Breakthrough Therapy Designation- Spring 2014 Reg. Intelligence

Breakthrough Therapy Designation

Chuck KemmererRegulatory Intelligence02March2014

Topics

1) What is Breakthrough Therapy Designation?1) Legislative Implementation2) 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 BTD3) Examples

Comparison of the FDA's Various Expedited Programs for Serious Conditions.

Sherman RE et al. N Engl J Med 2013;369:1877-1880.

Comparison of FDA Expedited Programs

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

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• FDA Draft Guidance Issued in June 2013 “Guidance for Industry- Expedited Programs for Serious Conditions- Drugs and Biologics”

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.

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.

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)

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

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.

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.

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.

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.

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/

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.

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.

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

Drugs with Breakthrough-Therapy Designations Announced as of September 30, 2013.

Sherman RE et al. N Engl J Med 2013;369:1877-1880.

Examples of Drugs with Breakthrough Therapy Designation

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

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.

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

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.

Pricing and Market Access:

http://obroncology.com/obrgreen/article/FDAs-New-Breakthrough-Therapy-Designation

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.

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

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/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/fdasia/ucm329491.htm

• http://www.fda.gov/regulatoryinformation/legislation/federalfooddrugandcosmeticactfdcact/significantamendmentstothefdcact/fdasia/ucm341027.htm

• http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/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/