Date post: | 16-Aug-2015 |
Category: |
Documents |
Upload: | josep-m-badenas |
View: | 131 times |
Download: | 2 times |
Facts and Trends in Clinical Development 2013
Josep M. BadenasSenior Medical Director, Neuroscience
CovanceCell: +34 629 52 73 84
Máster Universitario en Liderazgo y Gestión de la Ciencia y la Innovación / Màster Universitari en Lideratge i Gestió de la Ciència i la Innovació / Management and Leadership in Science and Innovation
Universitat Pompeu FabraBarcelona, Spain27 April 2013
2
Investment
• Invested almost $50 billion in 2011 in discovering and developing new medicines, representing the majority of all biopharmaceutical research and development (R&D) spending in the U.S.
Pharmaceutical Research and Manufacturers of America, PhRMA Annual Membership Survey (Washington, D.C.: PhRMA, 2012)
3
Need for continued development of new treatments• Direct costs to all payers of
caring for those with Alzheimer’s disease, including out-of-pocket costs to patients and their families, is estimated to increase five-fold, from $172 billion in 2010 to $1.1 trillion in 2050, unless new treatments are found that delay its onset or slow its progression. Alzheimer’s Association, “2012 Alzheimer’s Disease Facts and Figures” (2012)
4
DISCOVERY
Toxicology and Safety Pharmacology
Biomarkers/Genomics
DEVELOPMENT COMMERCIALIZATION
PHASE IVRESEARCH PRE-CLINICAL PHASE I PHASE II PHASE III
Clinical Pharmacology
Clinical Development
Market Access
Central Laboratories
Drug development at Covance
Bioanalytical Small & Large Molecule, Biopharmaceutical, Drug Metabolism & Pharmacokinetics,Immunology & Vaccines; CMC Pharmaceutical Development Services, Environmental Sciences
Antibody Products &Research Models
Discovery Pathology, Discovery Toxicology, In Vivo Pharmacology
5
The drug discovery and development process
• Long and complex, risk of failure at each step• Average cost to yield a single FDA-approved drug is
approximately $1.2 billion (including the cost of development failures) (*)
• Entire research and development and FDA approval process time: 10 and 15 years (**)
* In 2005 dollars, when capitalized using an 11.5% discount rate, and including the cost of development failures. J.A. DiMasi and H.G. Grabowski, “The Cost of Biopharmaceutical R&D: Is Biotech Different?” Managerial & Decision Economics (2007) 28:469–479.
** Dickson and J.P. Gagnon, “Key Factors in the Rising Cost of New Drug Discovery and Development, ”Nature Reviews Drug Discovery 3 (May 2004): 417–429; J.A. DiMasi, R.W. Hansen, and H.G. Grabowski, “The Price of Innovation: New Estimates of Drug Development Costs,” Journal of Health Economics 22 (2003): 151–185.
6
Probability of success model
Source: Jim Grace, Ph.D., Lilly Research Labs
Cost per NME has grown exponentially over the past 60 years• Costs per NME have been growing at an annual rate of 13.4%
for 5 decades.• An update by DiMassi 2000 estimate yields $3.9 billion• Only 27% of companies have NME costs smaller than $1 bn• All big pharmas have NME costs greater than $4 bn• PhRMA members’ R&D budgets have only grown at an annual
rate of 12.3%• Drug companies are getting more efficient, but less productive
Source: Rodney Zemmel, PhD., McKinsey & Company, Bernstein Pharmaceuticals Longview Conference, May 5, 2010
The cost of clinical trials
The total cost can reach $300−600 million to implement, conduct, and monitor a large, multicenter trial to completion.
Source: Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Series http://www.nap.edu/catalog/12900.html
Success rates 2006 Are we doing better?
9
Quick win, fast fail drug development paradigm
Translational Medicine
Growth in talk of "New Pharmaceutical Research Paradigms" inversely correlated with NME approvals
12
Annual and cumulative new drug approvals by the FDA’s CDER, including both NMEs and BLAs
Innovation in the Biopharmaceutical Pipeline: A Multidimensional View. Long G, Works J. Analysis Group, Inc., Boston, Massachusetts, January 2013
Exponential growth in inputs with no numerical increase in outputs
Source: Rodney Zemmel, PhD., McKinsey & Company, Bernstein Pharmaceuticals Longview Conference, May 5, 2010
R&D productivity has stagnated despite technological advances
We produce no more new drugs than 50 years ago.Over 4300 companies engaged in drug innovation
Only 261 (6%) have ever registered a drug with FDA.Only 30 (11%) have existed for the entire 60 years.89% have failed, merged, or were created by M&A.
The fact that 30 companies have existed for the entire period shows sustainability is possible but hard.The fact that 23 (out of 30) are small firms suggests there are ways to thrive despite small size.
Source: Rodney Zemmel, PhD., McKinsey & Company, Bernstein Pharmaceuticals Longview Conference, May 5, 2010
Life cycle of small molecule drugs versus biologics
• Slower rate of decay with biologics
• Average sales levels of biologics has surpassed average sales of small molecule drugs.
• Assumption: biologics will start to face generic competition downstream of 2015
R&D productivity
• Merck, Eli Lilly, and Roche have the best 60-year track records
• Have produced innovation at constant rates for 60 years: slightly short of 1 NME/year (industry average is 1 NME every 6 years)
• Nothing drug firms have done in the last 60 years has changed these dynamics
• Probability of producing 2 to 3 NMEs per year: 0.06% - 0.003%
Pharma still a source of value creation
18
Innovation - Pipeline
• Total numbers of medicines in development, by therapeutic area
PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients Analysis Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013
19
Innovation - Pipeline• Potential first-in-class medicines introduce a new
mechanism of action or pharmacological class for attacking a given disease or condition.
PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients Analysis Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013
20
Innovation - Pipeline
Innovation in the Biopharmaceutical Pipeline: A Multidimensional View. Long G, Works J. Analysis Group, Inc., Boston, Massachusetts, January 2013
21
Innovation - Pipeline• Medicines targeting rare orphan diseases affecting 200,000
or fewer patients in the U.S.
PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients Analysis Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013
22
Innovation - Pipeline
• Medicines targeting rare orphan diseases affecting 200,000 or fewer patients in the U.S.
Innovation – Pipeline
Orphan Medicinal Products - Europe• Objective criteria for designation based on the prevalence of
the condition for which diagnosis, prevention or treatment is sought:– Prevalence Threshold: not more than 5 affected persons per 10,000– Medicinal products intended for a life-threatening, seriously
debilitating or serious and chronic condition should be eligible even when the prevalence is higher than 5 per 10,000
REGULATION (EC) No 141/2000 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 1999 on orphan medicinal products
24
Innovation - Pipeline• Medicines targeting diseases for which there have been no
recently approved therapies
PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients Analysis Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013
25
Innovation - Pipeline
• Medicines that incorporate a personalized medicine approach, tailored to specific subpopulations of patients based on molecular or genetic characteristics.
PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients Analysis Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013
26
Innovation - Pipeline
Personalized medicines are a growing proportion of the pipeline
27
Innovation - Pipeline• Medicines that are among the first to apply new scientific strategies to
address disease and that may hold promise in enabling other future therapies previously impossible with existing technologies (e.g., gene therapy, therapeutic vaccines for cancer).
PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients Analysis Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013
ABPI, www.abpi.org.uk
28
Innovation - Pipeline
Novel Scientific Strategies • 245 projects using cell therapy.• 127 projects using antisense RNA interference therapy (an approach that
targets RNA, which carries genetic information that creates proteins, rather than proteins themselves).
• 102 projects using monoclonal antibodies joined to cytotoxic agents to target and kill tumors while sparing nearby healthy cells.
• 99 projects using gene therapy.
PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients Analysis Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013
29
Innovation - Pipeline
PhRMA Report: The Biopharmaceutical Pipeline: Evolving Science, Hope for Patients Analysis Group, Innovation in the Biopharmaceutical Pipeline: A Multi-Dimensional View, 2013
Innovation – Pipeline
Gene Transfer Designs • NIH Re-Combinant Advisory Committee (RAC)• RAC reviews new gene transfer trials• Mostly very early phase studies• Designs often not appropriate
– No objectives clearly stated– Borrowed from other settings that are not relevant
• Design guidelines need further development
30
Innovation – Pipeline
Gene Therapy Submissions • Many health authorities have a specific division for Gene
Therapy• All follow the recommendations of the EU Directive• Mean time for approval in the countries is 6 months• Some of the ECs in these countries are specific to gene
therapy e.g. GTAC in the UK
32
Innovation – PipelineGene Therapy in Parkinson’s Disease• Intraputaminal delivery of CERE-120 (adeno-associated virus
serotype 2–neurturin) to patients with idiopathic Parkinson’s disease
• Most experts acknowledge that if these goals could be achieved…it would revolutionize the treatment of PD
Lancet Neurol 2008; 7: 400–08
Stereotactic neurosurgery for Parkinson’s disease gene therapy
33
Methods in order to improve R&D efficiency
• Computer-based models:– Predict how a candidate drug is absorbed, distributed, and eliminated
from the body
• Better predictive models: – Narrowing the patient population where the drug has the best chance
of success– Eliminating candidate drugs before risky and costly clinical trials begin
• Simplify Clinical Trials: – 2004-2007: increase of 49% in median procedures per clinical trial as
compared to 2000-2003 (1)– Decrease of 21% patient enrollment rates as a result of more
demanding eligibility criteria (1)
(1) Tufts Center for the Study of Drug Development, “Rising Protocol Complexity, Execution Burden Varies Widely by Phase and TA,” Impact Report 12, no. 3 (May/June 2010).
34
Methods in order to improve R&D efficiency
• If we:– Decrease amount of variables, Decrease amount procedures, Keep it
focused and simple (“Less is more”)
• We will see immediate positive consequences: – Less cost, less total clinical staff time, better enrollment and retention
of patients, increase reliability of assessments
• If not offset:– These developments may lead to future increases in the expense and
time required to successfully develop new drugs (1)
(1) Tufts Center for the Study of Drug Development, “Rising Protocol Complexity, Execution Burden Varies Widely by Phase and TA,” Impact Report 12, no. 3 (May/June 2010).
Simplify Clinical Trials (Cont.)
35
Methods in order to improve R&D efficiency
• Enhance communication between FDA and sponsors during drug development
Chart from Vikram Sinha, PhD, DirectorDivision of PharmacometricsOffice of Clinical PharmacologyOTS, CDER, FDAA SCPT Annual Meeting Open Forum, March 6, 2013Model-Informed Drug Development and Regulatory Review
36
Methods in order to improve R&D efficiency• Clinical trial design: Adaptive Study Design
37
Methods in order to improve R&D efficiency• Clinical trial design: Adaptive Study Design
• Objectives of Learn: Disease-based Learning; Identify and recommend most attractive molecules; Identify and recommend the best ways to use the molecule for therapeutic purposes (dosage, delivery) before going to Confirm
• Improve POS
Learning Versus Confirming in Clinical Drug Development. Sheiner, LB, Clin. Pharm Ther 1997; 61:275-291
38
Methods in order to improve R&D efficiency• Clinical trial design: Adaptive Study Design
39
Methods in order to improve R&D efficiency
• Development of biomarkers and pharmacogenomics, use of enrichment strategies• We look for variability in drug response for every molecule and the
source of that variability • Biomarkers are typically in the causal pathway of disease pathology or
drug pharmacology • Qualification of biomarkers refers to the extent of information needed
to understand its clinical utility • Qualification is for a specific intended use that informs a regulatory
and/or medical decision• Genomic biomarkers are the foundation of personalized medicine
40
Methods in order to improve R&D efficiency
• Development of biomarkers and pharmacogenomics, use of enrichment strategies• Diagnostic • Prognostic: outcome related to disease, but not necessarily to drug
therapy• Predictive: outcome necessarily related to therapeutic intervention• Validated• Clinical trial vs. Clinical utility• Study design: Enrichment or a stratification strategy implementation
41
Methods in order to improve R&D efficiency
42
Methods in order to improve R&D efficiency
Putative Biomarkers for the Alzheimer Disease Pathophysiological Process Currently Being Used
1. Markers of amyloid-beta (Ab) protein deposition in the brain
a. Low cerebrospinal fluid Ab42
b. Positive PET amyloid imaging
2. Markers of downstream neurodegeneration
a. Elevated cerebrospinal fluid tau (total and phosphorylated)
b. Decreased metabolism in temporal and parietal cortex on 18flurodeoxyglucose positron emission tomography
c. Atrophy on magnetic resonance imaging in temporal (medial, basal, and lateral) and medial parietal cortex
43
Methods in order to improve R&D efficiency
Criteria for Dementia Unlikely to be Due to Alzheimer Disease (AD)
(1) Does not meet clinical criteria for AD dementia
(2) Regardless of meeting clinical criteria for probable or possible AD dementia
a. There is sufficient evidence for an alternative diagnosis such as
HIV dementia, dementia of Huntington disease, or others that rarely overlap with AD
b. Biomarkers for both amyloid b and neuronal degeneration are negative
Methods in order to improve R&D efficiency
44
45
Methods in order to improve R&D efficiency• Use of enrichment strategies
– Prospective use of any patient characteristic to select a study population in which detection of a drug effect (if one is in fact present) is more likely than it would be in an unselected population.
– 3 enrichment strategies: • Practical enrichment: Decrease heterogeneity and “noise” (1)• Prognostic: Identifying high risk patients‐• Predictive enrichment: Choosing patients likely to respond to
treatment
(1) Noise reduction is one of the variety of ways researchers try to include people who can be measured precisely and correctly, so if they have a drug effect it can be detected.
FDA, Guidance for Industry, Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, December 2012
46
Methods in order to improve R&D efficiency• 5 Predictive Enrichment Categories:
– Empiric strategies• Open Trial Followed by Randomization• An Individual’s History of Response to a Treatment Class• Factors Identified in Results from Previous Studies
– Pathophysiologic strategies• Metabolism of the Test Drug • Effect on Tumor Metabolism • Proteomic Markers and Genetic Markers Linked to a Proteomic Marker
– Genomic strategies– Randomized withdrawal studies– Studies in non-responders or patients intolerant to other therapy
FDA, Guidance for Industry, Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, December 2012
47
Methods in order to improve R&D efficiency• Randomized withdrawal studies: In a randomized withdrawal study,
patients who have an apparent response to treatment in an open label period or in the treatment arm of a randomized trial are randomized to continued drug treatment or placebo.
FDA, Guidance for Industry, Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, December 2012
48
Methods in order to improve R&D efficiency• Use of enrichment strategies
– The increased study power facilitates “proof of principle” (there is a clinical effect in some population) but it leaves open:
• The question of generalizability of the result• How much data are needed before or after approval in the “non‐
selected” group. (Do these patients benefit at all? Are they harmed?)
FDA, Guidance for Industry, Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products, December 2012
49
Methods in order to improve R&D efficiency• Enriching Trials for Early Responders:
– Tests that are being developed in conjunction with the drug and are required for drug use (e.g. Her2/neu measurement for trastuzumab (Herceptin®) therapy.
– Genentech’s trastuzumab (Herceptin®) was studied only in people expressing the Her2 protein, which represents roughly 1/3 of the population.
– If an unselected population had been studied, a two-month improvement on survival would probably have been seen rather than a six-month improvement on survival.
Biomarker Study Design 1: Upfront stratification
• Produces data on all patients• Completely prospective
50
Test
M+, randomize
M-, randomize
Treatment A
Treatment B
Treatment A
Treatment B
Biomarker Study Design 2: Biomarker-based strategy
• May not produce data for all patients (although it can)• Can include retrospective design aspects.
51
Randomize
Marker-based
Non-marker based
Treatment A
Treatment B
Treatment A
Treatment B
Test
Randomize
Biomarker Study Design 3: Biomarker-based strategy
• May not produce data for all patients (although it can).• Dose selection
52
Randomize
Marker-based
Non-marker based
M+ Dose 1
M- Dose 2
Test
Standard Dose
Targeted therapy is not a new concept
ASCPT Annual Meeting March 6, 2013 Open Forum, Contemporary Issues in Clinical Pharmacology: Development and Regulatory Evaluation of Targeted Therapies, Mike Pacanowski, PharmD, MPH, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
Personalized Medicine• Development of biomarkers and pharmacogenomics. Genomic
biomarkers are the foundation of personalized medicine • FDA: Development of individualized approaches to therapeutics and
nutrition, such as toxicogenomics, pharmacoselection, and complex prognostic and predictive devices, and the use of these techniques to accelerate product development and provide enhanced product and food safety (1)
54
(1) 2009 Report on Status of Regulatory Science at FDA: Progress, Plans and Challenges. Office of the Chief Scientist and Principal Deputy Commissioner. US Food and Drug Administration. Frank M. Torti, M.D., M.P.H. FDA’s overarching scientific priority
Personalized Medicine
55
Our future: targeting the molecular basis of disease
ASCPT Annual Meeting March 6, 2013 Open Forum, Contemporary Issues in Clinical Pharmacology: Development and Regulatory Evaluation of Targeted Therapies, Mike Pacanowski, PharmD, MPH, Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration
57
Methods in order to improve R&D efficiency• Adaptive Licensing – Balancing Evidence and Access
Eichler 2012. PMID: 22336591
58
Methods in order to improve R&D efficiency
• Adaptive Licensing – Balancing Evidence and Access
Exploratory(Learn)
Confirmatory(Confirm)
Monitored release Full release
Biomarker Development
Model and Simulation
Targeted Approval Full Approval
59
Conclusions1. Cost per NME/NBE will grow at annual rates above 13%2. Cost estimate for developing a new drug between $ 1.2-3.9 billion3. Pharmaceutical industry will continue to be a source of value (20-year ROIC of
30% that beats most other industries (average of 9%)4. Time for “me too” drugs, “enantiomers”, is over, no way back5. It is time for innovation: this is a one way street with no return6. Innovation leads to an increase of translational medicine activities and the
number of POC studies (“learn and confirm”, “quick win, fast fail” drug development paradigm)
7. Innovation focused on: a) pipeline, b) study designs and analysis, c) development of biomarkers, d) orphan drugs, e) pharmacogenomics and personalized medicine, f) adaptive licensing
8. Communication with regulatory agencies should be a two way street. Ask for early advice. Work closely with agencies.
9. Outsourcing (from discovery to late phase) will continue to increase (outsourcing rate increased from 35% in 2010 to 41% in 2012, Source: Health Care Distribution & Services. Baird Equity Research. April 2, 2013)
Abbreviations (1)1. ABPI: Association of the British Pharmaceutical Industry 2. ADMET: Absorption, Distribution, Metabolism, Excretion and Toxicity3. BLA: Biologic License Entity4. CBER: Center for Biologic Evaluation and Research5. CCLS: Covance Central Laboratory Services6. CDER: Center for Drug Evaluation and Research7. CDS: Clinical Development Services8. CLS: Central Laboratory Services9. CMC: Chemistry Manufacturing and Control10. CPP: Certificate of Pharmaceutical Product (Taiwan)11. CRO: Contract (also Clinical) Research Organization12. CSDD: Tufts Center for the Study of Drug Development 13. CT: Clinical Trial14. CTA: Clinical Trial Application15. CTD: Clinical Trial Directive16. CTTI: Clinical Trials Transformation Initiative (US)17. DCG: Drug Controller General (India)18. DCGI: Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India19. DOH: Taiwan Department of Health20. DSMC: Data Safety Monitoring Committee21. EC: European Commission22. EC: Ethics Committee23. EMA: European Medicines Agency24. EMEA: Europe, Middle East & Africa25. EMRC: European Medical Research Councils26. ESF: European Science Foundation27. FD&C Act: Federal Food Drug and Cosmetic Act 28. FDA: Food & Drug Administration29. FDAMA: Food and Drug Administration Modernization Act 199730. FDASIA: Food and Drug Administration Safety and Innovation Act 31. FSC: Free Sales Certificate (Taiwan)32. GCP: Good Clinical Practice33. GMP: Good Manufacturing Practice34. GRS: Global Regulatory Submissions35. GSS: Global Site Services36. GSF: Global Science Forum37. GT: Gene Transfer
Abbreviations (2)28. GTAC: Gene Therapy Advisory Committee (UK) 29. HTA: Human Tissue Authority (UK)30. HTS: High Throughput Screening 31. HSE: Health and Safety Executive (UK)32. ICH: International Conference of Harmonisation33. IDCT: Investigator-Driven Clinical Trials34. IFPMA: International Federation of Pharmaceutical Manufacturers and Associations35. IMPD: Investigational Medicinal Product Dossier36. IND: Investigational New Drug Application37. IRB: Institutional Review Board38. IRR: Internal Rate of Return39. LO: Lead Optimization 40. MHRA: Medicines and Healthcare products Regulatory Agency (UK)41. NBC: Italy’s National Bioethics Committee42. NBE: New Biologic Entity43. NCE: New Chemical Entity (Taiwan)44. NDA: New Drug Application 45. NME: New Molecular Entity46. NPV: Net Present Value47. OECD: Organisation for Economic Co-operation and Development48. PASS: Post-authorization safety studies49. PDUFA: Prescription Drug User Fee Act50. PhRMA: Pharmaceutical Research and Manufacturers of America51. PHS Act: Public Health Service Act52. POC (or PoC): Proof-of-Concept53. POS: Probability of Success54. R&D: Research & Development55. RA: Regulatory Authority56. RAC: Re-Combinant Advisory Committee57. REMS: Risk Evaluation and Mitigation Strategies58. ROIC: Return On Invested Capital 59. SCRS: Society for Clinical Research Sites (US)60. SFDA: State Food & Drug Administration of China61. TFDA: Taiwan Food and Drug Administration
62
Moltes gràcies
Muchas gracias
Thank you
Josep M. BadenasSenior Medical Director, Neuroscience
CovanceCell: +34 629 52 73 84