key issues impacting the future of biosimilars

©2009 Foley & Lardner LLP • Attorney Advertising • Prior results do not guarantee a similar outcome • Models used are not clients but may be representative of clients • 321 N. Clark Street, Suite 2800, Chicago, IL 60654 • 312.832.4500

Key Issues Impacting The Future of Biosimilars


Michael A. Swit, Esq., Vice President, The Weinberg Group Inc

David L. Rosen, Partner, Foley & Lardner LLP

©2009 Foley & Lardner LLP

Standard Disclaimers

Views expressed here are solely mine and do not reflect those of my firm or any of its clients.This presentation supports an oral briefing and should not be relied upon solely on its own to support any conclusion of law or fact.


Agenda

Biosimilars– Overview of Current Situation in Europe– Regulatory and Scientific Issues– Product Development Issues– U.S. Legislative Options

Waxman/SchumerEshoo


Biosimilars in Europe: The story so far ... Guidances

1998 – Concept paper: Development of a CPMP Guideline on Comparability of Biotechnology –Derived Products2005 – General / Introductory guidance 2006 – Similar Biological Medicinal Products ..... Quality Issues2006 – Similar Biological Medicinal Products ..... Non-clinical & Clinical issues2006 – First specific guidances issued


Biosimilars in Europe: The story so far ... Guidances

Somatropin - Non-clinical & Clinical gG-CSF - Non-clinical & ClinicalHuman insulin - Non-clinical & ClinicalErythropoietins - Non-clinical & Clinical

(under revision)Interferon alpha - Non-clinical & Clinical

(draft)Low Molecular - Non-clinical & ClinicalWeight Heparins


Biosimilars in Europe: Current Approval Status

Somatropin - 2 “Biosimilar Products”Erythropoietin Alpha - 3 “Biosimilar Products”Erythropoietin Zeta - 2 “Biosimilar Products”Filgrastim - 6 “Biosimilar Products”


Biosimilars in Europe: Current Regulatory Status

Europe is the only major territory with formal guidance for the development and approval of BiosimilarsCommitment to post-marketing safety studiesMarket is developing slowlyInterchangeability – not awarded at EU level– National rules on substitution e.g. France, Spain

National rules on pricing and reimbursementEMEA: “… the decision to treat a patient with a reference or Biosimilar medicine should be taken following the opinion of a qualified healthcare professional”


FDA Hasn't Defined the Processes

Biologics approved under Public Health Services Act – no abbreviated pathway– Precursor? – Comparability Guidance, April 1996

NDAs – for few biologics (e.g., HGH, insulin) – were approved– No set criteria on appropriate data set to support approval– Evaluated on a case by case basis

Ambiguity results in potential for challenges throughout the development and life of a biosimilar drug versus small molecule generic drugs– Active ingredient – Marketing– Equivalence – Pricing– Substitutability – Reimbursement


Equivalence

Lynchpin to traditional generic process – depends on:– Pharmaceutical “equivalents” – active ingredient, dosage form,

strength, etc., must be SAME– Highly unlikely with Biosimilars –

Characterization – still a challenge even for the innovators – clinical trials may be needed to show comparability after process changes.

– Chances of “equivalence” conclusions faint as even a single amino acid can throw off conclusion (e.g., HGH)

– Lovenox – only 70% characterized (but, is under an NDA)

– Janet Woodcock, Director, Center for Drugs (before Congress, March 2007):

“there is general recognition that the idea of sameness, as the term is used in the generic drug approval process under the Federal Food, Drug, and Cosmetic (FD&C) Act and applied to small molecules, will not usually be appropriate for more structurally complex molecules of the type generally licensed as biological products under the Public Health Service Act.”


Equivalence …

Lynchpin to generic process – depends on:– Bioequivalence study (occasionally clinical studies with

efficacy endpoints – e.g., topicals) –– Accurate predictability also allegedly an issue with

Biosimilars– Biosimilars – even under an abbreviated pathway, will

most likely more resemble an NDA than an ANDA – clinical studies to show efficacy and monitor immunogenicity concerns likely

Omnitrope® – Sandoz’s HGH product – rumored to have cost tens of millions of dollars to develop


Substitutability

Substitution – core of classic Generic Industry Business Model– Depends on therapeutic equivalence – Allows for minimal sales forces– Price drivers

Multiple generics common – drives price to commodity status

Biosimilar world –– Substitution – aka “interchangeability” – may evolve, but on a very,

very limited basisWoodcock – must be able to handle repeated brand/follow-in switching without adverse eventsHHS – June 2007 letter to Senate HELP Committee – no interchangeabilityThus, business model will not be multiple generics & not a commodity

– Without interchangeability, the Generic’s Biosimilar IS really a branded drug


Marketing Challenges

Classic Generic – substitutability pushes salesBiosimilar– “Generic” – will have to go out and detail

Costs higherNot their sweet spot traditionallyWill they run into greater resistance on “substitution” from doctors and patients?

– Innovator – may need to distinguish vs. its “generic”Internal and external pressure for outcomes studies


Active Ingredient Issues

Classic Generic – many sources of APIBiosimilar– Technological barriers to API development greater; fewer

sources– Foreign sources – particularly from China – will be under

great scrutiny from FDA, even more so after Heparin scandal

– Immunogenicity concerns are very high –FDA – on record that immune response is “impossible to predict”

– see Dr. Janet Woodcock, FDA Deputy Commissioner, Congressional Testimony, March 26, 2007


Small vs. Large Molecule Realities

Small Molecule– Therapeutically equivalent

Same molecule

– Substitutable – Price drives– and multiple

generics drive price down– Insurance coverage follows

ANDA approval– Marketing – cost sells; little

need for formal sales & marketing staff

– Legal Pathway – clear under Waxman-Hatch Act

Biosimilar– Not therapeutically equivalent

Not same molecule

– Not substitutable– Price difference to brand

likely smaller– Separate coverage likely

needed for the Biosimilar– Will require professional sales

and marketing staffs to drive utilization vs. “Brand”

– Legal Pathway –505(b)(2) – case-by-casePHSA – nonexistent


Extensive Data Packages Needed

Generics: – Physicochemical identical to innovator drug– Healthy subject pharmacokinetic equivalence to innovator

Biosimilars: – Physicochemical characterization: similar to innovator– Variable extent of preclinical data– Extensive clinical database– More like new drug application (NDA) than abbreviated

new drug application (ANDA)


Biosimilar: Extensive Data Package

DataOmnitrope®

(vs. Genotropin®)

Valtropin®(vs.

Humatrope®)Physicochemical characterization, purity

√ √

Nonclinical pharmacodynamics √ √

Nonclinical toxicology √ √

Standard BE pharmacokinetic study √ √

Additional human pharmacodynamics

√ √

Clinical studies – in growth hormone deficient children

√ √

Additional immunologic data √ √


FDA Perspective – Somewhat Clarified through Public Discussion

Torti Letter – September 2008 – concise statement of FDA’s then (Bush Admin.) views on Biosimilars– “Highly similar” active ingredients are sufficient standard for

determination of “sameness” to allow some reliance on innovator’s approval (but so far only for NDA’d products)

Similarity can be established without reference to proprietary chemistry and manufacturing data of innovatorIdentical manufacturing process is not required

– Formulation differences may be allowable if they don’t impact critical features (e.g., product stability, immunogenicity)

– Current medical knowledge of potential drug risks may deem certain animal toxicology studies necessary, others unnecessary

– Interchangeability –possible, but very unlikely– FDA – switching should not occur and, when it does, must be

approved by patient’s doctor


Lessons Learned

Terminology – “generic biologic” or “biogeneric”replaced by “biosimilar” – other aliases:– Follow-on protein products (FOPPs) – one U.S. version– Follow-on biologics (FOBs) – one U.S. version– Subsequent entry biologics (SEBs) – Canada– Subsequent entry protein products (SEPPs) – Japan

“Abbreviated” biosimilar development programs have been extensive in CDER– Data sets much closer to that of innovator drug than

generic


Lessons Learned …

Substitution based on therapeutic equivalence – the driver of small molecule generic utilization – highly unlikelyFDA pathway likely to be highly iterative … and slowConsumer cost savings – modest:– Evidence suggests discount may only be 20-25%– Utilization slow – only about 1% of somatropin Rxs were

filled with Omnitrope in 2007 (source: Torti letter)Senate Finance Committee – 9/24/09 – backed an amendment to Baucus Health Care Reform to reimburse doctors for prescribing biogeneric or biosimilar drugs at an additional six percent over the competitive rate.


Legislation

The Future?


Will It Happen This Year?

Top Democrat pushes for action on biotech drugsBy MATTHEW PERRONE – 18 hours ago (June 8, 2009)

WASHINGTON (AP) — As the Obama administration renews its health care reform effort on Capitol Hill, a top Democrat is calling for speedy action on a years long effort to create generic competition for costly biotech drugs.President Barack Obama used his weekly radio address on Saturday to call on Congress to act on his proposal to overhaul the nation's health care system.In a letter Monday, Rep. Henry Waxman, D-Calif., reminded the president of his stated commitment to lower the price of biotechdrugs, high-tech injectable medications that cost more than $40 billion per year.


The Current Bills

Waxman Bill – HR 1427 & Schumer Bill – S 726 –“Promoting Innovation and Access to Life-Saving Medicine Act”

Original Eshoo Bill – HR 1548 – “Pathways for Biosimilars Act”

Eshoo Health Care Reform “mark” – HR 3200


Key Issues in Debate

“Biosimilar” – How Defined?– How similar must Biosimilar be to Reference Product (RP)?

How to handle heterogenicity, impurities

– What kind of studies must be done to show extent of similarity?AnalyticalAnimal?Clinical

– Must mechanisms of action be same?– Can any requirements be waived?

Interchangeability – allowed?– How proven– Guidances needed?

Naming of Biosimilar Actives


Key Issues in Debate …

Exclusivity– Types:– “Data” – can not even submit BP application– “Market” – can not get approval, but FDA can review BP

application– Length: Major area of dispute – 5 to 14??

Exclusivity for First Interchangeable Biosimilar– Possible?– Likely?– Figment of imagination?


Key Issues in Debate …

Authorized Generics– Waxman – bars them– Eshoo – silent

Patents and Litigation – two very different and complicated systems for learning about patents and notificationsGuidances –– Waxman – not needed before FDA may approve– Eshoo #1 – arguably essential (like EU) before approval– Eshoo #2 – not needed before FDA approval


Questions?

Call, e-mail, fax or write:Michael A. Swit, Esq.

Vice PresidentThe Weinberg Group Inc.

336 North Coast Hwy. 101Suite C

Encinitas, CA 92024Phone 760.633.3343

Fax 760.454.2979Cell 760.815.4762

[email protected]


About Your Speaker…

Michael A. Swit, Esq., is a Vice President at THE WEINBERG GROUP, where he develops and ensures the execution of a broad array of regulatory and other services to drug, biologics and medical device/diagnostic clients seeking to market products in the United States. His expertise includes product development strategies, compliance and enforcement initiatives, recalls and crisis management, submissions and related traditional FDA regulatory activities, labeling and advertising, and clinical research efforts.

Mr. Swit has been addressing critical FDA legal and regulatory issues since 1984. His multi-faceted experience includes serving for three and a half years as corporate vice president, general counsel and secretary of Par Pharmaceutical, a prominent, publicly-traded, generic drug company and, thus, he brings an industry and commercial perspective to his work with FDA-regulated companies. Mr. Swit then served for over four years asCEO of FDANews.com, a premier publisher of FDA regulatory newsletters and other specialty information products for the FDA-regulated community. His private FDA regulatory law practice has included service as Special Counsel in the FDA Law Practice Group in the San Diego office of Heller Ehrman White & McAuliffe and with the Food & Drug Law practice at McKenna & Cuneo, both in the firm’s Washington office and later in San Diego. He first practiced FDA regulatory law with the D.C. office of Burditt & Radzius.

Mr. Swit has taught and written on a wide variety of subjects relating to FDA law, regulation and related commercial activities, including, since 1989, co-directing a three-day intensive course on the generic drug approval process and editing a guide to the generic drug approval process, Getting Your Generic Drug Approved. A former member of the Food & Drug Law Journal Editorial Board, he also has been a prominent speaker at numerous conferences sponsored by such organizations as RAPS, FDLI, and DIA. A magna cum laude graduate of Bowdoin College, he received his law degree from Emory University Law School and is a member of the California, D.C. and Virginia bars.


For more than twenty-five years, leading companies have depended on The Weinberg Group when their products

are at risk. Our technical, scientific and regulatory experts deliver the crucial results, using sound

science, to get products to the market and keep them there.

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Navigating the Regulatory Pathway to Achieve Investment Success


Agenda

Current climate in D.C.Hot Topics Impacting FDAPending LegislationPractical advice for obtaining clearance/approvals to market medical products Maintaining credibility at FDAChallenging FDA’s decisions


Greetings from the Nation’s Capitol


The President and Cabinet Send Their Regards


Bo – Also Sends His Greetings


New Administration

President Obama – understands FDA-related issues– Need for strong leadership– New Commissioner and Deputy Commissioner of FDA –

commitment to change– Product safety

Foods, Drugs, Medical Devices, Dietary Supplements, CosmeticsIncreased emphasis on regulatory action and enforcement

– Biosimilar legislation– Healthcare cost control– Federal pre-emption concerning labeling – Tough enforcement


Key Officials – Center for Drug Evaluation and Research

Director: Janet Woodcock, M.D.Deputy Director Douglas Throckmorton, M.D. Associate Director for Policy Jane A. Axelrad J.D. Office of Compliance - Director Deborah M. Autor, LLB, J.D.Office of New Drugs – Director John K. Jenkins, M.D.Office of Pharmaceutical Science – Director Helen Winklehttp://www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/ucm135674.htm


Key Officials – Center for Biologics Evaluation and Research

Director: Karen Midthun, M.D. (Acting) Office of Compliance: Director Mary Anne MalarkeyOffice of Blood Research and Review: Jay S. Epstein, M.D.Office of Vaccines Research and Review: Norman W. Baylor, Ph.D.Office of Cellular, Tissue and Gene Therapies –Organization: Celia M. Witten, M.D., Ph.D.http://www.fda.gov/AboutFDA/CentersOffices/OrganizationCharts/ucm135943.htm


Key Officials – Center for Devices and Radiological Health

Director: Jeffrey Shuren, M.D., J.D. (Acting) Senior Associate Director: Lillian J. Gill, DPAAssociate Director for Clinical Research & Government Affairs: Casper Uldriks Associate Director for Management & Executive Office: Ruth E. McKeeDirector Office of Compliance: Tim Ulatowski Ombudsman/Quality Assurance Manager: Les S. Weinstein Office of Device Evaluation: Donna-Bea Tillman, Ph.D.http://www.fda.gov/AboutFDA/CentersOffices/CDRH/CDRHOffices/ucm127854.htm#OSM


“Get Tough” Enforcement Priorities

Commissioner Hamburg has recently outlined a new “get tough” approach to warning letters and enforcement generally– “The FDA will no longer issue multiple warning letters to noncompliant

firms before taking enforcement action. If we find that we must move quickly to address significant health concerns or egregious violations, we will consider immediate action – even before we have issued a formal warning letter.”

– This will likely include an increase in the issuance for warning letters as Hamburg has indicated that OCC review will not be required in all instances. This policy under the Bush administration was intended to coordinate the issuance of WLs but also significantly decreased their numbers.


New Media and Internet Promotion of FDA Products

FDA has instituted twitter and podcasts feedsFDA recently announced a public meeting to discuss issues regarding the promotion of FDA-regulated products – specifically prescription drugs, prescription biologics, and medical devices – via the Internet and social media– Issues related to fair balance, use of links, monitoring of

adverse event information.– November 12-13th in Washington D.C.


Proposed Rule on cGMPs for Combination Products

Parts 210 and 211 would apply to combination products that include a drug.Part 820 would apply to combo products that include device.If biologic product, part 606 would be applicable.If HCT/P, Part 1271 current good tissue practice would be applicable.


New Acting Center Director – Dan Schultz Resigns Last Month

Potential significant changes underwayJeff Shuren is current actingFDA has requested the IOM to study the 510(k) clearance process and answer two questions:– Does the current 510(k) process optimally protect

patients and promote innovation in support of public health?

– If not, what legislative, regulatory, or administrative changes are recommended to achieve the goals of the 510(k) process?


Doctors Wary of Consumer Ads for Complex Devices

Physicians are skeptical that adequate safety information can be conveyed to the public in a simple ad


Hot Topics For CDRH

House Republicans Keep Pressure on FDA to Review Warning Letter Appeals Process– House Republicans claim the agency’s decision to seek

civil penalties against TMJ implants, before letting the company appeal 17 warning letters, undermines confidence that the appeals system is fair and impartial.


Hot Topics For CDRH

Agreement Will Tighten China’s Device Export Standards– According to the HHS secretary, bind agreements, will be

consistent with a plan to improve import safety– Contaminated Heparin used in devices and drug products

has raised the visibility of product quality issues


Hot Topics For CDRH

House Panel Probes Foreign Device Facility Oversight– FDA oversight of foreign device manufacturing is getting

pulled into the process of improving safety checks for foreign products

– Risk based approach


New Legislation Has The Potential to Alter the Landscape

Biosimilar Legislation– 12 -14 Year Biologics exclusivity – Currently House and Senate bills are included in Health

Care legislation

Health Care Legislation– Cost and reimbursement issues– Coverage for all


New Legislation Has The Potential to Alter the Landscape

Pharmaceutical Settlement (Reverse Payment) Bill– Legislation proposed that would restrict settlement

between brand and generic companies engaged in patent litigation.

– FTC has repeatedly opposed these types of deals, but Courts have upheld them.

– “Under the [most recent] compromise, the agreements would be presumed illegal but the FTC would have to pursue legal action to challenge an agreement," Sen. Kohl said.


Understand the Current Climate at FDA

Significant safety issues have surfaced with devices and drugs There has been a challenge to the fundamental integrity and the ability of the medical device approval/clearance process to safeguard the public health– Increased Congressional scrutiny– Public awareness and criticism



FDA’s response:– More conservative decision making– Greater scrutiny of the data– Seeking consensus review– Increased focus on FDA field inspections– MDUFA time pressure for completing reviews



Recommendation – Understand FDA’s expectations– Seek guidance from FDA and outside experts– Companies often understand their products more

thoroughly than FDA EducateHear FDA’s concernsAttempt to respond

Remember – FDA does not get it right every time – Can challenge FDA decision making


Be Ready for FDA Inspection

FDA inspectors will visit when there is a safety issue, recall, consumer complaint or when there is a potential data integrity issueTo prep – they will evaluate the company’s compliance history


Be Ready for FDA Inspection

What are the first items they want to see:– Product Complaints– Adverse Event / Medical Device Reports– Rejected Lots– Trending of issues– Thorough and complete investigations– Communication with headquarters staff about the issues

and how they are going to be further investigated and addressed

– Corrective and preventative action plans– Revised SOPs and staff training

Be prepared


Maintaining Your Credibility and Tips for Influencing the FDA

Scientific issuesPolicy mattersLegal Battles



Good science is critical to success– In today’s environment – safety and effectiveness are

paramount– Examine your company’s responses – are changes

needed?



Meet with CDRH/ODE staff early on in the development process– Take advantage of pre-IDE meetings– Try to reach agreement on key development parameters– Understand FDA’s expectations for clearance/approval– Best opportunity to present and get feedback on your

development pathway– Build an administrative record

If the science is questionable– Are additional studies necessary – pre-or post marketing?– Were issues discussed during the development process?



Sound public policy– Are the data being requested or issues being raised by

CDRH consistent with sound public policy?– Is it consistent with the Federal, Food Drug and Cosmetic

Act, FDA regulations, published guidance, or precedents?

If not – have you appealed?– Up the supervisory chain– Have you utilized the informal and/or formal dispute

resolution process?– Do you have any support inside FDA for your position?– Have you spoken with the CDRH or FDA Ombudsman?



Is it time (and wise) to seek Congressional intervention?



Is it time for legal action?Have you exhausted all administrative procedures?Has there been a “final” agency action?Has FDA acted in an arbitrary or capricious manner? Has FDA abused it’s discretionary authority?What is the legal relief that you are seeking?– Stay of a decision or action or injunctive relief– An overturning of a scientific determination or finding– Judicial review of FDA’s application or reading of the law,

regulations, guidance



Does the relief sought make practical sense in light of the legal principles or economics of the specific situation?



What price do you pay when you challenge the system? – Do you win the battle but lose the war?– Will FDA retaliate?– What other products are pending at FDA?– What is the company’s compliance profile?

How much disruption will there be around the company if there is a protracted legal action?

key issues impacting the future of biosimilars

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