Panel 2 Discussion - Friends of Cancer Research 2_Final.pdfInnovative trials which established “proof of concept” for ... –Eltrombopag plus backbone therapy for severe aplastic

Data Generation to Support Cross-labeling of Indications for

Combination Products

#FriendsAM17

Panel 2 Discussion

Panel 2 Participants

Moderator: Kenneth Anderson, Dana-Farber Cancer Institute, Harvard Medical School

• Roger Dansey, Merck

• Ann Farrell, U.S. FDA

• James Myers, U.S. FDA

• Jim Omel, Cancer Research Advocate

• Marc Scheineson, Alston & Bird LLP

2

#FriendsAM17

Working Group Objectives and Goals

Kenneth Anderson, MD

Dana-Farber Cancer Institute, Harvard Medical School

3

#FriendsAM17

Remarkable efficacy of combination novel therapies

, ie lenalidomide, bortezomib, and dexamethasone in

multiple myeloma

Urgent need for flexibility in clinical trial designs of

combination therapies (3 or more agents) utilizing

efficacy, toxicity, and MOA data of approved

single agents

Regulatory and legal implications of cross labelling as

new combinations are approved, ie inadequate

cross-labelling may limit sharing of product information

with patients and providers, and impact patient care.

.

PANEL 2

1. To develop a framework to inform level of evidence

for combination therapies

2. To identify alternative clinical trial designs to

generate data

3. To suggest regulatory modifications to better

facilitate up-to date labeling of combination

therapies without compromising FDA standards

for patient safety.

OBJECTIVES

Innovative trials which established “proof of concept” for

adaptive trial designs include umbrella and basket trials:

Biomarker-integrated Approaches of Targeted Therapy

for Lung Cancer Elimination (BATTLE) program, the

Lung Master Protocol (LUNG MAP),

and National Cancer Institute-Molecular Analysis for

Therapy Choice (MATCH) Trial.

The BATTLE program was an umbrella trial that used

adaptive randomization to assign patients with a single

cancer type, advanced non-small cell lung cancer, to a

trial arm for a targeted therapy based upon the presence

of one of several tumor biomarkers detected by real-time

biopsies. Completion of the BATTLE program signaled a

pivotal shift to innovation in streamlining clinical trials.

LUNG MAP is an umbrella trial that has harnessed the

power of innovative designs to minimize patient

screening and accruals for trials in advanced squamous

cell lung cancer. Similar to BATTLE, LUNG MAP assigns

patients to trial arms based upon tumor biomarkers but

the trial arms in LUNG MAP are more diverse, including

drugs sponsored by different manufacturers or an

immunotherapy for patients with unmatched tumor

biomarkers. LUNG MAP establishes a master protocol

for phase 2-3 clinical trials that assigns all patients to a

treatment and minimizes patient attrition at screening

with the intention of supporting drug approval.

NCI-MATCH is a pioneering basket trial, which studied

targeted therapies in patients with specific biomarkers

whose cancers have progressed or did not respond to

standard therapies. MATCH streamlined clinical trials by

assessing treatment efficacy in patients with diverse

cancer types that shared a biomarker in a single trial.

Complex trials with more arms, more patients required

Balance speed with level of evidence

Innovative ways to assess contribution of components in

combination to facilitate expedited approval.

Ie add on trials can identify contribution of novel agent

Kinetics of response and toxicity can vary, ie immune therapies

19 of 30 new drugs in oncology which received accelerated

approval were based on single arm trials.

Combination Clinical Trial Design

Historical data can replace an active control arm in support of

combination therapy when evaluating non inferiority in response

rate of a new treatment or for applying inclusion/exclusion criteria

based upon patient level demographics and risk factors to the

single arm trial.

Daratumumab was FDA approved with pomalidomide

and dexamethasone in 2016 using only a single arm trial,

since a prior randomized trial for pomalidomide and

dexamethasone could be used as a control for the new

three drug combination.

Myeloma Example

Use sources of real world data if adequate standards for

quality of data and guidelines formed for collection, ie ASCO

Cancer LinQ

Surrogate markers as endpoints to shorten trial times, ie.

response rate, progression free survival, MRD

Close monitoring for unexpected drug interactions or

adverse effects, ie IMiDs and anti-PD1 in myeloma.

Additional Issues to Expedite Combination Clinical Trials

Current Issues with Labelling

Updates may involve different sponsors

Irregular practices in updating labels may lead to inadequate

efficacy and toxicity information for patients and physicians

Regulatory requirements now mandate updating label when

it becomes inaccurate, false or misleading

Non uniform practices in updating labels, ie superior activity

of lenalidomide bortezomib and dexamethasone is

referenced on label for lenalidomide, but not bortezomib.

Reasons for Developing Framework for Updating Labels

When Combinations Approved

Communicate up to date information for patient care

Expand the label indications for marketing purposes

Update the label with new safety information

Ensure global access to the combination in countries where

the initial product label is used for coverage determinations

Emerging Challenges

Discrepancies between standard of care and clinical trials

for FDA approval.

Ie, ixazomib, carfilzomib, elotuzumab, and daratumumab each

were FDA approved together with lenalidomide dexamethasone

based upon prolonged PFS in patients with relapsed myeloma

compared with lenalidomide dexamethasone. However, in North

America, lenalidomide dexamethasone is used as initial therapy

and relapsed myeloma is therefore refractory to lenalidomide

dexamethasone. Label does not reflect standard of care.

Need trials leading to FDA labels that inform practice.

The Patient Perspective

Jim Omel, MD

Cancer Research Advocate

16

#FriendsAM17

Therapy Combinations

Ann T. Farrell, MD

Division of Hematology Products

Office of Hematology and Oncology Products

Center for Drug Evaluation and Research

FDA

18

Basis for Approval

• Demonstration of efficacy with acceptable safety in adequate and well-controlled studies

• Ability to generate product labeling that

• Defines an appropriate patient population

• Provides adequate information to enable safe and effective use

19

Approval pathways

• Regular approval – demonstration of clinical benefit

• Accelerated Approval

– improvement over available therapy

– Surrogate endpoint reasonably likely to predict clinical benefit

– Requires further study

20

Trial Designs

• 2 x 2 Factorial trial design

• Three arm trials

• Sequential Studies/Add on trials

• Alternatives

www.fda.gov

21

2 x 2 factorial design

Drug/Trial Arm Drug A Drug B

A Yes Yes

B Yes No

C No Yes

D No No

www.fda.gov

22

2 x 2 factorial design

• Typically not used in Hematology/Oncology

• Version - three arm trial

– oxaliplatin approval based on three arm trial of oxaliplatin plus 5-FU/Leucovorin versus oxaliplatin versus 5-FU/LV

www.fda.gov

23

Sequential/Add on Studies

• Sequential Studies

– Study drug A

– Study drug B

– Study Drugs A and B versus either A or B (add on)

– Study Drug C

– Study Drugs C and A and B versus A and B

• Numerous Examples particularly in multiple myeloma setting

www.fda.gov

24

Alternatives

• Single Arm Trials

• Master Protocols

• Meta-Analyses/Pooling Data

• Real World Data/Evidence

www.fda.gov

25

Single arm trials for combination

• External Data

• Commonly used in setting of refractory malignancies

• Examples

– Daratumumab plus pomalidomide plus dexamethasone

– Eltrombopag plus backbone therapy for severe aplastic anemia

26

Master Protocols

• Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations led to approval for Erdheim Chester Disease

www.fda.gov

27

Pooled Strategy

• Pembrolizumab for the treatment of adult and pediatric patients with:

– unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or

– metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

www.fda.gov

28

Real World Data

• Genentech, Novartis and KITE Pharma partnered to allow data sharing within the FDA

• Result

– Both CAR-T products approved with information on use of tocilizumab in their label

– Tocilizumab approved for adults and pediatric patients 2 years of age and older with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome.

29

Guidance for Industry

• Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination

• How to develop two investigational agents when single agent therapy is not feasible or is ineffective Intended to treat serious disease or condition

• Non-Clinical versus Clinical Development

• Unique trial designs based on the mechanism of action of the two novel products

www.fda.gov

•31

DATA GENERATION TO SUPPORT CROSS LABELING OF INDICATIONS FOR COMBINATION PRODUCTS

Roger D Dansey MD

Oncology Clinical Research

Merck Research Laboratories

Drug Development Challenges in the Current Era

Immunotherapy treatments have exploded onto clinical trial scene:

• Many innovative treatments being proposed for evaluation, particularly in combinations

• Pre-clinical models not sufficiently predictive to eliminate options

• Many clinical trials being initiated to test new concepts

Drug development should be efficient and fast from FIH to approval:

• Early phase trials have adapted to new environment with basket, umbrella, platform and master protocols

• Late phase trial designs have yet to adapt:• Approvable clinical endpoints ORR and PFS may not capture efficacy• OS improvements may become difficult to achieve with widespread use of

immunotherapies outside of clinical trials

•32

Phase 3 Trials and Impact of Immunotherapies

PD/PD-L1 monotherapies:

• Altered treatment of melanoma, NSCLC, SCCHN, Hodgkin’s Lymphoma, Bladder Cancer, Gastric Cancer, MSI-H cancer, RCC, and HCC

• Clinically meaningful responses in other cancers at varying frequencies

PD-1/L1 combination therapies:

• Hold great promise beyond monotherapy with PD-1/L1 as backbone

• Extensive registration efforts underway with diverse combinations

• Partner drugs include other immunotherapies, chemotherapies, targeted therapies and oncolytic viruses

Phase 3 trial designs need to be able to account for contribution of individual components and be suitable to support potential labelling of combinations

•33

Ongoing Phase 3 Combination Trials with Approved PD-1/L1 Agents

• Bladder Cancer

• Ovarian Cancer

• Small Cell lung Cancer

• Melanoma

• Renal Cell Cancer

•34

• Non-Small Cell Lung Cancer

• Breast Cancer

• Colo-Rectal Cancer

• Prostate Cancer

• Head and Neck Cancer

Expectations for approval of combinations in Successful Phase 3 Trials

Contribution of individual drugs to efficacy of combination:

• Individual component treatment effect needs to be clearly defined to justify including each component of combination in labeling.

• Factorial clinical trial designs most precise method to measure effects by contemporaneous evaluation of each component

Labeling of individual products in the combination (Cross Labeling):

• Inclusion in individual product labels requires demonstrating contribution of components

• Sponsors of individual products collaborating/supportive of cross labeling

•35

Contribution of Components in Registration Trials

Problem:

• Precisely isolating effect of each component by direct comparisons requires trials that are factorial and multi-arm in design

• Number of trial arms dependent on number of individual drugs

• Multi-arm trials require more patients, take longer to complete, are more complex to execute and result in repetitive generation of data

Potential solution:

• Accept utilizing data from previous trials or other sources to indirectly infer contribution of individual components

• Reduces the number of patients needed, shortens trial duration and avoids repeated generation of similar data

•36

Cross-Labeling in Combination Trials

Problem:

• Lack of clarity on the potential to achieve cross-labeling prior to embarking on adequate and well-controlled combination registration trials

• Lack of cross-labeling creates disparity in publically available label information for each product in combination, potentially affecting patient care

Solution:

• Acceptance that combination trials with results sufficient to support labeling of one component of the combination should support labeling for other components

• Ensures consistent and broad communication of the safety and effectiveness of the combination

•37

Common Trial Constructs:Proposed alternatives to multi-arm designs

In an A+B vs B where B is established standard of care:

• No requirement to isolate the contribution of B by including A as a third arm

• Sufficient for cross-labeling if trial meets endpoints

•38

Common Trial Constructs:Proposed alternatives to multi-arm design




In an A+B vs B design where A is inactive/minimally active as monotherapy

• No requirement to include A as a third arm

• Sufficient for cross labeling if positive

•39

Common Trial Constructs:Proposed alternatives to multi-arm design




In an A+B vs B design where A is inactive/minimally active as monotherapy

• No requirement to include A as a third arm

• Sufficient for cross labeling if positive

In an A+B vs C design where C is established standard of care:

• No requirement to isolate the individual contributions of A and B if contributions can be inferred based on indirect comparisons

• If A + B superior to C should support cross-labeling

•40

Patents and Exclusivities Under Hatch-Waxman

Friends of Cancer ResearchAnnual Meeting

November 15, 2017

James Myers, J.D.Office of Generic Drug Policy

CDER, FDA

42

Disclaimer

• This presentation reflects the views of the author and should not be construed to represent FDA’s views or policies.

43

Patents and Exclusivities Generally

• Hatch-Waxman Amendments of 1984– Created abbreviated approval scheme for abbreviated new drug

applications (ANDAs) and 505(b)(2) new drug applications (NDAs)

– Created new exclusivities and patent listing/certification process to resolve patent disputes before approval

– Congress intended to strike balance between encouraging innovation and accelerating availability of lower cost alternatives

• Patents and exclusivities are forms of protection for innovator products that are intended to protect and encourage innovation

• However, patents and exclusivities have the ability to delay or block the approval of certain ANDAs and 505(b)(2) NDAs

44

Patents

• FDA plays ministerial role with respect to patents– Patents are granted by U.S. Patent and Trademark Office

• NDA holder informs FDA of patents that claim the drug product, drug substance, or method of using the drug

• FDA lists these patents in the Orange Book under the relevant NDA

• 505(b)(2) NDA and ANDA applicants generally must certify to each relevant patent listed in the Orange Book for the relied-upon listed drug– Patents may be challenged by 505(b)(2) NDA and ANDA

applicants in court before approval

45

• ANDA and 505(b)(2) applicants generally do not have to certify to method-of-use patents if the applicant is not seeking approval of protected use– ANDA applicant can elect to submit a “section viii

statement” (section 505(j)(2)(A)(viii)) and not seek approval of protected use

– 505(b)(2) applicant can elect to not seek approval of protected use

• ANDAs and 505(b)(2) NDAs can omit (and “carve out”, in the case of ANDAs) information protected by method-of-use patent so long as product is safe and effective for remaining conditions of use

Method-of-Use Patents

46

Three-Year Exclusivity for New Clinical Studies

• NDA for a drug with a previously approved active moiety(ies) qualifies for 3-year exclusivity if it contains1. New2. Clinical Investigation(s) 3. Excluding BA/BE studies4. Essential to Approval5. Conducted by or for the applicant

• Blocks the approval of 505(b)(2) NDAs and ANDAs that seek approval of the exclusivity-protected “conditions of approval”

• ANDAs and 505(b)(2) NDAs may be able to omit (and “carve out”, in the case of ANDAs) information protected by 3-year exclusivity– Must still be safe and effective for remaining conditions of use

47

Additional Issues

• Cross-labeling without a right of reference between NDAs may raise complicated patent and exclusivity issues – 505(b)(1) NDA (e.g., Drug B) seeking to incorporate information from

another NDA’s labeling (e.g., Drug A) that has been granted right of reference from Drug A would generally be treated as a 505(b)(1) and would not be subject to patent and exclusivity provisions described above

– However, if Drug B does not have right of reference from Drug A and relies on FDA’s prior finding for Drug A, Drug B may be considered 505(b)(2) NDA and may be subject to patent and exclusivity provisions described above applicable to 505(b)(2) NDAs

• Cross-labeling involving biologics license applications (BLAs) and NDAs raise important and complicated legal and regulatory considerations– BLAs and NDAs are governed by different statutory and regulatory

schemes

Panel 2: Data Generation to Support Cross-Labeling of Indications for Combination Products

By: Marc J. Scheineson, Esq.PartnerAlston & Bird ([email protected]; 202-239-3465)

mailto:[email protected]

50©Alston & Bird 2017

Legal Ramifications Re: Cross-Labelling

▪ Brand collaboration re: approved drugs with remaining exclusivity

▪ No Brand collaboration re: approved drugs with remaining exclusivity

▪ NCE + Generic

▪ NCE + NCE

▪ Legal Ramifications▪ Infringement (Brand v. Brand and Brand v. Generic)

▪ Protect Against Generic Entry

▪ Available patent and regulatory exclusivities – (NCE-1 and PTE)

▪ Section viii carve outs


Benefits of Secondary Patents

▪ Patents that cover more than just the pharmaceutical compound can significantly prolong a new drug’s patent-based exclusivity after expiration of compound patent

▪ Formulation patents add an average of 6.5 years of incremental patent life (5.9 to 7.3 years)

▪ Method of use patents add an average of 7.4 years of incremental patent life (6.4 to 8.4 years)

▪ Polymorphs, isomers, prodrug patents add an average of 6.3 years of incremental patent life (5.3 to 7.3 years)


Primary and Secondary Patents

▪ Compound

▪ Formulations

▪ Compositions

▪ Methods of use

▪ Mechanisms of action

▪ Delivery mechanisms

▪ Dosing regimens

▪ Dosing ranges

▪ Dosing routes

▪ Drug Combinations

▪ Screening Methods

▪ Bulk forms

▪ Kits

▪ Pediatric Applications

▪ Geriatric Applications

▪ Patient Compliance

▪ Adverse Events

▪ Contraindications

▪ Stability Data

▪ Isomers

▪ REMS

▪ Stereoisomers

▪ Crystalline Forms

▪ Polymorphs

▪ Enantiomers

▪ Fixed Dose Combinations

▪ Label

▪ Packaging

▪ Systems

▪ Metabolites (Prodrugs)

▪ Processes and intermediates


Carve-Out, Carve-In, Carve-Up (Millennium-VELCADE)

▪ Citizen Petition (CP) Response (Nov. 6, 2017)

▪ Innovator VELCADE (bortezomib) sought to block generic ▪ Patents; layers of exclusivity for multiple myeloma (MM) retreatment; mantle cell lymphoma

(MCL)(first-line)▪ Older label w/ no exclusivity/patents– first-line MM and second-line MCL▪ CP argued generic not safe or effective if most recent information not provided

▪ Fresenius 505(b)(2) permitted as follows:▪ Generic can “carve out” (omit) retreatment and label for MM ▪ Can “carve-in” nor add language to treat pts. with MCL “who have not received at least one prior

therapy” (reinstituting old second-line label)▪ Combination with dexamethasone allowed in Clinical Trials section of label because used in older

pivotal SUMMIT Trial

▪ Response likely not litigated because composition patent validated for more stable form of API—potentially delaying generic VELCADE until 2022


Scenario 1: Therapy with accelerated approval as monotherapy in combination with drug having existing exclusivity/patents and/or generic

▪ Daratumumab (Darzalex®, Janssen Biotech)

▪ Biologic approved for multiple myeloma in combination with:▪ lenalidomide (Revlimid®- Celgene) and dexamethasone (generic)

▪ bortezomib (Velcade®- Takeda/Millennium) and dexamethasone (generic)

▪ Darzalex®▪ Approved as monotherapy for multiple myeloma, in patients who have had at least

three prior lines of therapy.

▪ Many patents for Revlimid® and Velcade®


Scenario 1 (cont.): Therapy with accelerated approval as monotherapy in combination with drug having existing exclusivity/patents and/or generic

▪ Revlimid® and Velcade® both have indications directed to treating multiple myeloma

▪ Darzalex®’s combo therapy indication could, in theory, infringe patents directed to Revlimid® and Velcade® method of use patents

▪ FDA biosimilar labeling guidance allows approval for fewer indications than reference product; allows biosimilar to “carve out” either monotherapy or combo therapy indication from Darzalex® label for quicker market entry


Scenario 2: Novel therapeutic in combination with drug with existing exclusivity/patents and/or generic

▪ Elotuzumab (Empliciti ®, PDL Biopharma) ▪ Biologic approved for multiple myeloma in combination with lenalidomide (Revlimid®

Celgene) and dexamethasone (generic)

▪ Revlimid® ▪ Covered by number of primary and secondary patents

▪ Compound, polymorph, and method of use patents

▪ Market exclusivity ends in 2018; but several orphan drug exclusivities exist expiring 2020, 2022, and 2024 for respective indications


Scenario 2: Novel therapeutic in combination with a drug having existing exclusivity/patents and a generic (cont.)

▪ As with Scenario 1, Empliciti®’s combo therapy indication could infringe patents directed to Revlimid® method of use patents

▪ Empliciti ® not approved for monotherapy, but only combo therapy with lenalidomide and dexamethasone

▪ Any patents (primary or secondary) protecting Empliciti ® could protect against biosimilar competition


Scenario 3: Brand product combined with brand product

▪ Palbociclib (Ibrance®, Pfizer) and fulvestrant (Faslodex®, AstraZeneca)▪ Both products have patent protection and regulatory exclusivities.

▪ Approved for breast cancer following endocrine therapy after a single clinical trial

▪ Labels for each drug approved independently

▪ Ibrance® approved for use in combination with Faslodex® (February 2016)

▪ Falsodex® approved for use in combination with Ibrance® (March 2016)

▪ Both drugs have patent protection and regulatory exclusivity protection for combination therapy

▪ Both innovators updated labels to include combination therapy


Scenario 3: Brand product combined with brand product

▪ Both drugs have multiple FDA-approved indications

▪ ANDA applicant may carve out new combo therapy indication from its label, arguing use of drug for other approved indication(s) would be safe and effective without the combo therapy indication


Options to Encourage Cross-Labeling

▪ Section 706 FDARA-Medical Imaging Drugs/Devices▪ Imaging and contrast drug labels specific to imaging devices and areas of body (CAT,

CT, ECHO, PET, MRI, X-Ray)

▪ New use may involve difference in drug concentration, rate of administration, route, etc.

▪ Need to conform device and imaging drug labels

▪ If new device use cleared/approved, contrast drug maker authorized to submit sNDA, sANDA, etc. to CDER with device maker’s right of reference to refer to CDRH device data


Options to Encourage Cross-Labeling (cont.)

▪ CDER could encourage cross-labeling with existing authority▪ Following approval of NCE Drug A combination, sponsors of Drug B (brand) and Drug C

(generic) could be granted right to reference Drug A data; file sNDA/sANDA for conforming labeling changes

▪ Sponsors of Drug B and C permitted to summarize pivotal Drug A combination study in Clinical Trials portion of labels

▪ Use of “bully pulpit” to persuade combination sponsors to collaborate▪ Good Reprint Practices/Washington Legal Foundation allows sponsors of B and C to circulate

peer-reviewed published studies of combination

▪ Legislation could create incentives for cross-labeling▪ Pathway similar to FDARA imaging device-drug ▪ Curtailing exclusivity if NCE refuses to permit cross-labeling▪ Simplified sNDA/sANDA procedure requiring only revised labeling review▪ Prohibit ANDA applicants from “carving out” indications for combo therapy for treating cancer

(generally), or late stage cancer or aggressive cancers (specifically)


Questions and Comments

Panel 2 Discussion

Moderator: Kenneth Anderson, Dana-Farber Cancer Institute, Harvard Medical School

• Roger Dansey, Merck

• Ann Farrell, U.S. FDA

• James Myers, U.S. FDA

• Jim Omel, Cancer Research Advocate

• Marc Scheineson, Alston & Bird LLP

63

#FriendsAM17

Documents

Panel 2 Discussion - Friends of Cancer Research 2_Final.pdfInnovative trials which established “proof of concept” for ... –Eltrombopag plus backbone therapy for severe aplastic