US FDA update: Recent Trends in the Regulation of Biopharmaceuticals

Christopher DowneyDivision of Biotechnology Review and Research IV

Office of Biotechnology Products

OPQ,CDER, FDA

CMC Strategy Forum Japan 2019

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A quality product of any kind consistently meets the expectations of the user.

Pharmaceutical Quality

www.fda.gov

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A quality product of any kind consistently meets the expectations of the user.

Pharmaceutical Quality

Drugs are no different.

www.fda.gov

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Patients expect safe and effective medicine with every dose they take.

www.fda.gov

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Pharmaceutical quality is

assuring every dose is safe and effective, free of contamination and defects.

www.fda.gov

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It is what gives patients confidence in their next dose of medicine.

www.fda.gov

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Disclaimer

The views and opinions expressed should not be used in place of regulations, published FDA guidances, or discussions with the Agency.

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Outline

• Product Quality Assessment in CDER

• Updates on expedited programs and CDER biologics approvals

• Biosimilars updates

• Established Conditions Pilot Program

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• Emerging Technology Program

• Botanical Review Team

Office of Testing & Research

(OTR)

Office of Pharmaceutical Manufacturing

Assessment (OPMA)

Office of Biotechnology Products (OBP)

Office of Lifecycle Drug Products

(OLDP)

Office of Quality Surveillance

(OS)

Office of NewDrug Products

(ONDP)

Office of Program & Regulatory Operations

(OPRO)

Office of Policy for Pharmaceutical Quality (OPPQ)

CDER Office of Pharmaceutical Quality

One Quality Voice

https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/office-pharmaceutical-quality

Assure that quality medicines are available for the American public

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Team-based Integrated Quality Assessment (IQA)

• Integrates all elements of CMC review and pre-license and pre-approval inspection activities

– Drug substance, drug product, microbiology, manufacturing, and facilities

• Aligned, patient-focused, and risk-based drug product quality assessments

http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM442666.pdf

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OPQ Strategic Priorities

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• COLLABORATE: Strengthen OPQ’s collaborative culture

• INNOVATE: Promote availability of better medicines

• COMMUNICATE: Elevate awareness and commitment to the importance of pharmaceutical quality

• ENGAGE: Strengthen partnerships and engage stakeholders

OFFICE OF PHARMACEUTICAL QUALITY 2018 ANNUAL REPORThttps://www.fda.gov/media/120781/download

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Office of Testing & Research

(OTR)

Office of Pharmaceutical Manufacturing

Assessment (OPMA)

Office of Biotechnology Products (OBP)

Office of Lifecycle Drug Products

(OLDP)

Office of Quality Surveillance

(OS)

Office of NewDrug Products

(ONDP)

Office of Program & Regulatory Operations

(OPRO)

Office of Policy for Pharmaceutical Quality (OPPQ)

Who reviews the CMC sections of your BLA?

https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/office-pharmaceutical-quality

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Office of Testing & Research

(OTR)

Office of Pharmaceutical Manufacturing

Assessment (OPMA)

Office of Biotechnology Products (OBP)

Office of Lifecycle Drug Products

(OLDP)

Office of Quality Surveillance

(OS)

Office of NewDrug Products

(ONDP)

Office of Program & Regulatory Operations

(OPRO)

Office of Policy for Pharmaceutical Quality (OPPQ)

Who reviews the CMC sections of your BLA?

https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/office-pharmaceutical-quality

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DBRR I

OBP

DBRR II DBRR IVDBRR III

*DBRR: Division of Biotechnology Review and Research

- Responsible for comparative analytical assessment for biosimilars

- Four functionally equivalent divisions

- Operates as a fully integrated unit within OPQ

OBP: responsible for product quality assessment of therapeutic biotechnology products

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Office of Testing & Research

(OTR)

Office of Pharmaceutical Manufacturing

Assessment (OPMA)

Office of Biotechnology Products (OBP)

Office of Lifecycle Drug Products

(OLDP)

Office of Quality Surveillance

(OS)

Office of NewDrug Products

(ONDP)

Office of Program & Regulatory Operations

(OPRO)

Office of Policy for Pharmaceutical Quality (OPPQ)

Who reviews the CMC sections of your BLA?

https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/office-pharmaceutical-quality

https://www.fda.gov/news-events/fda-brief/fda-brief-fda-begins-reorganization-phase-modernization-efforts-increase-efficiency-and-further

OPMA: responsible for facility and microbiology assessments

16* As of November 2019, does not include 351(k) BLAs

CDER Novel Biologics Approvals

*

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1(a

) ap

pro

vals

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Expedited Programs

• For drugs that address an unmet medical need in the treatment of a serious or life-threatening condition

• Intended to help ensure that therapies for these conditions are approved and available to patients as soon as it can be concluded that the therapies’ benefits justify their risks

• Allow for earlier attention to drugs that have promise in treating such conditions

Fast Track Designation: Section 506(b) of FD&C Act added by section 112 of the Food and Drug Administration Modernization Act of 1997 (FDAMA), amended by section 901 of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA)

Breakthrough Therapy Designation:Section 506(a) of the FD&C Act, as added by section 902 of FDASIA, 2012

Priority Review Designation: Prescription Drug User Fee Act of 1992

Accelerated Approval: Section 506(c) Food, Drug & Cosmetic Act (FD&C Act) of the FD&C Act of 1992, amended by section 901 of FDASIA

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

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• Nonclinical or clinical data demonstrate potential to meet unmet medical need

• Features: – Actions to expedite

development and review: frequent interactions with review team

– Rolling review – Eligible for

Accelerated approval and priority review

Draft Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics 2013

Fast Track Designation

https://www.fda.gov/drugs/ind-activity/fast-track-designation-requests

0

50

100

150

200

250

1998 2001 2004 2007 2010 2013 2016 2019

Total Requests Received

Granted

Denied

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Breakthrough Therapy Designation

• Clinical evidence indicating substantial improvement for one or more clinically significant endpoint over available therapies

• Features:

– Guidance on efficient drug development• Increasing frequency of meetings throughout the development of the drug

• Providing timely advice to facilitate an efficient development program

• Ensuring 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

– Organizational commitment• Assigning a cross-disciplinary team lead to facilitate an efficient review,

coordinate internal and external communications

• Involving senior managers and experienced review staff

– Rolling review

– Other actions to expedite review (e.g., priority review designation)

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Update on Breakthrough products

https://www.fda.gov/drugs/nda-and-bla-approvals/breakthrough-therapy-approvals

Fiscal Year Requests Granted Denied Withdrawn

2012 2 1 1 02013 92 31 52 92014 96 31 51 142015 93 32 43 182016 106 46 48 122017 111 50 49 122018 139 51 50 162019 157 54 63 18

CDER Breakthrough requests received:

Marketing Approvals2012 – 2016: 30 new drug approvals (9 BLAs); 22 supplement approvals (7 BLAs)2017: 16 new drug approvals (6 BLAs); 10 supplement approvals (5 BLAs)2018: 18 new drug approvals (8 BLAs); 20 supplement approvals (10 BLAs)2019: 7 new drug approvals (1 BLAs); 10 supplement approvals (6 BLAs)* 2019 data through September 30

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• Would provide a significant improvement in safety or effectiveness

• Features:– Shorter clock for review of marketing application compared

with standard review: • 6 months from filing vs. 10 months

Priority Review Designation

https://www.fda.gov/drugs/nda-and-bla-approvals/priority-nda-and-bla-approvals

Priority Approvals

CY 2018: 13 BLA approvals, 11 of which also had Orphan designation*CY 2017: 9 BLA approvals, 5 of which also had Orphan designationCY 2016: 3 BLA approvals, 1 of which also had Orphan designationCY 2015: 7 BLA approvals, 5 of which also had Orphan designationCY 2014: 8 BLA approvals, 7 of which also had Orphan designationCY 2013: 2 BLA approvals, 1 of which also had Orphan designation

* Orphan Designation - Pursuant to Section 526 of the Orphan Drug Act (Public Law 97-414 as amended).

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Accelerated ApprovalApproval based on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict a drug’s clinical benefit

– Requires post-marketing confirmatory trials to verify the anticipated clinical effect

– Approval of a drug may be withdrawn if trials fail to verify clinical benefit or to demonstrate sufficient clinical benefit to justify the risks associated with the drug

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/UCM404466.pdf

Accelerated Approvals2019: 2 approvals (1 BLA)2018: 7 approvals (0 BLAs)2017: 8 approvals (3 BLAs)2016: 7 approvals (2 BLAs)2015: 9 approvals (2 BLAs)2014: 8 approvals (3 BLAs)

Biotechnology product approvals include: Polivy (polatuzumab vedotin-piiq), Keytruda (pembrolizumab), Blincyto (blinatumomab) , Opdivo(nivolumab), Praxbind (idarucizumab), Darzalex (daratumumab), Tecentriq (atezolizumab), Lartruvo(olaratumab), Bavencio (avelumab)

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Successful accelerated development requires careful planning

• Align CMC development with clinical development– Process capable of supplying market at launch– All needed supporting data are available for the CMC submission– Timing of process enhancements, scale-ups, and site transfers

• Plan for CMC development activities that cannot be compressed or delayed– Some development activities are inherently fixed in timing (e.g.

comparability studies) or duration (e.g., collecting long term of stability data to support expiry)

– Some review activities have fixed timing (e.g. pre-approval inspection)

• Robust product characterization and understanding of CQAs• Early development of analytical methods and reference

standards– Thorough bridging when making changes

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Biosimilars: Background

• The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) creates an abbreviated licensure pathway for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product.

• Biosimilar or Biosimilarity means that:

– the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and

– there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.

• The ability to rely on FDA’s previous finding regarding the reference product to support approval of the biosimilar product allows for a potentially shorter and less costly drug development program.

• Once a biosimilar or interchangeable is approved by FDA, patients and health care providers are able to rely upon the safety and effectiveness of an FDA-approved biosimilar or interchangeable product just as they would for the reference product that the biosimilar was compared to.

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Biosimilars Program

• As of November 12, 2019, 74 programs were enrolled in the Biosimilar Product Development (BPD) Program. CDER has received meeting requests to discuss the development of biosimilars for 38 different reference products.

• Since program inception and as of November 12, 2019, 12 companies have publicly announced submission of 25 351(k) BLAs to FDA.

• As of November 12, 2019, twenty-four 351(k) BLAs for biosimilar products have been approved. – Zarxio (filgrastim-sndz) − Inflectra (infliximab-dyyb)– Erelzi (etanercept-szzs) − Amjevita (adalimumab-atto)– Renflexis (infliximab-abda) − Cyltezo (adalimumab-adbm) – Mvasi (bevacizumab-awwb) − Ogivri (trastuzumab-dkst)– Ixifi (infliximab-qbtx) − Retacrit (epoetin alfa-epbx)– Fulphila (pegfilgrastim-jmdb) − Nivestym (filgrastim-aafi)– Hyrimoz (adalimumab-adaz) − Udenyca (pegfilgrastim–cbqv)– Truxima (rituximab-abbs) − Herzuma (trastuzumab-pkrb) – Ontruzant (trastuzumab-dttb) − Trazimera (trastuzumab-qyyp) – Eticovo (etanercept-ykro) − Kanjinti (trastuzumab-anns)– Zirabev (bevacizumab-bvzr) − Ruxience (rituximab-pvvr) – Hadlima (adalimumab-bwwd) − Ziextenzo (pegfilgrastim-bmez)

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FDA Biosimilars Guidance

1. Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act (Draft, 2014)

2. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product (Final, 2015)

3. Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product (Final, 2015)

4. Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (Final, 2016)

5. Formal Meetings Between the FDA and Sponsors or Applicants of BsUFA Products (Draft, 2018)

6. New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2) (Draft, 2018)

7. Questions and Answers on Biosimilar Development and the BPCI Act (Final, 2018)

https://www.fda.gov/drugs/guidances-drugs/all-guidances-drugs

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FDA Biosimilars Guidance 2019

8. Considerations in Demonstrating Interchangeability With a Reference Product (Final, 2019)

9. Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations (Draft, 2019)

10.Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products (Draft, 2019)

https://www.fda.gov/drugs/guidances-drugs/all-guidances-drugs

https://www.fda.gov/drugs/guidances-drugs/newly-added-guidance-documents

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May 2019 Draft Guidance updates and clarifies FDA thinking on comparative analytical

assessmentRevises Final Guidance:

• Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product

Replaces withdrawn Draft Guidance:

• Statistical Approaches to Evaluate Analytical Similarity

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May 2019 Draft Guidance updates and clarifies FDA thinking on comparative analytical

assessment• Updates recommendations on

collection and analysis of analytical similarity data

• Clarifies certain CMC expectations• Flexibility to consider new

approaches to comparative assessment

• Reflects receptiveness to state-of-the art methods

• Does not change rigor of assessment or evidentiary standards

• Analytical similarity evaluated from totality of data

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Biosimilar development issues are often related to manufacturing and cGMP, or to

analytical data collection and documentation

Abbreviated clinical pathway, not abbreviated CMC

– Same standards for manufacturing, GMP, and product quality as 351(a) application

Analytical similarity data considerations

• Changes in test methodology or reference standard during biosimilar development are accounted for

• Submitted data is complete and can be traced to lot number and testing occasion

• Manufacturing facilities and analytical similarity testing facilities are subject to inspection

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CDER Established Conditions Pilot Program

• Established Conditions: description of the product, manufacturing process, facilities and equipment, and elements of the associated control strategy…defined in an application…that assure process performance and quality...

• Changes to ECs must be reported to FDA• Existing regs and guidance leave ambiguity about what changes

must be reported vs. managed by quality system• Draft ICH Q12 Guideline describes how applicant may specify

identify and propose ECs and reporting category for changes to ECs• Accepted (9) applicants to participate in Pilot Program to propose

“explicit” ECs for NDA, ANDA, or BLA

https://www.federalregister.gov/documents/2019/02/15/2019-02364/established-conditions-pilot-program

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Objectives of Pilot

Gain practical experience in:

• Assessing proposed ECs

• Engaging with applicants during the review cycle to refine proposed ECs

• Ensuring assessment decisions are made without negatively impacting the ability to meet user fee timeframes

• Identifying agreed-upon ECs at the time of approval

https://www.federalregister.gov/documents/2019/02/15/2019-02364/established-conditions-pilot-program

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Acknowledgements

William Hallett

Cecilia Tami

Joel Welch

Emanuela Lacana

Thank you

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