Timo Minssen - Helex Presentation on Law & Antibiotics

- The legal ecology of resistance, or why normal IP rules
shouldn't apply to antibiotics –
– Recent EU/US Initiatives
Centre for Health, Law and Emerging Technologies
HeLEX
Seminar Room 1, Rosemary Rue Building,
Old Road Campus, Headington
25 April 2014- 2 pm
Prof. Dr. Timo Minssen, University of Copenhagen
Visiting Research Fellow,
Faculty of Law
University of Oxford

AGENDA
• Problem- facts & reasons
• Potential solutions
• Recent EU & US initiatives
• Recent EU initiatives
• A success story from Danmark?
• Transatlantic cooperation
• Conclusions & points for further discussion
Centre for Information & Innovation Law

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The problem I. (2009 EU study)
•More infections with multidrug-resistant bacteria vs. less R&D in new Abs
• Resistance high among Gram-positive & -negative bacteria
•Up to 25% or more in several EU Member States
• Increasing resistance among Gram-negative bacteria
(e.g. Escherichia coli)
• Ca. 25 000 EU patients per year die due to multidrug-resistant bacteria .
• Extra healthcare costs & productivity losses of at least EUR 1.5 bill. per
year.

The problem II. (2009 EU study)
• Only 15 AB-agents with new mechanism of action or directed against new
bacteria under R&D with potential to tackle multidrug resistance.
• Most in early phases of R&D and primarily developed against bacteria with
existing treatment options.
• Particular lack of new agents with new targets or mechanisms of action against
multi-drugresistant Gram-negative bacteria.
• Only 2 (!) such agents with new or possibly new targets and documented activity
were identified, both in early phases of development.
• A European and global strategy to address this gap is urgently needed.
Centre for Information &
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US Data- Centers for Disease Control and Prevention (CDC).
• Every year, more than two million people in the US get infections that are resistant
to antibiotics and at least 23,000 people die as a result.
• In addition to the illness and deaths caused by resistant bacteria, the report found
that C. difficile, a serious diarrheal infection usually associated with antibiotic use,
causes at least 250,000 hospitalizations and 14,000 deaths every year.
• The loss of effective antibiotic treatments will not only cripple the ability to fight
routine infectious diseases but will also undermine treatment of infectious
complications in patients with other diseases.
• Use of antibiotics is the single most important factor leading to antibiotic
resistance around the world. Antibiotics are among the most commonly
prescribed drugs used in human medicine. However, up to half of antibiotic use in
humans and much of antibiotic use in animals is unnecessary or inappropriate.
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2013 EU data on AMR
 (EU Commission Survey)
• 35% of respondents took antibiotics in the past year, a 5% decrease since the 2009 survey.
• 2% fewer people took antibiotics for the flu in 2013 compared with 2009 (18% vs. 20%).
• In 2013 more people aware that antibiotics do not kill viruses than in 2009 – 40% vs. 36%.
 (ECDC data)
• Increasing resistance to carbapenems, a last-line class of antibiotics
- ex: - resistant Acinetobacter baumannii (CRAb)
• CRAb show very large variations. Generally higher resistance percentages reported in
southern Europe and lower percentages in the north of Europe.
• Infections with these multidrug-resistant bacteria are almost impossible to treat.

US Numbers 2011-2013
Figure 1 Number of New Molecular AB Entities Approved by the FDA per 5 year period through March 2011.
Source: Infectious Diseases Society of America (IDSA), Spellberg B, Blaser M, et al: Combating antimicrobial resistance:
policy recommendations to save lives. Clin Infect Dis 2011, 52(5):S397–428 (Oxford University Press).
• total annual cost of antibiotic resistance ca. US $26 billion
• direct mortality from AB resistance infections : 23,000 deaths annually

New Developments
• Washington Post, Summer 2016:
The superbug that doctors have been dreading just reached the U.S.
• September 2016: UN meeting tackles the 'fundamental threat' of antibiotic-resistant
superbugs
All 193 UN member states have agreed to combat the proliferation of drug-resistant infections,
estimated to kill more than 700,000 people each year.
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Multiple reasons for these problems I
• Inappropriate use
• Insufficent precautions and lack of education
• Additional external factors/climate change/travel behaviour
• Insufficient funding of research & collaboration vs. scientific
complexities
• Traditional pharma innovation
system/incentives/business model fails
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Why does the traditional pharma innovation model fail?
(P1) Low re-embursement (!) and prescriped for rather short periods
(P2) Most effective ABs today generic or combinations thereof
hard for new products to gain ground (low fruits picked)
(P3) Consumption intentionally kept low for fear of AMR
(P4) Neverthess resistance is futile
(P5) High cost & efforts to find new ABs, particularly vs. Gram negative
(P6) Particularly complex clinical trials and unpredictable market

Multiple strategies to tackle the problems
- Pro-actions: Conservation & Prevention
1. Appropriate use
2. Prevention of drug resistant infections
3. Public awareness
- Re-actions : Push and Pull incentives/mechanisms
1. More R&D in antibiotics
2. Legal & regulatory responses
- Both global & local (glocal) responses necessary
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US Centers for Disease Control and Prevention (CDC)
• Four core actions that must be taken:
• 1.Preventing Infections, Preventing the Spread of Resistance: Avoiding infections in the first place reduces
the amount of antibiotics that have to be used and reduces the likelihood that resistance will develop
during therapy;
• 2.Tracking: CDC gathers data on antibiotic-resistant infections, causes of infections and whether there are
particular reasons (risk factors) that caused some people to get a resistant infection;
• 3.Improving Antibiotic Use/Stewardship: Perhaps the single most important action needed to greatly
slow the development and spread of antibiotic-resistant infections is to change the way antibiotics are
used;
• 4.Development of Drugs and Diagnostic Tests: Because antibiotic resistance occurs as part of a natural
process in which bacteria evolve, we will always need new antibiotics to keep up with resistant bacteria as
well as new diagnostic tests to track the development of resistance.
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Recent EU Initiatives
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EU Commission in AMR Action Plan 2011
• Call for
• ‘unprecedented collaborate research and development efforts to bring
new antibiotics to patients’
•
• by, among other things, launching an IMI programme
• ‘for research on new antibiotics aimed at improving the efficiency of
research and development of new antibiotics through unprecedented
open sharing of knowledge’.
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June 2012: EU Innovative Medicine’s Initiative (IMI)
•PPP between EU & European Federation of
Pharmaceutical Industries & Associations (EFPIA)
•each donate €1 billion ($1,23 billion) to stimulate health
innovation.
•IMI has initially dedicated €224 million ($275 million) to
AB initiative: NewDrugs4BadBugs.
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NewDrugs4BadBugs (ND4BB)
• total of €600 million ($738 million) expected to be spent up to 2020.
• ND4BB participants:
GlaxoSmithKline (GSK), AstraZeneca, Johnson & Johnson, Sanofi , and Basilea
etc.
• 2 initial Subprojects:
• COMBACTE:
– improving the efficiency of clinical trials on new antibiotics through better
laboratory tests and better trial design.
• TRANSLOCATION:
- Creation of info and data center, training & networks for researchers,
facilitating and increasing the exchange of research data.
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COMBACTE
• high quality, pan-European clinical trial network (COMBACTE CLIN-Net)
• a pan-European laboratory network (COMBACTE LAB-Net)
• 1st
antibiotic to undergo clinical trials under COMBACTE is GSK1322322.
(inhibiting bacterial enzyme relating to multi-drug resistant respiratory and skin
pathogens such as methicillin-resistant Staphylococcus aureus (MRSA)).
• 2nd
compound to be tested will be MEDI4893.
(designed to prevent S. aureus disease by neutralising a specific toxin produced by the
bug which results in much tissue and organ damage).
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TRANSLOCATION
• Discover important new information to improve selection and
optimization of promising molecules in antibiotic drug discovery.
• increase overall understanding of how to get antibiotics into multi-
resistant Gram-negative bacteria such as E-coli & Klebsiella pneumoniae.
• create an information centre for pre-existing and on-going antibacterial
research data.
• develop guidelines for designing and developing new drugs to tackle AMR.
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EU Commissions Strategy AMR 2013 Roadmap
A. Appropriate use of antimicrobials
B. Prevent microbial infections and their spread
C. Develop new effective antimicrobials or alternatives for treatment
D. Global collaboration against AMR spreading from trade, travel & via environment
E. Monitoring and surveillance
F. Additional Research and Innovation
G. Communication, education and training
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EU Commission Memo Nov. 2013
• Six fold increase in the amount being invested, from some €84 million during the EU's 1998-2002 research
programme to about €522 million for the 2007-13 period.
•
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Other important agencies on the European scene
• The European Centre for Disease Prevention and Control (ECDC).
http://ecdc.europa.eu/en/healthtopics/antimicrobial_resistance/Pages/index.aspx
• The European Medicines Agency (EMA)
http://www.ema.europa.eu/ema/index.jsp?
curl=pages/special_topics/general/general_content_000439.jsp
-cf. 2013 addendum to the 2012 guidelines on the evaluation of medicinal products
indicated for treatment of bacterial infections
- similarities to US GAIN Act and ADAPT BILL
• The European Food Safety Authority (EFSA)
• National authorities

http://www.ecdc.europa.eu/en/eaad/Pages/Home.aspx
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National initiatives: Get pigs off antibiotics
28 JUNE 2012 | VOL 486 | NATURE | 465
Frank Aarestrup explains how he helped Denmark to cut the use of antibiotics in its livestock by 60%, and calls
on the rest of the world to follow suit.

Bacon Boost (with less antibiotics)
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Reasons for the (initial) Danish successes
• Good and early data indicating problems.
• Political will to enforce regulations.
• Cross sector collaboration between farmers, researchers & authorities.
• Ban of antibiotics & efficient surveillance tracking (“DANMAP” -covering
resistance and usage).
• No profit incentives for veterinaries from selling/prescribing antibiotics.
• Good communication science/society, incl. open debates with industry
• No economic growth problems for chicken and pics (to the opposite) due to mart
and highly efficient farming techniques
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International cooperation I.
• EU Commission, ECDC, EMA, EFSA and national authorities involved in international
cooperation to address AMR.
• 2009 Collaboration with US via the trans-Atlantic taskforce on AM resistance (TATFAR)-
• Objectives : mutual activities and programs relevant to AMR to promote information
exchange, coordination and co-operation.
• 3 key areas (2011 report)
1. Monitoring and encouraging appropriate use of antibiotics in the medical and
veterinary communities
2. Prevention of drug resistant infections
3. Developing strategies to enhance the antibiotic Pipeline
• A TATFAR progress report will be published in 2014.

But new problems have emerged
• Poor results: Giving up on resistant bacteria in
Danish pigs
• http://www.ir-d.dk/2016/09/poor-results-
giving-up-on-resistant-bacteria-in-danish-pigs/
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International cooperation II.
• Commission collaborates also with international organizations
• On-going dialogue between Commission, China & Russia.
• Commission also strongly supports work of WHO.
• WHO Expert Committee:
• “free market competition best mechanism to achieve affordable new products,
but should be accompanied by a delinking of R&D costs and drug price”
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Selected US Initiatives
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GAIN Act in the US (July 9th
2012)
•Extends the exclusivity for new antibiotics
•Speeds development and review of new antibiotics
•Requires additional and/or updated clinical trial guidance
•Requires listing of pathogens posing threat to public health

Progress (Oct. 2013)
• At least 16 antibiotics as qualified under GAIN
• Most are in early R&D sages and may not be approved.
• 2 companies submitted market-appl. for GAIN products in late 2013.
• GAIN implementation is ongoing. FDA has:
• Created AB Drug Development Task Force to develop guidance.
• Released draft list of pathogens posing serious threats
• Drafted preliminary guidance for companies developing Abs
• Reviewed & updated several antibacterial drug development guidelines.

What’s next?
• GAIN important (pull) incentive for moving antibiotics from labs to patients
• BUT: New regulatory approval pathway for limited-population AB drugs needed
• Pull incentives not always sufficient
• 3 main areas in which development incentives can be improved:
■ “Push” incentives, such as R&D tax credits
■ Reforms to streamline and make MA proc. more predictable
■ Reimbursement and pricing reform
• More needs to be done to incentivize antibiotic development.
• Conservation, sustainability and prevention targets?
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US ADAPT Bill. December 12th 2013 –
(cf. EMA adaptive licensing debate & 2013 addendum to the antibacterial guidance)
1.New accelerated pathway: AB drug developer may request FDA to approve drug “to treat a
limited population of patients for which there is an unmet medical need.”
2.FDA “may rely on tradition. endpoints, alt. endpoints, or combination of tradition. & altern.
endpoints; datasets of limited size; pharmacologic or pathophysiologic data; data from phase 2
clinical studies; & other confirmatory evidence as [Agency] deems necessary.”
3.Improved monitoring & data access: FDA required to use appropriate systems to monitor the
use of antibacterial and antifungal drugs , and to monitor changes in bacterial and fungal
resistance to drugs. NB: Data made public.
4.Regular updates on break points: FDA required to “identify upon approval and subsequently
update susceptibility test interpretive criteria (“breakpoints”) for AB drugs ¨, including qualified
infectious disease products.”
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(Interim) Conclusions
• Many EU/US initiatives starting to take effect
• EU Commission: much focus on push mechanism, research & awareness
• Pull mechanisms embedded in new EMA guidelines
• Gain bill (pull incentive) hudge improvement for US
• Important transatlantic co-operation
• ADAPT bill important next step
• Q: But which solutions are truly sustainable? Pros & Cons of different
approaches?

How to proceed from here? Pros/Cons?
• Antibiotic conservation: Infection control, monitoring and rational use?
• Reducing drug development costs by more efficient clinical trial regime?
• Push incentives:
- Governmental funding of R&D & tax incentives
• Pull incentives for new drug development
- Patent term extensions other IP exclusivities
- Prizes & patent buy outs
- Orphan drug act mechanisms (pull & push)
• What about integrated approaches?
– Value-based reimbursement & conservation-based market exclusivity
Cf. Kesselheim & Outterson, Fighting Antibiotic Resistance: Marrying New Financial
Incentives to Meeting Public Health Goals, Health Affairs 29:9, 1689 (2010).

Antibiotic delinkage?
• E.g. prizes, patent buy-outs and governmental licensing agreements
• Outterson, New Business Models for Sustainable Antibiotics, February
2014, Chatham House, Working Groups on Antimicrobial Resistance |
Paper 1, available at:
http://www.chathamhouse.org/sites/default/files/public/Research/Global
%20Health/0214SustainableAntibiotics.pdf
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User-generated, open activities
• BioStrike: Open Antibiotics Discovery
• See:
http://brmlab.cz/project/biolab/biostrike
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Further Questions
• What approach for least developed countries?
• What approach for developing countries?
• Curtailed, integrated solutions?
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Questions or Comments?
Thank for your attention !
•E-mail: Timo.Minssen@jur.ku.dk
•Web: www.ciir
•Training for Professionals: CPH Summer School in Pharma Law & Policy:
http://copenhagensummeruniversity.ku.dk/en/courses/pharmalawpolicy
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Additional slides
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New EMA Guidelines (Addendum Nov. 2013)
• Recommendations for design of clinical studies intended for antibiotics.
• Specifies conditions for primary assessment of efficacy.
• With few exceptions not required that primary assessment of efficacy should be confined to patients with a confirmed
pathogen relevant to the type of infection under study.
• Detailed guidance is provided for studies in five types of infection in which it is accepted that indications for use can be
supported by a demonstration of non-inferiority of the test agent to an appropriate comparative regimen.
• In indications for which a demonstration of superiority over placebo or an active comparative regimen could be required
some suggestions are made for exploring appropriate patient populations and endpoints in the light of the current lack of
data to support definitive recommendations for study design.
• For acute otitis media recognition is given to accepting evidence of efficacy from non-inferiority studies subject to
restriction of the study population and conduct of appropriate analyses.
• Limited evidence of clinical safety and efficacy could be accepted to support an initial approval for the treatment of
infections caused by MDR organisms for which there are few therapeutic options.
• Limited guidance is provided regarding the clinical assessment of treatment modalities intended to exert a local
antibacterial effect as a result of direct administration to the site of infection.
• Finally, consideration is given to the assessment of efficacy to support use of an antibacterial agent for treatment of some
other types of infections.
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