Nicky KalafatisDept of Anaesthesia & Critical careUKZN11 July 2015

Disclaimers

• Sponsorship from and/or lectures provided for

– Astra Zeneca

– MSD

– Fresenius Kabi

– Abbott

– Aspen

• Non-specific

FAKE!

Brand name v Generic medicines

What’s in a name?

Definitions

• Brand name

– Originator(Gold std)• Dormicum

– Patented

• Generic

– Basic ingredient• Midazolam

– ‘identical’

– Non-patented version

– Registered locally

• Biologics (non chemicals)

– Living system/organism

– Immunogenic

– difficult to replicate

– Complex manufacture

• Biosimilars

– Follow-ons after patent

– NOT identical

Rank Company TotalRevenues(Billions)

R&D Expenses(millions)

Fortune 500 Rank

1 Johnson&Johnson USD 61,90 USD 6,986 103

2 Pfizer USD 50,01 USD 7,845 152

3 Roche USD 47,35 CHF 9,874 171

4 GlaxoSmithKline USD 45,83 £ 4,106 168

5 Novartis USD 44,27 USD 7,469 183

6 Sanofi USD 41,99 € 4,583 181

7 Astra Zeneca USD 32,81 USD 4,409 268

8 Abbott Laboratories USD 30,76 USD 2,744 294

9 Merck&Co USD 27,43 USD 5,800 378

10 Bayer Healthcare USD 22,30 € 1,845 154

11 Eli-Lilly USD 21,84 N/A 455

12 Bristol-Meyers Squibb USD 18,81 USD 3,647 435

Wikipedia, March 2010

Cost-effectiveness-R&D-Patents

Encourage competition

Not cheaper-resistance-side effects

Medico-legal

Ethics?

‘Health economics’ of Generic medicines

Ethics & the Law (SA)

• Autonomy

• Social Justice

• Beneficence

• Non-Maleficence

Autonomy & Generic medicines (SA)

• The Medicines & related substances Control Amendment Act no 90 of 1997

– Government supply cheaper drugs (generics)

– Implementation 2003:

• pharmacists – offer generics to ALL

– Unless patient refuses OR doctor refuses OR more expensive

– Goal achieved

• Mandatory in public sector

Deroukakis M. SAMJ 2007, 97; 63-64

Social Justice & Generic medicine

• Cheaper manufacturing in developing world

• ARVs, anti-TB, anti-malarials

• Medical aid savings for all

Anderson T. The Lancet 2010,375;1597-8

• More drugs to more patients

Holmes CB et al. JAMA 2010;304(3):313-320

Beneficence & Generic Medicines

• Proof of benefit to patients

• Efficacious

– Bioequivalence

– (Therapeutic equivalence)

• Safe

• Cost-effective

Mastoraki E et al. Journal of Infection 2008;56 :35-39

Bioequivalence

• No significant difference in ratio & extent that active ingredient becomes available at drug’s site of action

• Differs in different countries– Standardisation

• Same route of admin, standards– ( purity, strength, quality)

• Inactive compounds

Meredith P. Clin Therapeutics 2003; 25(11):2875-2890

Bioequivalence issues

• WHO guideline Geneva 1996:– Cross-over trials, n=18-30,18-55yrs, healthy

• Critically ill/ geriatrics, small cohorts

– PK parameters• AUC (>0.7); Cmax (>1.24)

– Single doses only for multidose drugs• ?accumulation data/ renal • PK change with time/duration dose/genetic polymorphisms

– Parenteral drugs • Manufacturing stds, amount of active drug

• Bioequivalence v therapeutic equivalence

Meredith P. Clin Therapeutics 2003; 25(11):2875-2890Snyman JR. South Afr J Epidemiol Infect 2005;20(3):78-79

Drug trials

Ethicals

• Phases

– l-pharmacokinetics• Healthy patients

• 30-80

• No comparison group

– ll- in group of interest• Larger group

• Dose-response

– lll-larger, RCTs

Generics

• Phase(s)

– Pharmacokinetics• Bioequivalence

• Phase l

Beneficence & Generic Medicines

Local data: Generics vs Branded cephalosporins

In vitro data all comparable: MICs

Beneficence & Generic Medicines

Local data: Generics vs Branded cephalosporins

In vitro data all comparable: MICs

Sponsored by: Generic manufacturer

Beneficence & Generic Medicines

• Clozapine vs generics: Canada

– Outpatients

– No difference noted

– Sponsored by : Generic manufacturerOluboka O et al. J Clin Pharm 2010;50:531

Beneficence & Generic Medicines

Results: No in vivo testingEquivalence with originator : MIC

Beneficence & Generic Medicines

Results: No in vivo testingEquivalence with originator : MIC

Sponsored by : Generic manufacturer

Maleficence & Generic medicines

Rocephin vs 34 generic ceftriaxone

– Quality/ adverse effects

– Results:

• 4 unstable

• 8 particulate

• 34 failed Roche (Gold std) specs

• 18 violations European quality stds– 10 in single drug!!

– Content variation: up to 5%-sig in ICU

Lambert PA et al. J of Chemotherapy 2003;15(4):357-368

FDA confirms falsified generic drug testing by Ranbaxy, IndiaFalsified records/resultsRanbaxy labs approved by FDA-25 drugs for US markets

Extra, extra, read all about it…

Washington Post, Feb 26 2006. Pg A02

Stopped all pending approvals Drugs not withdrawn: ‘not thought to be a health risk’

Maleficence & Generic medicines

Ciprofloxacin eye drops (UK)

– Random, 30 samples from India

– Results:

• 6/30: concentration <95% std

– Drug resistance/clinical failure

• 24/30: concentration >105%

– Toxicity/ adverse effects

Weir RE et al. British J Opthalmol 2005; 89(9):1094-6

• Parent drug byproducts

? activity

• Therapeutic equivalence v bioequivalence

• Parenteral drugs

Maleficence & Generic medicines

• Piperacillin-Tazobactam

– 46 batches, 17 countries

– 16% subpotent

• Resistance/clinical failureMoet GJ et al.Diag Micro & Infect Dis 2009;65:319-322

• FDA inspection trial sites

– 37% foreign, higher domestic

– ? Using FDA-required standardsVoelker R. JAMA 2010;304(8):844-5

• Animal trial: Pharmacodynamics

• neutropaenic mice, S.aureus

• All generics proven equivalent in vitro

• ALL failed in vivo

Therapeutic equivalence

• Oxacillin & anti-staph activity: 11 generics– 7 bioequivalent, 4 not

– All failed therapeuticallyRodriquez CA et al. BMC Infect Dis2010;4(10):153

• Gentamycin : 20 generics– 19 bioequivalent

– 10 failed therapeuticallyZuluaga AF et al. Plos one 2010;5(5):e10744

• Meropenem: 1 generic– Failed therapeutically

Agudelo M et al. in print.

So, what’s going on?

• Suggestion : agonist-antagonist effect (PD)

– Generics lack antagonist blocking molecules

• Have patients been dying with generics?

– Assumption of therapeutic equivalence

• Critically ill

– ‘expected outcome’

Vesga O et al. Antimic agents & chemother 2010;54(8):3271-9

Maleficence & Generic medicines

• Hot off the press…• Enoxaparin (Biologic)

– Generics• Manufacture process complex, immunogenicity, safety

– FDA approval 2010– No trials required

• Case report: life-threatening haematomas : maleficence

– EMA, MCC-not approved– KZN

• Several registered versions, no generics

• ?Insulins/protamine/clotting factors/EPO

Kaffenberger BH. Clin Appl thromb hemost 2011;Aug (25)

Maleficence & Generic medicines

Hotly debated…antiepileptics

– Generics approved FDA & EMA

• Literature Review of psychotropic drugs

• No ICU data

• Results:

– Clinical deterioration, Adverse events

– Esp with carbamazepine, valproate, antidepressants

– costs !!!!

Desmarais et al.CNS neurosci Ther 2010; Nov 30

Antiepileptics & generic substitution

• 5 agents: generic use

– Results (previously controlled)

• 20% injury risk

• epilepsy-related medical utilization (IRR 1.24)

• outpatient visits (IRR 1.14)

• Length of stay (IRR 1.29)

Labiner DMet al. Neurology 2010;72(20):1566-74

• Review

– Failure of therapy– Adverse events– need for monitoring– medical costs– Medicolegal aspects– Ethical to cause events in

controlled patients• Daily living, work

Europ J Epilepsy 2006;15(3):165-176

So, what should we do?

• MCC guidelines 2003

– No generic substitution of drugs:

• Narrow Therapeutic index

• Have shown erratic intra & interpatient responses

• In dosage forms that can cause bioavailability problems eg slow-release

• Intended for critically ill, geriatric or paediatric patient

– Taking above into account…

Non-substitutables

• Amiodarone/Atenolol PO

• Carbamazepine PO

• Dexamethasone PO

• Digoxin PO

• Furosemide PO

• Glibenclamide PO

• HCT/hydrallazine PO

• Hydrocortisone PO/injection

• Pen G injection

• Phenytoin PO

• Prazosin PO

• PrednisolonePO/injection

• Warfarin

Biologics: April 2010 update (Replaced list )

The bottom line…brand name v generics ?

My opinion…

• Principles apply to all drug types – Anaes/ICU drugs,fluids,volatiles etc

• NO place for blanket use generic in ICU/OT– Specific drugs; in vivo trials;specific companies

• But…?useful in other populations

• Bioequivalence v therapeutic equivalence

• Medicolegal obligation?– Primum non nocere

• Ethical obligation– Maleficence

– Beneficence: perverse incentives?