Spring 2014 Presentation on FDA Breakthrough Therapy Designation for Regulatory Intelligence class.

1. Breakthrough
Therapy Designation
Chuck Kemmerer
Regulatory Intelligence
02March2014

2. Topics
1) What is Breakthrough Therapy Designation?
1) Legislative Implementation
2) How is it different from other programs
2) How can it impact the approval process?
1) How to get Breakthrough Therapy
Designation (BTD)
2) Benefits of BTD
3) Examples

3. Comparison of the FDA's Various Expedited Programs for Serious Conditions.
Comparison of FDA Expedited Programs
Sherman RE et al. N Engl J Med 2013;369:1877-1880.

4. Why is Breakthrough Therapy Designation Needed?
• Increasing development in the field of molecularly targeted therapies for
treatment of cancer, genetic diseases, and other serious illnesses. These
new therapies are often developed along with companion diagnostic
tests.
• These new therapies can be directed at subgroups of a population with
the disease that are predicted to benefit from them.
• Some targeted therapies offer much greater treatment effects than
currently available therapies, and these effects can be seen in initial
clinical trials.
• “When a large treatment effect is observed early in the development of a
drug, it seems excessive to conduct a prolonged clinical development
program that encompasses traditional phases.”
• http://www.nejm.org/doi/full/10.1056/NEJMp1311439

5. Legislative Implementation
• Part of the Food and Drug Administration Safety and Innovations Act
(FDASIA), signed into law on 09Jul2012
• Title IX “Drug Approval and Patient Access”, Section 902 “Breakthrough
Therapies”- Added Section 506(a) to the FD&C Act
• FDA Draft Guidance Issued in June 2013 “Guidance for Industry-
Expedited Programs for Serious Conditions- Drugs and Biologics”

6. Section 506(a) of the Food, Drug, & Cosmetic Act
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 355 (i) of this title or
section 262 (a)(3) of title 42.
3) Desgnation-
A) 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 355 (i) of this title or section 262 (a)(3) of title
42.

7. Section 506(a) Continued
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 nonclinical 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.

8. What is a “Serious Condition?”
“A disease or condition associated with morbidity that has a substantial impact on
day-to-day functioning. Short-lived and self-limiting morbidity will usually not be
sufficient, but the morbidity need not be irreversible if it is persistent or recurrent.
Whether a disease or condition is serious is a matter of clinical judgment, based on
its impact on such factors as survival, day-to-day functioning, or the likelihood that
the disease, if left untreated, will progress from a less severe condition to a more
serious one.”
21 CFR 312.3000(b)(1)

9. What is an “Existing Therapy?”
FDA considers “Existing Therapy” to be therapy that:
• Is approved or licensed in the United States for the same
indication being considered for the new drug and
• Is relevant to the United States standard of care for the indication

10. What is “Preliminary Clinical Evidence”
• Breakthrough Therapies require preliminary clinical evidence of a
treatment effect that would represent a substantial improvement
over available therapies.
• Evidence may include both clinical benefit and the effects on
biomarkers.
• Nonclinical evidence may be used to support the clinical evidence of
drug activity.
• A sufficient number of patients is required to be considered credible,
but FDA recognizes that data may not be definitive at time of
designation.
• Preliminary Clinical Evidence may be gathered from studies
comparing the new drug to an available therapy (or placebo if none is
available) or comparing the new treatment plus the current Standard
of Care to the current Standard of Care alone.

11. What is “Substantial Improvement”?
• Preliminary clinical evidence should show a clear advantage over available
therapy.
• Ways to show “Substantial Improvement:”
• Direct comparison of a new drug to available therapy in either treatment
naïve individuals or poor responders. New drug should show either a
much greater or more complete response.
• The new drug added to current therapy results in a much greater or more
important response compared to available therapy in either a controlled
study of compared to a historical control.
• The new drug treats the underlying cause of the disease while current
therapies treat only symptoms of the disease, and preliminary clinical
evidence shows significant efficacy.
• The new drug reverses disease progression while available therapies only
provide symptomatic improvement.
• The new drug has an important safety advantage that relates to serious
adverse events compared to current therapies and has similar efficacy.

12. Clinically Significant Endpoint
• An endpoint which measures an effect on irreversible morbidity of mortality
(IMM) or on symptoms that represent serious consequences of the disease. It
can also refer to findings that suggest an effect on IMM or serious symptoms
including:
• An effect on an established surrogate endpoint
• An effect on a surrogate endpoint or intermediate clinical endpoint likely
to predict a clinical benefit.
• An effect on a pharmacodynamic biomarker that does not meet criteria
for an acceptable surrogate endpoint, but strongly suggests potential for a
clinically meaningful effect on the underlying disease
• A significantly improved safety profile compared to available therapy with
evidence of similar efficacy.

13. How is Breakthrough Therapy Designation applied for?
• Sponsors may request Breakthrough Therapy Designation at the time of IND
submission, or any time afterward, as long as they have clinical data that
shows “the drug may demonstrate substantial improvement over existing
therapies over 1 or more clinical endpoints.
• FDA expects most BTD requests to be submitted as an amendment to the IND,
ideally no later than the end of Phase 2 meeting.
• FDA doesn’t anticipate BTD being requested after submission of an NDA or
BLA.
• FDA will respond to BTD requests within 60 days of receipt of the request.

14. Will a request for BTD be approved?
Designation
Category
CBER
Designations
CDER
Designations
Total
Designations
Requests
Received
22 127 149
BTD Requests
Granted
1 39 40
BTD Requests
Denied
16 64 80
BTD Requests
Pending
5 24 29
% BTD Requests
Granted
4.5% 30.7%
FDA does NOT publish the granting of BTD, it’s at the sponsor’s discretion.
As of 24Feb2014, 34 BTD’s have been announced by their sponsors.
http://orphandruganaut.wordpress.com/2013/05/20/fda-breakthrough-therapy-designation-chart/

15. Benefits of Breakthrough Therapy Designation
• All Fast Track Designation Features:
• Rolling Review: FDA may begin reviewing portions of the NDA before
the complete NDA is submitted.
• Actions to Expedite Development: Frequent interactions with the
review team, including Pre-IND, end of Phase 1 and end of Phase 2
meetings along with meetings about study design, safety data,
biomarkers, dose-response issues, and other topics.
• Intensive Guidance on Effective Drug Development, Beginning as early as
Phase 1:
• Clinical trial development assistance- the clinical trials must be strong
enough for the FDA to consider the drug “Safe and Effective” and FDA
will meet with and assist the sponsor in trial development and other
issues.
• Assistance in designing clinical trials to ensure they are as efficient as
possible, such as by minimizing the number of patients exposed to less
effective treatment.

16. Benefits of Breakthrough Therapy Designation
• Organizational Commitment Involving Senior Managers:
• FDA will involve senior managers and review staff in a proactive, cross-disciplinary
review. FDA also intends to assign a cross-disciplinary project
lead to facilitate an efficient review and serve as a liaison between the
members of the review team (ex. Clinical, pharmacology-toxicology, CMC,
and compliance) for coordinated internal interactions with the sponsor
through the review division’s Regulatory Health Project Manager.
• The goal is coordinated communications with the sponsor and coordinated
internal interactions to speed the review process.

17. Breakthrough Therapy Designation Caveats:
• Breakthrough Therapy Designation may be removed either by the
FDA or the sponsor:
• A drug may show less of an effect in larger scale trials than it
did in initial clinical testing.
• If two drugs are granted BTD for the same indication and one is
granted traditional approval, the other would not retain BTD
unless it could show “Substantial Clinical Improvement” over
the traditionally approved drug.
• BTD Requests must be made separately for each indication
• BTD approval doesn’t guarantee Priority Review

18. Drugs with Breakthrough-Therapy Designations Announced as of September 30, 2013.
Examples of Drugs with Breakthrough Therapy Designation
Sherman RE et al. N EnglJ Med 2013;369:1877-1880.

19. Only four drugs/indications that have received BTD had their NDA’s approved so far
Drug Generic Indication Mfg. BTD
Received
Approval
Date
Gazyva Obinutuzumab Chronic
Lymphocytic
Lymphoma
Genentech May2013 01Nov2013
Imbruvica Ibrutinib Mantle Cell
Lymphoma
Pharmacyclics Feb2013 13Nov2013
Sovaldi Sofosbuvir Hepatitis C Gilead Oct2013 06Dec2013
Imbruvica Ibrutinib Chronic
Lymphocytic
Leukemia
Pharmacyclics 08Apr2013 12Feb2014

20. How Might Breakthrough Therapy Designation help?
If a breakthrough therapy is approved on Phase 2 data, it can reach
the market about 3 years faster than a “standard” new drug.

21. Clinical Trial Comparison:
Drug Indication Status Trial Size Trial Type
Imbruvica CLL BTD 48 Open Label
Campath CLL Standard 297 Randomized
Sovaldi HCV
(treatment Naïve
Type 1)
BTD 327 Open Label,
compared to
historical data
Incivek HCV
(treatment Naïve
Type 1)
Standard 3457 in 3
trials
Randomized,
placebo
controlled, or
current SOC

22. Bringing a product with Breakthrough Therapy Designation to Market
• Pricing and Market Access strategies which are generally developed during
Phase 3 will need to be developed during Phase 2.
• Drugs with BTD may reach market sooner, giving them more time to
generate revenue for a company. Drugs may be brought to market with
more remaining patent protection than drugs which undergo a standard
development process.
• Limited data available for a drug using BTD makes it more important to
decide what’s important in promoting a drug’s “message.”
• Critical endpoints and advantages over existing therapies may be vital in developing a
marketing program.
• Some payers may not be willing to reimburse for drugs without full
development pathways while others may be more willing to be early
adopters based on early data.
• Understanding other manufacturer’s pipelines to see potential competitors
for a drug with BTD is also important.

23. Pricing and Market Access:
http://obroncology.com/obrgreen/article/FDAs-New-Breakthrough-Therapy-Designation

24. Conclusions:
• Given the rise in molecularly targeted drugs and pharmacogenomics,
Breakthrough Therapy Designation is a necessary process because it focuses
on drugs which provide a “Significant Improvement” over current SOC.
• Breakthrough Therapy Designation is still a relatively new Designation and it’s
difficult to say if it has had any significant impact given the relatively few
drugs approved using it at this time.
• Breakthrough Therapy Designation allows drugs to be submitted for approval
using smaller trials where the exposure to placebos or less effective
treatments may be minimized.

25. References
• http://www.nejm.org/doi/full/10.1056/NEJMp1311439
• http://obroncology.com/obrgreen/article/FDAs-New-Breakthrough-Therapy-
Designation
• http://www.fiercebiotech.com/story/analysts-score-winners-fdas-new-breakthrough-
category/2014-01-06
• http://www.fiercebiotech.com/story/uk-mulls-breakthrough-drug-program-its-own/
2014-01-22
• http://www.fiercebiotech.com/story/jurys-still-out-fdas-breakthrough-designation/
2014-01-28
• http://www.fiercebiotech.com/story/us-rep-rips-fdas-efforts-speed-drug-approvals/
2014-02-07
• http://delauro.house.gov/images/pdf/rld_letter_to_hamburg_drug_and_device_
approval.pdf

26. References
• http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/103948s5070lbl.pdf
• http://www.imbruvica.com/downloads/Prescribing_Information.pdf
• http://Incivek.com
• http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticact
fdcact/significantamendmentstothefdcact/fdasia/ucm329491.htm
• http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticact
fdcact/significantamendmentstothefdcact/fdasia/ucm341027.htm
• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gu
idances/UCM358301.pdf
• http://blogs.fda.gov/fdavoice/index.php/2014/02/why-fda-supports-a-flexible-approach-
to-drug-development/
• http://orphandruganaut.wordpress.com/2013/05/20/fda-breakthrough-therapy-designation-
chart/