By
Donald Zuhn —

In
an Op-Ed appearing in Tuesday's San Jose
Mercury News, two physicians have asked Rep. Anna Eshoo (D-CA) to close
what they believe is a loophole in follow-on biologics (FOB) legislation
currently before Congress ("Eshoo needs to close loophole in biologics
legislation").  The authors of the piece, psychiatrist
Dr. Alexander Tsai of the Langley Porter Psychiatric Institute at the University
of California, and Dr. Nicholas Rosenlicht, a clinical professor of psychiatry
at UCSF who is in private practice in Berkeley, CA, directed their request
to Rep. Eshoo because of her successful efforts to secure passage of FOB
legislation in the House.

Last
spring, Rep. Eshoo (at left) introduced an FOB bill (H.R. 1548)
in the House that would establish a pathway for the licensure of biosimilar
biological products (otherwise known as follow-on biologics or biogenerics) and
provide up to 14.5 years of data exclusivity for biologic innovators (see "Second Follow-on Biologics
Bill Is Introduced in House").  The bill was introduced one week after
House Energy and Commerce Committee Chairman Rep. Henry Waxman (D-CA)
introduced his own bill (H.R. 1427),
which would establish a regulatory pathway for the licensing of biosimilar or
biogeneric biological products and provide up to 5.5 years of exclusivity (see "Waxman Introduces Follow-on
Biologics Bill").  Currently, H.R. 1548 enjoys the support
of 150 members of the House while H.R. 1427 has the backing of only 17 members.

While
the relative support of the two bills served as something of an indicator of where
the House stood on the issue of data exclusivity, over the summer, the debate over FOB
legislation merged with the heath care debate.  In late July, the House Committee on Energy
and Commerce approved a health care bill (H.R. 3200)
containing FOB provisions that are similar to the follow-on biologics
legislation introduced by Rep. Eshoo back in March (see "House Committee Approves Health Care Reform Bill Calling
for 12-Year Exclusivity Period").  And in November, the House passed a
separate health care bill (H.R. 3962)
that would provide for the establishment of a licensure pathway for biosimilar
biological products, and which would preclude a biosimilar application from
being approved "until the date that is 12 years after the date on which
the reference product was first licensed" (see "Follow-on Biologics News Briefs – No. 10").

While
the FOB debate over the past few years has been heavily focused on the length
of an appropriate exclusivity period (see
"Follow-on Biologics Data Exclusivity Debate Scorecard – Part III"),
some opponents of current FOB legislation contend that another issue, known as
evergreening, has been overlooked. 
As the Mercury News article
suggests, current FOB legislation would "reward[] branded biologic drug
manufacturers with additional years of exclusivity if they make slight changes
to their existing drugs, a strategy known as 'evergreening.'"  The authors note that "[a]ccording
to the FTC, [Rep. Eshoo's] bill would stifle innovation by encouraging
manufacturers to focus their research efforts on making minor modifications to
existing drugs rather than on developing 'new inventions to address unmet
medical needs,'" and add that "[a]s psychiatrists, we are very
familiar with how evergreening has adversely affected our patients."  Drs. Tsai and Rosenlicht find fault
with Rep. Eshoo's contention that her bill would not permit evergreening,
countering that the legislation "actually contains a glaring loophole
whereby simple, inexpensive modifications to drug structure could trigger
additional years of exclusivity." 
The authors conclude by asking Rep. Eshoo to "reconcile her
priorities with those of the marginalized and excluded — and close her
evergreening loophole" as negotiations on the health care bill progress.

Drs.
Tsai and Rosenlicht are not the first to call attention to an alleged
evergreening loophole in current FOB legislation.  In early November, Jane Hamsher, writing for The Huffington Post, disagreed with Rep.
Eshoo's interpretation of her bill, saying that "a number of experts including
Ethan Guillen, Executive Director of Universities Allied for Essential
Medicines (UAEM), Chris Manz, UAEM student at Duke University, and Sarah
Rimmington, Attorney at Essential Action, Access to Medicines Project, . . . all
concur that Rep. Eshoo's bill doesn't say what she believes it does"
("Anna Eshoo's PhRMA Boondoggle: The Devil Is In Her Details").  In the health care bill recently passed by the House (H.R.
3962), the portion of the legislation that has been drawing criticism is contained within the following section (which also includes a provision providing for a 12-year data exclusivity period):

(7)
EXCLUSIVITY FOR REFERENCE PRODUCT.—

(A)
EFFECTIVE DATE OF BIOSIMILAR APPLICATION APPROVAL.—Approval of an application
under this subsection may not be made effective by the Secretary until the date
that is 12 years after the date on which the reference product was first
licensed under subsection (a).
(B)
FILING PERIOD.—An application under this subsection may not be submitted to the
Secretary until the date that is 4 years after the date on which the reference
product was first licensed under subsection (a).
(C)
FIRST LICENSURE.—Subparagraphs (A) and (B) shall not apply to a license for or
approval of—

(i)
a supplement for the biological product that is the reference product; or
(ii)
a subsequent application filed by the same sponsor or manufacturer of the
biological product that is the reference product (or a licensor, predecessor in
interest, or other related entity) for—

(I)
a change (not including a modification to the structure of the biological
product) that results in a new indication, route of administration, dosing
schedule, dosage form, delivery system, delivery device, or strength; or
(II)
a modification to the structure of the biological product that does not result
in a change in safety, purity, or potency.

Rep.
Eshoo's interpretation of the passage above appeared in an article she wrote
for The Hill's Congress Blog ("Setting
the record straight on our health care legislation"),
where she said that she was "quite frankly outraged by the falsehoods and
misrepresentations" made by Ms. Hamsher in one of her earlier articles.  As for the accusation that her legislation
contained an evergreening loophole, Rep. Eshoo explained that:

There is no 'evergreening' clause in my
legislation.  There is in fact an
'anti-evergreening' clause which explicitly provides no new exclusivity period
would be granted for "a change (not including a modification to the
structure of the biological product) that results in a new indication, route of
administration, dosing schedule, dosage form, delivery system, delivery device,
or strength."  My amendment
prohibits by its plain language exactly what Ms. Hamsher alleges it would
encourage.

Ms.
Hamsher's experts, however, countered with their own post ("UAEM and AMSA
Respond to Rep. Eshoo — Point by Point"),
arguing that:

The clause Representative Eshoo refers
to does appear on its face to exclude changes that result in a new indication,
route of administration, dosing schedule, dosage form, delivery system,
delivery device, or strength from being eligible for a new 12-year exclusivity
period.  Unfortunately, her
understanding of how the language operates is incorrect.  The existence of the language in the
bracket "(not including a modification to the structure of the
biological product)" — actually does create a huge evergreening
loophole.  If you look closely at
the tricky language of the sentence you will see that changes to biologics that
result in new indications, routes, dosing schedules, delivery systems,
strengths, etc., are ineligible for another 12- year exclusivity period under
the Eshoo approach only if they come about without a modification
to the structure of the product.

In
other words, if a company makes a modification to the structure of the
already approved biologic that results in a new indication or any of the other
items listed, they will be eligible for a brand new 12-year exclusivity
period.  Unfortunately, because the
term "structural modifications" is not defined, interpretation is
open to a very wide range of possible changes that will qualify for a brand new
12-year monopoly, many of which are relatively simple and inexpensive to do,
and which do not change a drug in any material way.

As
the health care debate moves to the Senate — and the FOB debate moves along with it — the
Senate's response to the evergreening loophole argument merits watching.