Subsequent Entry Biologics: Legal Subsequent Entry Biologics: Legal Aspects of Interchangeability and Aspects of Interchangeability and

LiabilityLiability

Alan WestAlan West

PartnerPartnerGowling Lafleur Henderson LLPGowling Lafleur Henderson LLP

22

IntroductionIntroduction

�� SEB approval pathway creates potential for liabilit y of federal SEB approval pathway creates potential for liabilit y of federal and provincial regulators, pharmacists and physicia ns.and provincial regulators, pharmacists and physicia ns.

�� Reasons: Reasons:

�� widely conceded that SEBs are not simply widely conceded that SEBs are not simply ““ genericgeneric ””versions of innovative biologicals. SEB approval i s not a versions of innovative biologicals. SEB approval i s not a declaration of equivalence; declaration of equivalence;

�� However, the SEB process appears to do exactly that : However, the SEB process appears to do exactly that : create an abbreviated or truncated route to approva l based create an abbreviated or truncated route to approva l based on equivalence. on equivalence.

�� When a patient is harmed as a result of a SEB, this fact may When a patient is harmed as a result of a SEB, this fact may form the basis of an allegation of negligence. form the basis of an allegation of negligence.

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Differences Require Different TreatmentDifferences Require Different Treatment

�� Widely accepted by global regulatory agencies and Widely accepted by global regulatory agencies and innovative and generic industries that subsequent innovative and generic industries that subsequent entry biologics cannot be identical copies of the entry biologics cannot be identical copies of the innovator products they seek to imitate. innovator products they seek to imitate.

�� These significant differences necessitate a These significant differences necessitate a regulatory regime unique to biologics.regulatory regime unique to biologics.

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Differences Recognized in CanadaDifferences Recognized in Canada

�� Distinction between biologics and other drug Distinction between biologics and other drug products has long been recognized in Canada. products has long been recognized in Canada.

�� December 2000: the Office of the Auditor General of December 2000: the Office of the Auditor General of Canada released a report (Chapter 26 of the yearly Canada released a report (Chapter 26 of the yearly report) entitled report) entitled ““ Health CanadaHealth Canada ——Regulatory Regime Regulatory Regime of Biologicsof Biologics ”” . .

�� In this report, the Auditor General highlighted the In this report, the Auditor General highlighted the unique concerns posed by biologics as follows:unique concerns posed by biologics as follows:

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AuditorAuditor --GeneralGeneral ’’s Reports Report

“…“… there is a wide range of safety risks associated there is a wide range of safety risks associated with biologics. Some of the risks are known, such a s with biologics. Some of the risks are known, such a s risks associated with the transmission of infectiou s risks associated with the transmission of infectiou s diseases, transfusion reactions and bacterial diseases, transfusion reactions and bacterial contamination. However, others are not as well contamination. However, others are not as well understood or are emerging risks associated with understood or are emerging risks associated with the transmission of unknown infectious agents.the transmission of unknown infectious agents. ””

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Biological DrugsBiological Drugs

�� Unlike Unlike ““ small moleculesmall molecule ”” drugs, biologics are drugs, biologics are produced from living cells, biologic produced from living cells, biologic precursors and substrates. precursors and substrates.

�� Thus, Thus, processprocess is all important in determining is all important in determining safety and efficacy.safety and efficacy.

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““ Process is the ProductProcess is the Product ””

�� The following are examples of factors:The following are examples of factors:

�� Cell lines themselves, in which metabolic activitie s Cell lines themselves, in which metabolic activitie s necessary to produce compounds that will become necessary to produce compounds that will become the biologic drug take place; the biologic drug take place;

�� the growth media, in which the cell lines and/or mi crothe growth media, in which the cell lines and/or mi cro --organisms used to produce the end product are organisms used to produce the end product are grown; grown;

�� The fermentation methods used in the production The fermentation methods used in the production process and the harvesting and purification, process and the harvesting and purification, inactivation, etc., techniques employed;inactivation, etc., techniques employed;

�� all contribute, in a unique fashion, to the end all contribute, in a unique fashion, to the end productproduct ’’s quality, efficacy and safety. s quality, efficacy and safety.

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Other Differentiating FactorsOther Differentiating Factors

�� Moreover, most of these aspects are proprietary to Moreover, most of these aspects are proprietary to the innovator company and not available or known the innovator company and not available or known to third parties. to third parties.

�� Not necessarily disclosed in patents. Not necessarily disclosed in patents.

�� Many of the processes used in the manufacture of Many of the processes used in the manufacture of biologics are proprietary trade secrets which are biologics are proprietary trade secrets which are difficult to difficult to ‘‘ reverse engineerreverse engineer ’’ . .

�� Finally, biological products are particularly Finally, biological products are particularly susceptible to contamination by adventitious agents susceptible to contamination by adventitious agents (for example, viruses and prions).(for example, viruses and prions).

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Assays/Tests May Be Unable to Measure End Assays/Tests May Be Unable to Measure End ProductProduct

�� ConventionallyConventionally --used immunoassays and biomimetic used immunoassays and biomimetic assays and various physicochemical tests may assays and various physicochemical tests may characterize the major form of a protein present in a characterize the major form of a protein present in a heterogeneous mixture. heterogeneous mixture.

�� However, in drug development, these assays and However, in drug development, these assays and tests are not validated predictors of a biologic dr ugtests are not validated predictors of a biologic dr ug ’’s s potency or safety potency or safety in vivoin vivo. .

�� Therefore, physiochemical testing does not permit Therefore, physiochemical testing does not permit one to establish one to establish ““ samenesssameness ”” with respect either to with respect either to the identity or composition of one producerthe identity or composition of one producer ’’s s biologic to that of another. biologic to that of another.

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Biologics: Potential for Immunogenic Biologics: Potential for Immunogenic ResponsesResponses

�� Antibodies may be formed against a therapeutic Antibodies may be formed against a therapeutic protein can trigger serious clinical effects, inclu ding protein can trigger serious clinical effects, inclu ding loss of efficacy and neutralization of the bodyloss of efficacy and neutralization of the body ’’s own s own essential biological functions. essential biological functions.

�� Many biotechnology products are designed to Many biotechnology products are designed to replace a deficiency in the bodyreplace a deficiency in the body ’’s own endogenous s own endogenous proteins. proteins.

�� An immune response to such a product may result An immune response to such a product may result not only in the body neutralizing the therapy, but not only in the body neutralizing the therapy, but also in neutralizing the bodyalso in neutralizing the body ’’s own native supply of s own native supply of the protein.the protein.

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Difficulties Created by Difficulties Created by ““ Subsequent EntrySubsequent Entry ””BiologicsBiologics

�� Unfortunately, neither analytical testing nor testi ng Unfortunately, neither analytical testing nor testi ng in animals can predict whether, or at what rate, a in animals can predict whether, or at what rate, a biological product may trigger an adherent immune biological product may trigger an adherent immune response in humans. response in humans.

�� It is also unlikely, if not impossible, that two It is also unlikely, if not impossible, that two biological products produced by different biological products produced by different manufacturers would have the same immunogenicity manufacturers would have the same immunogenicity profile. profile.

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Differences Create Unique Legal Liability Differences Create Unique Legal Liability ConcernsConcerns

�� Introduction of Introduction of ““ subsequent entrysubsequent entry ”” biologics create biologics create potential liability concerns for:potential liability concerns for:

�� Healthcare professionals who prescribe SEBs;Healthcare professionals who prescribe SEBs;

�� Pharmacists who dispense SEBs; Pharmacists who dispense SEBs;

�� Regulators, who approve SEBs as safe and effective Regulators, who approve SEBs as safe and effective for use in Canada. for use in Canada.

�� Provincial payors who list SEBs on provincial Provincial payors who list SEBs on provincial formularies; formularies;

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Liability ConcernsLiability Concerns

�� Basic source of the liability concern is that a pat ient Basic source of the liability concern is that a pat ient will be:will be:

�� Prescribed an SEB by a health care professional;Prescribed an SEB by a health care professional;

�� Dispensed an SEB by a pharmacist;Dispensed an SEB by a pharmacist;

�� Required to accept a lowerRequired to accept a lower --cost SEB by a cost SEB by a provincial public payor;provincial public payor;

�� If a patient is injured, what are the legal If a patient is injured, what are the legal consequences? consequences?

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Sources of Liability: If a Patient is InjuredSources of Liability: If a Patient is Injured

�� Physicians:Physicians:

�� Negligence in prescribing a subsequent entry biolog ic when it isNegligence in prescribing a subsequent entry biolog ic when it isreasonably foreseeable that such a product carries greater risksreasonably foreseeable that such a product carries greater risksthan an existing alternative drugthan an existing alternative drug

�� Pharmacists:Pharmacists:

�� Negligence in interchanging an Negligence in interchanging an ‘‘unprovenunproven ’’ subsequent entry subsequent entry biologic for a safer existing drugbiologic for a safer existing drug

�� Provincial Drug Plans:Provincial Drug Plans:

�� Negligence in declaring a subsequent entry biologic Negligence in declaring a subsequent entry biologic ““ interchangeableinterchangeable ”” with the with the ‘‘ innovativeinnovative ’’ drug, thus encouraging or drug, thus encouraging or requiring acceptance of the (presumably) less expen sive but lessrequiring acceptance of the (presumably) less expen sive but lesswellwell --characterized drug characterized drug

�� Health Canada:Health Canada:

�� Negligence in approving the subsequent entry drug f or sale in Negligence in approving the subsequent entry drug f or sale in Canada by a truncated or abbreviated review processCanada by a truncated or abbreviated review process

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““ InterchangeableInterchangeable ”” vs. vs. ““ SubstitutableSubstitutable ””

�� These terms refer to the ability of a pharmacist to provide a These terms refer to the ability of a pharmacist to provide a drug other than the drug other than the ‘‘originaloriginal ’’ drug to a consumer (usually drug to a consumer (usually because the because the ‘‘alternativealternative ’’ drug is cheaper).drug is cheaper).

�� Terms are defined under various provincial laws.Terms are defined under various provincial laws.

�� ““ InterchangeabilityInterchangeability ”” generally refers to the requirement to generally refers to the requirement to ““ interchangeinterchange ”” a lower cost generic version of a name brand a lower cost generic version of a name brand drug (a drug (a ‘‘ financialfinancial ’’ decision).decision).

�� ““ SubstitutabilitySubstitutability ”” or or ““ therapeutic substitutiontherapeutic substitution ”” generally refers generally refers to substituting an altogether different drug as fun ctionally to substituting an altogether different drug as fun ctionally equivalent to a prescribed drug for treating the sa me condition equivalent to a prescribed drug for treating the sa me condition (a medical decision).(a medical decision).

�� General rule: pharmacists may (or in some cases, mu st) General rule: pharmacists may (or in some cases, mu st) ““ interchangeinterchange ”” but, in general, do not have the legal power to but, in general, do not have the legal power to ““ substitutesubstitute ”” ..

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Basis of Liability Basis of Liability

�� Unlike Unlike ‘‘small moleculesmall molecule ’’ drugs, where bioequivalence is drugs, where bioequivalence is sufficient to show that the active ingredients are identical, wisufficient to show that the active ingredients are identical, wi th th biologicals even minor differences in the biologicals even minor differences in the ““ processprocess ”” can lead to can lead to profound differences in clinical activity and side effect profilprofound differences in clinical activity and side effect profil e e

�� These differences may not become apparent until the drug is in These differences may not become apparent until the drug is in widespread usewidespread use

�� Almost never happens with small molecule drugs that have Almost never happens with small molecule drugs that have been demonstrated to be been demonstrated to be ““ bioequivalentbioequivalent ””

�� Accordingly, all parties (doctors, druggists, provi ncial drug Accordingly, all parties (doctors, druggists, provi ncial drug plans and regulator) may be found by the courts to have plans and regulator) may be found by the courts to have knowledge of thisknowledge of this

�� Accordingly, it is possible liability will be fixed if any or alAccordingly, it is possible liability will be fixed if any or al l are l are held to have fallen below the standard of care requ ired when held to have fallen below the standard of care requ ired when approving SEBs with anything less than the full pan oply of approving SEBs with anything less than the full pan oply of tests and protections used to evaluate the innovati ve drugtests and protections used to evaluate the innovati ve drug

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Health Canada: Guidance for SEB Sponsors Health Canada: Guidance for SEB Sponsors

�� Final version released March 10, 2010Final version released March 10, 2010

�� Attempts to address the safety concerns described a bove by:Attempts to address the safety concerns described a bove by:

�� Stating as policy that authorization by Health Cana da is Stating as policy that authorization by Health Cana da is “…“… not a declaration of pharmaceutical or therapeutic not a declaration of pharmaceutical or therapeutic equivalence to the reference biologic drugequivalence to the reference biologic drug ”” (para. 1.3.4)(para. 1.3.4)

�� Requiring clinical trials as part of an approval pa thway that, Requiring clinical trials as part of an approval pa thway that, while less onerous than that for an innovator produ ct, is not while less onerous than that for an innovator produ ct, is not abbreviated to the extent of that for generic drugs (section abbreviated to the extent of that for generic drugs (section 2.3).2.3).

�� A regimen of postA regimen of post --marketing requirements such as periodic marketing requirements such as periodic safety update reports (section 2.4). safety update reports (section 2.4).

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Liability Risk: Health CanadaLiability Risk: Health Canada

�� Health Canada appears to want two fundamentally inc ompatible Health Canada appears to want two fundamentally inc ompatible things:things:

�� (i) to state that authorization of SEBs is not a de claration of (i) to state that authorization of SEBs is not a de claration of pharmaceutical or therapeutic equivalence; pharmaceutical or therapeutic equivalence;

�� (ii) to accept a reduced data package for SEB based on (ii) to accept a reduced data package for SEB based on “…“… demonstrated similarity between the SEB and the sui table demonstrated similarity between the SEB and the sui table reference drugreference drug ”” (para. 1.3.3). (para. 1.3.3).

�� While Health Canada may While Health Canada may statestate it is not declaring SEBs to be it is not declaring SEBs to be ““ pharmaceutically or therapeutically equivalentpharmaceutically or therapeutically equivalent ”” , it is in effect , it is in effect treatingtreatingthem as such. them as such.

�� An injured patient will have a potential claim that the reduced An injured patient will have a potential claim that the reduced requirements for SEBs is, on its face, evidence of negligence; requirements for SEBs is, on its face, evidence of negligence; statements to the effect that Health Canada is well aware that Sstatements to the effect that Health Canada is well aware that S EBs EBs are not really are not really ““ equivalentequivalent ”” merely demonstrate that the requirements merely demonstrate that the requirements should not have been minimized. should not have been minimized.

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Liability Risk: InterchangeabilityLiability Risk: Interchangeability

�� Health Canada spokesman has stated at the February 17, 2009 Health Canada spokesman has stated at the February 17, 2009 PMDA Symposium on Biologics, that PMDA Symposium on Biologics, that ““ interchangeability interchangeability remains a provincial decisionremains a provincial decision ”” . This places the burden on . This places the burden on CADTH and the provinces.CADTH and the provinces.

�� CADTH has accepted that SEBs are suitable for consi deration CADTH has accepted that SEBs are suitable for consi deration for listing on provincial formularies:for listing on provincial formularies:

�� CDR UpdateCDR Update ——Issue 59: Issue 59: “…“… drugs that align with Health drugs that align with Health CanadaCanada ’’s draft [guidance for SEBs] should be filed with th e s draft [guidance for SEBs] should be filed with th e CDR CDR ……

�� CDR UpdateCDR Update ——Issue 62: announcement of SEB Pilot Project, Issue 62: announcement of SEB Pilot Project, including additional process re comparison of SEB a nd including additional process re comparison of SEB a nd ““ similar productssimilar products ””

�� To date, there is no indication as to whether provi ncial To date, there is no indication as to whether provi ncial authorities will consider SEBs as suitable for inte rchangeable authorities will consider SEBs as suitable for inte rchangeable status. status.

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Liability Risk: Recent DecisionsLiability Risk: Recent Decisions

�� Recent appellate decisions in Ontario (Recent appellate decisions in Ontario ( Attis v. CanadaAttis v. Canada and and Drady v. Drady v. CanadaCanada, released concurrently in 2008) suggest that the O ntario , released concurrently in 2008) suggest that the O ntario courts would be highly reluctant to find liability against a regcourts would be highly reluctant to find liability against a reg ulator for ulator for simple negligence relating to it regulatory duties.simple negligence relating to it regulatory duties.

�� These cases both involved allegations that Health C anada was These cases both involved allegations that Health C anada was negligent in approving medical devices that caused injury to usenegligent in approving medical devices that caused injury to use rs.rs.

�� The Court refused to find a private duty of care ow ed by Health The Court refused to find a private duty of care ow ed by Health Canada, citing lack of proximity to the alleged vic tims and publCanada, citing lack of proximity to the alleged vic tims and publ ic ic policy concerns.policy concerns.

�� These decisions may be distinguishable:These decisions may be distinguishable:

�� In those two cases, the allegation was lack of adeq uate regulatIn those two cases, the allegation was lack of adeq uate regulat ory ory oversight and a failure to protect Canadians from h armful deviceoversight and a failure to protect Canadians from h armful device s: s: the courts found that the implication of imposing a duty in suchthe courts found that the implication of imposing a duty in suchcases was to create cases was to create ““ indeterminate liabilityindeterminate liability ”” , in effect making the , in effect making the government the insurer for any defect. government the insurer for any defect.

�� With SEBs, the allegation would be that the regulat ory system With SEBs, the allegation would be that the regulat ory system establishes incompatible goals, thus establishes incompatible goals, thus creatingcreating new risks.new risks.

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Interchangeability in OntarioInterchangeability in Ontario

�� In Ontario, In Ontario, ““ interchangeabilityinterchangeability ”” is defined as follows in the is defined as follows in the Drug Interchangeability and Dispensing Fee Act:Drug Interchangeability and Dispensing Fee Act:

““ interchangeable productinterchangeable product ”” means a drug or combination of means a drug or combination of drugs in a particular dosage form and strength iden tified by a drugs in a particular dosage form and strength iden tified by a specific product name or manufacturer and designate d as specific product name or manufacturer and designate d as interchangeable with one or more other such product sinterchangeable with one or more other such product s’’

�� A condition of designation is that the drugs must b e A condition of designation is that the drugs must b e bioequivalent.bioequivalent.

�� ““ Therapeutic substitutionTherapeutic substitution ”” is defined as follows:is defined as follows:

““ therapeutic substitutiontherapeutic substitution ”” means the substitution of a drug that means the substitution of a drug that contains chemically different active ingredients th at are contains chemically different active ingredients th at are considered to be therapeutically equivalent, withou t considered to be therapeutically equivalent, withou t authorization from a person authorized to prescribe drugs authorization from a person authorized to prescribe drugs within the scope of his or her practice of a health profession.within the scope of his or her practice of a health profession. ’’

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Analysis of Liability in Ontario [1]Analysis of Liability in Ontario [1]

�� It is unclear whether or not an SEB may be declared It is unclear whether or not an SEB may be declared ““ interchangeableinterchangeable ”” under Ontario legislation.under Ontario legislation.

�� Assuming it is, all parties are protected from liab ility for intAssuming it is, all parties are protected from liab ility for int erchanging erchanging such a product by legislation. Section 8 of the such a product by legislation. Section 8 of the Drug Interchangeability Drug Interchangeability and Dispensing Fee Actand Dispensing Fee Act states as follows:states as follows:

““ 8. If an interchangeable product is dispensed in a ccordance wit8. If an interchangeable product is dispensed in a ccordance wit h this h this Act, no action or other proceeding lies or shall be instituted aAct, no action or other proceeding lies or shall be instituted a gainst gainst the person who issued the prescription, the dispens er or any perthe person who issued the prescription, the dispens er or any per son son who is responsible in law for the acts of either of them on the who is responsible in law for the acts of either of them on the grounds grounds that an interchangeable product other than the one prescribed wathat an interchangeable product other than the one prescribed wa s s dispensed.dispensed. ””

�� This section has not yet been judicially challenged . It is uncleThis section has not yet been judicially challenged . It is uncle ar ar whether it could withstand a whether it could withstand a CharterCharter challenge (as in challenge (as in Chaoulli v. Chaoulli v. Quebec Quebec where a ban on private health insurance was struck down as where a ban on private health insurance was struck down as infringing s.7 rights). The better view is that the right to sueinfringing s.7 rights). The better view is that the right to sue would not would not be subject to the same degree of protection by the courts.be subject to the same degree of protection by the courts.

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Analysis of Liability in Ontario [2]Analysis of Liability in Ontario [2]

�� Accordingly, in Ontario, the only parties facing Accordingly, in Ontario, the only parties facing potential liability are:potential liability are:

�� The physician who prescribes an SEB in the first The physician who prescribes an SEB in the first place. He would not be able to shelter under the place. He would not be able to shelter under the legislative protection.legislative protection.

�� Health Canada, for approving such a product as safe Health Canada, for approving such a product as safe and effective.and effective.

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Interchangeability in QuebecInterchangeability in Quebec

�� No definition or standard for No definition or standard for ““ interchangeabilityinterchangeability ”” ..

�� Under the Under the ““ 15 year rule15 year rule ”” the full cost of an innovative product the full cost of an innovative product will be reimbursed for 15 years; thereafter, only t he cost of thwill be reimbursed for 15 years; thereafter, only t he cost of th e e lowest cost alternative will be reimbursed.lowest cost alternative will be reimbursed.

�� Pharmacists may provide a medicine with the same ge neric Pharmacists may provide a medicine with the same ge neric name (unless the physician indicates otherwise) und er s. 21 of name (unless the physician indicates otherwise) und er s. 21 of the Quebec the Quebec Pharmacy ActPharmacy Act. .

�� In general, this will not apply to SEBs.In general, this will not apply to SEBs.

�� There are no provisions insulating the pharmacist f rom liabilityThere are no provisions insulating the pharmacist f rom liabilityfor the for the ‘‘ interchangeinterchange ’’ ..

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Interchangeability in British ColumbiaInterchangeability in British Columbia

�� British Columbia permits pharmacists to British Columbia permits pharmacists to ““ adaptadapt ”” a prescription a prescription by policy approved by the College of Pharmacists (M arch 2009)by policy approved by the College of Pharmacists (M arch 2009)

�� Policy states as follows:Policy states as follows:

““ A pharmacist may dispense a drug contrary to the te rms of a A pharmacist may dispense a drug contrary to the te rms of a prescription (adapt a prescription) if the action i s intended toprescription (adapt a prescription) if the action i s intended tooptimize the therapeutic outcome of treatment with the optimize the therapeutic outcome of treatment with the prescribed drug and meets all of the following elem ents of a prescribed drug and meets all of the following elem ents of a protocol to adapt a prescription protocol to adapt a prescription …”…”

�� Permits Permits ““ therapeutictherapeutic ”” substitution. substitution.

�� No statutory protections: Pharmacist remains liable for No statutory protections: Pharmacist remains liable for ““ adaptionadaption ”” . .

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Interchangeability in AlbertaInterchangeability in Alberta

�� In Alberta, In Alberta, ““ interchangeabilityinterchangeability ”” is purely a designation used for is purely a designation used for purposes of determining reimbursement under the pro vincial purposes of determining reimbursement under the pro vincial drug plan.drug plan.

�� Like British Columbia, Alberta has by policy author ized Like British Columbia, Alberta has by policy author ized pharmacists to pharmacists to ““ adaptadapt ”” prescriptions.prescriptions.

�� Described by the College as follows: Described by the College as follows:

““ prescription modificationprescription modification ——modifying a prescription written by modifying a prescription written by another prescriber to alter dosage, formulation, re gimen or another prescriber to alter dosage, formulation, re gimen or duration of the prescribed drug, or provide a thera peutic duration of the prescribed drug, or provide a thera peutic alternative to improve drug therapy or provide cont inuity of alternative to improve drug therapy or provide cont inuity of therapy.therapy. ””

�� There is no statutory protection for this activity.There is no statutory protection for this activity.

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Liability Across CanadaLiability Across Canada

�� The situation concerning liability is highly depend ent The situation concerning liability is highly depend ent on the specifics of provincial law.on the specifics of provincial law.

�� Each province has different:Each province has different:

�� Definitions of Definitions of ““ interchangeabilityinterchangeability ”” ; and; and

�� Different levels of protection for dispensing an Different levels of protection for dispensing an interchangeable product.interchangeable product.

�� This means that each province must be specifically This means that each province must be specifically examined for liability concerns in respect of examined for liability concerns in respect of subsequent entry biologics.subsequent entry biologics.

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