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Comparator Sourcing for Clinical Trial Materials
9th Annual Clinical Trial Supply East Coast 2011 Cutting
edge technologies and essential new strategies to optimize the efficiency of your clinical supply chain
October 19th and 20th 2011, Philadelphia, PA
Patricia Thomas Senior Clinical Supply Program Manager
Takeda Global Research & Development Center, Inc.
Takeda, after the newly completed acquisition with Nycomed,
is now a company of 30,000 people. The 12th largest
pharmaceutical Company in the world.
10/27/2011 2
Outline
Alphabet soup (IMPs, NIMPs and Comparators)
Possible stakeholders in the decision process for comparator sourcing
Comparator blinding options considered
Items considered when sourcing comparators
Import / Export considerations
Protocol considerations
Resources
Case Study: Issues with comparator tablets as a result of the over-encapsulation (O/E) process
Selection of a replacement lot of comparator tablets
QA release of over-encapsulation (O/E) material
Lessons learned / conclusions
Questions
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Alphabet Soup
•What is an IMP?
•What is a NIMP?
•What is a Comparator?
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Alphabet Soup
IMP - Investigational medicinal product
• Directive 2001/20/EC defines in Article 2 (d) an IMP as “a pharmaceutical form of
an active substance or placebo being tested or used as a reference in a clinical trial,
including products already with a marketing authorization but used or assembled
(formulated or packaged) in a way different from the authorised form, or when used
for an unauthorised indication, or when used to gain further information about the
authorised form.”
• It follows that medicinal products with a marketing authorisation are IMPs when
they are to be used as the test substance, reference substance or comparator in a
clinical trial, provided the requirement(s) in the definition are met.
Reference: THE RULES GOVERNING MEDICINAL PRODUCTS IN THE EUROPEAN UNION VOLUME 10 - GUIDANCE DOCUMENTS APPLYING
TO CLINICAL TRIALS GUIDANCE ON INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) AND 'NON INVESTIGATIONAL MEDICINAL PRODUCTS' (NIMPS) (REV. 1,MARCH 2011)
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Alphabet Soup NIMP - Non-investigational medicinal product • NIMPs are medicinal products that fall within Article 3(3) of Directive 2001/83/EC, while not
falling within the definition of IMP as defined in Article 2(d) of Directive 2001/20/EC.
• For instance, some clinical trial protocols require the use of medicinal products such as concomitant or rescue/escape medication for preventive, diagnostic or therapeutic reasons and/or to ensure that adequate medical care is provided for the subject. They may also be used in accordance with the protocol to induce a physiological response.
• Medicinal products that do not have a marketing authorisation, but prepared in accordance with a magistral formula, i.e. prepared in a pharmacy in accordance with a medical prescription for an individual patient, and medicinal products prepared in a pharmacy in accordance with the prescriptions of a pharmacopoeia4 and intended to be supplied directly to the patients served by the pharmacy in question, i.e. officinal formula, as referred to in Article 3(1) and (2) of Directive 2001/83/EC may also be an NIMP.
• Types of NIMPs – rescue medication, challenge agents, medicinal products used to assess end-points in the clinical trial, concomitant medicinal products
Reference: THE RULES GOVERNING MEDICINAL PRODUCTS IN THE EUROPEAN UNION VOLUME 10 - GUIDANCE DOCUMENTS APPLYING
TO CLINICAL TRIALS GUIDANCE ON INVESTIGATIONAL MEDICINAL PRODUCTS (IMPS) AND 'NON INVESTIGATIONAL MEDICINAL PRODUCTS' (NIMPS) (REV. 1,MARCH 2011)
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•Comparator product
•An investigational or marketed product (i.e. active control), or placebo, used as a reference in a clinical trial. •Please reference the description of an IMP
Alphabet Soup
Possible Stakeholders in the Decision Process for Comparator Sourcing
•Regulatory Affairs
•GMP QA
•Clinical Operations
•Clinical Science
•Pharmaceutical Development (CMC)
•Clinical Supplies
•Import/Export
•Vendors (Specialty Wholesaler, CRO, Packager)
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Comparator Blinding Options Considered
•Over-encapsulation
– Comparator tablet in a capsule with inert filler (avicel or lactose).
– Capsule size may be a compliance issue due to difficulty swallowing.
– Dissolution to prove equivalence
– Shorter lead-time as compared to placebo tablet manufacturing.
•Manufacture of matching placebo tablets
– Long lead time to implement contract and manufacture product.
– Regulatory concerns with the use of marked placebo tablets will lead to over-coating of both the placebo and active
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Items Considered When Sourcing Comparators
•Sufficient quantity. First choice is a single lot.
•Tablet shape fits into a capsule
•Matching placebo
•Manufacturer acceptability.
– Established / reputable company with sufficient capacity
– 483’s , import / export issues
•Date of Manufacture / Shelf – Life (Expiry date) is sufficient for length of study.
•Acceptable for use globally.
– Statement of Bioequivalence between EU and USA
•Bottle packaging preferred over blisters.
•Re-supply intervals (if needed) i.e. ensure continuity of supply
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Import/Export Considerations
• Availability of BSE/TSE documents, especially if the product is O/E • If product sourced outside of US and will be imported into US for
further packaging – Does the product contain any ingredient from animal source? If yes, a
need for USDA permits – Cannot import the product into US without active IND, unless its
imported for exports or in a bonded warehouse.
• Is the product available commercially in the country conducting the clinical trial? – Country may not allow the import for the product
• If the product is being over-coated for blinding – Issues with countries flagging the product as counterfeit product
during import/export, due to color that is selected – Legal issues due to trademarks
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Protocol Considerations
•Study quantities
•Global requirements – Countries from the following regions: US, EU, LA, ROW
– All languages to fit onto booklet label
•Timing
•Logistics – Over-encapsulation site
– De-blistering required at over-encapsulation manufacturer
– Labeling site
– Distribution
– Suggest that you add all possible sites to the IMPD to avoid delay if logistics change
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Resources
•Specialty Wholesalers used to identify possible manufacturing sources.
•Generic Manufacturer
•Innovator
•In Country CRO
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Case Study: Issues with Comparator Tablets as a result of the Over-Encapsulation (O/E) Process
•Chipped tablets discovered during Identification testing of O/E product
•Investigation included ANSI (American National Standards Institute\ASQ (American Society for Quality) Z 1.4-2003 Sampling Plan. Current version is 2008
– Identified probable cause as deblistering tool
– Resulted in rejection of one O/E lot
•Generic Manufacturer unable to provide a commercially packaged lot of comparator in the time frame needed
•Product from other manufacturers still not acceptable due to lack of bioequivalence data
•Study already started using previously released O/E product.
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Case Study: Selection of Replacement Lot of
Comparator Tablets
•Manufacturer offered tablets packaged in bulk containers
– Provided – Expiry date support and batch documentation
– Same manufacturing site as first two blister lots.
– Replacement lot of tablets procured in bulk
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Case Study: QA Release of O/E Material From Comparator Procured as Bulk Lot
•Information needed from manufacturer (obtained through specialty wholesaler)
– Manufacturer produces the same commercial product in bottles.
– Batch records were provided
– Material was in bulk form not commercial packaging
– Certificate of analysis for final bulk product provided
– GMP statement from manufacturing provided
– Any issues identified during manufacturing
– Stability data/expiry date
• Document obtained from manufacturer since not in finished commercial packaging
•Site Audit
– No site audit needed based on review of documents (above) and use of approved commercial manufacturer.
Lessons Learned/Conclusions •Target the perfect solution, but be prepared to accept a compromise.
– Example – original goal was to source a universally accepted comparator that could be packaged in one location and distributed globally. The acceptable compromise would have been a comparator that would be sourced and packaged in both the USA and EU and distributed regionally.
– Two wholesale distributors were requested to locate a generic drug that would be identified as bioequivalent to both EU and USA formulations
– Contacting many sources may create a false demand within the market place resulting in an inflated price.
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Lessons Learned/Conclusions
•To avoid study delays, be prepared to act quickly
– Once comparator/manufacturer was accepted, an over-encapsulation issue caused the QA rejection of one lot (1 million tablets). A resupply need was identified.
– Problem Identified: Resupply inquiries indicated that the manufacturer did not have a finished packaged lot of the requested drug available in either the EU or the USA due to a planned relocation of manufacturing sites
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Lesson Learned/Conclusions
•Keeping the team informed of requirements and previous agreements allows for a quicker response to unexpected issues
– Wholesaler worked with the same manufacturer to find a solution and was able to locate bulk drug of the same origin as the previously supplied comparator.
– The Takeda team met and accepted the bulk lot based on previous information and manufacturer assurance of expiry dating documentation.
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Lessons Learned/Conclusions
•The constant flow of communication regarding needs, issues and timelines is essential.
•Work well and closely with vendors – Successful problem-solving in an ongoing study means
keeping your team involved and informed.
Questions?
• Contact: Patricia (Pat) Thomas
•Takeda Global Research & Development Center, Inc.
•Phone: 224-554-2658
•email: [email protected]
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