The FDA’s 505(b)(2) Drug
Approval Process And
Implications For Managed Care
Pharmacy
AMCP 2004 Educational Conference
Baltimore, MD
October 15, 2004
Paul J. O’Connor, RPh, MBA
Aon Consulting
Rebecca L. Dandeker, J.D.
Kirkpatrick & Lockhart, LLP
What Is a 505 (b)(2) Drug?
♦ Not a generic
♦ Not totally new
♦ Similar, but with limited differences, to
previously approved drug
♦ Often an innovative variation of previously
approved drug(s) containing the same active
moiety
Statutory Origins
♦ The Federal Food, Drug, And Cosmetic Act
of 1938
– Proof of safety and manufacturing information
Required for New Drugs
– Copycat Drugs go directly to market
– Not Required:
• Proof of effectiveness
• Affirmative FDA approval- Effective if no objection
Kefauver-Harris Drug
Amendments, 1962
♦ Revision of NDA requirements
– Proof of Effectiveness
– Affirmative FDA approval
– Retrospective review (DESI) for compliance to
new standards of all NDA’s from previous 24
years
– FDA’s published rulings on effectiveness
applied to pioneer and copycat (me-too) drugs
Kefauver-Harris (Con’t)
♦ Early version of ANDA
– Only for products subject to a DESI notice
– Submitted manufacturing data & labeling
– Relied on safety & effectiveness (S&E) of
pioneer
♦ Paper NDA
– Approval of duplicate drug
– Based solely on publicly available medical
literature
The Hatch-Waxman Amendments, 1984
♦ Patent extension and market exclusivity for
pioneer drugs
♦ Modern ANDA created
– Based on Reference Listed Drug (RLD)
– New Bioequivalence testing requirement
– Manufacturing & labeling requirements
continue
Hatch-Waxman: 505(b)(2) Pathway
♦ 505(b)(1) - Traditional NDA for pioneer
products
♦ 505(b)(2) - Streamlined approval process
for new products with same active moiety
as previously approved drug (RLD)
Hatch-Waxman: 505(b)(2) Pathway
– Requires full reports of investigations of S&E
– But allows Sponsor to rely on “investigations” not
conducted by the Sponsor and with no right of
reference
• Public scientific data from RLD
• Published medical literature
• Non-public data on file with FDA/Prior FDA S&E
decision
– Differences from RLD must be supported with
Sponsor’s clinical data of safety and effectiveness
Summary of Differences
505(b)(1)
505(b)(2)
ANDA
User Fees
Yes
Yes / No
No
Review Schedule
12 mo.
12 mo.
21 mo.
Scientific Studies
Full
Partial
Bioequiv
alence
New Active Moiety
Yes
No
No
New Chemical Entity (Ingredient)
Yes
Yes / No
No
New Indication
Yes
Yes
No
New Formulation
Yes
Yes
Yes*
New Dosage form or Strength
Yes
Yes
No*
Patented
Yes
Yes
No
Market Exclusivity
Yes
Yes
No**
* Limited changes
** Except against other generics
Legal Controversy
♦ 2001 Pfizer Petition against FDA Policy
♦ 2002 Pfizer Petition against Dr. Reddy’s Labs’
(b)(2) NDA for amlodipine maleate tablets
(RLD was besylate salt)
♦ 2003 Torpharm Petition against Synthon’s
(b)(2) NDA for paroxetine mesylate tablets
(RLD was hydrochloride salt)
♦ All denied by FDA, Oct. 14, 2003
Legal Arguments
♦
♦
♦
♦
♦
Opponents
Codifies paper NDA
policy
Reference to NDA
‘investigations’ can be
only published parts, not
proprietary parts
Undermines patent
Inadequate Studies on
(b)(2) drug
Can’t support AB rating
♦
♦
♦
♦
♦
Proponents
Step beyond paper NDA
policy
FDC Act expressly says
‘no right of reference’ and
doesn’t say limit to
‘published’
Not permitted to infringe,
must ‘design around’
Needless treatment with
placebo avoided
AB rating is appropriate if
bioequivalent to RLD
Legal Controversy Continues
♦ 2003 Bio Petition on subset of biologically-
derived products – Pending
– FDA says “unique scientific issues”
♦ 2004 Abbott Petition on differences in active
ingredient only – Pending
– Depakote (divalproex) vs. Andrx’ valproate sodium
– FDA says these (b)(2) NDA’s may not offer a
therapeutic benefit and may lead to marketplace
confusion due to pharmaceutical alternatives
Really, What Are
505(b)(2)’s?
What Are The Practical
Implications?
How Does a 505 (b)(2) Differ
From the Innovator Drug?
♦ Dosage form
♦ Strength
♦ Delivery mechanism
♦ Different formulation
– (e.g., different salt, complex, enantiomer, new
combination of previously approved drugs)
Examples of 505(b)(2) Approvals
♦ New Delivery Mechanism
– Canasa® (mesalamine) suppositories – Axcan
– ClobexTM (clobetasol proprionate) lotion – Galderma
– LuxiqTM (betamethasone valerate) foam - Connetics
– TestimTM (testosterone) gel - Auxilium
♦ New Dosage Form
– AltoprevTM (lovastatin) extended release tablets - Andrx
– DepoDurTM (morphine Sulfate) liposomal injection – Skye Pharma
– Doxil® (doxorubacin HCl) liposomal injection
♦ New Formulation
– PexevaTM (paroxetine mesylate) tablets – Synthon
– Stalevo® (carbidopa/levodopa/entacapone) tablets – Orion
– Xopenex® (levabuterol HCl) inhalation – Sepracor
♦ New Indication
– Avodart® (dutasteride) capsules - GlaxoSmithKline
– Thalomid® (thalidomide) capsules - Celgene
Sponsor’s Benefits of the
505 (b)(2) Pathway
Vs. traditional NDA
♦ Simplified approval process
– Use of previously published studies
♦ Quicker to market
♦ Lower cost
♦ Lower risk – “proven” commodity
Benefits (Cont’d)
Vs. ANDA (Generic)
♦ “Branded” generics to market sooner
♦ 505 (b)(2)’s may qualify for patent or
additional marketing exclusivity
– 3 to 5 years vs. 180 days for “first” ANDA
– Length depends on amount of additional data
required to support the application
• 180 day exclusivity not available
Practical Implications for
Managed Care Pharmacy
Formulary & Benefit Issues
♦ Likely simplified P&T review
♦ Pricing less than innovator
– Possibly more expensive than generic
♦ Formulary positioning
– Tier 1 or Tier 2?
♦ 505 (b)(2) may not be substitutable under
state pharmacy law
– Will the innovator drug be covered?
Management Issues
♦ Timing
– When will generic equivalents reach market?
– Do you invest in an intervention to move
market share that has only short-term value?
– Alternatively, if 505 (b)(2) represents
opportunity for significant savings, can you
wait?
Other Considerations
♦ Provider and/or patient education
♦ Need for pull-through
– Unlike generic manufacturers, some assistance
may be available from 505(b)(2) supplier
♦ Off-Label use for generics
♦ Potential for confusion
Potential for Substitution
♦ Avita (tretinoin cream) – AB rated
♦ AmVaz (amlodipine maleate tablets) – not
AB rated, but approved labeling says the
bioavailability of amlodipine is not altered
by salt form
♦ GA, LA, MI – pharmacist’s judgment
♦ CT, OR, TX – dosage form switch
♦ FL, IL, VA – state formulary
Future
♦ Possible pathway for Biologic “generics”
– FDA moving toward using 505(b)(2) as generic
biologic pathway
– But denied (b)(2) approval for Sandoz’
Omnitrope (DNA human growth hormone)
• FDA: “Unable to reach a decision due to uncertainty
regarding scientific and legal issues.”
– Statutory changes needed?
Future (cont’d)
♦ Most likely an increase in use of 505(b)(2)
pathway
– Medicare Modernization Act, 2003 limited the number
of 30-Month Stays that can be granted by the FDA to
innovator company
• Reduced barrier to entry for 505(b)(2)’s
• In practice, it increases window of opportunity to gain return
on investment
♦ A more rigorous patenting of “similar”
compounds by Pharmaceutical Manufacturers
possible
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