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Regulatory Considerations in the Development of Bacteriophage for Clinical Use

Cara Fiore, Ph DDivision of Vaccines and Related Products ApplicationsOffice of Vaccines Research and Review, Center For Biologics Evaluation and ResearchUS Food and Drug Administration

CASSS DC Area Discussion Group on Thursday, February 20, 2020

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My comments are an informal communication and represent my own best judgment. The information presented here does not bind or obligate the FDA.

Outline

Regulation

Investigational bacteriophage (phage) therapy

Regulatory considerations for use of phage therapy products in clinical trials intended to support licensure

Expanded access use (compassionate use) of phage therapy products

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Center for Biologics Evaluation and Research

Office of Vaccines Research and Review

Office of Tissues and Advanced Therapies

Office of Compliance and Biologics Quality

Office of Communication Outreach and Devel.

Office of Blood Research and Review

Office of Biostatistics and Epidemiology

Office of Management

*This diagram is not necessarily complete

Regulation in the US

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Pre-clinical Phase 1 Phase 2 Phase 3 Licensure

Definitions and Regulatory AuthorityDrugs/BiologicsDrug

“A finished dosage form containing an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or any function of the body of man or animals…”Drugs are primarily regulated under the

Federal Food, Drug and Cosmetic Act (FD&C Act).

Specific regulations can be found the Title 21 of the Code of Federal Regulations (CFR)

Biological Product

“Any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man…”Vaccines, live biotherapeutic products,

allergenic products, blood and blood products, recombinant products and gene therapy.

Statutes contained in Section 351 of the Public Health Service Act (PHSA).

Specific regulations can be found the Title 21 of the Code of Federal Regulations (CFR)

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When in product development does FDA get involved?

Guidance for Clinical Investigators, Sponsors, and IRBs Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND https://www.fda.gov/downloads/drugs/guidances/ucm229175.pdf

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First in human use (21

CFR 312)

Drug definition: “… articles intended for use in the

diagnosis, cure, mitigation, treatment, or prevention of

disease in man”… “and …articles (other than food) intended to

affect the structure or any function of the body of man….” (Food Drug and Cosmetic Act)

In the US an investigational new

drug application (IND) is required to conduct

clinical investigations of unapproved new drugs

When an IND is in effect, an IND an investigational new

drug is exempt from premarket approval requirements and

may be shipped lawfully for the purposes of clinical

investigation.

Human studies are conducted under IND,

whether or not the intention is to market (license) the product.

Biologic Development

Pre-IND

Early IND Development

Late IND Development

Licensing (BLA)

Marketing/Post Marketing

OVRR/CBER/FDA 9

Investigational New Drug (IND) Biological License Application (BLA)

Studies in HumansProduct not tested in humans yet

FDA Oversight

Development of Biological Products

Phase 1Safety,

(PK)(N~20-80 )

Phase 2Safety,Dose-finding,Effective-ness(N~100s)

Phase 3Safety, Effective-ness

(N~100-1,000s)Powered forhypothesis testing

Approval

Phase 4Safety,Effective-ness,Inspections,Lot release,Post-approvalChanges

Pre-clinicalSafety

Rationale, Animal studies

SAFETYEffectiveness

Manufacturing Consistency

IND, Pre-marketing Post-marketing

Review

Assay development Qualification Validation

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FDA’s Primary Objectives in Reviewing an IND

In all phases of investigation, to assure the

safety and rights of subjects.

In Phase 2 and 3, to help assure that the quality of

the scientific evaluation of drugs is adequate to permit an evaluation of the drug’s

effectiveness and safety

*Assessment of the scientific quality of the investigations*Likelihood that investigations will yield data capable of meeting statutory standards for marketing approval

OVRR/CBER/FDA 11

Consultation Between Sponsor and FDA (Formal Communications)

PreC

linic

alDe

velo

pmen

t Early review of toxicology protocols,Type C meetings: unique products/ issues before Pre-IND meeting,Pre-IND (Type B)

Clin

ical

Dev

elop

men

t Studies in human have been initiated:Type A, B, C Meetings such asEOP2 and Pre-BLA Li

cens

ing

Subm

issio

n During BLA review: Early, mid and late cycle communications

OVRR/CBER/FDA 12

Communication between FDA and SponsorFormal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products: Guidance for Industry https://www.fda.gov/downloads/Drugs/.../Guidances/UCM590547.pdf

Formal Meetings with FDA (21 CFR 312.47)Pre-Clinical Phase 2 Phase 3 License

ApplicationPre-IND (Type B)Meeting:Phase 1 protocolCMCLot release (C/A)Animal studies (PK)

End-of-Phase 2Meeting:Effectiveness trial

protocol(s)Phase 1/2

data, etc.Assay validation, dataCMCAdvisory Committee

Pre-BLAMeeting:Clinical dataFacilities updateProduct - CMCOutline of BLA

IND = Investigational New Drug ApplicationBLA = Biologics License ApplicationCMC = Chemistry, Manufacturing and Control

Type CMeeting:Focused on unique aspect of development

Phase 1

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Pre-IND Meeting (Type B)Highly recommended!Type B Meeting (written responses or telecon)Briefing package – represents the data to be provided in the

IND Objectives and purpose Product description Proposed indication Specific questions for FDA Supporting data summaries (product, preclinical, clinical) Rationale for clinical studies Clinical protocol summary or draft Planned clinical development of product

OVRR/CBER/FDA 14

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Phage Therapy

https://www.cleanpng.com/png-bacteriophage-biology-cell-art-virology-phage-ther-3255403/

Investigational Bacteriophage (phage) Therapy:What are phages?

Phages are viruses that infect bacteriaUbiquitous and specificDiscovered by Twort and d’Herelle in early 1900sUsed in Eastern block countries since before penicillin discoveryRecent press (“Phagoburn” and individual treatments) Phage therapy is an investigational therapy in the US

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*A group of phages, in green, attacks an E. coli cell, injecting their DNA through the cell membrane.Image from Eye of Science / Science Source (via New Yorker)

*

Phage Therapy

17*Wikipedia https://commons.wikimedia.org/w/index.php?curid=63789040

Data to Support Initiation of Clinical Development

Clinical

• Proposed clinical protocol for each study

CMC

•Drug substance•Drug product• Product

characterization

Animal Studies

• Proof of concept studies in relevant animal model

•Depends on product characteristics and intended use

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CMC: Chemistry, manufacturing and control [of drug]

The study has a reasonable probability of yielding information that will support

development of the product

The

Bott

om L

ine

What does the FDA want to know about the study design?

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PRODUCTStandard or Personalized

phage(s)

Purity (relative freedom from

extraneous matter (e.g. bioburden, endotoxin, exotoxin) Potency

(pfu/mL)

Non Transducing

Genome analysis (host

strain and phage)

Stability

Future + phage(s)

should be supported by

adequate CMC information

Safe

ty: C

MC CMC Data to

Support Initiation of Clinical Development of Phage Products

20“Guidance for Industry: CGMP for Phase 1 Investigational Drugs” (https://www.fda.gov/media/70975/download)

Development of Preventive Vaccines

Safety Safety, EffectivenessSafety, Immunogenicity

IND EOP2 Pre-BLA BLAPhase 1 Phase 2 Phase 3 Phase 4

Initial product characterizationPreclinical Safety & Immunogenicity

Optimization of Manufacturing ProcessAssay and Process Validation

Final Product SpecificationsFinal Formulation/Dosage

Meetings Pre-IND

Post-approvalChanges:New IndicationsDosing

New ManufactureEquip./FacilitiesInspections

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Phage Clinical Development

Proposed Use/Indication One product but potentially multiple types/sites of infection; Stand alone therapy

or use as an adjunct to standard of care (i.e., antibiotics), or rescue therapy

Flexibility of clinical design based on your product characteristics (personalized, standard, +/-phages

during treatment)

Product use: kinetics (immune clearance) and

developing resistance

Potentially acutely ill subjects

Route of administration topical, intravenous,

inhalation, others (+/-device)

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?

Expanded Access

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expanded ACCESS (EA)

Primary purpose of EA is to provide access to investigational drugs, not to collect systematic safety or effectiveness data (e.g., data from adequate and well-controlled clinical trials intended to support licensure). It is not a product development pathway.

Expanded Access (EA) IND can be issued when the patient has a serious or immediately life-threatening disease or condition (21 CFR 312.305). A serious disease or condition is defined as a disease or condition associated with morbidity that has substantial impact on day-to-day functioning (determined by treating physician.)

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Categories of Expanded Access INDs

Expanded Access

Single Patient(includes

Emergency Use)

Intermediate-size populations

Treatment IND (wide spread use)

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Primary purpose of EA is to provide access to investigational (unlicensed) drugs, not to collect systematic safety or effectiveness data

Expanded Access Single Patient INDs

Probable risk to the person from the investigational drug is not greater than the probable risk from the

disease

No satisfactory alternative therapy is available

The patient cannot receive the product through any existing clinical trials or expanded access protocols

Providing the investigational product will not interfere with investigational trials that could

support a product’s development or marketing approval for the treatment

indication

Single Patient EA IND(21 CFR 312.310)

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Emergency EA individual INDs can be issued in the situation that requires a patient to be treated before a written submission can be made.

Thanks!

Cara Fiore cara.fiore@fda.hhs.govMicrobiologist, Primary ReviewerDivision of Vaccines and Related Biologics ApplicationsOffice of Vaccines Research and ReviewCBER/FDACara.fiore@fda.hhs.gov

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References Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products: Guidance for Industry

https://www.fda.gov/downloads/Drugs/.../Guidances/UCM590547.pdf Guidance for Industry: GMP for Phase 1 Investigational Drugs

https://www.fda.gov/downloads/drugs/guidances/ucm070273.pdfThe website for expanded access information

https://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm To request an emergency EA IND, please call 301-796-2640 during regular business hours. If this is outside of

normal business hours (M-F 8 – 4 p.m.) and/or require immediate assistance, please call the CBER Call Center at 240-402-8020, or 301-796-8240; or toll free 800-835-4709, or 866-300-4374. For non-life threatening inquiries, email industry.biologics@fda.hhs.gov [CBER's Office of Communication, Outreach and Development]. The websites for expanded access information are below.

If you want to submit a new non-emergency expanded access IND, you may submit it to CBERSPIND@fda.hhs.gov If you want to submit an amendment to an existing expanded access IND, you may also use the above email address.

https://www.fda.gov/news-events/expanded-access/expanded-access-information-physicians#SubmitRequests

http://wcms-internet.fda.gov/news-events/expanded-access/expanded-access-how-submit-request-forms

https://www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm

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