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Interchangeability, Switching and Substitution of Biosimilars: Clinical Issues, Challenges Dr. Freddy J Faccin Lazo

Associate Medical Director – Biotherapeutics

GMA – AbbVie

BIO Latin America Conference

September 9-11, 2014

Rio de Janeiro, Brazil

Company Confidential © 2014 2

DISCLOSURE

• Dr. Freddy José Faccin Lazo is a full time

AbbVie employee


• Interchangeability: Health or Regulatory Authority Designation

‒ US FDA: (1) Expected to produce the same clinical result as the reference product in any given patient; (2) Repeated switching between biosimilar and reference product presents no greater safety or efficacy risk than continued use of the reference product1

• Substitution: Pharmacist Action

‒ When a pharmacist substitutes a certain prescribed product by another equivalent product

‒ If without the prescribing physician’s involvement, it is considered “automatic” or “involuntary” substitution

• Medical Switching: Treating Physician Decision

‒ When a prescribing physician changes medication, usually because of efficacy or safety issue(s)

1. BPCI Act. Biologics Price Competition and Innovation Act of 2009. Federal Register 2010; H.R. 3590-686-702;

Interchangeability and Substitution: Working Definitions


Interchangeability and Substitution

GENERICS

• Regulatory agencies may designate the two as interchangeable

• Depending on local or institutional rules, pharmacists may be authorized or even required to substitute a generic for the original without informing the prescribing physician (automatic substitution)

BIOSIMILARS

• Biosimilarity status by a regulator does not imply interchangeability

1: FDA Biosimilar Guidance Webinar, February 15, 2012; 2: EMA, Questions and Answers on biosimilar medicines; European Biopharmaceutical Enterprises (EBE) Survey on Biosimilars, May 2011; 3: MHLW Guideline for Ensuring Quality, Safety and Efficacy of Biosimilar Products, March 2009 ; 4: FDLI Update, July 2012; 5: Discussion paper on Similar Biological Medicinal Products (SBMPs), Australia PBS; 6: Health Canada Interchangeability and Substitutability of Subsequent Entry Biologics, July 2010


Interchangeability/Substitution for Biosimilars: US/FDA

Following passage in 2010 of the Biologics Price Competition and Innovation Act (BPCIA), FDA can deem certain biosimilars as “interchangeable”

Under U.S. law, interchangeable means:

‒ the biological product is biosimilar to the reference product;

‒ it can be expected to produce the same clinical result as the reference product in any given patient; and

‒ for a product administered more than once, the safety and reduced efficacy risks of alternating or switching are not greater than with repeated use of the reference product without alternating or switching

Substitution is regulated at state level

1. BPCI Act. Biologics Price Competition and Innovation Act of 2009. Federal Register 2010; H.R. 3590-686-702


Interchangeability/Substitution for Biosimilars: EU/EMA

• The EMA’s evaluations do not include recommendations on whether a biosimilar could be used interchangeably with its reference medicine:

‒ the MA dossier does not contain evidence to substantiate an interchangeability determination

‒ “For questions related to switching from one biological medicine to another, patients should speak to their doctor and pharmacist.”1

• The legal decision on interchangeability is left to Member States

• No country has explicitly authorized interchangeability for biologicals, including biosimilars

1. EMA Questions and answers on biosimilar medicines, 27 Sept 2012. EMA/837805/2011 ; 2. European Medicines Agency (EMA). Concept paper on the revision of the guideline of similar biological medicinal product. Committee for Medicinal Products for Human Use. London, Nov 17, 2011. 3. Dranitsaris G, Amir E, Dorward K. Biosimilars of biological drug therapies: regulatory, clinical and commercial considerations. Drugs 2011; 71:1527-36 . 4..European Comission: What you need to know about biosimilar medicinal products . Consensus Information Paper 2013.

Company Confidential © 2014 7 7

US1 FDA requirements to meet

interchangeability threshold still unclear, automatic substitution of interchangeable drugs to be determined at state level

Japan3 Interchangeability and

automatic substitution highly discouraged

EMA2 Decision on automatic

substitution left to member states - no country has explicitly authorized it. France considers allowing pharmacist substitution for bio-naïve patients9

Brazil4, Argentina5, Mexico6

Developed guidelines for biosimilars, but have not yet

addressed interchangeability or automatic substitution

Australia7 TGA Guideline states the biosimilar’s PI should include

“Replacement of [Reference product name] with [biosimilar product name], or vice versa, should take place only under the supervision of the prescribing medical practitioner."

Canada8 Health Canada does not

support automatic substitution, but allows provinces to determine interchangeability

1: FDA Biosimilar Guidance Webinar, February 15, 2012; 2: EMA, Questions and Answers on biosimilar medicines; European Biopharmaceutical Enterprises (EBE) Survey on Biosimilars, May 2011; 3: MHLW Guideline for Ensuring Quality, Safety and Efficacy of Biosimilar Products, March 2009 ; 4: FDLI Update, July 2012; 5: ANMAT, Disposición N° 7729/2011 (publicado el 21 de Noviembre de 2011); 6: Proyecto de PROY-NOM-257-SSA1-2013; 7: TGA Biosimilar Guidance; 30 July 2013; 8: Health Canada Interchangeability and Substitutability of Subsequent Entry Biologics, July 2010; 9: GaBiOnline.net France to allow biosimilars substitution Accessed 2/24/2014

Interchangeability & Substitution / External Materials / March 2014

Interchangeability and Substitution for Biosimilars


WHO Guideline on Evaluation of SBPs

1. WHO Guidelines on Similar Biotherapeutic Products. http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf

It was recognized that a number of important issues associated with the use of SBPs need to be defined by the national authorities. They include but are not limited to the following:

‒ intellectual property issues; ‒ interchangeability and substitution of SBP with RBP; ‒ labelling and prescribing information.


Interchangeability and Substitution: Switching Studies – Design

No one single proposal fulfills requirements for all product classes / disease states

Common needed elements:

‒ Should be DB, randomized, controlled trials (not open labeled)

‒ Should include multiple switches (alternation)

‒ Should include appropriate control groups

Careful consideration should be given to the biotherapeutics’ half-life when defining washout periods

1. Lu Y; Chow SC et al. : Drug Designing 2013, Vol. 2; Issue 3; page 2 to 6; 2.. Endrenyi L et al. Statist. Med. 2013,32, 434-441; 3. Chow S-C et al. Statist. Med. 2013,32, 442-448

Drug B

Drug R

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Drug B

Drug R

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Interchangeability and Substitution: Switching Studies – Population

Should switching studies be conducted in the most sensitive populations ?

Can clinical interchangeability data themselves be extrapolated from one tested indication to another?

For an indication approved on basis of indication extrapolation can interchangeability be adequately determined?

1. Lu Y; Chow SC et al.: Drug Designing 2013, Vol. 2; Issue 3; page 2 to 6; 2. Endrenyi L et al. Statist. Med. 2013,32, 434-441; 3. Chow S-C et al. Statist. Med. 2013,32, 442-448; 4. Declerck P. J. GaBi Journal, Vol.1, Issue 1, 2012, 13-16 ; 5. Mould DR and Greens B- Concepts and Lessons for drug development Biodrugs 2010; 24(1): 23-39.; 6. Ebbers H.C. et al., Expert Opin Biol. Ther. 2012, 12 (11) 1473-1485.


Interchangeability and Substitution: Switching Studies – Ethical Considerations

• In accordance with the Helsinki declaration, the risk for the individual patient participating in a clinical trial should not overpass the potential benefit1

• How to consider a switching study where no clinical benefit is expected while the potential risk might be increased (i.e. an “infinite” risk/benefit ratio)?

‒ Should stable patients on their current treatment be included in switching studies?

• Can access to affordable medications be considered a sufficient benefit for patients included in switching studies?

• Should switching studies be conducted in patien populations with

‒ Limited therapeutic options

‒ Critical / life threatening diseases (e.g. oncology)?

• What will be the alternative treatment for patients who don’t accept the switch (e.g. NOR-SWITCH: continue Remicade™ or switch to Remsima™ to reduce costs – assuming that the drugs are similar)?

1. World Medical Association Declaration of Helsinki, JAMA Oct. 2013; 2. Ventola, C.L. P&T; vol.38, nº 6, June 2013: pag. 329-335; 3 Heath Canada/BiotecCanada Summit on regulatory and clinical topics related to subsequent entry biologics (biosimilars), Ottawa, 14 May 2012;.


Interchangeability and Substitution: Additional Considerations

Tracking and Traceability −Substitution with similar substances may complicate and slow the traceability

of an adverse event to a specific drug: long latency periods, non-distinguishable INNs. How will this issue be managed locally and globally?

Post-Market Manufacturing Changes −Can an interchangeability designation be maintained over time?

Labeling −Should an interchangeable biosimilar have the same label as the reference

product?

Devices −For self-injectable medications, should new patient be trained after

substitution? − In order to prevent injection errors how similar should the delivery devices be?

1. Gerald Gianutsos, PhD, JD. U.S. Pharmacist 2008; 2. Wieser C., Rosenkranz A.R. Clin Kidney J (2013) 0: 1-4; 3. Dorner T. et al. Ann Rheum Dis 2012; 00:1-7


Interchangeability and Substitution: Conclusions

• According to the FDA and other reference NRAs, approval of biosimilarity alone is insufficient to establish interchangeability or substitutability with the reference product

• The challenges facing the design, execution, interpretation and potential clinical consequences of interchageability studies for biotherapeutics are multiple, and must be addressed from a cross-functional perspective

‒ These challenges must be addressed based on a solid scientific/medical rationale

• Given the limitations of post authorization data, it is currently impossible to conclude an absence of a risk of switching biologics

• Until all challenges have been scientifically addressed, only a treating physician in consultation with the patient, should make the decision to switch a patient to an alternative treatment regimen

1.Ebbers H ,et al.Expert Opin. Biol. Ther. (2012) 12(11). 2.Biologics Price Competition and Innovation Act of 2009 . 3.Danese S. et.al. J Crohn's and Colitis 2013: 7,(7); 586-589; 4. TGA Biosimilar Guidance; 30 July 2013; 5: Health Canada Interchangeability and Substitutability of Subsequent Entry Biologics, July 2010


Antiepileptic Drugs: New advice on switching between different manufacturer’s products for a particular drug

1.MHRA: Drug Safety Update, November 2013, vol. 7, issue 4: A1


Obrigado! T Thanks!

Gracias! [email protected]

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