Expediting Drug Development:
Breakthrough Therapies
Jeff Allen, PhD
Executive Director, Friends of Cancer Research
Courtesy of the American Association of Cancer Research 2011 Cancer Progress Report
The New York Times
September 18, 2010
New Drugs Stir Debate on Rules of Clinical Trials
By AMY HARMON
“But critics of the trials argue that the new science behind the drugs has eclipsed
the old rules — and ethics — of testing them. They say that in some cases, drugs
under development, PLX4032 among them, may be so much more effective than
their predecessors that putting half the potential beneficiaries into a control group,
and delaying access to the drug to thousands of other patients, causes needless
suffering.”
Getting Breakthrough Therapies to Patients
•
The 2011 Conference included a panel entitled: Development Paths for New Drugs with Large
Treatment Effects Seen Early.
•
The workgroup proposed scientific strategies to ultimately expedite FDA approval for a drug
showing dramatic responses in the early stages of development while maintaining drug safety and
efficacy standards.
Goals of Breakthrough Therapy Designation
Goal 1: Expedite drug development process for products that show remarkable clinical
activity early
Goal 2: Minimize the number of patients exposed to a potentially less efficacious
treatment
Concept
Scientific Whitepaper
Bipartisan
Legislative Solution
Tool in use by FDA to expedite
drug development
Breakthrough Therapies
“(a) Designation of a Drug as a Breakthrough Therapy.—
“(1) IN GENERAL.—The Secretary shall, at the request of the sponsor of a drug, expedite the
development and review of such drug if the drug is intended, alone or in combination with 1 or
more other drugs, to treat a serious or life-threatening disease or condition and preliminary
clinical evidence indicates that the drug may demonstrate substantial improvement over existing
therapies on 1 or more clinically significant endpoints, such as substantial treatment effects
observed early in clinical development. (In this section, such a drug is referred to as a
‘breakthrough therapy’.)
“(2) REQUEST FOR DESIGNATION.—The sponsor of a drug may request the Secretary to designate the
drug as a breakthrough therapy. A request for the designation may be made concurrently with, or
at any time after, the submission of an application for the investigation of the drug under section
505(i) or section 351(a)(3) of the Public Health Service Act.
“(3) DESIGNATION.—
“(A) IN GENERAL.—Not later than 60 calendar days after the receipt of a request under
paragraph (2), the Secretary shall determine whether the drug that is the subject of the
request meets the criteria described in paragraph (1). If the Secretary finds that the drug
meets the criteria, the Secretary shall designate the drug as a breakthrough therapy and
shall take such actions as are appropriate to expedite the development and review of the
application for approval of such drug.
Breakthrough Therapies
“(B) ACTIONS.—The actions to expedite the development and review of an
application under subparagraph (A) may include, as appropriate—
“(i) holding meetings with the sponsor and the review team throughout the
development of the drug;
“(ii) providing timely advice to, and interactive communication with, the sponsor
regarding the development of the drug to ensure that the development program to
gather the non-clinical and clinical data necessary for approval is as efficient as
practicable;
“(iii) involving senior managers and experienced review staff, as appropriate, in a
collaborative, cross-disciplinary review;
“(iv) assigning a cross-disciplinary project lead for the Food and Drug Administration
review team to facilitate an efficient review of the development program and to
serve as a scientific liaison between the review team and the sponsor; and
“(v) taking steps to ensure that the design of the clinical trials is as efficient as
practicable, when scientifically appropriate, such as by minimizing the number of
patients exposed to a potentially less efficacious treatment.”;
Courtesy of AACR Annual Meeting 2013
Proposed Criteria for Breakthrough Therapy Designation
Category
Qualitative Criteria
1. No standard of care (SoC);
serious condition with poor
outcome
• Unprecedented early activity in Phase
I: CRR*, ORR* or CBR*
• Acceptable safety
2. Substantial efficacy
improvement over well
characterized SoC; serious
condition with poor outcome
• Exceptional early activity based on
response rates (CRR, ORR) and
durability or disease control
• Acceptable safety
3. Substantial therapeutic
index advantage over a well
characterized SoC; serious
condition with poor outcome
• Superior safety/tolerability combined
with superior or clearly maintained
efficacy
http://www.focr.org/sites/default/files/CCCR12Breakthrough.pdf
*CR=complete response, ORR=overall response rate, CBR=clinical benefit rate
Current Breakthrough Therapies
Breakthrough Therapy Designation Requests
Requests Received
Requests Granted
Requests Denied
CDER (as of 6/14/2013)
58
21
16
CBER (as of 5/31/2013)
6
0
5
FDA Total
64
21
21
Implementation of Breakthrough Designation
May
Mar/Apr
LDK378
Jan/Feb:
Kalydeco receives
two designations
July 2012:
Legislation
signed into
law
Ibrutinib given two
designations
Palbociclib
Ibrutinib (3)
Lambrolizumab
Daclatasvir
SD101
announce
Breakthrough
designations
Daratumumab
ABT-450
obinutuzumab
Selbelipase alfa
Asfotase alfa
announce
Breakthrough
designations
12 Breakthrough Designations Announced By Companies So Far
•
Kalydeco (Vertex) - 2 cystic fibrosis designations (combination and monotherapy)
•
Ibrutinib - (J&J/Pharmacyclics) - 3 designations (mantle cell lymphoma, WM, CLL)
•
LDK378 - (Novartis) – ALK+ NSCLC resistant to crizotinib
•
palbociclib - (Pfizer) - ER+, HER2- locally advanced or metastatic breast cancer
•
lambrolizumab – (Merck) – inoperable and metastatic melanoma
•
Daclatasvir – (BMS) – Hepatitis C in combination with two other direct-acting antivirals
•
Daratumumab - (Janssen) - multiple myeloma after three prior lines of therapy
•
SD101 - (Scioderm) - topical cream for the treatment of inherited Epidermolysis Bullosa (EB)
•
ABT-450 - (AbbVie) - interferon-free 3-DAA treatment of Hepatitis C in combination
•
Obinutuzumab - (Genetech) - Chronic Lymphocitic Leukemia (CLL)
•
Sebelipase Alfa - (Synageva) - early onset lysosomal acid lipase deficiency (LAL deficiency)
•
Asfotase Alfa - (Alexion Pharmaceutical) - hypophosphatasia (HPP) whose first signs or
symptoms occurred prior to 18 years of age, including perinatal-, infantile-, and juvenile-onset
forms of the disease.
Characteristics of Breakthrough Therapies
Kalydeco - cystic fibrosis transmembrane conductance regulator (CFTR) potentiator
•
Data: Phase 2 clinical trial of Kalydeco and VX-809 in multiple combinations showed significant improvements in
lung function
•
Phase 3 trial scheduled to be half the duration of original phase 3
•
Note: Combination drugs; supplemental indication; functional endpoint
ibrutinib - Specifically target and selectively inhibit BTK
•
Data: 12-month median progression-free survival is 93%
•
In patients for whom a bone marrow biopsy was done, tumor infiltration decreased by 82 percent
•
Note: No current treatment (WM); substantial improvement over SoC (CLL)
LDK378 – selective inhibitor of ALK
•
Data: Phase 1 – 80%RR in patients who progressed following crizotinib
•
Note: Substantial improvement over SoC; second-in-class
palbociclib - Cyclin-dependent kinases (cdk) 4 and 6 inhibitor
•
Data: Phase 2 – PFS = 26.1mo vs 7.5mo letrozole alone
•
Note: Substantial improvement over SoC; surrogate endpoint
lambrolizumab– PD-1 inhibitor
•
Data: Phase 1B – 51% of patients showed an objective anti-tumor response; 9% showed complete response after
the 12-week assessment
•
Note: Current SoC isn’t effective for some patients; relatively low incidence of high-grade adverse events
daclatasvir – interferon-free Hepatitis C drug
•
Data: Phase 2a - Stopped the virus from replicating in 15 of 16 patients during a 24 week trial
•
Note: Combination drugs; patients resistant to SoC