate RWE, what kind of RWD is usefu RWE and what are the optima uses of RWE. Nonetheess, recognition of the imitations of traditiona RCT s is widespread. Appropriatey utiized, RWE coud pay an important roe in reducing the time and cost of deveoping new drugs and medica devices, treating conditions which today have no effective treatments, and improving the quaity and reducing the cost of heath care. References 1. Deoitte, Getting rea with rea-word evidence. Documents/ife-sciences-heath-care/us-shc-2017-reaword-evidence-survey.pdf (visited Fed. 21, 2018). 2. Viceconti, M., C. Cobei, T. Haddad, A. Himes, B. Kovatchev and M. Pamer, In siico assessment of biomedica products: The conundrum of rare but not so rare events in two case studies. Proc IMechE Part H: J Engineering in Medicine 2017, Vo. 231 (5) whiterose.ac.uk/113971/1/pap%20isct%20x%20imeche%20 OA%20version.pdf (visited Mar. 9, 2018). 3. DiMasi J.A, H.G. Grabowski and R.W. Hansen, The Cost of Drug Deveopment. Correspondence, NEJM, May 14, 2015, (visited Mar. 9, 2018). 4. U.S. Department of Heath and Human Services, Food and Drug Administration, Use of Rea Word Evidence to Support Reguatory Decision-Making for Medica Devices. Issued August 31, MedicaDevices/DeviceReguationandGuidance/Guidance- Documents/UCM pdf (visited Feb. 11, 2018) (FDA RWE Guidance, 2017). 5. Duke Margois Center for Heath Poicy, A Framework for Reguatory Use of Rea-Word Evidence, Sept. 13, fies/rwe_white_paper_ pdf (visited Feb. 11, 2018) (Duke, 2017). 6. FDA RWE Guidance, Duke, NEHI (Network of Exceence in Heath Innovation), A New Era for Heath Care Innovation. September rwe_issue_brief_fina.pdf (visited Feb. 24, 2018) (NEHI, 2015). Pubic Law (Dec. 13, 2016). FDA RWE Guidance, Shuren, J. and B. Zuckerman, How Creative FDA Reguation Led to First-in-the-Word Approva of a Cutting-Edge Heart Vave. FDA Voice. Posted June 14, (visited Mar. 4, 2018). 9.Mezher, M., FDA Used Rea-Word Evidence in Heart Vave Approva. RAPS: Reguatory Focus, June 14, fda-used-rea-word-evidence-in-heart-vave-approva (visited Mar. 1, 2018) 10.FDA Web site, Nationa Evauation System for Heath Technoogy, (visited Mar. 9, 2018). 11. Brennan, Z., NEST Seeks Medica Device Test Cases for Using Rea Word Evidence. Posted Dec. 5, Reguatory Focus, (visited Mar. 9, 2018). 12.NESTcc, An Invitation to Submit Concepts for Rea-Word Evidence Test-Cases to the NEST Coordinating Center (NESTcc). Soicitation Date, Dec. 4, 2017, Updated, Jan. 10, upoads/2018/01/ nestcc-ca-for-concepts.pdf. (visited Mar. 9, 2018). Id. 13. NESTcc Demonstration Projects: demonstration-projects/ (visited Mar. 9, 2018). 14. NESTcc web site, Who We Are, about/who-we-are/ (visited Mar. 4, 2018). 15. Lim, David, Payers wade into rea-word evidence but tread ighty. Jan. 29, 2018, BioPharma DIVE. biopharmadive.com/news/spotight-rea-wordevidence-data-payers-mier-vaue/515591/ (visited Mar. 5, 2018). NEHI, PRECISION COGNOSCIENTI TOOLS Nei A. Beson is Of Counse at Potomac Law Group, in Washington, D.C., where he handes transactiona and reguatory compiance matters. He focuses on Precision Medicine, Life Sciences and Information Technoogy. Mr. Beson has aso been an entrepreneur, and has founded, run and sod an industria biotechnoogy business. This artice is for genera informationa purposes ony, and is not intended as ega advice.