White Paper May Patchwork Regulatory Guidance for Biosimilars: Impact on Biosimilar Development. Sally Amanuel, MA, MBA Victoria Coutinho, PhD

Transcription

1 Patchwork Reglatory Gidance for Biosimilars: Impact on Biosimilar Development Sally Amanel, MA, MBA Victoria Cotinho, PhD

2 Initial Reglatory Steps The Eropean Medicines Agency (EMA) released the first gidance for biosimilar prodction in It facilitated the initial wave of registrations for hman growth hormone, epoetin, and filgrastim biosimilars. In the United States, the Biologics Price Competition and Innovation Act of 2009, which became law in 2010, provided an abbreviated biosimilars licensre pathway. It wasn t ntil 2012, however, that the FDA issed three draft gidelines intended to bridge the gap and enable a biosimilar program across Erope and the U. S. 2-4 Nevertheless, FDA gidance arond the isses of interchangeability (ie, separate trials reqired?) and sbstittion (ie, biosimilar can be sbstitted for originator?) remained elsive. The FDA s 2013 introdction of gidance on formal meetings between the FDA and biosimilar sponsors and an EMA 2014 pdate of its 2005 gidance reslted in a more harmonized biosimilar development pathway for global biosimilar registration. 5,6 This progress was advanced by the April 2015 finalization of two of the FDA s initial draft gidelines. 2-3 The early sccess of biosimilars in Erope, copled with the cost incentive of many profitable drgs schedled to come off patent, have led Trkey, Soth Korea, Astralia, Mexico, Canada, Japan, Taiwan, Brazil, and India to establish national frameworks for biosimilars. 01

3 Some Considerations for Biosimilar Development Biosimilar development begins with state-of-the-art analytics to evalate mltiple batches of the originator medicinal prodct and select the most appropriate batch for biosimilar reference (heterogeneity between batches from the same manfactring process is common de to biopharmacetical complexity 3,7 ). Any changes to the originator marketing athorization shold be reviewed, as prodct amendments may have altered manfactring processes and affected prodct performance. 8 Following the appropriate preclinical and comparability tests, a stepwise approach is sally employed. Nmeros factors to be considered in the clinical development of biosimilars inclde 9 : 02 Selection of healthy volnteers verss patients for Phase I Choice of indication(s) Jstification for extrapolated indications Clinical viability based on associated oncology chemotherapy regimens that may have been applicable for the originator stdy Standard-of-care restrictions that may limit clinical participation in certain territories Challenges of prodcing batch data and/or stability data on schedle despite abridged developmental timeline (verss originator timelines). Sponsors shold seek scientific advice and consltation from reglators early in the biosimilar prodct s lifecycle. The timeframe for biosimilar development is shorter than that for originator development becase the preclinical program is abbreviated, a Phase II stdy is not reqired, and a Phase III stdy sally need occr only in one representative indication. Therefore, a clear reglatory strategy is paramont from the onset.

4 Case Stdy: A Biosimilar for Ritximab 03 Choice of Indication The choice of biosimilar indication is of primary importance. Ritximab (a chimeric anti-cd20 monoclonal antibody) is indicated for non-hodgkin s lymphoma (NHL), chronic lymphocytic lekemia, rhematoid arthritis (RA), and severe granlomatosis with polyangiitis. It might seem logical to develop the biosimilar for the indication that generates the most revene (ie, NHL). However, the originator stdies in NHL were performed with varios, evolving chemotherapy treatments. In biosimilar development, crrent standard of care is a critical consideration. Frther, a biosimilar trial for NHL wold have reqired a long treatment period ( 60 months) to demonstrate classic clinical endpoints sch as progression-free srvival, time-to-progression, and overall response rate. If the originator s mechanism of action is congrent across athorized indications, then data can be extrapolated. In this case, the data from the anti-cd20 mechanism of action in RA sbjects cold be extrapolated and applied to the oncology indications. Traditionally, a small-scale stdy wold have to be condcted to test for potential divergence in secondary signaling-mediated effects between the oncology and rhematology settings. It is now recognized that the indication chosen for reglatory approval of a biosimilar shold be the most sensitive and least variable, nless otherwise jstified. In this example, rhematology afforded greater sensitivity than oncology in pharmacokinetic (PK) and pharmacodynamic (PD) measres. Selection of Poplation Close involvement with networking grops sch as the Eropean Leage Against Rhematism (EULAR) and the American College of Rhematology (ACR) and a good nderstanding of the competitive environment were key for sccessfl biosimilar-ritximab development. In some areas, sch as the U. S. and Western Erope, a biosimilar trial need not show benefit to sbjects beyond standard of care. Therefore, the comparability stdy was best-served by recriting from regions with restricted standards of care (eg, Central Eastern Erope and the Commonwealth of Independent States).

5 Asia was also considered, bt to redce the cost of the overall development program, recritment was confined to central Erope and srronding areas. Selection of specific contries and sites depended on an analysis by Worldwide Clinical Trials (WCT) of reglatory timeframes, variable approval processes, depth of data scrtiny, and clinical feasibility. Risk-mitigation strategies were formed before stdy implementation, so that if the data was deficient on initial sbmission, sites and/or contries cold be rapidly added. 04 Optimization Plan Most gidelines recommend stepwise biosimilar development, inclding preclinical testing and comparability stdies, qality comparability between the biosimilar and originator, Phase I safety, PK and/or PD stdy, and Phase III comparability stdy. A combined Phase I and III protocol is a time-saving reglatory strategy, bt compressed developmental timeframes present manfactring challenges for scale-p, stability data, and procrement of the originator medicinal prodct. These processes wold benefit from the interval between the two Phases. Phase I may conclde faster by recriting healthy volnteers and administering pared-down therapetic doses sfficient to resolve a PK/PD profile. Certain reglators in Western Erope believe that parallel clinical development is possible if a robst comparability and preclinical package sing state-of-the-art technologies exists. These reglators may reqire the adoption of certain safety and monitoring precations for the first-dosed patients shold parallel Phase I and III trials be condcted. Ethics Committees also providing athorization, sally expect to see the Phase I data prior to athorising the Phase III comparability stdy, and therefore the timing of antecedent stdies is a differential. Parallel clinical development is an emerging and contentios concept. For example, some ethics committees in Western Erope demand Phase II data prior to Phase III biosimilar stdies. These committees and other athorities may benefit from additional edcation abot biosimilar developmental reqirements and permitted data exclsions, and from principal investigators inpt. Investigators cold profit from training in this fast-moving field, too. Bt it is eqally important that sponsors clearly present clinical-trial parameters and data similarities

6 throghot the application process. All stakeholders mst work together to facilitate market entry of more cost-effective biological medicines. 05 Facilitating clinical trial applications Early, solid inpt from key opinion leaders (KOLs) and scientific advice from reglators is pivotal to provide insight abot deviations from traditional clinical endpoints. For example, endpoints are emerging that may reveal greater sensitivity when compared to those sed in originator stdies. Carefl discssion on sch srrogate endpoints with national competent athorities (NCAs) can qickly secre lower-cost advice, de to NCA shorter sbmission and review timeframes, while the sponsor also makes plans to obtain EMA advice and schedles Biosimilar Prodct Development meetings with the FDA. The EMA and FDA often isse divergent opinions and therefore all of this planning mst occr well in advance of the comparability stdy so that potential problems can be addressed and roadblocks swept aside. Many biosimilar developers form partnerships. For example, a company that has the biological manfactring expertise may align with an established top-tier pharmacetical or generics company that is able to finance clinical development. Dring partnership negotiations, clases will be made as to which company will retain marketing rights across different regions of interest. Partners mst nderstand each other s marketing intentions becase the biosimilar program may need to inclde certain contries that reqire data from their poplations for marketing approval (eg, Japan, Soth Korea, Mexico). Even independent of reglatory reqirements, early discssions with KOLs, healthcare providers, and payers can identify contries where presence of data from that contry may facilitate ptake. WCT knowledge of reglatory and biosimilar environments and nderstanding of marketing objectives allow s to predict stdy permtations and ensre delivery. For biosimilar-ritximab, Phase I stdies in patients had been initiated bt recritment was delayed. Gaining athorization for the Phase III comparability stdy withot provision of the Phase I safety and PK data wold be challenging. When conditional approvals cannot be granted withot PK data, yor

7 CRO mst be ready with contingency plans for withdrawing applications prior to rejection and sbseqent resbmission with the PK data. In certain markets, WCT employed the strategy of sbmitting preliminary PK data from a sbset of the reqired poplation to provide some safety assrance. These minimal data were insfficient to spport sbmission of Clinical Trial Applications (CTA) in certain Western and Central Eropean regions. Therefore, WCT experts applied their knowledge of the biosimilar expectations of reglatory and ethics committees to compose a list of contries that wold mostly likely approve the sbmission with the minimal PK data package. These contries were emerging markets, where specific reglations did not exist and local specialists cold inflence and navigate biosimilar reqirements. The first tier of contries selected did not reqire the PK data, bt cold not recrit the entire stdy poplation in the reqired timeframe. A second tier of contries met with more sccess, and CTAs were both sbmitted and approved sing preliminary PK data. The strategy took into accont time needed to address qestions by national competent athorities. WCT s strategy allowed Phase III sbmissions to occr 2 to 3 months before fll PK data were available. The strategy inclded a biosimilar comparability gap analysis in the Investigational Medicinal Prodct dossier in advance of sbmissions. WCT s contry selection and reglatory strategy were sccessfl, and only one of approximately 13 contries raised concerns regarding the lack of PK data. While it is generally acceptable for biosimilars to have fewer stability batches and shorter dration of stability testing, compared to sal chemical or biologic development, not all reglators agree. Unfortnately, despite the robst qality testing and gap analysis, a central Eropean athority raised concerns abot the shorter stability timeframe that was sbmitted as part of the biosimilar CTA application. 06 Considering qality and spply One of the greatest challenges is p-scaling manfactring from Phase I to Phase III. Process optimization can case changes that introdce ndetectable alterations to the protein that cold impact safety and efficacy, ths limiting the vale of existing stdies.

8 If sbstantial changes are noted, additional comparability stdies, preclinical, and/or hman PK/PD stdies may be necessary. Another critical factor relates to the risk-management plan for sorcing the originator and/or blinding in the large scale, Phase III comparability stdy. De diligence evalations into appropriate batches and sorcing constraints may also impact trial commencement. For example, as a barrier to biosimilar development, originator manfactrers can restrict the qantity of batches prchased by biosimilar developers for competitor stdies or limit issance of certificates of analysis reqired for global biosimilar stdy importation. The WCT gap analysis in the IMP dossier for biosimilar-ritximab did identify some minor differences in the aggregate profiles of scale-p biosimilar batches when compared to earlier biosimilar batches and the originator prodct. The disparity also was noted by a Western Eropean athority. A satisfactory jstification was provided along with a commitment to frther examine the change in some aggregate fractions. Note that every detail of the comparability and imprity tests mst be scrtinized, and if any differences are identified, additional analysis may be necessary. 07 Some Considerations for Expediting Athorization After consltation with reglators, an abridged srrogate American College of Rhematology (ACR) endpoint was sed for the biosimilarritximab Phase III stdy. The PK/PD endpoint cold be realized 18 months faster than the ACR endpoint. WCT s strategy to complete a separate PK/PD stdy in advance of the formal Phase III acconted for the fact that, de to competition, there was a limited nmber of viable patients. Hence, contries and sites were careflly selected to inclde optimal centres with confirmed ability to yield reslts. This strategy reslted in several overlapping sites, and particlar attention was given to ensre sites were adeqately trained against the enrolment criteria. The strategy took advantage of the different enrolment periods for the two stdies. So once the PK/PD enrolment was completed, then the site cold contine on with the Phase III comparability

9 stdy. While the PK/PD data was a costly investment and extraneos to the comparability Phase III stdy, the biosimilar developer received the similarity reslts well in advance of the conclsion of Phase III. The sccess of WCT s strategy (see table) was in large part de to a strong partnership with the sponsor throgh protocol development and IMP dossier review. Or combined efforts spported clinical trial athorization in the most expedited manner. 08 Time for Athorization of Phase III Comparability Stdy Region Contries Mean Approval Time Central Eastern Erope months Western Erope months Commonwealth Independent States months References 1. Eropean Medicines Agency. Gideline on Similar Biological Medicinal Prodcts. CHMP/437/ October Available at gideline/2009/09/wc pdf 2. US Food and Drg Administration. Gidance for Indstry: Qality Considerations in Demonstrating Biosimilarity to a Reference Protein Prodct. (Final) April Available at GidanceComplianceReglatoryInformation/Gidances/cm htm 3. US Food and Drg Administration. Gidance for Indstry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Prodct. (Final) April Available at GidanceComplianceReglatoryInformation/Gidances/cm htm 4. US Food and Drg Administration. Gidance for Indstry: Biosimilars: Qestions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of (draft) Febrary Available at cm htm 5. U.S. Food and Drg Administration. Gidance for Indstry: Formal Meetings between the FDA and Biosimilar Biological Prodct Sponsors or Applicants. (draft) March Available at drgs/gidancecompliancereglatoryinformation/gidances/cm pdf 6. Eropean Medicines Agency. Gideline on Similar Biological Medicinal Prodcts. CHMP/437/04 Rev October Available at gideline/2014/10/wc pdf INTERNATIONAL: +44 (0) AMERICAS: Schellekens H. Biosimilar therapetics what do we need to consider? NDT Pls. 2009; 2 (sppl 1): i27 i Schiestl M, Stangler T, Torella C, et al. Acceptable changes in qality attribtes of glycosylated biopharmaceticals. Nat Biotechnol. 2011; 29: US Food and Drg Administration. Gidance for Indstry: Clinical Pharmacology Data to Spport a Demonstration of Biosimilarity to a Reference Prodct. (draft) May Available at downloads/drgs/gidancecompliancereglatoryinformation/gidances/cm pdf ). V.1 - May 15 - USL