Regulatory Expectations for Comparator

Regulatory Expectations for Comparator Product
Use in Clinical Trials
Roundtable: “Comparator Products –
Untold Stories”
Ravi S. Harapanhalli, Ph.D.
Principal Consultant and Practice Lead for
Late Stage Development Consulting
PAREXEL Consulting
November 11, 2009

- 2 -
Outline
• Why are comparator products needed
• Comparator selection considerations
• Why blinding or masking of comparators
• Blinding strategies
• Regulatory considerations (legal, import/export, controlled substances)
• Good blinding practices (GBPs) and regulatory expectations

- 3 -
Why are Comparator Products Needed
• NDAs filed under 505(b)(2), ANDAs filed under 505(j)
› Relative bioavailability, Bioequivalence assessments
› 21CFR 320
• Head-to-head clinical studies for S/E
› Therapeutic equivalence for generics
› Non-inferiority, superiority claims for “me too” drugs
› Same or different dosage forms and routes of administration
• Used as standard-of-care or add-on therapy
› E.g. 505(b)(1) NDAs for NMEs
• To facilitate approval of follow-on biologics (FOBs) under BLAs/NDAs
› Pending legislation to amend PHS act

- 4 -
Comparator Selection Considerations
• Nationally approved
• Most widely prescribed Rx drug
• Sourcing issues
• Suitability of approved product strengths
• Ruggedness to withstand modification/alteration
• History of product recalls
• Global availability in same dosage form, strengths, trade dress
• Reported BE inequivalences across regions
• Import/export issues

- 5 -
Comparator Selection Contd..
• Availability/acceptability of comparators in countries of investigation
› Unapproved comparators
› Import/export issues (under investigational use)
› Controlled substances
• Sourcing issues for long outcome studies
• Risk of changing comparators in the midst of clinical studies
• COAs for comparators
› From innovators
› In-house analysis
• Tracking comparators for possible recalls
• Comparators for global filing (Thinking globally and acting locally!
› Region-specific BE studies to support one comparator source

- 6 -
Comparator Selection for FDCs
• Combination rule 21 CFR 300.50
• Factorial design to show individual contributions to the claimed effect
• Often a 5-arm study: Drug A, Drug B, Free combination, FDC A+B, and
placebo
• Expectation is that comparator drugs A and B are individually approved
monotherapies in USA.
• Study to assess bioequivalence of comparator drugs to FDCs are
required to rule out PK/PD interactions.
• Studies using free combinations of comparators versus FDCs may also
be required.

- 7 -
Comparator Selection for FDCs: Contd…
• What if comparators are not approved as monotherapies
› Use of unapproved comparators
› Use of other approved FDCs containing the comparator drug
› Acceptable only if pharmacokinetic linkage to approved product/strength established
› Bioequivalence creep should be considered for multiple bridging
• Example: Use of 5 mg Roxicodone (oxycodone) tablets as comparator for
Combunox (oxycodone/Ibuprofen 5 mg/400 mg):
› 5-mg Roxicodone is an unapproved product
› Oxycodone in Combunox was BE to 5-mg Roxicodone
› Three 5-mg Roxicodone tablets were BE to the15-mg Roxicodone tablet in the
referenced NDA
› The 15-mg Roxicodone was BE to the oxycodone in three 5-mg Percodan tablets in
another study from the referenced NDA.
› Percodan is an approved product

Comparator Selection for Biologics
(WHO Draft Guidance on SEBs)
- 8 -
• Harmonization among National Regulatory Authorities (NRAs)
• Option to use non-national/non-regional comparator product
• Addressing scientific issues limiting use of comparator products
› Assess the effects of de-formulation and differences in formulation
› Use of publicly available information
› Data provided by the manufacturers,
› Information obtained by the NRA via information sharing with other NRAs,
› MOUs with other competent regulators to facilitate information sharing.
• Additional guide to use non-nationally licensed comparator products
• Acceptability of one comparator product across regions may streamline
the comparability exercise and minimize redundancies and cost.

- 9 -
Why Blinding or Masking of Comparators
• Double-blind, active-controlled and placebo-controlled studies are
required in many cases to establish efficacy
› Double-blinding improves quality of clinical data
› Minimal bias due to the invisibility of the marketed product
› Matching placebo to assess any potential placebo effect
› Helps in randomization of patients for statistical reasons

- 10 -
Blinding Strategies
• Oral dosage forms
› Over-encapsulation
› Film coating
› Wiping off printed inscriptions for solid dosage forms
› Repackaging for liquids or powders.
• Parenterals
› Choosing container closure systems that are indistinguishable
› Overlabeling with blinding codes

- 11 -
Over-encapsulation of tablets or capsules
• Widely accepted mechanism throughout the clinical supplies industry
• Packaging for clinical supplies is a complex process
› strictly controlled by good manufacturing practice (GMP)
• Addition of a product or products to a hard gelatin capsule
• Optional backfilling with an inactive bulk agent or excipient
• Can be used for comparator products, investigational medicinal
products (IMP) and/or placebos
• Visually identical capsules for each product or strength
• Maintains the blind and removes any potential bias.

- 12 -
Options for Over-Encapsulation
Courtesy: Richard Shannon, Head of Business Development (Eur), Almac Clinical Services

- 13 -
Manufacturing Challenges
• Over-encapsulation, bottling, blistering, and labeling
› Variation in batch size
› Multiple, operational set-ups
› Required in-process checks
› Variations in capsule size, coating thickness
› Multiple manufacturing sites
• Uniform flow of excipients used as backfill
• Unique shape or dimensions of input product
• Need to produce new strengths of comparator products
› Promote adherence to the prescribed dosing regimen
› Capsules may contain more than one unit of marketed product
• Re-containerization issues

- 14 -
Manufacturing Considerations
• Excipients
› Primarily to prevent rattling.
› Should remain inactive,
› Should not have effect on the quality of the product
› Should flow efficiently during the over-encapsulation process.
› Flood volume filling or dispensing controlled dose of excipient
• Capsule shells
› Wide range of hard gelatine capsules specifically for clinical supplies market
› Range of diameters and lengths allow many products to be over-encapsulated
› Opaque colorations promote better blinding
• Capsule weight check
› Manual inspection or automated vision systems
› Rejection of misfed capsules

- 15 -
Manufacture of Matching Placebo
• Not generally possible to manufacture placebos to branded products
› legal and ethical implications
• Over-encapsulation is a useful procedure
› Manufacture of placebo capsules to contain excipient only
› Manufacture of placebo capsules to contain a placebo tablet or capsule and
excipient
• The placebos should be manufactured to similar specifications as those
utilized during the active over-encapsulation process to maintain the
blind.

- 16 -
Assessing the Impact of Comparator Blinding
• The nature and extent of modification/alteration of comparator
• Label performance retained or altered
• CMC considerations
› Developing minimally invasive blinding process
› Packaging of blinded comparators
› Setting specifications (analytical methods, validation)-
Pharmacopieal/Nonpharmacopial testing
› ID, Assay, impurities, dissolution/performance
› Conducting appropriate stability program
• Conducting BA/BE studies when needed

- 17 -
Bioequivalence Criteria for Blinded Comparators
• Same as general BE criteria
• Ratio of geometric means must fall within the 90% CI for AUC and
Cmax: 80 – 125% of the unmasked comparator for the abovementioned
values.
• Some differences in Cmax and/or Cmin may be allowed provided:
› they are adequately characterized
› are not essential to the attainment of effective body drug concentrations on
chronic use
› are considered medically insignificant for the particular drug product studied.

- 18 -
Legal Challenges of Blinding
• Visible branding of commercial products
• Product/sponsor logos directly onto products
• Patented shapes/designs

- 19 -
Importing Comparator Drugs Under a US-IND
› 21 CFR 312.110 (a) Imports.
› Investigational drug label on the comparator product
• Name of the blinded comparator drug
• Manufacturing site
• Name and address of the proposed clinical site
• Contact information of the investigator (consignee)
• IND number (effective under 312.40)
• Warning statement “for investigational use only”

- 20 -
Exporting Comparator Drugs Under A US-IND
• 21 CFR 312.110 (b)(1); IND effective under 312.40
• Receiver named as investigator in IND
• Shipment of the drug for use in a clinical investigation authorized by FDA
• Written request by exporter of drug to FDA’s Office of International Affairs Staff
(HFY–50)
• Appropriateness for the proposed investigational use in humans
• Limited only for investigational purposes
• Legal basis for the use of investigational drug by the consignee
• Quantity of the drug to be shipped per shipment
• Frequency of expected shipments.
• Notification of authorization by FDA to the government of the importing country

- 21 -
Exporting Comparator Drugs Without A US-IND
• Formal request from an authorized official of the government of the
country to FDA (Office of International Affairs)
› adequate information about the drug
› proposed investigational use,
› Limited only for investigational purposes
› Reassurance that the drug may legally be used by the intended consignee in
that country.
› Quantity of drug to be shipped per shipment
› Frequency of expected shipments.

- 22 -
Controlled Substances as Comparators
• 312.69 Handling of controlled substances.
• Measures to prevent theft or diversion of the substance into illegal
channels of distribution
› Subject to controlled Substances Act
› Storage of the investigational drug in a securely locked, substantially
constructed cabinet, or enclosure
› Restricted access
• DEA requirements
› Registration of importing/exporting sites
› Permit for importation/exportation
› Declaration forms at the time of actual shipment.

Good Blinding Practices and Regulatory
Expectations
- 23 -
• Tightly control and scrutinize the manufacturing process
› To be minimally invasive
› To ensure the product is blinded appropriately
› To allow rapid product identification in case of emergency (e.g. recall of comparator
product)
• Demonstrate no significant quality change within the product
› Compendial and/or in-house specifications (ID, assay, impurities, degradants)
› Comparative in vitro product performance (e.g. dissolution, multi-media, multi-point
profiles and f2)
› Container closure system change and product stability
› Bioavailability (when needed)
• Justify and assign expiry dates and storage conditions
• Document batch records on file and file the information in the IND

- 24 -
Thank you for your attention!
Ravi.harapanhalli@parexel.com
Work: 301 634 8027
Cell: 240 404 8668