Regulatory challenges and opportunities for the use of

Real World Evidence for drug registration and labelling

Marianne Bork Samuelsen, Msc Pharm

Regulatory Affairs

Novo Nordisk A/S

Presentation title Date 1

Symposium

Drug Research Academy

14 March 2018

• “Real-World data” (RWD) is a term used to describe healthcare related data that is collected outside of randomised clinical trials.

• “Real-World Evidence” (RWE) meaning evidence coming from registries, electronic health records (EHRs), and insurance data…..

What is Real-world evidence?

Presentation title Date 2

Real World

Evidence

Real World AnalyticsReal World Data

Registries and databases

Social media

Electronic Health

Records

Case reports

Non-RCTs

Mobile technologies

Safety surveillance

Scientific communication

Pricing and reimbursement

Marketing claims

Label claims?

Use of RWE

• Regulatory agencies are more cautious regarding evidence of benefit and would prefer randomised studies, but are beginning to define areas suitable for using RWD

• The decision makers in regulatory agencies, healthcare organisations and healthcare professionals will have increased confidence in using the evidence and insights developed from RWD if there is • confidence in the quality of the data• good understanding of the methodology• consensus on the relevance of the results

Regulatory challenges

Presentation title Date 4

FDA draft guidance for medical devices

Presentation title Date 5

• FDA recommends use of the pre-submission process when considering the development of a study using RWD in a regulatory submission

• RWE to support a regulatory decision is based on the scientifically robust methods and approaches to determine whether submitted RWE is of sufficient quality to support a particular regulatory decision

• Protocols and analysis plan for RWD should address the same elements that a traditional clinical trial protocol and statistical analysis plan would cover

• By end 2018: one or more public workshops to gather input into issues related to RWE use in regulatory decision-making

• By end 2019: initiate activities aimed at addressing key outstanding concerns and considerations in the use of RWE for regulatory decision making

• By end 2021: Publish draft guideline on how RWE can contribute to the assessment of safety and effectiveness in regulatory submissions

FDA Performance goals

Presentation title Date 6

• Challenge move from a high degree of certainty to more of a degree of uncertainty and from structured data, represented by RCT data, to unstructured, unvalidated data of unknown provenance

• Need to address the prospect of cyber-attacks on data

• Senderovitz co-chair of the Heads of Medicines Agencies (HMA) and European Medicines Agency (EMA)’s joint task force on big data

• Assess whether label changes can be based entirely on real world data

Presentation title Date 7

Regulators need to move from ‘comfort zone’ and accept real world data

• If you intend to use RWE: Engage early for scientific advice• Agree on protocol • Alternative/additional data sources• Data quality • Representativeness for Europe

• Regulatory acceptability of RWE in product development generally more acceptable for • If an RCT is not feasible (time, ethics, rarity) • Hard endpoints (to offset bias) • Conditions with known and predictable progression (note: prospective natural history) • Well thought proposals and trust in their reliability and feasibility

EMA recommendation

Presentation title Date 8

• EU approval: 23-Feb-1996

• Indication: Treatment of bleeding episodes and prevention of excessive bleeding in connection with surgery in patients with inherited or acquired haemophilia with inhibitors to coagulation factors (FVIII or FIX).

• US approval: 25-Mar-1999

• Indication: Treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX

Example of use of RWE for NovoSeven

Presentation title Date 9

• 4 patients in the clinical trial were also included in the International Registry as well as six out of 10 published case reports

• Commitment to establish a post-marketing registry of the treatment of patients with Glanzmann’s thrombasthenia.

• In registry: focus on the administered dosage regimens, efficacy and safety

EU – Glanzmann’s thrombasthenia

Presentation title Date 10

• 4 patients in the clinical trial not enough

• 190 pts primarily from EU, but also from US and elsewhere from the Glanzmann’s Thrombasthenia Registry (GTR)

• 7 pts from Hemophilia & Thrombosis Research Society (HTRS) patient registry

• Published literature

US – Glanzmann’s thrombasthenia

Presentation title Date 11

• 70 patients with Factor VII deficiency treated with NovoSeven• 32 were enrolled in emergency and compassionate use trials conducted by

Novo Nordisk

• 35 were reported in the published literature

• 3 were from a registry maintained by the Hemophilia and Thrombosis Research Society

Compassionate use is a treatment option that allows the use of an unauthorised medicine. Under strict conditions, products in development can be made available to groups of patients who have a disease with no satisfactory authorised therapies and who cannot enter clinical trials. Only for life-threatening, long-lasting or seriously debilitating illnesses.

EU & US - Congenital Factor VII Deficiency

Presentation title Date 12

• Data collected from 4 studies in the compassionate use program conducted by Novo Nordisk and the Hemophila and Thrombosis Research Society (HTRS) registry.

• 70 patients with acquired hemophilia were treated with NovoSeven

• 61 patients were from the compassionate use program with 100 bleeding episodes

• 9 patients were from the HTRS registry with 13 bleeding episodes

EU & US - Acquired Hemophilia

Presentation title Date 13

Update of Summary of Product Characteristics section 4.6 Fertility, pregnancy and lactation

• Meta-analysis of published data on the use in pregnancy

• Additional available clinical data published

• Post-marketing data

• Cumulative summary of exposure reports

since the launch of the product

Lantus - Pregnancy data

Presentation title Date 14

• Regulatory applications of RWE for drugs could in the future be used for label updates for

• Safety

• Dosing

• Drug-drug interactions

• Sequence of therapies

• Subpopulations

• New indication

Use of RWE in the future

Presentation title Date 15

FutureNEXT EXIT

• RWE is already used in post-marketing safety surveillance and for price and reimbursement

• RWE can be used to demonstrate efficacy and safety in post-marketing label expansions for products, more common for rare diseases

• Use of RWE for initial Marketing Authorisation applications is uncertain

Summary

Presentation title Date 16