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Researcher’s perspective: benefits of complex clinical trial

designs.Sarah Blagden

Associate Professor of Medical Oncology

University of Oxford

BIA Meeting

17th September 2019

Current situation

• Worldwide in 2018

• 17 million new cancer cases were diagnosed.

• BUT, incidence is increasing1) WHO predictions based on GLOBOCAN data

By 2025, 19.3 million new cancer cases are expected to be diagnosed each year.Effective treatments are needed yet >600 investigational medicinal products (IMPs) await clinical development [Economist]

Researcher’s Perspective- BIA September 2019

Five drivers of change

1. A modernising pharma industry

2. An evolving NHS

3. The political landscape

4. Increased pressure on trialists

5. Changing patient expectations and experiences


1) Modernising pharma industry

• Growing, ageing population – pharma sector expanding

• Blockbusters coming off patent, pharma companies looking for new science, mergers with small biotechs

• Explosion in monoclonal antibody biosimilars, rise of supergeneric drugs

• Increased use of Artificial Intelligence (AI) to guide more efficient drug development

• Greater use of monitoring devices (smart phones and wearables) that give real-time data return - will this apply to eCRFs expectations too?

• In-life testing and live licensing, in collaboration with regulators and health care providers.

• Greater transparency around costing, spending, trials and reporting

• Greater power to CROs (as R&D budgets diminish) building capabilities in toxicology studies, bio-analytical services, providing central laboratories in addition to monitoring roles

Faster, cheaper, more

transparent and

technosavvy


2) The Evolving NHS

• Half the UK population obese by 2030, overtaking smoking as greatest cause of cancer

• Increased incidence of obesity-related cancers: breast, colorectal, endometrial, oesophageal, renal and pancreatic

• Greater use of digital technology, networking data

• Genetic information used to predict cancer risk and developing prevention strategies (including vaccines and chemo-preventatives)

• Need to address the looming crisis of ever-more expensive anti-cancer therapies

• Gaps in healthcare spending and Brexit uncertainty

• Staffing crisis

Financially

constrained, short-

staffed, reliant on a

digital revolution


3) The political landscape – the no deal Brexit

• UK will legally “time travel” to 1973.

• Existing EU trials will be required to replace UK-based legal sponsors

• Staffing of trials units with EU nationals will be impacted – 2 year, non-renewable visas

• Stockpiling drugs and excipients (2/3 medicines used in UK come from EU)

• Loss of some big-pharma from UK

• UK will need to play to its strengths

• Life Sciences Industry Strategy – continuing investment in UK R&D, clinical trials: emphasis on innovative trials and fast-tracked approval


Preclinical

Target identification and validation

Initial Drug synthesis

Animal Testing

Clin

ical trials auth

orisatio

n

Phase I

Dose escalation design

Dose level 1

Dose level 2

Dose level 3* Dose Expansion

Often all cancer types

Total = 50

The Traditional Drug Development Pathway


Preclinical



Animal Testing

Clin

ical trials auth

orisatio

n

Phase I Phase II

Dose escalation

Dose level 1

Dose level 2

Dose level 3

* Dose Expansion

Total = 50 Total = 150

Fixed dose, usually one tumour type



Preclinical



Animal Testing

Clin

ical trials auth

orisatio

n

Phase I Phase II

Dose escalation

Dose level 1

Dose level 2

Dose level 3

* Dose Expansion

Total = 50 Total = 150

Fixed dose

Phase III

Total = 1000s

Registration



Preclinical



Animal Testing

Clin

ical trials auth

orisatio

n

Phase I Phase II

Dose escalation

Dose level 1

Dose level 2

Dose level 3

* Dose Expansion

Fixed dose

Phase III

Registration

£1bn per drug



1-3 y 15y

Overall Survival

from 2x Ph3 trials

FDAEMA

licence

NICE approval

Preclinical



Animal Testing

Clin

ical trials auth

orisatio

n

Phase I Phase II

Dose escalation

Dose level 1

Dose level 2

Dose level 3

* Dose Expansion

Fixed dose

Phase III

Registration



Phase II/III

Phase I/II

Adaptive e.g. Accelerated-titration, Model-based design

Dose level 1

Dose level 2

Dose level 3

* Dose Expansion

Combination expansion modules

Cancer 1

Cancer 2

Cancer 3

BASKET design (all cancers in one

basket)

Randomised trial by biomarker or

treatment

e.g. NCI-MATCH study

Etc – 18 arms, >1000 centres in US

Speeding up the pathway – adaptive designs


Phase I/II

Adaptive e.g. Accelerated-titration, Model-based design

Dose level 1

Dose level 2

Dose level 3

* Dose Expansion

Biomarker1

Biomarker 2

Biomarker 3

Umbrella Design

Same cancer, therapy linked to biomarkers

e.g. UK Lung Matrix study

Speeding up the pathway – adaptive designs

Phase II/III


UK Lung Matrix


Or adaptive/modular design….

Phase I dose escalation design

(all-comers) determine MTD

Expand in biomarker-selected cohort

Combine with SoC in biomarker cohort

Randomised combo versus SoC in disease + biomarker selected cohort

e.g. OCTIMET study

Phase I Phase II Phase III EMA/FDA licence NICE approval

Compress this timeline by fast-tracking approval


Fast-tracking mechanisms – expediting marketing authorisation

• USA – 21st Century Cures Act: FDA priority review, breakthrough therapy, accelerated and fast-track approval status. Allow surrogate or intermediate endpoints of response (e.g. pathological CR)

• Europe - EMA’s PRIME Scheme (2019)

• Australia - Therapeutic Goods Association (TGA) worksharing agreements with EMA and FDA

• UK – Accelerated Access Pathway driven by Accelerated Access Collaborative (Lord Darzi)


InstitutionshospitalsRegulatory Bodies

Trials unit

CliniciansPatients

Overcoming hurdles in conducting

Complex Innovative Design (CID)

studies

ECMC Consensus Recommendations for CID trials - (2019 - hopefully)


http://www.google.co.uk/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0CAcQjRw&url=http://aehospitalgown.info/free-cartoon-hospital-clip-art&ei=kIWMVLP1CMHlUsTAgZAF&bvm=bv.81828268,d.d24&psig=AFQjCNFsMX5j8VjiL6zuMOINV3dyZqxSsw&ust=1418581765865817

1) Trial planning & design –

engagement with Regulators

Risk Assessment

Sponsorship

2) Protocol development

Management & monitoring

Contracts & Agreements

Final Protocol IRAS

CTA Submission

Ethics Submission

HRA Submission

Permissions & approvals obtained

Trial begins

Safety reporting

Progressreporting

Ongoing management & monitoring

MHRA inspection/

audit

Substantial amendments

Addition of new sites or investigators

Urgent safety measures

Temporary halt or early termination

End of trial declaration

Statistical data analysis

Clinical Trial Summary

Report

7) Dissemination of results

6) Defining Leadership and

Oversight

5) Statistical considerations

3) Patients and Public

involvement

10) Evaluating the impact on public

health

4) Patient-facing documentation

9) Licensing and Approval

8) Staff Training

Regulatory and Patient and public involvement

Overcoming hurdles in conducting Complex

Innovative Design (CID) studies

Early Engagement

with Regulators

Three part patient

information

Include (in protocol) future modules and defined study end

point

Strong, experienced Trial

Management Group. PI switching

between modules

Early and integrated

patient /public involvement in

study design

Release/publication of data after each

module

Research to evaluate the

impact

Training of CID trials in medical school/undergrad/post grad

curriculaResearcher’s Perspective- BIA September 2019

One-of-a-kind

• Research network

• ECMC Programme Office

Oxford is part of the ECMC network

18

11

20

The ECMC Research Network

• 17 adult solid tumour sites (haematology) and 11 paediatric

sites

• Patient Tracker Database

• Potential to pool genetic information

• Close links to academia

Capable of conducting

collaborative trials

5) Changing patient expectations

• Patient groups lobbying for change via social media

• Earlier release of trial data: • 5,855 of a possible 18,432 failing to adequately report results on

EudraCT within 12 months of closure– academic trials are worst offenders

• Calls to report results directly to participants via their NHS number

• Greater and more intelligent use of PPI engagement


Adjusting to the needs of the patient

• 72 year old female with stage T4, N0, M1a, EGFR wild-type, KRAS mutant non-

small cell lung cancer

• Previously treated and progressed after 2 courses standard chemotherapy.

• Not for resuscitation, referred to phase I trial

• Started Phase I trial in December 2016 – PD1 inhibitor plus chemo

• Ongoing stable disease, attending weekly

• We are collecting a cohort of “Frequent Fliers”


Emergence of Immuno-oncology agents has transformed cancer survival

5 year cancer survival rates in USA – 1970-77 to 2007-2013

Richie and Roser

Where Science Becomes Medicine - Manchester, July 2019

How do we manage the needs of

frequent fliers? Wesley Bedrosian – New York Times

• We are their GPs but can overlook their palliative care needs

• Patients stuck in a binary situation (in or out of study) and tolerate sometimes weekly treatments for fear they will have to stop otherwise. How likely to give honest assessment of their toxicities?

• Is this the promise of survival or a never-ending death sentence? Impact on family? Psychosocial support requirements?

• Do we collect relevant data on these long term patients?

• Many protocols do not de-escalate treatment or imaging intensity once response has been established - Should a de-escalation clause be a mandatory component of any IO protocol?

• Finally, should we utilise the experience of our frequent fliers in informing the design of upcoming IO trials?


In summary

• Phase I research finds itself at the cutting edge of (not only innovation but) Brexit, UK Life Sciences and the future UK economy

• The sector needs to speed up, become more transparent, techno-savvy, cost-efficient and collaborative

• Traditional trial designs and regulatory legislation are being overhauled to fast-track new therapies into the clinic

• The ECMC network is essential in providing a forum for collaboration, lobbying for change (genomic data?) and promoting UK clinical research capabilities

• Life as a phase I oncologist is more complicated, more collaborative and more time-consuming than ever before!

• No longer a “one-session” speciality: pressure to meet timelines, provide education and oversight, co-ordinate teams, interact with pharma and CROs while prioritising the evolving needs of patients.


How phase I units meet these demands

• Embrace sped-up designs

• Report data promptly

• Support R&D within own universities and from local biotech

• Invest in more technical and administrative support to manage adaptive trials

• Work collectively to amass targeted patient populations

• Look beyond Europe for partnerships

• Engage more with/embed PPI

• Support each other


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