Analiza i strategia R&D w biotechnologii i farmacji część 2 11-12.pdf · Analiza i strategia R&D w biotechnologii i farmacji część 2. Rafał Derlacz. Zakład Regulacji Metabolizmu,

Analiza i strategia R&D

w biotechnologii i farmacji część

2

Rafał

DerlaczZakład Regulacji Metabolizmu, Wydział

Biologii, UW

[email protected]@adamed.com.pl

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12 Ekonomia nowoczesnych technologii12 Ekonomia nowoczesnych technologii

RafaRafałł

Derlacz Derlacz ‐‐‐‐

ZakZakłład Regulacji Metabolizmu UWad Regulacji Metabolizmu UW

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Strategia rozwoju i funkcjonowania R&D

‐

struktura projektowa ??

‐

struktura macierzowa ??

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BA

DA

NIA N

AUKO

WE

3-6 LAT 6-7 LAT 0,5-2 LATA

WYNALEZIENIE LEKU BADANIA KLINICZNE REJESTRACJABADANIA

PREKLINICZNE

5 000 –

10 000 CZĄSTECZEK

250 5

LICZBA OCHOTNIKÓW

FAZA I FAZA II FAZA III

20-100 100-500 1 000 – 5 000

1 NOWY LEK

DOPUSZCZONY

NA RYNEK

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‐

struktura projektowa ??

‐

struktura macierzowa ??

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Small compound

Vs

Large compound

Technology

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KosztCzas

Zasoby

Sukces

vs

Porażka

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20042004 2035203520242024 2029202920072007

Application PatentApplication Patent

LaunchLaunch

LaunchLaunch

20142014

Patent protectionPatent protection for NCE SPC for NCE SPC

20102010

AdditionalAdditionalApplicatioApplicationn

20302030

Patent protectionPatent protection for XXXX SPC for XXXX SPC

20202020

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Development Program

GlobalPayorLead

GlobalOperations

Lead

GlobalProject

Manager

GlobalDevelopment

Lead

GlobalCommercial

Lead

GlobalRegulatory

Lead

PST

Clinical Development

Chemistry Manufacturing and Controls

Non- Clinical

Parallel Processes with Interdependencies

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Development ProgramAim: NDA Approval / Partnership

Nonclinical Pharmacology, ADME, Toxicology Program

Clinical Program

Labeling

NDA / Partner

Nonclinical Pharmacology, ADME, Toxicology Program

Clinical Program

Label /TPP

Typical DevelopmentPlan

NDA

Non-typicalDevelopment

Plan

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b

Safety Specification•Summary of important identified risks

•important potential risks • missing information (ICH E2E)

Pharmacovigilance

PlanBased on safety specification; Routine PV

practices and action plan to investigate specific safety concerns (ICH E2E)

Risk MinimizationActivities to be taken to minimize the

impact of specific safety concerns on the benefit-risk balance

Risk Management Plan

Basic Components of a Risk Management Plan

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Optimizing Benefit Risk

Benefit

Risk

Manageable Risk

Manageable Risk

Unacceptable RiskUnacceptable Risk

Acceptable Acceptable RiskRisk

Low High

High

Low

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Candidate selection -

FTIH

FTIH - PoC

PoC- Commit to

Ph3Phase 3 file and

launch lifecycle .

FTIH PoC Commit to Ph3

Commit to file

Approval and

launch

Post- launch reviews

Candidate Selection

Development Risk Management Plan created First Time in Humans

RMP

continues to be updated at

agreed milestones; coordination

with PSUR, labelling etc

Life‐cycle Risk Management Planning Model

DRMP updated

with significant new data at least

annually and before key development milestones

Evolves into the Risk Management Plan submitted

with the Marketing Application

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Key Findings –

Drivers & Resistors for Pharma

Key growth drivers and resistors for leading branded pharma companies between 2009 and 2014

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Factors responsible for declining internal R&D productivity and sales

• The leading pharmaceutical companies are finding it increasingly difficult to maintain their revenue growth, with several key factors affect R&D productivity and product sales.

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How are pharma companies improving R&D?

Niche, specialty care markets offer Pharma the greatest growth potential • In the face of traditional barriers

to R&D, Pharma companies are starting to employ a number of strategies.

• These include, targeting niche indications and increasingly focusing on specialty markets, employing more creative lifecycle management strategies, widening the R&D bottleneck, creating satellite start-up R&D companies, and increasing utilizing CROs to cut internal R&D costs.

Source: Datamonitor, PharmaVitae Company Comparator Tool, IMHC0080, January 2009

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Two key types of restructuring are available to Pharma

Restructuring Big Pharma

R&D operations to increase productivity

Source: Adapted from Man, 2009

• While acquiring pipeline and marketed drugs through M&A increases the acquirer’s portfolio, it does not necessarily address the core issue of low productivity.

• However, it does buy the company time with which it can use to implement R&D restructuring; be that horizontal or vertical restructuring in order to reorganize operations, creating smaller R&D units in an effort to re-create the entrepreneurial and innovative culture found in small biotech firms.

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Refocusing R&D onto biologics will increase efficiency

• In addition to emulating Biotech in terms of R&D structure and culture, Pharma is also increasingly targeting niche markets served by biologic drugs, which offer higher rates of efficacy compared to small molecule drugs (albeit in smaller patient populations), command a high price, and which can be marketed by small secondary care sales specialists.

• Also as biologics are more insulated against generic competition (at least in the short- term), the revenue streams of such products achieve greater longevity.

Source: Ernst & Young, Beyond Borders, 2008

Biologics will sharpen the focus of the R&D pipeline

Research Early development Late development

Oneapproved

drug

Thou

sand

s of

com

poun

ds

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Current barriers to R&D optimization

The R&D process is failing somewhere between initial innovation and market approval • Despite growing pipelines in

recent years, clinical trial success and approval rates have not improved.

• The key factors impacting Pharma’s R&D capabilities and output include: increasing cost, duration and number of delays in R&D, poor candidate selection with drugs chosen on their commercial rather than their therapeutic potential, more limited financial resources with lifecycle management and indication expansion strategies prioritized, rather than for the development of novel innovative drugs.

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R&D is expensive and carries significant risks, therefore optimizing the way it is carried

out is vital…

•

The level of R&D investment is balanced by benefits resulting from carrying it out (including the

economic value to both society and drug developers, and the benefits to the patient and their

family) against the risks and costs (including scientific risk and the costs of development)

•

These benefits and risks are substantial: the top‐selling drug of 2006—Pfizer’s Lipitor

(atorvastatin)—generated $10.3 billion that year across the six major markets that year1,

meanwhile total R&D spend by the pharmaceutical industry in 2006

was estimated at $55.2

billion (PhRMA Pharmaceutical Industry Profile, 2007)

•

As a result of the high level of investment and risk, strategies

to improve its productivity have

historically received considerable attention. Additionally, there are a number of factors that are

changing the R&D environment and making drug developers increase

their focus on improving

productivity and be more responsive so they are better placed to

capitalize on opportunities

1: 6 major markets = France, Germany, Italy, Spain, the UK and the US; MIDAS Sales Data, IMS Health, July 2007, Copyright©, reprinted with permission)

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There is a widespread belief that Big Pharma is facing an R&D productivity crisis,

however there are many who argue that this is not the case…

Big Pharma is facing a

productivity crisis

Of the drugs that are being approved,

only a low percentage are truly new,

innovative drugs

The overall number

of drug approvals

have been falling

over the last 15

years

The pharmaceutical industry is an ‘ultra‐slow

industry’, making it is very difficult to forecast

future performance and assess current

productivity

Big Pharma is not facing

a productivity crisis

The number of

priority approvals

has risen

consistently over

the last 40 years

Drug development costs have soared, with

estimates that the average cost to develop a

successfully‐launched drug ranging from

$0.8‐1.7bn (Gilbert et al., 2003; Adams &

Brantner, 2006)

The number of drugs entering clinical

trials increased 52% from 1998‐2002 to

the 2003‐2005 period (Tufts Impact

Report, May/June 2006)

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Irrespective of whether the industry is facing a R&D productivity crisis a number of

factors are changing the R&D environment and making drug developers increase their

focus on improving productivity, including…

Renewed focus on increasing reliance on generic and drugs

sourced from parallel importation in the major markets

Increasing internal pressures

Increasing regulatory pressures

An increasingly harsh P&R environment negatively impacts profitability and reduces R&D spending

Patent expiries on a number of

key drugs

Shorter periods of exclusivity

Pressure on Big Pharma

Failing in-house R&D productivity

?

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Deal activity is relatively constant, but spikes slightly at the

end of each year

End-of-year deal activity spikes are caused by:Deal activity per quarter, 2005-2006

Source: MedTRACK, April 2007, © Datamonitor plc

0

10

20

30

40

50

60

70

Q12005

Q22005

Q32005

Q42005

Q12006

Q22006

Q32006

Q42006

Dea

l num

ber

• The keenness of drug developers to use up their budgets by the end of the year

• The strong interest of deal partners in getting a deal signed and completed at the end of the year and not letting it drag into the next year – this is driven by the impact of deals on annual accounts and the resulting effect on the investment community

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Leading dealmakers during 2005–06

• During 2005–06, Novartis was the leading dealmaker, followed by Bayer-Schering, Roche, J&J and GSK, with the top 6 companies responsible for 50% of all deals made by the leading 20 Pharma.

Source: MedTRACK, September 2007, © Datamonitor plc

Novartis was the leading dealmaker during 2005–06

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Leading technology dealmakers

• Merck & Co. and Novartis were the leading technology dealmakers in 2005–06, collectively representing 24% of technology alliances made by the top 20 companies; with the leading six developers responsible for more than half (54 %) of all deals.

• However, replicating the falling number of drug discovery deals by the top Pharma as a whole, the average number of deals Merck & Co. and Novartis made per year has declined.

Merck & Co. and Novartis performed the most technology deals during 2005–06

Source: MedTRACK, September 2007, © Datamonitor plc

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How much should be spent on promotion? Companies with higher promotional spend in 2006 experienced a higher annual growth rate in 2005–06 • The larger the pharmaceutical

company, the more promotional spend it can afford.

• However, with the top 10 leading companies there is an inverse correlation between promotional spend and sales growth during 2005 and 2006.

• Therefore, in the face of ongoing patent expiries, combined with fewer novel products entering the market, and a declining return on investment, manufacturers are increasingly using promotion to drive drug sales

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Key determinants driving promotional spend

Source: Datamonitor

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Earlier stage companies dominate as both source and partner in deals

Earlier-stage companies are the most active deal makers from 2005-2006


Early-stage companies are the dominant source company and partner company in deals because:

Earlier stage47.0%

Private equity0.5% Technology

provider0.2%

Manufacturer1.2%

Top 5027.4%

University/ research center/

government9.0%

Top 2007.3%

CRO2.7%Emerging markets4.8%

Partner

Earlier stage72%

Emerging markets

1%

University/ research center/

government7%

Top 2008%

Top 5012%

Source

• They play a leading role in supplying novel drugs and technologies to the market

• They lack the full integration of Big Pharma companies – therefore, key functionalities, technologies, products and other resources are externally sourced

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Partnership‐focused co‐development deals, together with functional licensing deals are the

most popular deal types, in terms of primary deal goal

Co-development and licensing deals are the most common deal goals, accounting for more than two thirds of deals, 2005-2006


• Half of all deals were co- development deals, which are complex, partnership- focused multi-facet deals involving a number of elements, and are widely used among earlier-stage companies, to boost the value of their product or technology

• Almost one quarter of deals are more functional licensing deals, which are more frequently used by top-50 and top-200 companies to buy in a specific technological expertise or product portfolio

Licensing22.0%

Manufacturing 9.0%

Formulation/ delivery1.2%

M&A1.0%

Manufacturing0.5% Joint venture

0.2%

Other0.2%

Running clinical trials

4.6%

Cash injection5.6%

Marketing/ distribution

6.1%Co-

development49.6%

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Both the pipeline and the deal activity databases indicate that oncology is the

dominant pipeline therapy area

Oncology remains the dominant target, 2005-2006


• Oncology leads the therapeutic focus of pipeline development and deal activity, but patenting activity is lower than other therapeutic areas like CNS

• Both CNS and cardiovascular are dominant in terms of pipeline and deal focus, and in terms of patenting activity

• Infectious disease ranks high in terms of pipeline and deal focus, and patenting activity

CV & circulation

(432) 6%

AI & I (417)6%

Other (2150)31%

CNS (964)14%

Infections (613) 9%

Cancer (2409) 34%

Metabolic & Endo (27) 7%

CV & circulation

(22) 5%

Other (143) 35%

Infections (61) 15%

CNS (55)13%

Cancer (105)25%

Deal snapshotPipeline snapshot

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Biologics are popular, although small molecules remain the dominant focus

Reasons for these trends include:

Of the biologics deals, antibodies dominate the deal focus while

recombinant proteins lag behind, 2005-2006


• mAbs are currently the high-growth biotech sector because of their attractiveness, because biosimilars of antibodies remain a long way away, and the expanding range of targets in the oncology and IDI markets is helping to drive the development of a wide number of antibodies

• The therapeutic recombinant protein sector is the mature, low-growth sector of the biologics market; most of the low- hanging fruit have already been picked, therefore deal activity has fallen

Antibody32%

Vaccine28%

Cell-based therapy

1%Fusion protein3%

Nucleic acid therapeutic

11%

Recombinant protein15%

Other10%

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A number of factors underlie the therapeutic trends of deal activity and the

industry’s pipeline…

• Approval times are quickest for infectious disease and oncology/IDI drugs (Tufts Impact Report, May/June 2006)

• Both probability of progression through development and development speed are optimal for oncology, IDI and infectious disease drugs (Adams & Brantner, 2006; Tufts Impact Report, May/June 2006)

• Specific characteristics of therapy areas make some more attractive to drug developers – for example, therapeutic areas such as oncology and IDI are characterized by a high unmet need in niche markets; therefore, by targeting these markets, drug developers can charge high prices, reduce sales and marketing spending by targeting a small number of specialist physicians, and obtain higher pricing and reimbursement levels

• Cost of drug development is lowest for infectious disease drugs such as HIV/AIDS medications, compared to other therapeutic areas such as respiratory (Adams & Brantner, 2006)

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R&D tools

Optimize R&D model

Optimize R&D process

R&D strategy recommendations

Optimize outsourcing strategy (especially CROs)

Drive up access to early- stage research

Optimize macro drug

development strategy

Better utilize licensing & M&A to support R&D

The R&D model can be optimized using a number of improvements…

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A range of factors are driving the use of CROs…

CRO

usage

The opportunity to offset the capital

outlay the company needs to make to

build the capability up from scratch

The scope to quickly access

expertise in a specific area

CRO projects have a greater R&D

productivity

To help drug developers combat the

increasing complexity and size of

clinical trials

The greater number of non‐fully

integrated drug discovery

companies in the marketplace who

need to contract out clinical

research program management

To boost staff resources in drug

development companies, allowing

them to focus on their core

competencies

The opportunity to save cash, based on

increased productivity, leveraging

economies of scale; and making savings

related to the location where the work is

carried out

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CRO activity is moving away from Europe and the US for a number of reasons – advantages

and disadvantages of using emerging market CROs include…

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Optimize CRO strategies: India –

benefits and issues…

• Possible concerns that early-stage nature of scientific advancement in the ‘omics’ fields compared to the major Western markets

• Compliance and service levels vary widely

• Cultural issues: e.g. communication of bad news, plus importance of timelines

• Historically weak IP protection

• Corruption remains a problem

• Rapidly rising salaries for highly skilled workers & saturated quality manufacturing and R&D capacity

• High level of patient consent

• Strong chemistry history

• Talent pool of high- quality and enthusiastic medical staff, researchers and investigators with strong work ethics

• A range of governmental initiatives have improved the environment & reduced the risks associated with carrying out R&D (including improving the IP environment)

Negatives with using Indian CROs

Positives with using Indian CROs

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Optimize CRO strategies: China – benefits and issues…

• Political issues (including political uncertainty, governmental expectations of expertise, investment and commitment, plus issues over the Foreign Corrupt Practices Act)

• Ethics issues (including concerns over animal welfare, weak privacy protection and the fact that investigators are not used to gaining informed consent)

• Complicated regulations with different interpretations

• Concerns over animal quality

• Shallow senior management pool

• Increasingly strong IP protection

• Availability of non-human primates

• Increasingly harmonized regulatory process

• High numbers of professionals

Negatives with using Chinese CROs

Positives with using Chinese CROs

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A range of strategies can optimize the CRO experience…

• Ensure that communication between the CRO and the drug developer is strong, and that the right information is communicated:

• Set up a team to co-ordinate decision making• Ensure that each party understands their roles & responsibilities & clearly explain expectations• Be aware of the CRO’s concerns, and address them• Ensure there is honesty in what can and cannot be done

• Make significant commitments in the relationship with the CRO:• Keep senior management high-profile• Dedicate significant resources to monitor and manage the relationship• Enable effective know-how transfer and use this to build trust

• Ensure that the way that staff are used is optimal• Aim to keep turnover low• Invest significantly in finding the right higher-grade staff

• Drug developers should try to remain appropriately cautious and not take unnecessary risks with the CRO relationship

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• Companies must proactively seek licensing opportunities rather than waiting for companies to approach them

• Ensure that external and internal projects are judged equally

• Successfully identify suitable deals that are consistent with corporate strategy

• Securing deals by being a ‘partner of choice’

DealDeal--selection selection recommendationsrecommendations

There are a range of recommendations for optimizing licensing strategies and making

licensing more efficient, from both a time‐saving and a cost‐saving perspective…

• Ensure strong communication

• Boost transparency of process

• Enhance understanding of critical issues

• Carry out effective due diligence

• Optimize team infrastructure

DealDeal--execution execution recommendationsrecommendations

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…in addition to these recommendations, there are a range of factors that restrict a licensing

deal, which are to be avoided…

Factors restricting licensing dealsBudget limitations

Lack of flexibility Poor leadership & ineffective governance

Unrealistic timing

Incompatible objectives

Weak commitment

Merger/acquisitions change priority

Drastic changes in business environment, or changes in senior

management

Inconsistencies in decision making & slow

decision making

Ignoring key issues

Factors restricting licensing dealsBudget limitations

Lack of flexibility Poor leadership & ineffective governance

Unrealistic timing

Incompatible objectives

Weak commitment

Merger/acquisitions change priority

Drastic changes in business environment, or changes in senior

management

Inconsistencies in decision making & slow

decision making

Ignoring key issues

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Big Pharma can use four strategies to gain access to early‐stage research…

Greater collaborations with universities/ research

institutes/ governments

Use more open-source research for pre-

commercial work

Set up private equity funds

Set up incubators

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Ways to optimize macro drug development

strategy

Determine what weight should be placed on

developing follow-on drugs compared to first-in-class

innovative drugs

Broaden range of targets being targeted but in a

therapeutic focus-targeted way

Implement effective portfolio management

Tighten therapeutic focus

There are four key ways to optimize macro drug development strategies…

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R&D tools

Optimize R&D model



Optimize the use of biomarkers to segment the market to drive

future market growth

Identify potential opportunities for better use and

implementation of IT

Improvements to the way that R&D tools are used can also help to

optimize the R&D model …

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Increased biomarker

usage

To create a targeted therapy based on a

logical target choice, which is designed to improve safety and

efficacy of treatment

To reduce the government

expenditure on unnecessary

medicines To better define or even reclassify a disease, and to

identify the disease at an earlier stage

To reduce the costs of clinical

trials and improve the chance of

approval

To use in clinical trials as

surrogate endpoints

Biomarkers are used in a range of functions…

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• The movement from detection/screening to therapy monitoring

• The increasingly wide use of diagnostics in the clinical setting

• Evolution of technology

• Relative ease of development

• Evolution of use and integration of biomarkers into Big Pharma R&D strategy

• Alliances formed by diagnostics companies

• Increased use of biomarkers with imaging

Factors driving the evolution of biomarkers

Factors restricting the evolution of biomarkers

• Adequately assessing new biomarkers

• Low profit and reimbursement for biomarker developer, if biomarkers are developed independently from the drug developer

• Lack of ROI from genomics investments

• Issues with the IP

• Issues with new technologies

• Slow uptake and development of new biomarkers

• The biomarker field is becoming increasingly complex

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Increased IT usage

Handling data accumulated with

target identification/ validation

Optimized computer models used across the whole drug

development process

Clinical trial modeling

and simulation

Improved communication

There are many roles for increased IT usage…

Improving lead identification/

optimization with technologies such as

in silico modeling

Managing clinical trial data

Text searching, mining and

analysis

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Optimize R&D model

Improve the way clinical trials are carried out in-house


Optimize interaction with regulators


Introduce greater P&R input into R&D process

Improve patient enrollment

Build up close relationship with KOLs

Develop robust strategies to reduce attrition

Optimize safety assessment in preclinical trials

A range of strategies that can be used to improve R&D processes…

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There are two strategies to improve the way that safety testing is carried out in

the preclinical setting:

• Using better safety assessment tools

• Adopting a more rigorous safety testing program, based on the following safety goals…

Safety goals

Select the right animal model (based on factors such as previousdrug experience, similar pharmacology on target), carry out testing

and then determine the difference between animal models and human models, in terms of metabolism and pharmacokinetics

profile in lab animals

Use Phase Zero/microdosingand expINDs

Produce a preclinical data package for all necessary

stakeholders

Identify toxicity biomarkers to be used in human testing

Safety goals

Select the right animal model (based on factors such as previousdrug experience, similar pharmacology on target), carry out testing

and then determine the difference between animal models and human models, in terms of metabolism and pharmacokinetics

Define the toxicological profile in lab animals

Use Phase Zero/microdosingand expINDs

Produce a preclinical data package for all necessary

stakeholders

Identify toxicity biomarkers to be used in human testing

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‐

struktura projektowa

‐

struktura macierzowa

Documents

Analiza i strategia R&D w biotechnologii i farmacji część 2 11-12.pdf · Analiza i strategia R&D w biotechnologii i farmacji część 2. Rafał Derlacz. Zakład Regulacji Metabolizmu,