advances & best practices · glp and gcp compliant medicines and healthcare products regulatory...

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21st CENTUARY BIOEQUIVALENCE

Advances & Best Practices

David W Holt Emeritus Professor of Bioanalytics

ASI Ltd St George’s – University of London

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Disclosures

I have been a speaker for and a consultant to a variety of Pharma and Diagnostics companies including: Novartis, Astellas, Pfizer, Sanofi, Roche, Abbott, Applied Biosystems, Siemens, Thermofisher and Waters.

I am not on the pay role of any of these companies nor do I hold shares in any of them.

The content of the slides is mine.

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Background

Director Research and service laboratory in London

GLP and GCP compliant Medicines and Healthcare products Regulatory Authority (MHRA)

Accredited by ANVISA for bioequivalence studies Drug measurements

As a guide to therapy Regulatory studies Integrity of formulations

Past President Association of Therapeutic Drug Monitoring & Clinical Toxicology

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Overview

Why we need BE regulations Overview of regulations Complexities of regulating an expanding

market for generic formulations Some specific examples Regulation of biosimilars

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Phenytoin Formulations

Outbreak of Anticonvulsant Intoxication in an Australian City Tyrer JH, Eadie MJ, Sutherland JM & Hooper WD British Medical Journal, 272, 271 – 273 31st October 1970

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Phenytoin - Excipients

One patient taking 400mg/day phenytoin Outbreak of anticonvulsant intoxication in an Australian City. Tyrer et al BMJ 1970;272:27103

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The Impact of Formulation

Heart pill twice as strong as makers expected

Wednesday August 2, 1972

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Digoxin Bioavailability

Bioavailability affected by manufacturing process.

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Digoxin Bioanalytics

It seems extraordinary that none of this might have come to light without the advent of methods of measuring the concentration of digoxin in plasma.

The Lancet 1972

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Innovator Formulations

We know a lot about first into market Large regulatory dossier Pre-clinical and clinical studies Efficacy and safety studies Follow-up observations after approval

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Generic Formulations

Following patent expiry other manufacturers can make a new formulation of the innovator drug

The regulations to bring a generic drug to market are not the same as for the innovator of the drug

Abbreviated New Drug Application (ANDA)

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Regulations fundamentally unchanged since Hatch-Waxman Act of 1984

Established to make registration of generic products simpler No need for clinical trials of efficacy/safety Process based on bioequivalence of test

and reference products for solid dose formulations

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Not here to dismiss generic formulations Many are of excellent quality Essential for provision of health care But not all are made to acceptable standards Can impact on safety and efficacy Need appropriate tests to show comparability

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Much has changed since the passage of the Act Increased use of generics Of the order 75% - 80% of prescriptions

Much more complicated supply chain

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Drug Manufacture

About 80% of API produced in China or India In USA about 40% of finished drugs imported Whilst drug production was within national

borders it was easier to monitor quality of production

Many examples of poor quality have emerged Heparin scandal of 2008

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Recognising The Problem

“Today’s medical-product landscape blurs the line between domestic and foreign production, drawing attention to the need for global quality and safety oversight to prevent patient exposure to falsified products.”

Dr Margaret Hamburg, former US FDA Commissioner

American Journal of Tropical Medicine & Hygiene Published on line April 20, 2015

http://www.ajtmh.org/content/early/2015/04/16/ajtmh.14-0393

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Bioequivalence

Why do we need precise regulations? Increased use of generic formulations Increase in generic-generic substitution To engender confidence in therapeutic

efficacy and safety of multiple formulations of the same drug that are on sale

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FDA Guidance

http://www.fda.gov/ohrms/dockets/ac/03/briefing/3995B1_07_GFI-BioAvail-BioEquiv.pdf

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Proposed Guidance

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM377465.pdf

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EMA Guidance

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf

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International Regulations

International Generic Drug Regulators Pilot Australia, Brazil, Canada, China, Taipei, EMA, Japan, Mexico, Singapore, South Korea, Switzerland, FDA, WHO

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International Regulations

Demonstrate bioequivalence to the reference product

Mostly by randomised, single-dose, two-way crossover studies in healthy normal subjects

At least 12 subjects, often 18-24 Age range and body weight restrictions Mostly both male and female subjects

Davit B et al 2013

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Bioequivalence

For most products, the focus of bioequivalence (BE) studies is on the release of the drug substance from the drug product into the systemic circulation. During such BE studies, an applicant compares the systemic exposure profile of a test drug product to that of the Reference Listed Drug (RLD).

FDA Guidance

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Bioequivalence Blood Concentration Data

Blood concentration / time profile

Peak concentration – Cmax

Time to reach Cmax – tmax

Area under time/conc. curve – AUC

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Comparing Formulations

0

100

200

300

400

500

600

700

800

900

0 4 8 12 16 20 24

Time

Con

cent

ratio

n

AUC Cmax

tmax

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Bioequivalence

“A drug shall be considered to be bioequivalent to a listed drug if the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of the listed drug” FDA Guidance

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Bioequivalence

Study Types As noted in 21 CFR 320.24, in vivo

and/or in vitro methods can be used to establish BE. In general descending order of preference, these include pharmacokinetic, pharmacodynamic, clinical, and in vitro studies.

FDA Guidance

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Bioavailability measures the rate and extent of drug appearance in the systemic circulation

Bioequivalence demonstrates that

other drug formulations have comparable bioavailability to an already approved drug product

Bioequivalence

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Bioequivalence

The 90% confidence interval of the mean ratios for Cmax and AUC should lie within an acceptance interval of 80 to 125%

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The Fundamental Bioequivalence Assumption

If two formulations are shown to be bioequivalent, it is assumed that they will reach the same therapeutic effect, are therapeutically equivalent and, hence, can be used interchangeably.

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Generic Substitution Psychiatry

• Bupropion - Early 2007 Switch from 300mg Wellbutrin XL to Budeprion XL FDA received 85 post-marketing reports

78 specifically about loss of efficacy Also

• Increased incidence of adverse events • New or different adverse events

Bioequivalence at 150mg (90% CI) Cmax Fasted 80.3 – 98.2% Fed 103.2 - 118.0

www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm153270.htm, accessed January 12, 2012

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FDA’s Position January 2012

Small differences in the pharmacokinetic profiles

Not outside the established boundaries for equivalence

The FDA considers bupropion XL 300mg (Teva) bioequivalent and therapeutically equivalent to (interchangeable with) Wellbutrin XL 300mg


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FDA’s Position January 2012


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FDA Reviews Its Position

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm322161.htm, 2012/10/08

FDA Update: Budeprion XL 300mg Not Therapeutically Equivalent to Wellbutrin XL 300mg

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Generic Budeprion Withdrawn

NEnglJMed 2012;367:2463-5

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Generic Substitution

Br J Clin Pharmacol 2011;72:727-30

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“There are few prospective studies assessing potential additional risks associated with substitution and there are no established protocols by which switching is monitored or assessed.

This may make it difficult to know whether the money saved on the initial drug will still be saved as treatment outcomes on the substituted drug become apparent.”

Br J Clin Pharmacol 2011;72:727-30

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The FDA’s Position

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingGenericDrugs/ucm305896.htm, accessed August 19th, 2013

FDA is aware that there are reports that some people may experience undesired effect when switching from a brand name drug to a generic formulation …

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingGenericDrugs/ucm305896.htm

http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingGenericDrugs/ucm305896.htm

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http://www.jwatch.org/fw108810/2014/05/09/fda-planning-study-generic-metoprolol-over-safety

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http://www.peoplespharmacy.com/2014/05/15/metoprolol-mess-toprol-xl-reveals-serious-flaws-with-fdas-generic-process/

Wockhardt’s generic metoprolol succinate did not pass dissolution tests.

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Switching Formulations

The Annals of Pharmacotherapy n 2012 December, Volume 46, 1609-16

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Warfarin Formulations

“The use of both generic and branded formulations of warfarin interchangeably, or the use of generics from more than one manufacturer, was associated with increased use of all-cause health care resources and total costs in patients with AF.”

The Annals of Pharmacotherapy n 2012 December, Volume 46

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Warfarin Formulations

The Annals of Pharmacotherapy 2011;45:701-12

Thrombotic adverse events

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Phenytoin Formulations

Generic to generic switching of phenytoin Formulations approved as interchangeable 80 patients Primary outcome - increased seizure frequency Event rate increased significantly Need for increased monitoring emphasised

Shin J-W et al Int J Clin Pharmacol Ther 2014;52:1017-22

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Tacrolimus Formulations

Prescribers should prescribe oral tacrolimus products by brand name only. When prescriptions have previously been written using the generic name, the brand on which the patient is stabilised should be established to ensure that the patient is supplied with the same product. If a prescriber intends to switch between any tacrolimus brands, careful medical supervision and therapeutic monitoring are required. CORRESPONDENCE TO: SECRETARY OF COMMISSION, L.R. WHITBREAD, FLOOR 4-T 151 BUCKINGHAM PALACE ROAD, LONDON SW1W 9SZ TEL NO: 020 3080 6451/2 OR 020 3080 6477 ♦ EMAIL: [email protected]

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Generic tacrolimus was not bioequivalent in elderly renal transplant patients. The significantly higher systemic exposure of tacrolimus, despite similar trough concentrations, may in the long run increase the risk of adverse effects

Transplantation 2015; 99:528-32

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Therapeutically Equivalent?

Verapamil Young volunteers

Generic bioequivalent Generic PK more variable

Elderly patients Not bioequivalent

Generic Cmax +77% AUC +43%

Not therapeutically equivalent Generic prolonged PR

interval 60

80

100

120

140

160

180

200

220

240

Cmax AUC

Rat

io%

Tes

t to

Ref

eren

ce

177%

143%

Carter BL et al, Pharmacotherapy 13(4), 359, 1993

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Clinical Observations

Clinical indications requiring multiple observations tend to highlight any differences due to the formulation Anticoagulants Anticonvulsants Immunosuppression

Less easy to assess effects on chronic therapy when fewer clinical observations made Hypertension Lipid lowering

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20 pharmacies in Pennsylvania sampled for availability of atorvastatin

Sample × 4 for 4 months from 10/14 6 pharmacies – different generic each month 2 pharmacies – same product each month

Bate R et al 2015

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Pharmacovigilance of Generics

Often anecdotal Small patient numbers History of prescription may be poor Brands used Batch numbers Manufacturers Unknown to prescribing physician

Of particular importance for NTI drugs

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EMA Guideline

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EMA Guideline

Narrow Therapeutic Index Drugs “It is not possible to define a set of criteria

to categorise drugs as narrow therapeutic index (NTIDs) and it must be decided case by case if an active substance is an NTID based on clinical considerations”

Verbeeck RK & Musuamba FT 2012

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EMA Guideline

Narrow Therapeutic Index Drugs Ciclosporin and tacroimus classed as NTID

Ciclosporin 90.00 – 111.11% for AUC and Cmax

Tacrolimus 90.00 – 111.11% for AUC only No consensus on switchability within EU States

Verbeeck RK & Musuamba FT 2012

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Product-specific Guidance


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Sirolimus


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NTI Drugs

Clin Pharmacol Ther 2015;97:286-91

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NTI Drugs

Narrow therapeutic ratio 1. There is less than a two-fold difference in

median lethal dose (LD50) and median effective dose (ED50) values or there is less than a two-fold difference in the minimum toxic concentrations and mimimum effective concentrations in blood, and

2. Safe and effective use of the drug products require careful titration and patient monitoring.


21 CFR 320.33

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NTI Drugs

FDA now uses NTI Those drugs where small differences in dose or

blood concentration may lead to serious therapeutic failure and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The FDA believes that NTI drug products require tighter BE limits and product quality standards.


Follows FDA Advisory Committee meetings 2010 and 2011

Examples: Warfarin, lithium, digoxin, phenytoin, theophylline, tacrolimus

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NTI Drugs

Proposed FDA approach Four-way cross-over study Allows comparison of variability in

addition to means Termed reference scaled bioequivalence Described in draft guidance for warfarin


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Bioequivalence testing Quality of production Were the test batches used in the BE study the

same quality as the final marketed formulation? Continuing onsite inspections

Were the bioanalytical methods used in the study appropriate and to international standards?

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A Medicine

Is the sum of many parts Active pharmaceutical ingredient (API) Excipients Packaging Indications for its use Dosing instructions

We expect consistency Attained by the quality of manufacture

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Quality Issues

http://features.blogs.fortune.cnn.com/2013/05/15/ranbaxy-fraud-lipitor - accessed May 19, 2013

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Quality Issues

On May 13, Ranbaxy pleaded guilty to seven federal criminal counts of selling adulterated drugs with intent to defraud, failing to report that its drugs didn't meet specifications, and making intentionally false statements to the government. Ranbaxy agreed to pay $500 million in fines, forfeitures, and penalties -- the most ever levied against a generic-drug company.

http://features.blogs.fortune.cnn.com/2013/05/15/ranbaxy-fraud-lipitor - accessed May 19, 2013

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Flawed BE Studies

http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/GVK_Biosciences_31/WC500180899.pdf

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Regulatory Inspections

http://www.outsourcing-pharma.com/Contract-Manufacturing/Exporting-to-Brazil-ANVISA-is-tough-and-hands-on-says-Kemwell/ June 12, 2015

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Generic Ophthalmics

Can J Ophthalmol 2012;47:55-61

American and Canadian Timoptic XE eye drops vary significantly from the generics in drop volume, viscosity, surface tension and bottle tip.

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Generic Ophthalmics

Br J Ophthalmol 2013;97:253–7

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The Packaging

11 people arrested in Zhejiang, China, in connection with the manufacture of capsule casings that contained chromium above acceptable limits

No licence to manufacture for drug use Industrial grade gelatin used

RX-360 Flash Report, November 2014 www.Rx-360.org

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Imatinib

Treatment of chronic myeloid leukaemia Controversies surrounding form of API

and quality of manufacture Crystallises in two polymorphic forms alpha and beta forms

Regulatory data relates to the beta form

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Imatinib

http://www.bccancer.bc.ca/chemotherapy-protocols-site/Documents

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Imatinib Polymorphs

J Pharm Sci 2012;101:541-51

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Imatinib

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Product-specific Guidance

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Imatinib

http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002585/WC500134083.pdf

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Imatinib

MHRA licenced a generic form – Nibix – under the decentralised procedure

Refused a FOI request for information on the polymorphic form of the API

Transparency A key aim of the new legislation includes strengthening

medicines safety transparency and communication to increase understanding and trust of healthcare professionals and patients in the safety of medicines, and improving penetration of key warnings.

https://www.gov.uk/drug-safety-update/public-consultation-on-new-pharmacovigilance-legislation

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Bioanalytics

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Bioanalytics

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Bioanalytics

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Quality Issues

One of the recurring allegations made in the latest letter is that tests purporting to cover stability analysis over a nine month period were actually carried out on the “ same day or within a few days of each other.”

http://www.in-pharmatechnologist.com/Processing/Ranbaxy-made-untrue-statement-in-filings-says-FDA

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Bioanalytics

ANVISA For bioequivalence studies laboratory

must be accredited by ANVISA

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Biologicals

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Biologicals

Complex proteins derived from unique cell lines and purification processes

May trigger immune reactions Conventional BE for follow-on products

inadequate Process includes pre-clinical and clinical

studies

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Bioanalytical Comparisons

EMA Guidance “extensive state-of-the art characterization

studies need to be applied to the biosimilar and reference medicinal product (originator) in parallel, to demonstrate with a high level of assurance that the quality of the biosimilar is comparable to the reference medicinal product”

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Biological in Brazil

http://cphi-online.com/News/Show/19661/ANVISA_Approves_First_Infliximab_Biosimilar_in_Brazil?cid=digital_conews_week22#.VXQQ3-9FB9A

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ABPI - Biosimilars

Published 050213 http://www.abpi.org.uk/our-work/library/industry/Pages/biosimilars-position-paper.aspx

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ABPI - Biosimilars

Prescribe by brand name not by INN Facilitate identification and traceability for PV

No substitution without consent of physician Automatic substitution of one biological medicine

for another makes post-marketing surveillance more difficult

Patients must be informed and consulted Make a fully-informed decision on any switches

Published 050213 http://www.abpi.org.uk/our-work/library/industry/Pages/biosimilars-position-paper.aspx

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Conclusions

Differing levels of resources and commitment to regulatory procedures Production Testing of comparability

Fundamental to acceptance of generics Confidence in the Regulator Adherence to accepted quality standards Consistency of production Ongoing clinical assessment

Move away from One approach fits all

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Contact Details

David W Holt BSc, PhD, DSc (Med), CSci, EuSpLM, FESC, FBPhS, FRCPath

Emeritus Professor of Bioanalytics

Analytical Services International Ltd @

St George’s - University of London London SW17 0RE

UK

[email protected]

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Slides

URL http://www.bioanalytics.co.uk/BE_Brasilia_0615.html