US and EU Paediatric Legislation and its Impact on Drug Development - ICON hosted Webinar 2014

18 March 2014

US & EU Paediatric Legislation & its Impact on Drug Development

• ICON Signature Series is our thought leadership program that offers expert insights into value-driven strategies for clinical development.

• The program features ICON and external experts in all aspects of clinical development and post-approval product value strategies.

• For a list of featured topics and upcoming events go to: http://www.iconplc.com/icon-views/

• ICON Signature Series is our thought leadership program that offers expert insights into value-driven strategies for clinical development.

• The program features ICON and external experts in all aspects of clinical development and post-approval product value strategies.

• For a list of featured topics and upcoming events go to: http://www.iconplc.com/icon-views/

ICON Signature Series

• ICON plc is a global provider of outsourced development services to the pharmaceutical, biotechnology and medical device industries.

• The company specialises in the strategic development, management and analysis of programs that support clinical development - from compound selection to Phase I-IV clinical studies.

• ICON currently operates from 77 locations in 38 countries and has approximately 10,300 employees.

• Further information is available at www.iconplc.com

About ICON

Introductions

HansJurgen GrussSenior Director Medical Affairs, ICON Clinical Research, ICON

Hans has Clinical Development experience within both the Pharmaceutical and CRO industries for over 15 years. He has experience in medical Affairs, Clinical Development, Drug Safety and Regulatory Affairs. Hans joined ICON 2 years ago and has oversight of clinical trials in paediatric populations. His therapy area background is General Medicine with a focus on Gastroenterology, Hepatology, Metabolic Disease and Urology.

Introductions

Dr. Klaus RoseKlausrose Consulting

Dr. Rose is founder and Managing Director of Klausrose Consulting in Switzerland. He advises US & EU based companies on strategies in handling FDA & EU regulatory requirements and is editor of two textbooks on paediatricclinical trials.

Dr. Rose has worked with numerous pharmaceutical companies including Takeda, Novartis and Roche.

Introductions

Christopher Bell, MSProject Manager, ICON Clinical Research, ICON

Chris has Global Project Management experience within both the Pharmaceutical & CRO industries. He joined ICON in 2007 and has gained over 3 years’ experience in Paediatric trials as a Global Project Manager and Clinical Trial Manager. Chris also has extensive experience in Oncology trials as PM, CTM, and Lead CRA/CRA.

Chris additionally obtained his Master of Science degree in Health Sciences with a Major in Clinical Research Administration from the George Washington University.

• Overview & Introductions - Hansjurgen

• Background: EU & US Paediatric Drug Development & Legislation – Dr. Rose

• Children's Special Needs In Pharmaceutical Treatment & Clinical Trials – Dr. Rose

• Operational Challenges and Strategies – Chris Bell

• Challenges & lessons learnt in PIP negotiations – Dr. Rose

• US & EU Paediatric Legislation And Its Impact On Drug Development – Dr. Rose

• Conclusions

Agenda

A recording of this Webinar is also available

To view click on the link below http://www.iconplc.com/webinar/14/ComparisonofEUandUSPediatricLegislations.wmv

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http://www.iconplc.com/webinar/14/ComparisonofEUandUSPediatricLegislations.wmv

http://www.iconplc.com/webinar/14/ComparisonofEUandUSPediatricLegislations.wmv

Background: EU & US Pediatric Pharmaceutical Legislation

Dr. med. Klaus Rose, M.D., M.S.klausrose Consulting

Source: www.wellcomecollection.org

Labels A Century Ago

klausrose Consulting

Modern Drugs: Therapeutic Potential & Danger

• 1937 a liquid antibiotic was introduced

• Solvent: Ethylen Glycole; highly toxic; no tox testing.

> 100 deaths, 1/3 children

• Led to revision of FDA legislation

• Next catastrophe: Thalidomide1962

• Ten US cases through ‘clinical studies’

• Led to the Kefauver-Harris amendments


Modern Drug Labels: Started with US Legislation


• Date back to US legislation 1962:

- enforced proof of efficacy. Use in children mostly off-label since then

• Voluntary Paediatric Exclusivity (PE): - BPCA* 2007 after first laws 1997 & 2002. Biologics excluded

• Mandatory paediatric development:

- PREA*** 2003. All age groups. Biologics included. Applies to same indication as in adults only

• Re-authorized 2012 as FDASIA***

• BPCA &PREA have resulted in multiple Paediatric research on patented drugsBoth seen by FDA as major success

*BPCA Best Pharmaceuticals for Children Act

**PREA Paediatric Research Equity Act

***FDASIA FDA Safety & Innovation Act

• In force since January 2007• Combines mandatory development with reward• Paediatric Investigation Plan (PIP) mandatory end of human PK• PIP must cover all age groups• Paediatric Committee (PDCO) assesses PIPs, waivers & deferrals• Reward of six months SPC* prolongation

*SPC Supplementary Protection Certificate klausrose Consulting

EU Paediatric Regulation


EU Paediatric Regulation: Core Elements

• FDA started with looking for ‘some’ Paediatric data

• EMA wants, as far as possible, full Paediatric indication(s)

• Want the necessary data as soon as possible for marketed drugs and as early as possible for new drugs

• Expect each company to be knowledgeable + up to date

• EMA / PDCO style has evolved since 2007

- Claim to be science-driven, but have developed a tough attitude. So far backed by the EU Court of Justice

13

14

• Overview over new drug, targeted disease in adults & children 0-18 y

• Non-Clinical: juvenile animals etc.

• Quality: technical development, e.g. tablet, minitablet, pellets, liquid

• Clinical: modelling & simulation, safety & efficacy trials, extrapolation


PIP Core Elements

PIP Procedure: Milestones

• 3 months before start of procedure: send Letter of Intent (LoI)

• 1 month before start of procedure:

‒ Submission

‒ Validation by EMA, Qs to be answered fast

‒ Procedure starts after validation

• Day 30 discussion + report (D+R): no action required from applicant

• Day D+R: lists requested modifications: must be answered

• Day D+R: lists requested last modifications

• Day 120: Only chance for F2F Oral Explanation (OE)


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PDCO Oral Explanation: Room & Sitting

• Drug development no longer possible without considering children• All in all FDA handles pediatric in a reasonable way • The EU wants to outperform the US• Both legislation have increased the number of pediatric clinical trials • PIP skills needed: know PDCO, its decisions; good negotiation skills;• Potential for saving resources is highest during early PIP preparation • Aim for individual company: negotiate PIP that will serve child health

in the far future and lets company survive• Aim for a CRO: Either perform studies as per protocol or document

that this is impossible & support request for a PIP modification • Legislation will not disappear, but will be modified in 2018


Conclusions

Childrens’ Special Needs In Pharmaceutical Treatment & Clinical Trials


Term newborn infants(0 - 27 days)

Infants and toddlers(28 days to 23 months)

Children (2 - 11 years)

Preterm newborn infants(0 - 27 days)

Adolescents (12-16/17 years)

Age Groups as per ICH E 11



Physiology:

• Large body surface

• Increased skin permeability

• Reduced surfactant synthesis

• Aortopulmonary shunts

• Immaturity of the brain stem

• No circulatory autoregulation

• Incomplete retinal vascularisation

Preterm Newborn: Phase of survival born at <36 weeks of gestation



Physiology:

• Large body surface

• Increased skin permeability

• Increased body water

• Decreased blood brain barrier

• Incomplete neuronal maturation

• Increased hemolysis

Term Newborn: Phase of AdaptationAge: birth up to 1 month



Physiology:

• Small airways

• Ongoing cerebral myelination

• Naive (incompetent) immune system

• Relatively large liver & kidney

Infants and Toddler: Phase of proliferation and growthAge: 28 days to 24 months


Physiology:

• Slower growth rate

• Increased independence

• Increased school performance

• Shift to logical operations

Children: Phase of Differentiation and TrainingAge: 2 to 11 years


Physiology:

• Rapid body changes:

growth spurt

gonadal growth

• Emotional instability

Adolescents: Sexual Maturationage: 12 to 17 years


• Absorption, Distribution, Metabolization & Excretion in children are different from adults

• Maturation with age is not linear and not in parallel

• Variability much higher

Key PublicationKearns, 2003, NEJM

30

ADME in Children

Kearns et al, NEJM 2003

• Recruitment & consent of parents

• Rule of the thumb: recruitment the easier the more severe the disease

• > 90% of children with cancer participate in trials

• Parents’ associations can help recruiting

Operational Challenges Clinical Trials


• Patients dislike placebo control � recruitment ↓

• Facilities: if shabby, will hinder recruitment

• If there is no space for healthy brother to play, mother will not return

• If study personnel is unfriendly, mother will not return

• Monitor: should have pediatric experience

• Good monitoring as essential as good protocol

Operational Challenges Clinical Trials


• Justify every drop in protocol/ to ethics committee

• Define upfront maximum number of tries

• Define priorities of exams if not enough blood

• Offer anesthetic cream, but child/ parents decide!

Blood Withdrawals


• Use different texts for different age groups

• From around 7 years on, child will understand

• Child’s signature is not legally binding, but should be asked for as a token of respect

• Physician can override child’s dissent if there are serious medical reasons

Informed Consent & Assent


• Should have sufficient Paediatric experience

• Not all of them know about EU Paediatric legislation

• Not all of them focus on ethical questions

• Can be easy or difficult in the dialogue

• Should know today also Paediatric pharmaceutical legislation including EMA/PDCO

Ethics Committees / IRBs


• Make sure they have normal values for all ages

• Central Laboratory: negotiate with senior officer

• Central lab should have Paediatric experience

• Define upfront priorities if not enough blood

Laboratory/ Central Laboratory


Operational Challenges and Strategies

Christopher Bell, MSProject Manager

Agenda

• Robust Site Selection Process

• Navigation of Ethics Approval and Site Start-up

• Protocol and Assent Form Considerations

• Patient Recruitment/Retention Tactics

• Importance of Combined Parent/Site Partnership

• Operational Considerations

“STOP” to GO

• “STOP” and consider all factors of a Paediatric trial

Study SuccessStudy Success

Start-up• Feasibility• Site Selection• Navigating

Ethics Approval

Tailored Approach• Recruitment• Retention• Parent and

Patient Unit

Operational Management• Risk

Assessment and Mitigation

• IP Compliance• Oversight

Protocol Design• Scientifically

relevant• Paediatric

Specific• Assent form

design

Robust Site Selection – Approach

• General Principals to Paediatric Site Selection



• Begin to think of Site Selection, Start-up, and Recruitment as a whole

− Move away from sequential mindset

Robust Site Selection – Critical Success Factors

Understanding Previous

Performance

• Utilize database to determine feasible countries and sites

Projecting Future

Performance

• Go beyond the feasibility questionnaire

• Understand “workings” of site (not only how many patients, but how are patients recruited)

Early & Assertive

Engagement

• Build and maintain important relationships

• Work with Lead PIs to drive site and country submissions

ICON Medial Monitor & Sponsor

Involvement

• Review of protocol to ensure ability to enroll

• Discussion with Investigators for strategies

Successful Feasibility Process

Paediatric Oncology Clinical Trial Environment

• Small community of sites− Usually small number of sites per country

o “World as a Village”− Knowledge of already existing sponsor relationship− Sponsor engagement with site selection

• Sites organized in networks− Networks structure− Who is who in the network − Who should be contacted

• Competitive for patients and site resources− Number of ongoing studies − Majority of drugs first registered in adult population − Competition of site resources− Need to select back up sites from the beginning− Engagement of medical monitor early in the site selection process

Case Study - Phase 1/2 study in R/R HL or sALCL

• Global Study• 19 Sites (US, EU, Mexico)• Up to 42 patients

− Phase 1 enrolled over 3 dose escalation cohorts− Phase 2 enrolled at recommended Phase 2 dose

• Single Arm Study• Endpoints

− PK, Safety (Ph1)− Overall Response Rate (Ph2)

• Key Eligibility − Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell Lymphoma

(sALCL) patients, ages 2 to <18− HL patients in second or later relapse, sALCL beyond first remission or

refractory to front-line chemotherapy− Performance score ≥ 60− CD30+ disease

• Previous collaboration with multiple Paediatric Oncology Networks

• Recommend working with well-established oncology research networks:− Children’s Oncology Group (COG)− Innovative Therapies for Children with Cancer (ITCC)− Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL)− Paediatric Oncology Experimental Therapeutics Investigators' Consortium

(POETIC)

• Leverage vast reach of Oncology Networks− Ex. More than 90% of Paediatric cancers diagnosed each year in the US

are cared for at institutions within COG

Robust Site Selection – Paediatric Oncology Networks

• Case Study: Government vs. Industry Trial

− During feasibility process, made aware of EU Government study competing for similar

patient population

− Approached KOLs + Lead PIs to work EMEA and not against

o Resulted in collaborative effort to research disease; not competitive effort to

restrict progress

o At conclusion of EMEA trial, Phase 1/2 study endorsed by EMEA and referrals

obtained

Robust Site Selection – Case Study

Robust Site Selection – Case Study

0123456789

10

2 2 2 2

4 4

10Pa

tient

sEnrollment by Country

France, 3Germany, 5

Italy, 2

Mexico, 2

Netherlands, 1Spain, 1

UK, 1

US, 4

Site Selection by Country

Navigation of Ethics Approval and Site Start-up


• Country Challenges− Understand trial competition and if other regions appropriate− Tailor feasibility to understand processes− Verify submission requirements (parallel/sequential submissions)− Duration of approval timelines

• Lengthened timelines expected− Site pre-review Paediatric committees prior to IRB/EC submission− Complicated informed consent negotiations

o Sites will require Paediatric assent form, often 3 in addition to adult/parental consent form

− Expect IRB/EC queries, sometimes multiple rounds− Sites often have extensive workloads, with many studies

o Resources dedicated to start-up will vary

• Regulatory:− Seek and implement scientific advice (EMA) prior to protocol finalization

o Use evidence of scientific advice as supporting documentation for CA and EC submissions

− Early identification of KOL/NCI in each countryo To obtain EC requirements and aim for specific EC meetingo Obtain input on ICF requirements (age groups, specific EC templates)

− Actively shorten and simplify country ICFs− Streamline comments for all parties responding to CA/EC queries

• Contracts:− Flexibility with use of site contract templates− Agree on fallback language and budget tolerances in advance− Rapid responses on budget requests and robust escalation plan− Wherever possible, utilize previously negotiated contract language and budgets

to try to come to a faster agreement


Protocol Considerations

• Children are Not Small Adults

• Adult Protocols− Avoid Copying and Pasting

• Study Design− Scientific Necessity – Especially with Children− Timing of Visits and Procedures must be able to be followed− Procedure Considerations

o Placement of Procedures in Schedule of Eventso Minimization of painful procedureso Prevention of physical/emotional pain as much as possible

• Age and Disease appropriate and Validated endpoints− Needed to permit assessment of efficacy− Non-invasive options

• Long-term Studies− Needed to assess effects of chronic therapy

o Growth & Development

Protocol Considerations (cont.)

• Blood volumes are mass dependent− ~80 mL/Kg total blood volume− Limitations to the amount of blood which

may be drawn for research or clinical purposes

− Sites and/or ECs may set local limits

• Other Considerations− Dosing most commonly determined from

Adult Trialso By weight or body surface area (BSA)

− Formulation needs to be consideredo Capsule Oral Formula?

WHO: Key recommendations regarding blood sampling in children involved in

clinical research

Existing guidelines for blood sample volume limits (ranging from 1–5% of total blood volume within 24 hours and up to 10% of total blood volume over 8 weeks) are consistent with the limited evidence available on “minimal risk” to children.

Lower limits for sick children are advisable, and a maximum of 3 ml/kg post-neonatally within 24 hours (3.8% of total blood volume), in line with United States policy, seems to be a reasonable guideline, although each study must be judged on its own merits and greater caution may be needed in children with illnesses that impair the replenishment of blood volume or haemoglobin.

The blood volumes needed for clinical care and research should be carefully assessed and a clear justification should be provided to institutional review boards and ethics committees, which they can then assess and monitor.

Effective coordination of clinical and research activities is needed to minimize the burden to the child.

Collection procedures should minimize discomfort for the child as much as practically possible.

Blood collection volumes and procedures should be acceptable to the community in which the research is conducted.

More research on the impact of blood sampling is needed to better assess appropriate blood volume limits in particular patient groups.

Patient's Weight in Pounds

Patient's Weight kg

Avg Total Blood

Volume (TBV)

Max (3.8%)

TBV in 24 hours

26-30 11.8-13.6 984.3 37.4

31-35 14.1-15.9 1162.5 44.2

36-40 16.4-18.2 1340.8 50.9

41-45 18.6-20.5 1515.1 57.6

46-50 20.9-22.7 1689.5 64.2

51-55 23.2-25 1867.8 71.0

Assent Considerations

• Assent Process Varies by Age and Country

− In general, assent contents include:o 0-2: Informed Consent of Parentso 2-5: Informed Consent of Patents, with verbal explanation of study

procedures supported by pictures and/or videoo 6-8: Pictures, videos, comic strips, etc to help child understand expectationso 9-11: Short assent form directed to child with age appropriate language and

consideration for written agreement of childo 12-17: Closely resemble informed consent of parents, directed to

adolescent and include signature line

− Strong and definitive objections from the child should be respected

Assent Considerations

• Prepare Consents for Each Age Group− Be Prepared - IRBs/ECs will dictate assent waivers− Do not forget to generate adult consents

• Should be written towards the youngest person

• Beyond Assent − Control over treatment− Fosters relationships with site staff− Encourages active participant

• Site’s Role− Play essential role in addressing concerns

of both parents and children while enrolling child in study

Blue Chip (2013), White Paper on Accelerative Recruitment for Paediatric Clinical Trials

Patient Recruitment Tactics – Study Team

Proactive Site Engagement Plan – Critical to keep study front & center

Early, assertive study start up activities with good working relationships

• On-site visits from Core Study Team to each site to keep engaged• Rejuvenation Meetings

− Discuss site practices as well as successes and challenges − Maintain site focus on the study

• Open Communication− Personal emails to the PIs− Teleconferences with PIs/Site Staff− Use Newsletters and blast fax/emails to provide study updates

• Establish good working relationship with key Investigators early• Patient identification and screening efforts must be initiated immediately• Identification of Key Referral Centers

− Communicate to surrounding institutions that Study is actively seeking patients− Possibility of referral center reimbursement

Patient Recruitment Tactics – Addressing Logistics

Potential Long Distance Travel

Parents and the “educated patient”

• Patients with rare disease will travel to be seen by a specialist• Returning to the site for follow-up can be challenging; should consider:

− Travel and lodging reimbursement (mileage, train/bus, hotel, meal voucher)− Shipment of IP to subjects who have difficulty traveling to the center− Home Trial Support Services, using visiting nurses to travel to the subjects

home and conduct study visits (AEs, vitals, PK draws, drug accountability)

• “Getting the word out” - Participating centers advertise study on institution website• Working with Advocacy Groups

− Customized letters to advocacy groups discussing trial• Tools to explain the study to caregivers and subjects

− Firecrest− Training DVDs

Recruitment – The Paediatric Tailored Approach

Strategies

Tailor The Recruitment Process

• Familiarity with environment− Family atmosphere

• Proactively address challenges by age group• Comfort

− Snacks− Movies / DVD player accessible− Free WiFi− Think of the siblings

• Leverage outreach of Cooperative Groups/Networks• Age Specific Recruitment Materials

− Advertisements should be directed towards parents, but involve the patient• Continued assessment of Screen Failures

− Document reasons for ineligibility to decide if a protocol amendment is needed• Cooperative Enrollment Process between Parent and Child – “Keep the Control”

Retention – The Paediatric Tailored Approach

Communication

The Caregiver

• Keep it Frequent• Communication Media

− Many parents tend to favor in-person communication while children prefer digital communication

− Tailor, tailor, tailor• Smart phone apps for study compliance – keeping patients to their schedule

• Making it easy for the parent/caregiver and subject − Frequent follow up calls − Flexible Scheduling− Guidance materials (i.e. information packet, visit reminders)− What does this mean financially?

o Stipend/Gift Cards as designated intervals

Retention – The Paediatric Tailored Approach

Gamification

• Linking study-specific game to protocol requirements• Consider EC/IRB Requirements• Participants can be provided pre-loaded materials (available to each

visit or download)• Players rewarded for compliance

− Fosters relationship between Parent and Child as well as Child and Site

• More engaging clinical trial experience− “Play to Learn”

• Does not need to be electronic − Paper coloring

• Continue to assess new technology

Make the study fun and

interesting for the children

Gain Parent buy-in

Keep the sites motivated and

engaged

Manage study procedures & commitment

Parent/Site Partnership – Working Together as a Unit

FPFV

Phase 2 Opened (Early)

All HL Pts Enrolled (1 month early)

Major Recruitment Milestone (65% enrollment); 10 months early

Paediatric Recruitment – Case Study

Operational Considerations – Risk Assessment

Successful Risk Mitigation

Regulatory Submissions and Approvals

• Identification of Lead PI who will review protocol and provide to colleagues

• Protocol development/ endorsement by Ped Oncology Groups

• Familiarity with guidelines for individual age groups

• CA submission to all sites (incl back-up) in case sites to be activated quickly

Motivation of Site Staff• Robust Site engagement program• Increased communications with study

staff throughout peak periods of study • Study coordinator teleconferences to

discuss recruitment and retention• Engage sites for best practices and

recognize accordingly• Newsletters• Meeting investigators at National

Scientific Meeting

• Identifying the proper sites to conduct the study

• Collaboration with Ped OncCooperative Groups

• Develop Appropriate budgets for key referral centers

• Training and educating parents and caregivers on study

Paediatric Population

• Tracking of patients and sites• Provide ongoing updates to PIs

and study staff to maintain transparency

• Conduct solid feasibility and have site/country back up plan

• Individualized recruitment materials

• Caregiver considerationsEnrollment Rate

Operational Considerations – Investigational Product Compliance & eDiaries

• Compliance in Paediatric trials has historically been poor (can range from 11 – 93%) − Profound affect on efficacy− Complicates the relationship with the treatment team

• Implementation of eDiaries and general communication/patient management practices can have positive impact on compliance/adherence− Implement eDiary/Patient Reminders

o Multiple approved ICON vendors (ERT, CRF Health, Omniscience), therefore faster timelines expected

o Multiple options available for service (eDiary, Smart Phone App, Text Messaging Service)

− Patient campaigno Brochures to discuss importance of complianceo Improves communication between patient and study teamo Generate ownership by Parents to oversee child’s

compliance

Winnick, S., Lucas, D., Hartman, A., Toll, D. (2004), How Do You Improve Compliance? Paediatrics, 115(6), e718-e724

• Phase 1 studies require detailed oversight and tracking of samples• Many study teams are spending numerous hours manually tracking specific lab

samples− Both inefficient and can lead to mistakes (i.e. human error)

• Automated reports developed in collaboration with Central Labs and using reports from Lab Database to report projected, received, and analyzed samples

• Benefits:− Generated/re-generated whenever needed / increase efficiencies− More accurate than manual counting− Allow monitors to prioritize based on report of missing samples − Remote management of samples− Complete oversight of each sample aliquot

Operational Considerations – Vendor and Sample Management

• Case Study: Expediting timelines through intimate Vendor & Sample Management

− Required complex network of communications and activities for analysis

− Establish process early for all activities requiredo PK analysis primary endpoint of Phase 1, efficient process for tracking and

reconciling PK samples neededo Clear communication paths to be established with all vendors involved

− Oversight of vendors and samples helped to resulted in complete analysis 1.5 months ahead of schedule

o Phase 2 portion of study opened 1 month ahead of projections

− Other Considerations:o Review Original CA/EC/IRB submissions/approvalso Review CA/EC/IRB requirements for opening Phase 2o Additional submission required to register trial as Phase 2

Vendor and Sample Management – Case Study

Conclusion

• “STOP” and consider all factors of a Paediatric trial

Study SuccessStudy Success

Start-up• Feasibility• Site Selection• Navigating

Ethics Approval

Tailored Approach• Recruitment• Retention• Parent and

Patient Unit

Operational Management• Risk

Assessment and Mitigation

• IP Compliance• Oversight

Protocol Design• Scientifically

relevant• Paediatric

Specific• Assent form

design

The EU PaediatricInvestigation Plan (PIP): Challenges & lessons learnt in PIP negotiations


• PIP document template on the EMA website

• Part A: Administrative Issues: separate form (AF)

• Part B: Overall development of the medicinal product

• Part C: Applications for product-specific waivers

• Part D: Paediatric Investigation Plan

- D.1 Existing data & proposed overall paediatric strategy

- D.2 Quality Aspects

- D.3 Non-clinical Aspects

- D.4 Clinical Aspects

- D.5 Timelines of Measures

• Part E: Application for Deferrals

The PIP Document


- 70 -70

• Class Waivers & Individual Waivers

• Indication vs. Condition

• Epidemiology and PDCO assumptions

• Deferrals

• Therapeutics vs. Diagnostics

• PIP Measure Timelines


PIP Key Issues

• Waiver: no Paediatric development required by EMA • Are granted as total waivers or for some age groups• Only 3 reasons to grant a waiver:

- Disease does not exist in children- No significant therapeutic benefit to be expected- Drug could be dangerous for children

• Total waiver request: short procedure of 60 days only• List of class waivers is on the EMA website• So far, two class waivers have been revoked

- Postmenopausal osteoporosis- Malignant melanoma in adolescents


Waivers & Class Waivers


Condition Vs. Indication

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/09/WC500133065.pdf

• Class waiver for melanoma was revoked

• Justification: 1.7/ 100’000 15-19ys olds in US statistics Surveillance, Epidemiology & End Results (SEER), www.seer.cancer.gov

• Disease frequency grows exponentially with age of the 15-19ys olds, majority will be 18-19y old, i.e. adults by EU law

• And: ¾ of adolescent melanomas are only local no systemic treatment required - in contrast to most adult patients

• 5 melanoma PIPs

• (Ipilimumab; Dabrafenib; Trametinib; Vemurafenib) that ask for studies in advanced adolescent melanoma

• Separate clinical studies in adolescent melanoma ethically questionable

• Adolescents should have the right to participate at adult studies, but with these patient numbers no statistically significant results possible


Epidemiology: The Melanoma Paradigm

• Many Paediatric measures (studies, formulation development, animal studies) start after adult registration

• For this purpose, beginning and end of measures can be deferred

• Request for deferral is part E of the PIP

• For deferred measures, annual progress report must be sent to EMA

• Template on EMA website

• Longest deferral until December 2031 in an allergen PIP

- EMEA-000905-PIP01-10


Deferrals

• EMA Paediatric coordinator• PDCO rapporteur• PDCO peer reviewer • Interactions:

- Pre-submission teleconference (TC) before PIP submission - Clarification TC, usually 1 during the clock stop - Oral Explanation (OE) at the end of procedure (day 120)

76

Negotiation Partners


- 77 -klausrose Consulting

• PIP skills needed: know PDCO, its decisions; good negotiation skills

• Potential for saving resources is highest during early PIP preparation

• PDCO will only trust clinical experts in the discussion

- without one or several external scientific expert you are lost

• In-depth scientific preparation of the PIP is essential

• Brainstorm before PIP submission all potential thoughts of counterparts

• Discussion at clarification TC and OE can be very demanding

• Aim for individual company

- negotiate PIP that will serve child health in the far future and lets company survive


Consequences for Negotiation

US & EU PaediatricLegislation And Its Impact On Drug Development


• Key features: balances mandatory and voluntary elements

• Continues to offer voluntary incentive

• Limits mandatory requirements to the same indication as in adults

• Rare & orphan diseases are excluded

• Ultra-rare diseases are regularly waived for PREA

• Wants better medicines for children or information about them

• Not hostile to industry

US Paediatric Pharmaceutical Legislation


• EMA Report 2013: Successes of the Paediatric Regulation after 5 years August 2007-December 2012

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2013/06/WC500143984.pdf

• Report EU Commission 2013: Better Medicines for Children - From Concept to Reality

http://ec.europa.eu/health/files/paediatrics/2013_com443/paediatric_report-com(2013)443_en.pdf

EU Legislation: Recent Reports


• Enzyme replacement therapies

• Adult cancer types

• Cystic fibrosis

• Oncology: help the immune system to attack cancer cells


Examples for Breakthroughs

• CF, a genetic disorder, affects epithelial cells in the entire body resulting in respiratory, endocrine, GI & reproductive abnormalities

• Caused by defect(s) in the CF transmembrane conductance regulator (CFTCR) protein. Sweat, digestive fluids, and mucus are too thick.

• Life expectancy 1950: 2 (two) years; 2012: ~ 40 (forty) years

• Until 2012 treatment with mucoactive agents (e.g. DNAse), antibiotics, inhaled beta agonists, and other anti-inflammatory drugs

• ~ 5% of CF patients have the G551D mutation

• Kalydeco approved by FDA JAN2012 for patients > 6 y with the G551D mutation; registration based on two 48-week, placebo-controlled studies with 213 patients, one in > 12 years & another in 6 -11 y; good S&E; lung function improvement.

Ivacaftor (Kalydeco) for CF (Cystic Fibrosis)


• PIP submitted 2008, first RfM (request for modification) 2009, 8th modification accepted 2013 (EMEA-000335-PIP01-08-M08)

• PIP studies in the 2013 version: 1 quality, 1 non-clinical, 9 clinical studies to be performed until December 2016. Of the clinical studies, 2 in adolescents, 4 in > 6 y, 1 in 2-5y, 1 in < 2y, one in CF patients > 6 y with non-G551D CFTR gating mutation

• This drug is already approved in children > 6 years!

• What is that PIP good for? Was the PDCO helpful in developing this breakthrough medication? Or was it an obstacle?

• Well …. No EMA registration without a PIP. Even if the company develops a life saving drug in a pediatric disease

• EMA keeps only the most updated version of the modified PIP on its website. Details are confidential between Vertex and EMA.

Ivacaftor (Kalydeco)


• NBE developed only for use in premature neonates � rare condition

• Scientific Advice with German BfArM and Swedish MPA 2008, with CHMP in June 2009 to discuss clinical development plan

• PIP submitted FEB2010, OE JAN2011

• Agreement with PDCO on a plan that contained only minor modifications compared to the clinical program agreed with CHMP 19 months earlier

• Clinical program delayed at least 9 months

Case Study Rare Disease(presented at EFGCP/DIA/EMA Pediatric Conference 2012)


• So far > 1000 PIPs have been submitted

• The key elements are published, but not the details

• Details are always confidential

• Nevertheless, we can see trends in specific areas

• Pediatric oncology

• Vaccines

• Drugs for preterm newborns

• Drugs developed only for children

• Rare diseases

• Adolescents

PIP Decisions


• Is consideration of children possible at all in drug development?

- Some areas: yes. E.g. use of antibiotics in babies

- Some areas: no. E.g. terbinafine for fungal skin affections. Pivotal trials for FDA registration: > 2000 patients; 2 < 18 years. Statistical power?

• Where disease is very rare, case numbers too low for statistical power

• Challenging areas where the PDCO may be doing more damage than good: orphan diseases, Paediatric diseases, vaccines

• Ethics committees now confronted with two opposite challenges

- Clinical trials in children are ethical and necessary, and

- Some PDCO-triggered studies should be refused

Reflections


• Very high ambitions, partially based on wishful thinking

• Very enthusiastic, doesn’t treat companies as partners

• Increases costs of drug dev; for big pharma costs still marginal.

• Does not contribute to pharmaceutical innovation in Europe

• Has increased the weight of academic Paediatrics

• Has increased contract opportunities for CROs

• Most clinicians have still positive general view, but criticism starts

• Assessment of relation of resources assigned to resulting clinical benefit for children often difficult due to confidentiality

• However, there is a number of patterns we will discuss


EU Paediatric Legislation

• EMA & EU national regulatory authorities are not drug developers

• But they want to have a say in Paediatric drug development

• Companies mostly focus on profitable areas. Was in the past frequent adult diseases, e.g. hypertension, dyslipidemia, diabetes type 2

• Most of these diseases exist in children but are rare

• New challenge for research-based pharma: rare diseases

• In adult the case numbers are often still large enough for clinical trials

• Dilemma: where diseases are rare in children, one-size-fits-all regulatory methodology is not appropriate

• Where child diseases are frequent, industry develops anyway, see e.g. growth hormone

• In Paediatric oncology, aiming at registration is not the way forwardklausrose Consulting

Dilemmas of EU Paediatric Legislation

• Drug development no longer possible without considering children• EU Paediatric legislation & administration:

- Mosaic of goodwill, scientific input, reasonable decisions, abuse of power; lack of checks & balances, disproportionate use of resources, limited clinical benefit

• Aim for individual company- negotiate PIP that will serve child health in the far future and lets company

survive• The most positive aspect of the EU Paediatric legislation was to contribute to

acceptance of Paediatric research in the public perception

• Has in some areas started to damage child research, e.g. oncology

• The debate will grow stronger over the coming years


Conclusions

Rose K: A Paediatric Investigation Plan Case Study. Pharmaceutical Medicine 2012; 26 (5): 287-295

Rose K: European Union Pediatric Legislation Jeopardizes Worldwide, Timely Future Advances in the Care of Children With Cancer. Clinical Therapeutics 2014, 36 (2), 163-177

Rose K: Pediatric Pharmaceutical Legislation in the USA and EU and Their Impact on Adult and Pediatric Drug Development. In: Bar-Shalom D & Rose K: Pediatric Formulations – A Roadmap. Springer 2014

Rose K: Clinical Testing in Children In: Bar-Shalom D & Rose K: Pediatric Formulations – A Roadmap. Springer 2014

Rose 2008: Klaus Rose: Ethical, Regulatory and Scientific Challenges in Paediatric Drug Development: Pharm Med 2008; 22 (4): 221-234


References

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