CEMDCFrom Drug Discovery to Marketplace

Overview of the Development and Life-Cycle Management of Medicines

The changing role of medical affairs in life-cycle management and marketing

Peter Stonier

The Pharmaceutical Industry…..

… develops, produces, and markets pharmaceuticals for use as medications. Pharmaceutical companies may deal in generic or brand medications and medical devices. They are subject to laws and regulations that govern the patenting, testing, safety, efficacy and marketing of medicines.

Aims of research-based Pharmaceutical IndustryThe 6 ‘Rs’ – “To bring the Right medicine to the Right patient at the Right time, through the Right route at the Right dose - for the Right price.”

“Good Science makes Good Medicines makes Good Business.”

State of the industry: industry challenges

Risks• Up front investment required – industry funds & bears the risks

• 1 in 10 development candidates starts clinical trials

• 1 in 5 medicines launched recovers its costs

High attrition• Due to efficacy, safety, formulation

• Late stage failures are more costly

• Low frequency safety signals only detected once on the market

Intellectual property• Longer the development, shorter the time of patent exclusivity to market and recoup costs

• Market exclusivity and life-cycle revenues have been reducing

Drug development times increase

Less efficient – Pharma innovation gap

State of the Industry: Environmental challenges

Unmet medical need• Large social cost and burden: chronic disease, dementias, diseases of an ageing population

• New diseases emerging e.g. drug-resistance, pandemic threats –Ebola

Increasing regulatory demands• Increases risk of failures

• Increases costs

Pricing pressures from healthcare payers• Continued pressure on savings within budgets

Challenges of modern R&D• Multi-disciplinary teams and expertise

• Globalisation

• Communication, business leadership and entrepreneurial competencies

Patent expiry

A Changing World

10

Pressureson Clinical

Development

Stringent

Regulatory

environment

Pricing &

Reimbursement

uncertainty

Loss of patents

& threat of

generics

Falling approvals

& late phase

success rates

R&D budgets

under pressure

Competition for

Patients

intensifying

“Do more with less and faster”

Globalization – shift toEmerging markets

Increased use ofoutsourcing

Increasing trialcomplexity

•Leveraging IT – EDC,•Modeling & simulation

State of the Industry: The Future

Reorganisation of major pharma• Decentralisation and externalisation ‘integrated company to integrated network’

• Eco-System of research

Growth of pre-competitive and risk-sharing partnerships• Role of SMEs

• Require academic and collaborative culture

• Experiments in open innovation

• Sharing / swapping portfolios between companies e.g. GSK oncology, Novartis vaccines

Opportunities from emerging science and technology• Advanced therapies, regenerative medicine, nanotechnology

• Ensure there are associated capabilities (competencies)

SMEs Pharma

Universitiesclinicians

patients

Government

Medical &

research charities

The R&D EcosystemMultiple players and interdependencies

12

Challenges for Medicines Development

• Long development process

• Increasing and earlier costs

• Patent expirations

• Less efficient in recent years

• Unpredictable

• Shorter time frame to earn back investment and less revenues

• Long, complex and difficult regulatory

• More complex clinical trials

• Less funding of University research

• Product withdrawals

Developing innovative medicines is acomplex, risky and expensive process

POST-MARKETING SURVEILLANCE

3,000 - 10,000

10 - 20

5 - 10

1

2

2 - 5

QUANTITY OF CANDIDATES

1514131211109876543210

• HTA REIMBURSEMENT

EVALUATION

• MARKET LAUNCH

• PRICING

• SAFETY AND EFFICACY

REVIEW

DEVELOPMENT CLINICAL TRIALS (HUMANS)

BASIC

RESEARCH

(Estimated cost $2.6 billion discovery to successful launch)

I

PHASES YEARS

IV

III

II

V

PRECLINICAL TEST

(ANIMALS)

Developing innovative medicines is a complex, risky and expensive process

Source: Based on PhRMA analysis, updated for data per Tufts Center for the Study of Drug Development (CSDD) database.

5

Characteristics of pharmaceutical industry

• R & D basis greater than other industries (Innovation is key to success and survival)

• Operating within a high-level ethical, legal and regulatory framework (Bringing benefit & well-being to patients)

• Patient (consumer) is not the customer. Prescriber (learned intermediary) is also not the customer.

• A collection of competitive companies (not an industry working in unison).

• Need to commercialise, promote and sell medicines; for awareness, usage, recouping costs to re-invest in R&D, producing a Return on Investment for investors and shareholders.

• Life-cycle management of products & portfolios: a dynamic between protection from threat of withdrawal or demise and continuing product development including incremental improvements of therapy.

An industry with built-in tensions, contradictions & competing forces!

Drug Trade Type Indication Company

Adalimumab Humira Biologic RA Abbvie

Ledipasvir / sofosbuvir Harvoni Small Molecule Hep C Gilead

Etanercept Enbrel Biologic RA Amgen Pfizer

Infliximab Remicade Biologic RA / Crohn’s J&J

Rituximab Mabthera Riluxan Biologic Lymphoma Leukaemia

Autoimmune

Roche

Insulin Glargine Lantus Biologic DM Sanofi

Bevacizumab Avastin Biologic Metastatic cancers Roche

Trastuzumab Herceptin Biologic Breast cancer Roche

Lenalidomide Revlimid Small Molecule Multiple Myeloma,

Myelodysplastic syndrome

Celgene

Sofosbuvir Sovaldi Small Molecule Hep C Gilead

Fluticasone propionate /

Salmeterol

Seretide

Advair

Small Molecule Asthma COPD GSK

Rosuvastatin Crestor Small Molecule CVD AZ

TOP 12 Largest Selling Pharmaceutical Products 2015 (>US$ 5Bn)

18

New technologies

• Recombinant proteins

• Monoclonal antibodies

• Gene therapy

• Stem cell therapy

• Therapeutic vaccines

• Tissue regeneration

• Epigenetics

Drug development is the process of bringing a new pharmaceutical or biological drug to the market once a lead compound has been identified through the process of drug discovery.

In context of today’s healthcare marketplace:

• The average cost for R&D for each successful drug is $2.65 billion (Tufts). This includes the cost of failures.

• From 10,000 to 10,000,000 screened modules only a few receive approval. Attrition is fierce – at every stage of the process!

• For every 5-10,000 compounds entering the development pipeline only 1 will make it to the market. For every 5 marketed, only 1 will be commercially successful.

• Drug developers are tackling increasingly complex diseases, with greater scientific setbacks as new approaches to target disease are explored.

• Regulatory hurdles are higher today; clinical trials are larger, longer, more complex and expensive.

• These are some of the factors that contribute to increasing costs, time and uncertainty relating to drug development. A high-risk business!

Drug Development Time Line

8-15 years or more

A Road-Map of a Medicine Development

International regulatory and cultural considerations for drug development• Companies aim to have new products approvable in all major

markets.

• International Conference on Harmonisation (ICH) a significant initiative to bring Drug Regulatory Authorities and Pharmaceutical Industry to agree scientific and technical aspects of drug development.

e.g. ICH E8 ‘General considerations for Clinical Trials’

ICH E8

• Describes internationally accepted principles and practices in the conduct of both individual clinical trials and overall development strategy for new medicinal products.

• Facilitates the evaluation and acceptance of submitted data by regulatory authorities.

BUT -

• Despite ICH, regulatory harmony does not yet exist and regulators still have individual requirements and preferences.

• Evolution of drug development strategies and regulatory authority evaluation has led to establishment of regional guidance.

Key considerations for international development:• Different Health Technology Assessment in many countries.

• Country-specific reimbursement – products advance standard of care; what must convince payers that drug is worth having and at what price?

• Alignment of international and affiliate departments and offices.

• Problems of working internationally – regulatory differences, differing medical practices (e.g. treatment of cancers, US vs. EU).

• Differences in marketing – what is target audience for product in a specific country? How does product differ from competitors in a specific country?

• Medical culture – differences.

What is included in an international drug development plan?

•The strategic plans

•Target product profile (TPP)

•Regulatory plan

The strategic plan: the global clinical, regulatory & commercial situation in which the new medicine will be developed and come to market.

• Obligatory, comprehensible, executive summary

• Ensure alignment of scientific, commercial & regulatory views on mechanism of action: Initial pharmacological profile / galenic forms• Probable indication(s) (draft SmPC or Data sheet)

• Disease area & current science

• Scientific advice on TPP & gaps on Marketing Authorisation readiness in regions

• Current treatment & therapeutic issues

• Competitors

• Regulatory concept, strategy and geographic hurdles

• Initial market / commercial assessment/HTA/pricing hurdles

• Initial TPP including target population

Target product profile (TPP)Cross-functional strategic; one TPP (not possible); dynamic document, covering:

• Target population(s), indications, usage, dosage, administration, strengths, treatment duration, contraindications.

• Summary of specific studies (planned and completed), design of pivotal (Phase III) study, with primary endpoints, supporting proposed labelling claims.

• Summary of competitive environment; now and future.

• Customer groups and medical unmet needs

• Key claims for launch

• Pricing strategy

• Essential is demonstrating value and market access

Regulatory planning:following identification of promising compound

• Current regulatory policies, procedures & guidelines applying to product in each target market.

• Likely path to regulatory approval in different target markets, including accelerated approval (e.g. EU: centralised or decentralised procedure).

• Assessment of similar products approved or in development.

• Timeline for submission of regulatory documents in each market.

• Planning key milestones for different markets (e.g. IND application in USA before trials, and NDA/BLA for market permission).

• Scientific advice meetings in US and EU should be well-planned meetings at critical time-points: clarify expectations, shorten development time and anticipate fewer questions during regulatory review.

The Drug Development Plan

• Non-clinical development

• Clinical development

• Manufacturing and quality

• Product Life-cycle planning

• Market access

Non-Clinical Development

Feasibility and drug safety data collection. Main goal: product safety profile.

• Products may include new or repeat small molecules, biologicals, gene therapy products (advanced therapy medicinal products: ATMP).

• PD, PK, ADME and toxicity testing through animal testing.

• Data allows estimation of safe starting dose.

• Non-clinical studies adhere to GLP and ICH Guidelines (to be acceptable)

• In silico, in vitro and in vivo tests will be performed.

• Toxicity includes organs targeted by drug, carcinogenic effects and effects on reproduction.

Clinical Development Plan (CDP)

• CDP and draft SmPC to be prepared early, and before human trials begin. (But, not too early, and not dominated by one country).

• Discussed with DRA, consultants, physicians and scientists, research institutes and investigation centres.

• Core team of experts inc KOLs to develop Phase I-III strategy of the CDP.

• TPP (FDA TPP guideline) drives CDP.

• Detailed plans on study designs, investigators, special populations, specific country requirements, statistical analysis and timelines.

• Adaptive designs

• Contingency planning and risk management included

Clinical trials

• Procedures to allow efficacy and safety data to be collected for health interventions

• Phase 0 (micro-dosing; exploratory; not submitted)

• Phase 1 – Exploratory development

• Phase II – Exploratory therapeutic

• Phase III – Confirmatory therapeutic

• Phase IIIB – Peri-regulatory

• Phase IV – Post-licensing; post-marketing

34

Phase 1

• Clinical pharmacology studies

• First in to ‘human’ (FIH) – usually non-patient volunteers

• Single dose and repeat dose studies

• Key pharmacokinetic data

• Safety/tolerability data

• Pharmacodynamic measures where possible

• Usually defines dose for Phase 2 studies

• Participants n = 20-100

20

Pharmacokinetic data

• Absorption

• Distribution

• Metabolism

• Elimination

• Mass balance studies

• Genetic polymorphism

Plasma Conc

-1

0

1

3

2

5

4

0 100 200 300 400 500 600 700

Plasma Conc

8

Cmax

7

6

TmaxArea under the curve

Half life

36

37

Pharmacodynamic surrogates

• Blood pressure

• EEG

• Blood glucose

• Biological markers

• Respiratory challenge tests

• Gastric acid changes

• Pain

38

Special populations

• The elderly (over 65s and over 75s)

• Children

• Patients with renal impairment

• Patients with hepatic impairment

• Drug/drug interaction studies (pharmacodynamic)

39

Phase 1 exceptions

• Cytotoxic oncology products

• Some biologicals

Brian Gennery Dec 201640

TGN 1412 (Northwick Park)

• TGN 1412 was a ‘super agonist’ for treating some cancers and RA

• Used monkeys as preclinical species

• Started at 1/500 of the NOAEL

• Infused all 6 subjects almost simultaneously

• All 6 went into cytotoxic shock

• 2 lost parts of his fingers and toes

Brian Gennery Dec 201641

TGN 1412 (Northwick Park)

• Had full regulatory and ethics approval

• MHRA and police investigation

• No problem with the product

• Passed GCP inspection

• Company not properly insured

• Enquiry established new requirements for ‘high risk’ studies in the UK

42

Phase 2

• Proof of clinical effectiveness in patients

• Dose ranging

• Multiple measurements

43

Phase 2 considerations

• Need to establish proof of principle (proof of concept PoC) as soon as possible

• Smallest studies compatible with scientific rigor

• Use of placebo where possible

• Use only single centre studies to ensure homogeneous populations

• Studying no more than one indication at a time

44

Phase 2 – how large is the study?

• 8 patients in a placebo controlled trial in RA v prednisolone

• 300 patients in a dose ranging study in RA with an NCE v placebo v active comparator

• Participants n = 100-300

30

Phase 3

Confirmatory studies for efficacy and safety

46

Phase 3

• Confirm efficacy and safety profiles

• Large – usually multi-centre and often multi-national

• Sometimes versus placebo, more usually active comparator

• Usually 2 studies per indication

• Participants n = 300 – 3,000

47

Phase 4

• Usually means those trials done after the marketing of the medicinal product

• Various different definitions depending on the company

• Usually done against leading marketed products

• Must be done to GCP standards

48

Post marketing surveillance

• Systems designed to capture new safety information or changing safety profiles

• Spontaneous reports

• Cohort studies

• Case control studies

PROSPECTIVE DRUG PACKAGE INSERT

Patient Population

Indication

Clinical data

Clinical Pharmacology

Adverse Reactions

Contraintradictions

Precautions and Warnings

SCIENTIFIC RATIONALE FOR DEVELOPMENT

Non-Clinical studies i.e. Toxicity/reproductive/carcinogenicity

Non-clinical pharmacology i.e. ADME/In vitro/In vivo/PK/PD/Drug-Drug Interactions

Chemical and Physical structure i.e. chemical class and properties/formulation and manufacture

COMMERCIAL RATIONALE FOR DEVELOPMENT

Unmet clinical and market need

Clinical and disease implications

Epidemiological needs

Potential competition

International Considerations

CLINICAL TRIALS

Per Phase:

Protocol objectives and hypothesis

Trial design

Sample Size

Clinical supplies

Resource planning

Costings

REGULATORY MATTERS

Regulatory planning i.e. IND planning and documentation

Funding

STRATEGIC PLANNING

Pivotal decision areas

Setting the 'kill switch' criteria

Risk assessment

Licensing

Summary

• Comprehensive Drug Development Plan (DDP) is a guide to bringing a pharmaceutical or biological medicine to market world wide.

• A living document. DDP updated by science, regulatory or marketplace in the 10-15 years of product pre-clinical testing to approval.

Product Life-Cycle Management (LCM)

Product Life-Cycle Management (LCM)

• Maximising the value (Return on Investment) of a drug throughout its development and commercial life.

• Product LCM well established, only recently life-cycle management become a well known feature, because of rising pressures on development:• Reduced productivity

• Rising costs

• Increased competition

• Short exclusivity

• 1984. Hatch-Waxman Act (US Drug price competition and patent term restoration Act) – standardised procedures for recognition of generic drugs.

Cross-functional life-cycle management team

Drug discovery

Drug formulation

Market access

Pharmacokinetics

Marketing

Patent lawyer

LicensingDrug regulatory affairs

Early/Late clinical development

Medical affairs

Life-cycle management strategies

• Pre-launch

• Peak (launch to 2 years prior to patent expiry)

• Maturity (2 years prior to patent expiry and beyond

LCM Pre-launch ‘How can we maximise the revenue potential of our product, especially during market exclusivity?’

• LCM principles applied at early stage in product development.• Consider technical and commercial options to create integrated pre-

launch marketing strategies.• Therapy area focused, cross-functional team, breaking down silos,

meeting regularly, updating issues.• Maximum profits during 5-8 years of market exclusivity.• Road map to chart progress in realising full therapeutic potential, also vs.

competition. • Road map & progression points also allow for ongoing discussions

throughout development – formulation, line extensions, proactive partnering or divestment (to access an optimal marketing channel), clinical indications and labelling, publications strategy, pricing.

LCM Pre-Launch Contd.

• Personalised medicine means biomarkers and diagnostics identifying the patients most likely to respond.

• Pharmacogenomic influence on LCM in identifying responders.

• Increasing importance of effectiveness data (real-world), and now patient-centric data (Patient Reported Outcomes)…

• …Driven by reimbursement bodies e.g. NICE, and have impacted pre-launch strategies.

• Also: Patent issues and protection

Product Life-Cycle Planning

• Discussed since 1960s, more important today - fewer pipeline drugs, fewer blockbusters, patent expiries.

• Rise of LCM strategy.

• Critical stage of LCM is managing patent expiry:

• Maximise brand loyalty

• Innovation

• Indication expansion

• Regulatory and legal strategies

• Fixed-dose combinations

• Invest in generics

• Pricing strategies

• Switching – Prescription to Over-the-Counter (POM to OTC)

• Divestment

• Reformulation: drug delivery technologies

• Repurposing

Second generation: reformulation of products (drug delivery technologies)

• New patent coverage and market exclusivity.

• Change in dose form, dosing regimen, route of admin, drug chemistry.

• Drug delivery technology is the most popular and effective way to prolong product life. Provides technological barriers to generics, and flexibility on labelling and pricing.

• Added patent protection if it involves clinical research.

• Added patient benefit such as reduced dosing frequencies (once a day) and side effects, and optimal dosing forms for special populations : elderly, children.

Contd.

• Estimated (2003-5) 25% of all R&D molecular projects involved an existing product; 17% of development projects on new products used drug delivery technologies.

• Estimated (2002-5) >33% of products launched by top 50 companies were reformulations.

• Oral formulation is delivery vehicle of choice, but also pulmonary delivered products, sustained release injectablesand transdermal patches increasing.

• But this sector is evolving too: generic companies watching second generation reformulation.

Summary

• Modern market: shorter market exclusivity, rampant competition, increased pricing constraints.

• Resulted in LCM fully and cross-functionally integrated into business plans at an early stage.

• LCM options to be examined & debated and assisted by complete understanding of complex dynamics impacting a medicine.

• Executive management should drive LCM strategy.

• LCM strategy tailored to specific products and developed in the context of the company’s broader portfolio.

• Drug-specific factors impact on LCM options: PK, safety profile, disease, patient profile for benefit from the drug, profile of marketing company.

Changing Role of Medical Affairs in Life-Cycle Management and Marketing

• Medical Affairs a support function, a bridge between R&D & Clinical Development and Marketing & Sales

• Traditional role of Medical Affairs• Companies have two Scientific teams: R&D and

Medical Affairs• R&D: defines scientific direction and early phase development• Medical affairs provides scientific support for late phase

development and post-licensing support for medicines.• Medical Affairs usually functions alongside marketing to provide

technical support to internal teams and external customers.

Traditional Tasks of Medical Affairs

• Information Services

• Regulatory review of promotional materials

• Support marketing

• Liaison with healthcare professions and organisations

• Thought leader development

• Educational meeting support

• Medical liaison: field based medical information specialists

• Possible: post-licensing R&D

• Possible: post-licensing Safety monitoring, Pharmacovigilance

Changing role of Medical Affairs

• Shifting pharmaceutical landscape in recent years:• Conventional commercial interactions decreased

• Stakeholders seek scientific conversations, product claims to have more substantial data, produced throughout the life-cycle

• Life-cycle based data:• Real-world evidence to prove product value and define patient outcomes

• Patient-centricity recognised

• Strict regulations and codes of conduct reinforced:• Collaborating departments refocused and went in separate directions

Strategic medical affairs

A new medical operating model:

• Departments need to work together

• From an earlier stage in the Development

New Operating Model for Medical Affairs

• From supportive role to decision-maker and trusted scientific partner

• Leading on hard science, data, and patient-centricity

• Bridging development & commercial, earlier in development process

• Defining value of medicines

• Championing real-world evidence

• Often found in R&D, sometimes independent, rarely in commercial, despite trend to cross-functional working.

• Expanding capabilities embrace – evidence generation, scientific exchange and stakeholder management

Five pillars model for Medical Affairs

• Medical leadership

• Data generation

• Appropriate distribution of data

• Bring insights to company

• Stakeholder interactions

Shepard K. MAPS