What is the role of generics in the

treatment of viral hepatitis and other

dieases?

Dr Andrew Hill

Department of Pharmacology and Therapeutics

University of Liverpool

United Kingdom

Pharmacology Workshop, Turin, Italy

January 19th 2017

The UK National Health Service is

refusing patients treatment, because

of high prices

PrEP – TDF/FTC £4800 per year

HCV DAAs £30,000 to £100,000 per cure

Cancer Drugs Fund Shut down – prices too high

Global Burden of Disease report, Lancet 2014, 385: 117-171

Death

s p

er

year

(thousands)

Worldwide deaths from HBV, HCV, HIV,

tuberculosis and malaria in 2013

Africa, 1999: mass treatment for HIV/AIDS is not feasible

4

A key moment in the history of HIV

“My generics company

can manufacture

HIV antiretrovirals

for a dollar per day”

Dr Yussef Hamied

Cipla, G8 summit, 2000

Ref: http://fireintheblood.com/ 5

How cheaply can

medicines be

produced?

6

ActivePharmaceuticalIngredient

Raw drug substanceDatabase www.indiainfodrive.com shows exports of API from India to other countries, with costs per kilogram of API, for many drugs

7

Cost/kg of sofosbuvir API exports Jan 2015 to Jul 2016, weighted by size of shipment

Gotham D, Barber M, Fortunak J, Pozniak A, Hill A.

Abstract number A-792-0516-01639, presented at AIDS2016, Durban.

From API cost/kg to target price

API price/kg x grams per treatment course

+ $0.04 / tablet for excipients and tableting,

+ $0.35/month for formulation

x 10-50% profit margin

(10% for mass-produced drugs e.g. HIV, TB)

9Gotham D, Barber M, Fortunak J, Pozniak A, Hill A.

Abstract number A-792-0516-01639, presented at AIDS2016, Durban.

Target generic price of sofosbuvir

(12 weeks)

Gotham D, Barber M, Fortunak J, Pozniak A, Hill A.

Abstract number A-792-0516-01639, presented at AIDS2016, Durban.

50

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13

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08

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35

€

28

8 €

55

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30.000 €

45.000 €

60.000 €

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Sofosbuvir (Sovaldi)

German price: €50,426

Cost price: €55

Sofosbuvir prices:1. Canada (Quebec): http://www.ramq.gouv.qc.ca/SiteCollectionDocuments/liste_med/liste_med_2016_10_03_fr.pdf2. France: http://www.medecinsdumonde.org/actualites/presse/2016/09/29/mdm-soppose-au-brevet-sur-le-sovaldir-decision-le-5-octobre-2016

3. Germany: medizinfuchs.de4. Spain: http://politica.elpais.com/politica/2016/04/05/actualidad/1459873421_480033.html?id_externo_rsoc=TW_CC6. UK: British National Formulary 20167. Brazil: http://www.portaltransparencia.gov.br/despesasdiarias/empenho?documento=250005000012015NE8014938. Australia: Based on total annual government expenditure (AU$200 million) and 40,000 treated in 20169. India: http://hepcasia.com/wp-content/uploads/2016/03/31-Jan-2016-Indian-generic-sofosbuvir.pdf

Price of sofosbuvir by country (12 weeks)

Drug Current US price

(lowest)

Current lowest

Indian market

price

Target price

Sofosbuvir $49,680 $324 $62

Daclatasvir $50,653 $153 $14

SOF+LDV $56,700 $507 $96

SOF+VEL $74,760 - $181-216

HCV DAAs: Prices in USA and India versus Target

Gotham D, Barber M, Fortunak J, Pozniak A, Hill A. Rapidly falling costs for new hepatitis C direct-acting antivirals (DAAs): potential for universal access. Abstract number A-792-0516-01639, presented at AIDS2016, Durban.

Entecavir for Hepatitis Bone year’s supply (0.2g)

Entecavir for Hepatitis B

cost per person/year by country

Entecavir (Baraclude)

US price: $15,111

Cost price: $36

Published in: Hill et al. Journal of Virus Eradication 2015.

HIV: ARV Patent Expiry dates: 2016-2029

10 years (2016-2026) when many drugs are available as individual generics, but co-formulated versions are still on patent

2015: ZDV, 3TC, NVP, EFV, RTV – already generic

2016: ABC/3TC, LPV/r

2017: TDF/3TC, FTC

2018: ATV/r

2019: ETR, DRV/r

2025: Raltegravir

2026: TDF/FTC/EFV (Atripla), TDF/FTC/RPV (Complera),

2029: ABC/3TC/DTG (Triumeq), TAF/FTC/ELV/c

Medecins Sans Frontieres 2016: Untangling the web of ARV price reductions

How much could HIV drugs cost in USA and Europe?_____________________________________________________________________________

Price/year US list NHS List Minimum Patent expiry

US $ DHHS 2016 BNF 2016 generic prices date (UK)

_____________________________________________________________________________

ABC/3TC $18,600 $4664 $161 Dec 2016

TDF/3TC $21,120 $5553 $67 July 2017

TDF/FTC/EFV $34,428 $8314 $110 Dec 2017

Efavirenz $12,120 $1606 $38 Generic

Nevirapine $7,776 $1825 $28 Generic

Rilpivirine $12,900 $3120 $40 2021

Lopinavir/r $13,272 $4446 $243 Dec 2016

Atazanavir/r $19,872 $4726 $219 2018

Darunavir/r $19,584 $4648 $658 2019

Dolutegravir $20,484 $7768 $44 2027

_____________________________________________________________________________

Conversion rate = $1.3 to £1.

Ref: Hill and Pozniak. How can we achieve universal access to low-cost treatment for HIV? J Virus Eradication Oct. 2016

Target versus Global lowest prices:

HIV, TB and Hepatitis

Mass produced HCV DAAs should fall

to <$90 per 12-week course

The new “$90 $90 $90” in 2017

There should be standard prices to treat HIV, Hep B/C and TB

< $90 per year to treat HIV: TDF/3TC/EFV

< $90 per year to treat Hepatitis B: TDF/3TC or ETV

< $90 for first-line treatment for TB

< $90 for 12-weeks course of HCV DAAs: SOF/DCV

TDF/3TC, efavirenz, entecavir and most TB drugs will be generic worldwide in 2017. Prices should then fall in all countries, close to Indian / South African levels.

<$90 price to cure Hepatitis C will only be in low and middle income countries

$ 106.322

$ 35.216 $ 34.482 $ 31.867$ 28.675

$ 20.877

$ 8.370 $ 8.192

$ 790 $ 180$ 0

$ 20.000

$ 40.000

$ 60.000

$ 80.000

$ 100.000

$ 120.000

Pri

ce p

er

year

(U

SD)

Lowest available price for Imatinib (400mg) in selected countries

Imatinib (Gleevec)

US price: $106,322

Cost price: $180

Hill et al: Target prices for mass production of Tyrosine Kinase Inhibitors:

http://bmjopen.bmj.com/content/6/1/e009586.full

CancerDrugs Indication Target price per

treatmentLowest Indian(other) price

CurrentUS price

Imatinib Chronic Myeloid Leukaemia

$172 $803 $107,799

Erlotinib Non-Small Cell Lung Cancer

$240 $1932 $79,891

Sorafenib Renal Cell Carcinoma

$1450 $1332 $139,138

Lapatinib Breast Cancer $4020 $18,603 (Thailand) $75,161

Cabazitaxel Metastatic prostate cancer

$666 $30,810 (South Africa) $120,613

Dasatinib Chronic Myeloid Leukaemia

$15 $1183 (Brazil) $10,408

Pazopanib Renal Cell Carcinoma

$116 $1463 (Brazil) $8412

Abiraterone Metastatic prostate cancer

$3589 $27,570 (Thailand) $85,877

Gefitinib Non-Small Cell Lung Cancer

$16 $139 $6728

Capecitabine Metastatic Colorectal Cancer

$73 $126 (Latvia) $1941

Widespread access to generics

When patents have expired, drugs should be available worldwide, at close to the cost of production

However, few national health services know these costs

There is widespread over-charging. Pricing transparency is needed (WHO panel)

Lower costs for generics could drive down patented drug prices in the same therapeutic area

£0,21

£2,61

£0,00

£0,50

£1,00

£1,50

£2,00

£2,50

£3,00

Pri

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t (£

)

Date

Price of Busulfan 2mg tablets (GSK to Myleran) 2011-16

Indian Price 2016: £0.03

x

£0,55

£1,82

£0,00

£0,20

£0,40

£0,60

£0,80

£1,00

£1,20

£1,40

£1,60

£1,80

£2,00

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)

Date

Price of Melphalan (Alliance/Aspen) 2mg tablets 2011-16

Indian Price 2016: £0.08

x

Overcharging the

UK NHS for generics

Generic companies raising prices

Price increases >1000% add £260

million to NHS drug costs each year

Price increases >40% add £380

million to NHS drug costs each year

Parliament announced Health

Service Medical Supplies (Costs)

Bill in September 2016

Community prescriptions in England

only – real costs likely to be far

higher

Sources: The Times, 3rd June 2016. Houghton-Price V, Smith R, Hill A & Heath K, Rises in NHS drug prices, Oct 2016. Parliament

UK, Public Bills before Parliament, Health Service Medical Supplies (Costs) Bill (HC Bill 72), 14th Sep 2016.

Value of patented drugs before

generics have been approved

$0

$1.000

$2.000

$3.000

$4.000

$5.000

$6.000

$7.000

1 2 3 4

$1000

TDF/FTC TAF/FTC

Pharmaceutical companynegotiates additional value of new drug versus price of current branded version

For example: Tenofovir alafenamide (TAF) versus Tenofovr disoproxilfumarate (TDF)

Mayer K et al. Clin Infect. Dis 2016, 62: 915-918

Value of patented drugs after generics

have been approved

$0

$1.000

$2.000

$3.000

$4.000

$5.000

$6.000

$7.000

1 2 3 4

+ $1000

TDF/FTC TAF/FTC Generic TAF/FTC

TDF/3TC

$1000

In 2017, after approval of low-

cost generic TDF/3TC, the

price of TAF/FTC has to fall, to

remain cost-effective versus

generic alternative

Could pharmaceutical

companies lower their

prices, but then treat

more people?

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Sofosbuvir prices:1. Canada (Quebec): http://www.ramq.gouv.qc.ca/SiteCollectionDocuments/liste_med/liste_med_2016_10_03_fr.pdf2. France: http://www.medecinsdumonde.org/actualites/presse/2016/09/29/mdm-soppose-au-brevet-sur-le-sovaldir-decision-le-5-octobre-2016

3. Germany: medizinfuchs.de4. Spain: http://politica.elpais.com/politica/2016/04/05/actualidad/1459873421_480033.html?id_externo_rsoc=TW_CC6. UK: British National Formulary 20167. Brazil: http://www.portaltransparencia.gov.br/despesasdiarias/empenho?documento=250005000012015NE8014938. Australia: Based on total annual government expenditure (AU$200 million) and 40,000 treated in 20169. India: http://hepcasia.com/wp-content/uploads/2016/03/31-Jan-2016-Indian-generic-sofosbuvir.pdf

Price of sofosbuvir by country (12 weeks)

The Australian “All you can Treat”

contract for Hepatitis C

Contract for $1 billion Australian dollars, over 5 years, with a group of pharmaceutical companies.

For €138 million/ year, unlimited treatment numbers

In 2016, 40,000 people will be treated (20% of epidemic)

Unit cost per DAA treatment = €3,450 / person

If this price is acceptable in Australia, we should have access to DAAs at the same prices in Europe, to acheiveelimination of Hepatitis C across our region.

Adapted from “The New HCV treatment Era in Australia: Early Lessons”

Presented at: http://www.hepatitis.org.au/ehome/viralhepatitis2016/411320/

If drug prices were lower,

could pharmaceutical

companies

still afford

to do R&D?

31

Gilead sales and profits

Cumulative sales of Sovaldi & Harvoni to

3Q 2016:

$40 billion

Profits in 2015:

$18 billion

Reference: Gilead quarterly product sales summaries

Gilead: $10 billion in tax avoidance

33

Washington Post, July 13 2016. Gilead is using Ireland as

a tax haven for global profits.

“The drug company that shocked the world

with its prices dodged $10 billion in taxes”

$10 billion is enough

money to treat 100 million

people with HCV, at the

cost price of $100 each

https://www.washingtonpost.com/news/wonk/wp/2016/07/13/maker-of-84000-drug-avoided-10-billion-in-u-s-taxes-report-says/

Pharma profits and tax avoidanceMain tax havens: Bermuda, Cayman Islands, BVI, Bahamas, Luxembourg, Ireland

34

Company Profits held

offshore

US Taxes

Avoided

Pfizer $69 billion $20 billion

Merck $57 billion $16 billion

Johnson & Johnson $51 billion $14 billion

Amgen $26 billion $9 billion

Abbott $24 billion $7 billion

BMS $24 billion $7 billion

Source: Citizens for Tax Justice, 2016. http://gormanandjoneslaw.com/offshore-tax-havens/http://america.aljazeera.com/articles/2015/3/12/obama-gambit-for-corporate-cayman-cash.html

Options if drugs still patented -

Voluntary licenses

Some pharmaceutical companies allow cheap generics to be sold in certain low and middle income countries, with voluntary licenses. However:

1. China, South America, Russia and Eastern European countries are not included in most of these agreements. As a result, prices in these countries can be unaffordable

2. Other countries may have voluntary licenses but if the company does not register the drug for regulatory approval, then the drug cannot be accessed

3. Merck and AbbVie have no voluntary licenses for their Hepatitis C treatments.

Sofosbuvir voluntary license coverage

A new option for access to treatment:

HIV and Hepatitis C buyers clubs

There are many companies willing to export generic PrEPand DAAs into Europe and North America

Several generic ARVs are already approved by the US Food and Drug Administration and the World Health Organization.

Generic PrEP or DAAs can be bought online in 10 minutes. Prices are falling rapidly.

www.alldaychemist.com

www.iwantprepnow.co.uk

www.fixhepc.com

www.myhepc.info

Patented vs Generic drugs for HCV

Harvoni

€45,000Generic SOF/DCV

€900

Hepatitis C: https://www.youtube.com/watch?v=HBF5cf5zt9U

HIV: https://youtu.be/JXnaHYzyAq4

Routes of export: https://youtu.be/X1QSHkUAP50

The legal basis of personal importation

Article 60 of TRIPS - De Minimis Imports – states:

Members may exclude from the application of the above

provisions small quantities of goods of a non-commercial

nature contained in travellers' personal luggage or sent in

small consignments

In line with Article 60, most countries allow some

form of personal medication importation

Medicines are being sent from India, China, Egypt

and Bangladesh to countries all over the world

FixHepC Buyer’s Club

N = 438RVR: 85 %EOT: 99% SVR4: 89%[Poster 256 –HIV Glasgow 2016]

www.fixhepc.com

Hep C Treatment Without Borders

N = 151RVR: 74 %EOT: 93% SVR4: 96% SVR12: 96%

http://hepatitisctreatment.homestead.com/

42

South East Asia Buyer’s Club

N = 237RVR: 99%EOT: 99%SVR4: 100%SVR12: 92%[Poster 256 –HIV Glasgow 2016]

43

Russian Buyer’s Club

N = 213RVR: 85%EOT: 100%SVR4: 100%SVR12: 98%[Poster 261 –HIV Glasgow 2016]

$490 for

SOF/DCV,

12 weeks

InterPrEP: internet-based pre-exposure prophylaxis (PrEP) with generic TDF/FTC in London – analysis of pharmacokinetics, safety and outcomes

Nwokolo, Nneka1; Wang, Xinzhu3; Korologou-Linden, Roxanna3 ; Hill,

Andrew2 ; Whitlock, Gary2 ; Day-Weber, Isaac3 ; McClure, Myra3 ; Boffito, Marta2

Glasgow HIV Conference, Wednesday 26th October 2016, oral presentation

*Within www.Iwantprepnow.co.uk:

www.unitedpharmacies-uk.md n=131www.alldaychemist.com n=37www.Iwantprepnow.co.uk n=20www.aids-drugs-online.com n=3

**Other suppliers (1 person each):www.everydaypharmacy.co.ukwww.buylowdrugs.comwww.clearskypharmacy.bizwww.inhousepharmacy.vu

Dean Street Cohort: online suppliers of PreP

www.Iwantprepnow.co.uk n=191 (92%)

www.alldaypharmacy.co.ukn=13 (6%)

Other**n=4 (2%)

Dean Street Cohort:

Generic TDF/FTC tablets used (£40/month)

Cipla TENVIR-EM

n=181

Emcure TAVIN-EM, n=2 Mylan RICOVIR-EM, n=1

Conclusions - 1

In the next few months, we should see dramatic reductions in

HIV drug prices across Europe: ABC/3TC, TDF/3TC at least

90% cheaper. Fully generic combination treatments.

Generic TDF/FTC already costs only €500/year in UK – prices

should fall further. Eventually, under €90 per year.

People should be switched onto lower cost generic ARVs in

countries, where price of treatment is an issue.

Prices of branded ARVs should then be re-negotiated – their

high prices may no longer be justified.

Conclusions - 2

Elimination of disease is only affordable if drugs can be accessed at low prices, within national health budgets

We need new approaches to funding mass treatment programmes for Hepatitis C in Europe:

“All you can Treat” pricing – unlimited treatments for a fixed price

Or

Lower fixed prices. Under €4000 per cure for Hepatitis C.

Most drugs are fundamentally cheap to produce, so pharmaceutical companies can still make large profits from selling to larger numbers of people at lower unit prices.

Conclusions - 3

If pharmaceutical companies refuse to lower prices, we

need back-up mechanisms to ensure access:

• Compulsory licenses

• Buyers Clubs

• Windfall taxes on tax avoidance

Recovery of Gilead’s $10 billion in avoided tax alone would

provide sufficient funds to treat everyone with Hepatitis C

worldwide, at cost price.

Universal access to HIV treatment is one of the greatest success stories in medicine (>18 million treated).

This should not stand alone, but be repeated for mass treatment of cancer, viral hepatitis and other diseases– this time, more quickly 50

Thanks to:

St Stephens AIDS Trust

Anton Pozniak

Marta Boffito

Global Health

Melissa Barber

Dzintars Gotham

Vicky Houghton-Price

Jake Levi

Roxanna Korologou-Linden

Anna Savage

Bryony Simmons

Rachel Smith

Howard University, USA

Joe Fortunak

Hepatitis C and HIV Buyers Clubs:

HepC Treatment without borders: Greg Jeffreys

FixHepC James Freeman,

ITPC Russia: Sergey Golovin and Julia Dragunova

SE Asian Buyers Club

Giten Khwairakpan

IwantPrEPnow.co.uk

And all the people who took these generic DAAs and generic PrEP, especially in the early days