DrugShortages,Generics&% Biosimilars…Ohmy!communityoncology.org/pdfs/McBride Drug Shortages...

Drug Shortages, Generics & Biosimilars …Oh my!

Ali McBride, PharmD, MS The Arthur G. James Cancer Hospital and

Richard J. Solove Research InsAtute at The Ohio State University

ObjecAves

1.  Review the Impact of Oncology Drug Shortages

2.  Review Generic Drug Therapies in the Oncology Market

3.  Evaluate the role of Biosimilars in oncology

Drug Shortages in the Press

Headlines •  “Genzyme Drug Shortage Leaves Users Feeling Betrayed”-‐NY Times 3/15/2010-‐ ProducAon Plant ContaminaAon

•  “States Face Shortage of Key Lethal InjecAon Drug” NY Times -‐ Hospira decided to “exit the market.”

•  “Teva Propofol Recall Leads to FDA Warning, Drug Shortage”-‐ Failed to have proper quality control measures in place to prevent bacterial contaminaAon from entering batches of their generic version of the anestheAc propofol.

•  “Pharmacies run out of Potassium Iodide” •  The list goes on, with daily issues of drug shortages.

NaAonal MedicaAon Shortages

120$88$

73$58$

74$ 70$

129$149$

166$

211$

267$

100$

0$

50$

100$

150$

200$

250$

300$

2001$ 2002$ 2003$ 2004$ 2005$ 2006$ 2007$ 2008$ 2009$ 2010$ 2011$ 2012$

Data from University of Utah Drug InformaAon Service

MedicaAon Shortages

Data from University of Utah Drug InformaAon Service

Drug Manufacturing Process

Manufacturing

Raw Material

Manufacturing

Crude-‐Purified-‐Bulk

Regulatory

Q&A Analysis

Packaging

Labeling

DistribuAon

Purchasing Agent

Wholesaler/GPO

Regional VariaAons in

Supply

Pharmacy

Hospitals

Infusion Centers

Community Pharmacy

MedicaAon Shortages

Manufacturer DisconAnuaAon

Stockpiling

Economic Factors

DistribuAon

Regulatory Process

Manufacturer

FDA

U.S. Drug Supply

Financial Impact of Drug Shortages •  Financial effects of shortages

– Expends tremendous resources •  Costly alternaAve medicaAons for provider and paAent

•  Significant Ame spent on addressing shortages •  AddiAonal costs associated with treatment of adverse outcomes

•  UAlizing non-‐pedigree medicaAons from “Gray Market” Suppliers

Financial Impact of Drug Shortages

•  Drug shortage cost U.S. hospitals at least $200 million annually

•  Providers are paying an average of 11 percent more for shortage products

•  Grey Markets products are expensive –  10 to 1000 x usual cost

•  The research also does not include indirect costs such as added labor needed to manage shortages and secure alternaAve supplies, as data on these areas does not exist.

hep://www.premierinc.com/about/news/11-‐mar/drug-‐shortage-‐white-‐paper-‐3-‐28-‐11.pdf

Financial Impact of Drug Shortages

Drug Shortage Survey •  Overall, 70% of the respondents felt that the informaAon resources available to manage drug shortages were not good

•  The labor costs associated with managing shortages in the United States is an esAmated $216 million annually

•  Of these drugs evaluated, only three were oncology drugs (Dacarbazine, Mesna, Idarubicin)

AJHP 2011;68:e13-‐21

Cost of Drug Shortages (Jan-‐Dec 2010)

Gray Market

•  They buy up drugs for everything from cancer to infecAons, stockpile them, then sell them to hospitals at massive markups.

•  The average markup on drugs is 650% •  FDA is accepAng cases of gray market abuse that

it would refer to the Department of JusAce. •  If you are experiencing issues with gray market

suppliers, contact the FDA Drug Shortage Office.

Gray Market

Gray Market

Short-Supply Prescription Drugs: Shining a Light on the Gray Market (Hearings: U.S. Senate Committee of Commerce, Science, and Transportation)

Cost of AlternaAve Therapies

Shortage: Heparin

5,000 unit/dose

Shortage Dates:

9/22/09to 11/20/09

AlternaAve Agent:

Enoxaparin 40 mg

AddiAonal Expenditure: $122,307

hep://www.ichpnet.org/resources/events/AM10/10-‐049.pdf

Sampling of Chemotherapy /Suppor>ve Medica>on Shortages

Chemotherapy

BendamusAne Leucovorin

Bleomycin Mannitol

CarboplaAn Mesna

Cytarabine Methotrexate

Dacarbazine Methylene Blue

Daunorubicin Ondansetron

Dexrazoxane Paclitaxel

Doxorubicin Sodium Thiosulfate

Fludarabine Thiotepa

Fluorouracil VinblasAne

http://www.ashp.org/DrugShortages/Current


Primary CNS lymphoma •  3% of all primary brain tumors •  High-‐grade malignant non-‐Hodgkin's B-‐cell lymphoma in more than 90% of cases

•  Treatment regimens vary by physician and paAent – High-‐dose methotrexate – Whole Brain RadiaAon Therapy – Stem Cell Transplant


•  High Dose Methotrexate – Leucovorin

•  25 mg q 6 hours (Cost 50mg $20.85) –  3 days leucovorin rescue – Cost $125.10

– LevoLeucovorin •  7.5 mg q 6 hours (Cost 50mg $176.44)

–  3 days leucovorin rescue -‐ Cost $1056.60 »  If delayed eliminaAon, increase to 75 mg q 3 hours

– CarboxypepAdase G2 •  One Dose (Cost Approximately $$$$$$$ )


Colorectal Cancer •  FolFox6 Regimen

–  Leucovorin 400 mg/m2 or Levoleucovorin 200 mg/m2 – OxaliplaAn 100 mg/m2

2 a 2-‐hour IV infusion –  Fluorouracil 400 mg/m2as an IV injecAon –  Fluorouracil 1200 mg/m2/day as a conAnuous IV infusion over 23 hours on days 1 and 2

–  Cycle repeated every 2 weeks –  Infusions Centers are not being reimbursed for the added cost of Fusilev

J Clin Oncol. 2004;22: 229-‐37.

Cost of AlternaAve Therapies Colorectal Cancer CapeOx Regimen Day +1

–  OxaliplaAn 130 mg/m2 Day 1 –  Capecitabine 850-‐1000 mg/m2 twice daily PO for 14 days –  Cycle repeated every 3 weeks –  PaAents not able to afford Oral Chemotherapy under Medicare Part D

Tournigand, C et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: A randomized GERCOR study. J Clin Oncol 2004; 22:229


•  Reimbursement may not be enough for alternaAve therapies

•  AlternaAves may not be available, and delays may occur no maeer what changes are made

•  Increased burden falls on larger insAtuAons who may have a larger amount of drug in stock

Fiduciary Costs of Drug Shortages

•  Financial effects of shortages – Expends tremendous resources

•  Costly alternaAve medicaAons for provider and paAent

•  Significant Ame spent on addressing shortages •  AddiAonal costs associated with treatment of adverse outcomes

Generics and Biosimilars

Generic

•  Generic medicaAon savings rose nearly 22% in 2011.

•  Generic medicaAons savings totaled $193 billion in 2011.

•  Savings from generic oncology products soared over $10 billion in 2011.

•  57% of 2011 annual savings were from generic central nervous system drugs, such as anAdepressants, cardiovascular, and anA-‐convulsants drugs.

Generics •  Consumers saved more

than $1 trillion over the last decade — and $193 billion in 2011 alone — through their use of generic drugs

•  80 percent of the 4 billion U.S.prescripAons were for generic medicaAons. But, because of their cheaper prices, generic drugs accounted for only 27% of the total U.S.drug spending.

Source: Generic PharmaceuAcal AssociaAon

Patent ExpiraAons 2013 2014 2015 2016 2017 2018 2019

Neupogen Remicade Epogen Enbrel Neulasta Tarceva Revlimid

Zometa Leukine Aranesp Erbitux SandostaAn AvasAn ZyAga

Xeloda Rapamune

Rituxan Zevalin Tysabri HercepAn Exjade

Temodar Evista Epogen Elitek Iressa Clolar Boniva

Dacogen Xeloda Procrit Humira Velcade Orencia

Epogen Gleevec Prialt Xolair

Procrit Aloxi

Remicade Neulasta

Peg-‐Intron

Emend

Oncology Patent ExpiraAons Brand Name

Generic Name Common use(s)

Zometa® Zoledronic Aid Hypercalcemia, bone malignancy

Temodar® Temozolomide (generic approved, not launched 3/10)

Glioblastoma MulAforme

Rapamune® sirolimus Prevent organ RejecAon, lymphoma

Xeloda® capecitabine Colorectal, breast cancers

Epogen® epoeAn alfa injecAon Anemia

Procrit® epoeAn alfa injecAon Anemia

Aggrenox® aspirin/dipyridamole extended-‐release capsule

Prevent blood clots

Gleevec® imaAnib Chronic myeloid leukemia, GastrointesAnal stromal tumors

Aloxi® palonosetron Nausea, vomiAng

Neulasta® pegfilgrasAm injecAon Neutropenia

Rituxan® rituximab injecAon NHL, CLL

Lupron® leuprolide injecAon Advanced prostate cancer

Velcade® bortezomib injecAon MulAple myeloma, lymphoma

InformaAon current as of June 2012. EsAmated dates are subject to change due to patent liAgaAon, addiAonal patents, exclusiviAes heps://host1.medcohealth.com/art/corporate/anAcipatedfirsvme_generics.pdf

Generics

•  The IMS predicts that the use of generic medicaAons will reach almost 87 percent by 2015 as brand-‐name drugs with annual sales of $67 billion will lose patent protecAon

•  Over the next 10 years there will be an increase in generic and biosimilar drugs by greater than 180%

LegislaAon HR 6611

•  Bill Introduced in House Would Exempt Certain Generic Injectables from 340B Pricing

•  A bill introduced in the U.S. House would exempt certain generic injectable drugs from 340B pricing, ostensibly in an effort to address drug shortages in that category.

•  PaAent Access to Drugs in Shortage Act of 2012 (HR 6611)

hep://thomas.loc.gov/cgi-‐bin/query/z?c112:H.R.6611

LegislaAon HR 6611 •  Amends the Public Health Service Act to exclude such mulAple source drugs from the term "covered outpaAent drug" subject to specified price limitaAons under the "340B" drug pricing program.

•  Directs the Secretary to contract with an independent enAty to study the effects of this Act on paAent access to sterile products.

•  Amends the PaAent ProtecAon and Affordable Care Act to exclude certain branded prescripAon drugs on a specified drug shortage list from the annual fee imposed on branded prescripAon pharmaceuAcal manufacturers and importers

hep://thomas.loc.gov/cgi-‐bin/query/z?c112:H.R.6611

LegislaAon LegislaAon HR 6611 •  Medicare reimbursement would move to wholesale acquisiAon cost (WAC) from the current average sales price (ASP+6%); the change would increase Medicare payments for the drugs in an effort to boost manufacturers¹ supply incenAves.

•  AddiAonally, these drugs would be exempt from Medicaid rebates, from 340B pricing equirements, and from Affordable Care Act manufacturer fees (while the drugs are in shortage as designated by the U.S. Food and Drug AdministraAon (FDA)).

Biosimilars

What is a Biosimilar

•  A biological product that is demonstrated to be “highly similar” to an FDA-‐licensed biological product (the reference product) may rely on certain exisAng scienAfic knowledge about the safety, purity, and potency of the reference product.

•  This new licensure pathway permits a “biosimilar” biological product to be licensed based on less than a full complement of product-‐specific nonclinical and clinical data.

What is a Biosimilar •  Technical definiAon from U.S. Code of Federal RegulaAons

"any virus, therapeuAc serum, toxin, anAtoxin, or analogous

product applicable to the prevenAon, treatment or cure of diseases or injuries of man."

•  Derived from living sources -‐Various cultures of bacteria or viruses -‐Human or animal sources

•  Biologics do not always have a therapeuAc intent •  For our purposes, think of biologics as “therapeuAc

proteins”

Biologics Price CompeAAon and InnovaAon Act

•  The Biologics Price CompeAAon and InnovaAon Act (BPCI

Act) was passed as part of healthcare reform (Affordable Care Act) that President Obama signed into law on March 23, 2010.

•  The BPCI Act creates an abbreviated licensure pathway for biological products shown to be biosimilar to or nterchangeable with an FDA-‐licensed reference product.

•  The objecAves are similar to those of Hatch-‐Waxman (the Drug Price CompeAAon and Patent Term RestoraAon Act of 1984),which established abbreviated approval pathways for drug products under the Food, Drug, and CosmeAc Act (FD&C Act).

Biosimilar Guidance Webinar. February, 2012. hep://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicaAons/TherapeuAcBiologicApplicaAons/Biosimilars/UCM292463.pdf

First Biotechnology Process Yeast FermentaAon 4,000 BC

•  Budweiser

•  Amstel

•  Heineken

•  St. Pauli Girl

•  Molson

ARE THESE EQUIVALENT ? ? ?

Biotech History At an AcceleraAng Pace

•  500 BC AnAbioAc (moldy soy for treatment of boils, China ) •  1590 Janssen invents the microscope •  1675 Leeuwenhoek discovers bacteria •  1797 Jenner invents smallpox vaccine •  1833 First proteins and enzymes discovered •  1902 “Immunology”, “geneAcs” •  1920s Human growth hormone synthesized, penicillin •  1940s “Molecular biology”, “geneAc engineering” •  1950s Interferon, Watson and Crick discover DNA •  1960s First automaAc protein sequencer •  1970s Synthesis of a gene, DNA manipulaAon •  1980s Recombinant vaccine •  2000 Human genome mapped

Equivalence of Biotech Drugs •  Chemically similar drugs could infringe upon the originator’s patents. •  New products may not be therapeuAcally equivalent to originator (FDA) •  The “pracAce world” considers drugs in a similar therapeuAc category,

with equivalent outcomes, to be “therapeuAcally equivalent”. -  Supported or required by many payers

•  AnAbioAc classes, LHRH Antagonists, Interferon alfa-‐2a + 2b, CSFs, EPOs) •  CriAcal QuesAons

-  Are generic biotech drugs inevitable? •  They’re common throughout the world.

-  Can different chemical structures be equivalent? •  They target the same receptor site?

-  Can equivalence be proven? •  Not yet, therefore FDA requires an NDA •  To truly answer, switching studies must be performed

-  Will payers determine equivalence? •  Remember CMS “funcAonal equivalence”

-  Why should providers support drug originators if the payers reimburse based on lowest cost within their designated “categories”

Biosimilars ProducAon •  Process important for biologics producAon •  ProducAon process for biologics has more steps and is more complex than process for tradiAonal drugs

•  Requires significant capital investment

Benefits of Biotechnology

•  Provides new approaches to discovery, design, and producAon of drugs

•  Biotechnology makes possible –  PrevenAon, cure, and treatment of more diseases –  Targeted, more effecAve, less toxic medicines –  ProacAve vs. reacAve approach –  ProducAon of replacement human proteins –  ProducAon of “pure” drugs (no contaminaAon by infecAous pathogens from human or animal sources)

General Classes of Biologics

•  Monoclonal anAbodies •  Complex sugars •  Blood derivaAves •  Vaccines •  Recombinant or purified proteins, such as

– Cytokines – ThrombolyAc agents – Enzymes

Current Biologics on the Market Generic Brand Indica>on

Human insulin Several Diabetes mellitus

Interferons: α, β, γ Several Several EpoeAn alfa DarbepoeAn alfa

Procrit® , Epogen®, Aranesp®

Anemias

FilgrasAm

PegfilgrasAm

SargramosAm

Neupogen®

Neulasta® Leukine®

Febrile neutropenia

Trastuzumab HercepAn® Her2Neu cancers Rituximab Rituxan® Lymphomas, NHL

Cetuximab Bevacizumab

Erbitux® AvasAn®

EGFR-‐expressing cancers

Current Available Biosimilars in Europe

Impact on Price

Response From

Originators

Result

§  Clinicians comfortable with the introducAon of biosimilars

§  No unexpected safety concerns idenAfied in 24 months

§  Extensive “Post AuthorizaAon Safety Studies” have been undertaken by the biosimilar manufacturers to monitor safety of their products in the market

European EPO Commercial Experience

§  Branded EPOs are switched to biosmiliars on tenders today (interchangeability)

§  75% cost reducAon announced during FIP 2010 World Conference

§  EU payors are driving biosimilar uptake if funding mechanisms give them influence

§  Prior to biosimilar entry, originators had already introduced price discounts

§  Biosimilar EPOs are priced at ~ 20% less than the originator brands

§  Originators responded to limit biosimilar uptake

§  QuesAons on the quality, safety, and efficacy of biosimilars

§  Advising clinicians against switching EPO products

§  QuesAoning the adequacy of EU pharmacovigilance systems to effecAvely monitor biosimilars in clinical pracAce

Biotech Drug PreparaAon

•  Specific diluents (preservaAve free) •  Specific i.v. infusion soluAons •  I.V. infusion containers may become an issue (polyvinyl

chloride, glass, or plasAc) •  Environmental safety issues related to i.v. preparaAon

and disposal (hazardous materials?)

•  Special “training” for drug preparaAon? •  Unique reconsAtuAon techniques •  Storage

Biotech Drug AdministraAon ConsideraAons

•  Drug compaAbility data are limited

•  Special infusion pumps

•  FiltraAon may be a problem

•  PaAent teaching for self-‐administraAon

•  Monitoring paAents for hypersensiAvity reacAons during administraAon is essenAal

AnAbody FormaAon “Immunogenicity”

•  PotenAal increases with changes in amino acid sequence

•  Some anAbodies produce neutralizing effect against rDNA product (interferon alfa)

•  Human anAbody formaAon seen with some MoAbs (especially human anA-‐mouse anAgen [HAMA]) –  HAMA: neutralizing effect or hypersensiAvity reacAons

•  Can we use desensiAzaAon processes? •  Should we document exposure on a paAent’s lifeAme medical

record?

Kessler M et al. Nephrol Dial Transplant. 2006; 21(suppl 5):v9-‐12.

Generic Equivalents “The Orange Book”

•  FDA sApulates that “pharmaceuAcally equivalent” drug products must be formulated to –  Contain the same amount of acAve ingredient in the same dosage form and

–  Meet the same or compendial or other applicable standards (i.e., strength, quality, purity, and idenAty)

•  TherapeuAc equivalents only if –  They are pharmaceuAcal equivalents and –  They can be expected to have the same clinical effect and safety profile when administered to paAents under the condiAons specified in the labeling

Equivalence of Biotech Drugs

•  New products, chemically similar to the originator, could infringe upon one or more of the originator’s patents

•  New products may not be therapeuAcally equivalent to the originator (per FDA)

•  The “real world” considers drugs in similar therapeuAc category, with equivalent outcomes, to be “therapeuAcally equivalent” –  Supported or required by many payers –  AnAbioAc classes –  Leuprolide acetate – goserelin acetate –  Interferon alfa-‐2a and alfa-‐2b –  Colony-‐sAmulaAng factors (granulocyte vs. granulocyte macrophage;

epoeAn alfa vs. darbepoeAn alfa) –  “Taxanes”

Difference Between Approval Pathways

Clinical TherapeuAcs 2012;34:400-‐419

BioSimilar Drugs

•  Formulary Development •  AutomaAc SubsAtuAon

–  Interchangeability Standards •  Naming •  REMS •  Cost •  Post-‐MarkeAng Studies

•  Drug shortages have taken a foothold in oncology pracAce

•  TherapeuAc alternaAves are o�en limited due to the lack of comparaAve studies and guidelines

•  The upcoming overload of generics coming to market will lead to potenAal decreased costs to health-‐systems

•  Biosimilars will become a key player in reducing costs of specific disease state therapies

Conclusions

QuesAons

"You can observe a lot just by watching.” -‐Yogi Berra

DrugShortages,Generics&% Biosimilars…Ohmy!communityoncology.org/pdfs/McBride Drug Shortages...

Documents

Transcript of DrugShortages,Generics&% Biosimilars…Ohmy!communityoncology.org/pdfs/McBride Drug Shortages...