BACKGROUND AND PROSPECTS FOR THE FUTURE?

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1 BACKGROUND AND PROSPECTS FOR THE FUTURE? Superbugs & Superdrugs London 5 th -6 th March 2014 R. Bax TranScrip Partners LLP Richard.Bax@transcrip-partners.com

2 Contents 1. Background 2. Regulatory changes 3. Policy 4. What next? 5. Appendix

3 Antibiotic Market Global - $35 billion / 21 billion UK 325 million 1.5% of global market 2.4% of primary care 0.66% of overall global pharmaceutical market 2.36bn doses of antibiotics / year adjusted for population 63 million 36.5 / head (duration around 5-7 days)

4 Likelihood of Successful Antibiotics Antibiotics in Phase 1 25% will enter Phase 2 Antibiotics in Phase 2 50% will enter Phase 3 Those that complete Phase 3 75% will be marketed Around 25% chance of being marketed 20 compounds in R&D =? 4 will be successful? CRM April 2003

5 World Changes 2014 Technological Innovation Unpredictable economic times High levels of unemployment Acute skills shortage Agenda for sustainability and resilience Infrastructure problems Organisations needed Growth of global, international social and government enterprises

6 The Antibiotic Economy Economies underpinned by antibiotics Massive benefits to individual health and societies Survival, longevity, productivity, quality of life Modern medicine relies on antibiotics Dentistry, surgery, transplants Prevention and cures Access to effective antibacterials has shaped the last half-century Can it be quantified?

7 The benefits: from cradle to grave; HIV / AIDS related infection Tuberculosis Neonatal infection STDs: Chlamydia Gonorrhoea Cancers Cardiovascular Diarrhoea Mother/child child-birth sepsis Otitis media Tonsillitis Trauma: war, wound, accidents genetic based cystic fibrosis Animals: pets, food Surgery: emergency, elective Crops: food Prostheses COPD AECB Pneumonia

8 Unmet Medical Need Requiring Solutions New infections and emerging resistance in developed countries particularly in Gram negatives (ESBLs, CRE, Pseudomonas) Community-acquired resistant infections in all markets (DRSP, MRSA, ESBLs) New drugs for diseases that predominantly occur in developing countries (Resistant TB, drug-resistant typhoid fever)

9 WHO Priority Medicines for Europe and the World 2004 Preliminary Ranking of pharmaceutical gaps Infections due to bacterial resistance Pandemic influenza Cardiovascular disease (secondary prevention) Diabetes (type 1 and 2) Cancer (Preliminary list based on relative importance and potential for publicly funded research to have a major impact in reducing the burden of the disease) Priority Medicines for Europe and the World, Warren Kaplan and Richard Laing, World Health Organisation, Department of Essential Drugs and Medicines Policy, November (WHO/EDM/PAR/2004.7

10 A unique medical situation Antibacterials have enormous benefits Use can lead to loss of benefits New class agents can restore the benefits Lack of incentives and success Antibiotics are running out

11 UK 5 year Antimicrobial Resistance Strategy AMR huge public health issue Local, National, Global issue Emergence of MDR causing serious life threatening infections MDR Infections increasingly cannot be treated effectively R&D of new antibiotics is at an all time low Antibiotic stewardship and infection control required Rapid new diagnostics urgently required

12 AMR UK Slow the development and spread of AMR Improve the knowledge and understanding of AMR Conserve and steward the effectiveness of existing treatment Stimulate the development of new antibiotics, diagnostics and novel therapies

13 AMR UK Improve infection prevention and control practices Data and diagnostics Optimise prescribing practices Improve professional education, training and public engagement Develop new drugs, treatments and diagnostics Better surveillance data Better identification and priority for research needed Strengthen international collaboration

14 Key area 4: Developing new drugs, treatments & diagnostics Scientific difficulties of finding new agents Inadequate return on investment Duration of drug use is limited Concerns over the cost and complexity of the regulatory approval process Uncertainty about the regulatory environment Work to reform and harmonise regulatory regimes for licensing and approval of antibiotics especially clinical trial requirements

15 Key area 4 R&D of novel approaches: strengthen immune responses (pro probiotics). Naturally occurring bacteriophages Industry and academic collaboration Research councils, industry and academics should work together to establish a range of new mechanisms: consortia

16 The Pharmaceutical Industry has a corporate and social responsibility to contribute to work to tackle AMR by finding ways of extending the life of antibiotics, making the supply of effective antibiotics sustainable and facilitating society in being better custodians of these valuable resources.

17 MHRA expert group on innovation in 2013 Best use of existing regulatory flexibility Learn from developments abroad that support regulatory innovation Facilitate access to medicines of high unmet medical need a year before marketing authorisation

18 MHRA Continue to develop guidance to make clinical trials effective and help companies through the regulatory process. Support the development of a new business model for drug development and furthering international work.

19 Policy Domains - Pharma Policy Building Human Capital (labour & skills) Increasing Access to Investment Capital Scientific and technological innovation Taxation/subsidisation Demand side Offer scholarships and Fellowships, Public Private Partnerships Offer incentives for private investment in pharma/vc partnerships Reform university and public/private R&D systems Offer tax incentives. Low corporate tax Develop and reform regulations to reduce barriers, increase the speed and predictability of pricing and reimbursement. Facilitate public procurement of innovative goods and services

20 Tier process Rex et al, Lancet 2013

21 Proposed Labelling FDA 2013 Drug X is indicated in (approved patient population) for the treatment of A, B, C caused by the following susceptible pathogens (i.e.). Drug X has been approved for A, B, C where limited or no alternative therapies are available. The safety and effectiveness of Drug X has not been established beyond this patient population.

22 Proposed Labelling FDA 2013 This indication is based on (summarising the limitations of available data) If approved under LPAD and for one resistant organism Drug should only be used if other alternatives are known or suspected to be less suitable"

23 Expedited Programs for Serious Conditions FDA June 2013 FOR FAST TRACK DESIGNATION, BREAKTHROUGH THERAPY DESIGNATION AND PRIORITY REVIEW SERIOUS CONDITION: A disease associated with morbidity that has substantial impact on day-to-day functioning. Shortlived and self-limiting morbidity needs to be irreversible if it is persistent or recurrent.

24 FDA Antibacterial Therapies for patients with unmet medical need for the treatment of serious Bacterial Diseases July 2013 Guidance is NOT intended to establish a new approval pathway or standard for such drug products Development of new antibiotics has declined substantially coupled with increases in MDR resistance resulting in bacterial infections that do not respond to currently available drugs with serious consequences including increased mortality

25 FDA HABP, VABP, cuti, CAPB, ABSSSI and others Exploring approaches to streamline development programmes for unmet medical need. Contains non-binding recommendations

26 Impetus for revision and additional guidance - EU Core guidance revised To address issues that had arisen since the adoption of Rev 1 (Applications; CHMP SA) To state EU position due to new FDA requirements (endpoints; NI margins; selection criteria) Addendum developed To provide additional details on study designs for major indications (no details in core guidance) To provide options for clinical development of antibacterial agents to address unmet need

27 Important features of core guidance - EU If the PK/PD analyses are convincing it may be possible to completely omit clinical dose-finding studies For major standard indications a single pivotal study may be acceptable if it meets CHMP criteria Adult efficacy data in some indications can be extrapolated to children; focus in children on safety and PK Discuss trials in situations in which only very limited clinical data are possible, including rarely encountered MDR/XDR; further guidance given in Addendum

28 Addendum 4 Parts - EU Clinical development programme for antibacterial agents with potential to address unmet need; especially MDR pathogens when there are few therapeutic options Specific guidance covering the five major indications for which non-inferiority studies are acceptable Indications for which a superiority study is needed Indications for which study design may be problematic and/or requires some special considerations

29 Development specific for MDR pathogens - EU Eligibility criteria for accepting limited clinical development New drug in new class (new target) New drug of existing class with novel spectrum New or known drug of existing class coupled with new protective agent (beta-lactam/beta-lactamase inhibitor) Range of possible clinical programmes depending on Properties of the agent (e.g. limited or broader spectrum) Aims specific indication + unmet need or only a claim for use in circumstances of unmet need

30 Regulatory Challenges- EMA/FDA 2014 Public Health New and Emerging Science Increasing Globalisation New Model for Medicines Regulation Ensuring Patient Safety Transparency and Openness

31 HOW REGULATORS MEET THESE CHALLENGES - EU Public/Political consultation 5 year Roadmaps Annual reporting cycle: Work programs Annual reports

32 It s all about Benefit-Risk Safety Usual preclinical assessments Safety data from all trials to identify AEs in the % range Focus on situations where both potential benefit and tolerance of unexpected safety events are greater

33 But resistance is increasing However the rate of change and the magnitude of effect on spread, colonisation, infection and patient outcome is unknown R. Bax 2013

34 ignoring XXXX will eventually damage economic growth. Our actions over the coming decades could create risks of major disruption to economic and social activity later in this century and the next given that XXXX is happening, measures to help people adapt to it are essential. And the less mitigation we do now, the greater the difficulty of continuing to adapt in future.

35 ignoring XXXX will eventually damage economic growth. Our actions over the coming decades could create risks of major disruption to economic and social activity later in this century and the next given that XXXX is happening, measures to help people adapt to it are essential. And the less mitigation we do now, the greater the difficulty of continuing to adapt in future. STERN REVIEW: The Economics of Climate Change, 2006, UK

36 Sustainability? CARBON FUEL Societal need/benefits Running out Use impacts benefits Need for better use Use less Only when necessary Transportation (walking /cycling) Heating/lighting Manufacturing ANTIBIOTICS Societal need/benefits Running out Use impacts benefits Need for better use Use less Only when necessary Bacteria not viruses Diagnosis Not for self-limiting

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38 Many More Questions than Answers - 1 AB stewardship New marketing through scientific liaisons? Labelling should not detail the practice of medicine After labelling what are the post marketing commitments Who will police use?

39 Many More Questions than Answers - 2 Pricing and Cost Reimbursement Global availability Manufacture/Supply Off label use When to prescribe What pathogen where? Can rapid diagnostic help when? Does use on label mean it is appropriate?

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