PS160718

Pharma intelligence
informa
SheetPinkpink.pharmamedtechbi.com Vol. 78 / No. 29 July 18, 2016
Continued on page 4
Brought to you by the Editors of Scrip Regulatory Affairs, The RPM Report, Tan Sheet, Gold Sheet, Pink Sheet Daily and Pink Sheet
Biosimilars
Amgen’s Humira Biosimilar
Gains Nod From Panel Perplexed
By Regulatory Pathway, P. 13
New Products
Antibiotic Incentives Helped Spero
Get Where It Is Today, p. 7
Regulatory
Settle Terms Before Brexit Divorce
Is Final, Former EMA Chief Says, p. 6
FDA Meets ANDA Backlog Goal Early,
Still Doesn’t Feel Out OfWoods
Derrick Gingery derrick.gingery@informa.com
O
ffice of Generic Drugs reviewed
more than 90% of official GDUFA
backlog of pending applications,
but many still will require more work.
FDA is celebrating a major review mile-
stone for generic drugs, but the reality re-
mains that much of that weight has yet to
come off the agency’s shoulders.
AmemofromCenterforDrugEvaluation
and Research Director Janet Woodcock
released July 11 trumpeted the achieve-
ment: as of July 1 FDA had reviewed more
than 90% of the official generic drug user
fee backlog, meeting the goal 15 months
ahead of the Sept. 30, 2017, deadline.
The backlog included nearly 2,900
ANDAs that were pending at the agency
when the Generic Drug User Fee Act
(GDUFA) program launched in October
2012. As part of the agreement with in-
dustry, the agency committed to provide
a first action, such as a full or tentative
approval, “complete response” (CR), or
refuse-to-receive action.
The official backlog increased leading
into GDUFA’s launch, which was a surprise
to FDA. The agency had hoped the total
would plateau or drop.
Woodcock wrote in the first sentence of
the memo that she was happy to report
that the goal had been met. But the fourth
sentence gave another assessment of the
situation, which dampened the joy she
was trying to convey.
“Most applications from the backlog will
need to come back to FDA for additional
review before approval is possible, so we
still have a lot of work ahead of us,” she
said.“But this is a significant milestone.”
Meetingthegoal,whichWoodcockinthe
memo called a “heavy lift” and required an
“all hands on deck approach” to succeed,
should free up FDA’s generics staff for oth-
er priorities. But applications do not truly
come off the books until an ANDA is ap-
proved. CRs or refuse-to-file actions only set
the stage for what is likely a resubmission.
FDA said it is difficult to estimate the
amount of applications from the backlog
receiving CRs that will be resubmitted, but
expects it will be “the vast majority,” the
agency said in an email to the Pink Sheet.
Still, pushing nearly all of the applica-
tions through the review system, even if
they all were not approved, should en-
courage industry.
The backlog at the Office of Generic
Drugs (OGD) has long been a source of
complaint from firms, in part because of the
lengthy review times, which still are more
than 30 months on average. Those in the
backlog did not receive a shorter formal re-
view goal unlike those submitted today.
The Generic Pharmaceutical Association
has argued that the agency would have
to dramatically increase its approval rate
to eliminate its backlog before the end of
GDUFA I. But FDA has countered that there
are not enough applications ready to be
cleared to work at the necessary pace.
DA said it is difficult
to estimate how
many applications
receiving complete
response actions will be
resubmitted, but
expects it will be “the
vast majority.”
Photocredit:PiyapongWongkam/shutterstock.com

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pink.pharmamedtechbi.com July 18, 2016 | Pink Sheet | 3
9cover 7
340B“Mega-Guidance”Delayed To December
(Or Beyond)
HRSA official stresses importance “good faith” by manufacturers
and purchasers to assure US discount program’s integrity while
key definitions remain in limbo.
‘Surrogate Of A Surrogate’Not Good Enough
For Raxone Accelerated Approval
FDA’s decision to require second pre-approval trial for Santhera’s
DMD candidate is just latest example of the inability of rare
disease treatments with surrogate endpoints to qualify for
pathway.
FDA Backs Off From Early Citations Of Compounder
Sterility Issues
A month after compounding pharmacists’ latest annual visit
to Congress, FDA has acted on one of their chief complaints –
investigators citing them for GMP violations even in cases where
the agency later acknowledged they were exempt.
India Will Miss Investment Boat If New IPR Policy
Just All Talk
India’s more muscular intellectual property protection policy is a
good first step but the government will have to“walk the talk”to
attract significant new investment from global pharmaceutical
companies, say US experts. Implementation of the policy will be
the key measure of its success, they say.
exclusive online content
COVER FDA Meets ANDA Backlog Goal Early, Still Doesn’t
Feel Out Of Woods
Regulatory Update
6 Settle Terms Before Brexit Divorce Is Final,
Former EMA Chief Says
7 Antibiotic Incentives Helped Spero Get Where It Is Today
Generic Drugs
20 FDA’s ANDA Approvals
New Products
25 FDA’s NDA And BLA Approvals
Advisory Committees
26 Recent and Upcoming FDA Advisory Committee Meetings
Biosimilars
13 Biosimilar Sponsors May Be Going Overboard On Clinical
Data, FDA Says
15 Amgen’s Humira Biosimilar Gains Nod From Panel
Perplexed By Regulatory Pathway
17 Biosimilar Advisory Committee Features Actual Debate
About Biosimilarity
18 Sandoz Climbs‘Pyramid’To Reach Biosimilar Success
Consumer Drugs
21 Galderma Pioneers NDA Path Into OTC
Acne Treatment Market
Manufacturing
22 Second Time Around: EU GMP Guideline For ATMPs
Out For Consultation Again
23 FDA Backs Off From Early Citations Of Compounder
Sterility Issues
24 Upcoming ICH Q11 Guide To Clarify What Constitutes
Starting Materials
Market Access & Reimbursement
9 Revisionist History On Health Care Reform Deal
10 Korean Pro-Innovation Pricing Steps Draw Mixed
Responses
inside:
Regularly updated information about new submissions,
pending applications and FDA actions, online-only
interactive content at your fingertips 24/7 at
www.pharmamedtechbi.com/tracker
FDA performance
tracker
online only!

4 | Pink Sheet | July 18, 2016 © Informa UK Ltd 2016
G e n e r i c D r u g s
FDA also continues to work toward
reducing the number of review cycles
needed for ANDA approval. Applications
have averaged between two to five cy-
cles before clearance.
AsOGDmovestoamandated10-month
review goal for most applications submit-
ted beginning Oct. 1, sponsors will have
to pay closer attention to submission
quality in order to help limit the number
of review cycles and lower review times.
Complete Responses Jump In
Recent Months
Indeed, CR actions have far outnumbered
full approvals since GDUFA launched and
recently have jumped considerably.
The ratio of “complete response” letters
to approvals was more than 3/1 in FY 2014,
but has decreased since then as approvals
have increased. Through nine months in
FY 2016, it is about 2.4 CRs per approval.
OGD has ramped up its CR output dur-
ing the most recent four-month period.
It issued more than 650 CRs from March
through June and each monthly total was
higher than any of the months leading up
to that stretch (seegraphic).
Agency officials warned in February that
CRlettersandrefuse-to-receiveactionsmay
increase as a result of a rush of submissions
in December 2015, many of them appar-
ently of low quality.
The overall increase in CR letters is part
of an across-the-board productivity im-
provement at OGD that also has resulted in
increased approvals, although ANDA sub-
missions are increasing along with them
(see graphic).
OGD significantly increased its approval
output in FY 2016 as GDUFA-funded hiring
and IT improvements began to take hold.
It exceeded the FY 2015 approval total in
nine months.
Even though it may not drastically reduce
FDA’s workload, meeting the goal should
provide some confidence as efforts to re-
new the user fee program continue.
Along with meeting the backlog com-
mitment, FDA also is making progress
in other areas, including meeting formal
ANDA review goals.
Negotiations remain ongoing, FDA con-
firmed. The most recent discussions have
focused on the program’s financial issues,
including fee structure and resource needs.
The group recently reached a tentative
agreement on changes to the review sys-
tem and other enhancements.
GDUFA will be the last human drug-relat-
ed user fee program to complete reauthori-
zation negotiations.
Prescription drug user fee talks wrapped
up in January, and biosimilar user fee talks
ended a few weeks ago.
Published online July 12, 2016.
Continued from cover
Source: Office of Generic Drugs data
FDA'sOfficeofGenericDrugshasdramaticallyincreaseditsmonthlycompleteresponseletteroutputinrecentmonths.
ANDA Complete Response Letters Jump
40
60
80
100
120
140
160
180
200
Oct12
Dec12
Feb13
Apr13
Jun13
Aug13
Oct13
Dec13
Feb14
Apr14
Jun14
Aug14
Oct14
Dec14
Feb15
Jun15
Aug15
Oct15
Dec15
Feb16
Apr15
Apr16

Source: Office of Generic Drugs data
15
20
25
30
35
40
45
50
55
60
65
70
75
80
0
50
100
150
200
250
300
350
400
450
500
550
600
650
OGDcontinuestomaintainitselevatedANDAapprovalpaceandalreadyhassurpassedthetotalsseenforalloffiscalyears2013,2014and2015.
ButsubmissionsalsoareincreasingagainandareaheadofthetotalforFY2015.
ANDA Approvals Continue At Elevated Level...
... But ANDA Submissions Are Increasing Again
Oct12
Dec12
Feb13
Apr13
Jun13
Aug13
Oct13
Dec13
Feb14
Apr14
Jun14
Aug14
Oct14
Dec14
Feb15
Jun15
Aug15
Oct15
Dec15
Feb16
Apr15
Apr16
Oct12
Dec12
Feb13
Apr13
Jun13
Aug13
Oct13
Dec13
Feb14
Apr14
Jun14
Aug14
Oct14
Dec14
Feb15
Jun15
Aug15
Oct15
Dec15
Feb16
Apr15
Apr16

r e g u l ato ry u p dat e
SettleTerms Before Brexit Divorce Is Final,
Former EMA Chief Says
Ian Schofield ian.schofield@informa.com
I
f the European Medicines Agency has to desert London as a re-
sult of the UK’s decision to leave the EU, it will have to take care
in managing issues such as the loss of expert input from the UK
regulator, the MHRA, says former EMA head Thomas Lönngren.
FollowingthedecisionbytheUKtoleavetheEuropeanUnion,itwill
behardtotellwhatthefutureholdsforthecountrywithintheEurope-
andrugregulatorysystemandfortheLondon-basedEuropeanMedi-
cinesAgencyitselfuntilweknowjustwhatkindofrelationshiptheUK
will eventually forge with the EU and its 27 other member states.
The EMA has said that it’s business as usual for the time being, and
that the implications for its location and operations will depend on
the UK’s future relationship with the EU. But if, as incoming Prime
Minister Theresa May has just declared, “Brexit means Brexit” and
the UK relinquishes its EU membership altogether, there will be sig-
nificant consequences for both the EMA and the UK Medicines and
Healthcare products Regulatory Agency.
In such an event, the EMA would need to be relocated from the
UK to another EU country, with all the upheaval this would involve.
According to Thomas Lönngren, who led the EMA for 10 years from
January2001toDecember2010,theagencywouldneedtomanage
such a situation very carefully, not least because of the loss of expert
input from the MHRA and the possible departure of other EMA staff
amid the uncertainty over its future location.
At present we don’t know what form the negotiations over the
UK’s future will take or how long they will last. The process will start
when the government triggers Article 50 of the Treaty on European
Union, marking the start of the two-year negotiations on extricating
the UK from the EU. EU leaders want the process to kick off as soon
as possible, but May, who takes over from David Cameron as prime
minister on July 13, is likely to want to wait as long as possible to al-
low the government to prepare its negotiating position.
Opinion differs as to what will be covered by the negotiations.
Some, including EU Trade Commissioner Cecilia Malmström, insist
that the two-year“divorce”proceedings must be completed before
any talks can begin on the future trading relationship between the
UK and the EU. Others suggest that it would make more sense for
the two sets of negotiations to be carried out in tandem, otherwise
theUKcouldbelefttooperateunderWorldTradeOrganizationrules
until it has forged its own trade agreements.
Inthedrugregulatoryarea,theconsequencesfortheEUregulato-
ry system and the EMA“will depend on how Article 50 is interpreted
and on what a new deal after the divorce will look like,” Lönngren
said in an interview with the Pink Sheet.
ItwilldependonwhethertheEuropeanCommissionmaintainsits
opinion that there is a two-year process on the divorce, and that the
negotiations start after that, he said.“I don’t know if this will be the
final policy of the commission or the remaining member states. But
if we go by what we heard yesterday from the commission, that will
be a tough stance, it will take years, and it will be complex. From the
regulatory point of view it will be not so good to do a complete di-
vorce and have to negotiate afterwards some kind of collaboration.”
LönngrensaidthatintheeventofacompletepulloutfromtheEU,
the talks in the drug regulatory area would have to cover the reloca-
tion of the EMA, the position of UK nationals working at the agency
and in the European Commission, as well as the UK’s place in EU col-
laborative research ventures like the Innovative Medicines Initiative
and projects under the seventh framework program.
The parties will have to decide where the EMA should be located,
whenitwillhavetomove,andwhetherstaffarepreparedtorelocate
to another country. For the current EMA executive director, Guido
Rasi,“it will be a tough task to manage, this transition, with such un-
certainty,”Lönngren said.“One of the risks is of course that the EMA
losesstaffbecauseofuncertainty,thattheyfindotheropportunities.”
Lönngren is one of just three executive directors the EMA has
had since it was set up in 1995. Before joining the agency, he was
deputy director of the Swedish Medical Products Agency, from 1993
to 2000; he is now a strategic advisor at pharmaceutical consultants
NDA Group.
Loss Of Expertise
The EMA would also have to deal with the loss of expert input from
the MHRA, not least because the UK agency accounts for some 30%
of rapporteurships in the centralized drug approval procedure,
Lönngren observed.“A substantial number of experts would have to
be replaced by those from the remaining 27 member states.”Also, as
recently reported, several MHRA staff hold key positions at the EMA,
including June Raine, chair of the Pharmacovigilance Risk Assess-
ment Committee, and Rob Hemmings, who heads up the Scientific
AdviceWorking Party.
As to whether any loss of expertise would represent a risk to the
performanceoftheEUregulatorysystem,Lönngrensaid“itdepends
Photocredit:worradirek/shutterstock.com

R e g u l ato ry U p dat e
Antibiotic Incentives Helped Spero GetWhere It IsToday
Joseph Haas Joseph.Haas@informa.com
T
he progress made by antibiotic
start-up Spero Therapeutics LLC
offers a clear example of how the
Generating Antibiotic Incentives Now pro-
visions have helped reinvigorate research
in the infectious disease space. In an inter-
view with the Pink Sheet, Spero CEO Ankit
Mahadevia noted that the GAIN incentives
enabled his firm not only to raise about
$65m across Series A and B financings, but
also will open up an accelerated approval
pathway for the firm’s novel drugs.
Approved in 2012 as part of the last
Prescription Drug User Fee Act reauthori-
zation, the GAIN provisions added regu-
latory clarity, additional exclusivity and
faster regulatory reviews. It has been used
for products like Allergan Inc.’s Avycaz and
The Medicines Co.’s Carbavance, and Spero
anticipates its lead candidate, SPR741, will
follow the same pathway.
“What that pathway does is reduce the
hurdle for us to get a novel lifesaving ther-
apy to market and enables us to get that
drug to patients who might most need it
as soon as we can,”Mahadevia said.
Mahadevia spoke effusively about the
various incentives available now to en-
courage companies to develop novel
antibiotics. For example, the GAIN Act
how you manage it. There is a lot of capacity in the 27 member
states, so with good planning and willingness from the other mem-
ber states to fill the gap it could be managed in a way that you re-
duce the risk of delays and things like that.”
Much would depend on timelines and other factors, according to
Lönngren, but“when you are moving an agency and losing people
you need to plan for that. I know the EMA management today is ex-
cellent, and I have full confidence that they will be able to manage it,
but it is highly dependent on the remaining member states putting
in the necessary resources.”
A question mark would also hang over the future role of the
MHRA.“It is highly speculative regarding what participation the UK
would have in the European regulatory system – that depends on
the negotiations, but I suppose it will be on a very high level and will
probably take many, many years depending on the complexity of
the negotiations,”Lönngren noted.
Asked whether the MHRA would, for example, simply recognize EU
centralized approvals or conduct its own evaluations in parallel with
those of the EMA, the former agency head said that if there were“no
cleardealbetweentheUKandtheEU,theMHRAwillhavetomakeits
own decisions, whether to trust the EU regulatory system.That will be
onewayiftheywanttotrustus,soitisentirelyuptotheUKtodothat.”
EMA and MHRA view
Given the uncertainty over the eventual terms of a Brexit, the EMA
is understandably reluctant at this stage to speculate on what the
future might hold.
In a statement it said that it was“now up to the UK government
to decide how to act upon the outcome of the referendum,” al-
though it noted that its procedures and workstreams were not
affected by the vote and that it would continue its operations as
usual. It noted that no member state had ever decided to leave
the EU,“so there is no precedent for this situation.The implications
for the seat and operations of EMA depend on the future relation-
ship between the UK and the EU. This is unknown at present and
therefore we will not engage in any speculations.”
A number of countries including Italy and Sweden have ex-
pressed interest in hosting the EMA should it have to leave its new
London premises.The agency said it welcomed the interest shown
but noted that the decision on the location of the agency “will
however not be taken by EMA, but will be decided by common
agreement among the representatives of the member states. We
are confident that the member states will take the most appropri-
ate decision on EMA’s location and arrangements in due course,
taking also into account the complex political and legal environ-
ment generated by the outcome of the UK referendum.”
The EMA noted that the European regulatory network as a
whole was“a very strong and flexible system that is able to adapt
to changes without jeopardising the quality and effectiveness of
its work.” It added that it was in close contact with the EU institu-
tions and that as soon as concrete information became available,
“EMA will share it with its stakeholders.”
The MHRA, which like the other national agencies plays a key
part in the non-centralized approval systems, said that there
would be no immediate changes and that it would “continue to
fulfil all its obligations in decentralized and mutual recognition
procedures.” It added that it would continue to offer “the same
level of commitment, excellence and quality, working with and
supporting our customers, partners and stakeholders to deliver
medical products to patients.”
From the editors of Scrip Regulatory Affairs. Published online July
12, 2016.
Photocredit:SperoTherapeuticsLLC
Spero CEO Ankit Mahadevia

provides a five-year extension of the exclu-
sivity period for novel antibiotics that ad-
dress serious or life-threatening infections.
The expanded exclusivity offers the poten-
tial for increased profitability, providing an
inducement for investment in companies
developing novel antibiotics.
Based in Cambridge, Mass., and based on
research conducted at Massachusetts Gen-
eralHospitalbyLaurenceRahme,acompany
founder, Spero is working on novel class of
antibiotics that not only will address multi-
drug-resistant Gram-negative bacteria but
also enable drugs for Gram-positive infec-
tions to fight the Gram-negative spectrum.
The company’s Potentiators disrupt the
lipid outer membrane of Gram-negative
bacteria, thus permitting entry to antimi-
crobial agents that previously were active
only in Gram-positive infections. The dis-
ruption of what Mahadevia compared to
a “raincoat” that protects Gram-negative
bacteria allows the agent used in combi-
nation with the Potentiator access through
theperiplasmandcytoplasmicmembrane.
“SPR741 is an agent that binds to a spe-
cific part of that raincoat and creates per-
turbations in it,”he explained.“Think if you
had a picket fence around your house and
took some rails out – that allows a variety
of Gram-positive agents to get through
and do their work. So that’s a combination
paradigm that enables multiple therapies.”
Spero unveiled preclinical data last
month at the American Society for Micro-
biology’s Microbe 2016 conference dem-
onstrating SPR741’s potential to work in
combination with existing drugs such as
rifampicin, azithromycin, meropenem and
others, its ability to increase the potency
of other antibacterial agents, and confirm-
ing its mechanism of action, as well as its
safety/tolerability profile and dosing range
for human subjects. The biotech plans to
file an IND and get initial clinical trials with
SPR741 underway before year’s end.
If approved, Potentiators will be the first
novel class of antibiotics for Gram-nega-
tive infections since the first carbapen-
ems in the 1980s, Mahadevia added. It
also makes them eligible for the full suite
of GAIN incentives.
The Qualified Infectious Disease Prod-
uct classification and extended exclusiv-
ity allowed under the GAIN Act played
important parts in making Spero viable,
he said. It raised a Series A from Atlas
Venture, SR One and Partners Innovation
Fund in 2013, which was topped off to
$30m by investments from Lundbeck-
fond Ventures, Merck Research Ventures
and Kraft Group in June 2015. All of those
backers returned in a $35m Series B round
closed this past February.
SperoexpectstoconductaPhaseIsafety
and tolerability study for SPR741 that will
provide “a deep understanding of phar-
macokinetics of the drug, how it behaves
in the body, where does it go and at what
timeandhowlongdoesitstickaround,”the
exec said.Then, a moderately sized efficacy
study in in patients with complex urinary
tract infections (cUTI) will be undertaken
to show ‘741’s effect in Gram-negative in-
fections. The company would hope to use
those studies as the basis for“a specific set
of approvals,”Mahadevia added.
The investment incentives under GAIN
enabled about $150m in venture capital and
public funding to be raised for antibiotic de-
velopers over the past year, the CEO said.
While GAIN has been a success, he now
looks to additional incentives to be es-
tablished in order to create a “sustainable
ecosystem” for the development of novel
antibacterial drugs, Mahadevia said.
“The second step is will we be able to
buildonthepositivemomentumthatGAIN
has created for this field and for patients by
executing on one of several, I think, well-
written programs within Congress under
21st Century Cures to enabled to us to cre-
ate a sustainable market,”he said.
The21stCenturyCurespackageincludes
the Promise for Antibiotics and Therapeu-
tics for Health Act (S. 185), which is intend-
ed to shorten the development of new
treatments to combat life-threatening su-
perbugs. The bill is under consideration by
the Senate; the House of Representatives
passed its 21st Century Cures legislation in
July 2015, including similar provisions for
Photocredit:Tashatuvango/shutterstock.com
Will “we be able to build on the positive momentum
that GAIN has created for this field and for patients
by executing on one of several, I think, well-written
programs within Congress under 21st Century Cures
to enable us to create a sustainable market?”

Revisionist History On Health Care Reform Deal
Michael McCaughan pinkeditor@informa.com
P
resident Obama is quite literally writing his legacy on the Af-
fordable Care Act. His account includes a telling discussion
of“special interests”that reflects the current state of the rela-
tionship between the brand name industry and the Administration
– but overlooks the key role that pharma played in helping make
health reform happen.
The Journal of the American Medical Association features a high
profile author in its latest issue, a “Special Contribution” offering
an overview of the impact of the Affordable Care Act and poten-
tial next steps in health care reform by none other than President
Barack Obama.
Given the importance of the ACA to Obama’s historical legacy, it
isn’t too surprising that the President would want to lay out a first
draft of history before he leaves office.
The article also serves as a campaign document to support the
presumptive Democratic nominee, Hillary Clinton, by formally offer-
ing Obama’s support for steps to improve the ACA. The headlines
have focused on Obama’s embrace of the public option to address
areas where private plan competition is not robust. While Obama
notes his support for the public option going into the ACA process,
his endorsement of the idea now is also an acknowledgement that
the ACA exchanges haven’t been as fully successful as the Adminis-
tration hoped they would be in the early years of the program.
Clinton has recently reiterated her support for adding a public op-
tion to the ACA, setting up a clear point of distinction heading into
the November elections. The Republican party and its presumptive
nominee, Donald Trump, remain firmly committed to repealing the
ACA – not adding a government run plan to the program.
Less newsworthy is Obama’s call for more action on drug pric-
ing, with the JAMA article urging enactment of proposals from his
2017 budget, including Part D rebates, price negotiation and price
“transparency”proposals. That is also a coordinated message with
accelerated antibiotic development.
“A lot has been said about push incen-
tives … that have helped us push drugs to
the market because they reduced the capi-
tal burden that is required to get a drug
to patients and enabled a broader range
of firms to be able to do that,” Mahade-
via continued. “The next thing that we’re
working on – which is under discussion
in Europe as well as the US – are so-called
pull incentives, which means once we get
a drug approved, how do we ensure that
when a larger company looks ahead to de-
veloping and launching multiple antibiot-
ics, they see a sustainable ecosystem.“
Push incentives, which provide mecha-
nisms to reduce research and develop-
ment costs for new drugs, and pull incen-
tives, which ensure future revenues for
drugs that successfully complete the de-
velopment and regulatory process, were
featured in the UK’s Review on Antimicro-
bial Resistance, which will come to final
conclusions this summer.
Since Potentiators will work in tandem
with antibacterials, Spero has a pair of strate-
gies for finding agents to pair with its candi-
dates, the exec said. Earlier this year, the bio-
tech signed deals with Promiliad Biopharma
Inc.and Vertex Pharmaceuticals Inc. to bring
in assets to pair with its Potentiators.
The Promiliad deal in-licensed RD,
manufacturing and commercial rights to
dihydrofolate reductase (DHFR) inhibitors,
while the Vertex deal conferred global
rights to the preclinical gyrase inhibitors
VXc486/VXc100 as well as a portfolio of
antibacterials targeting bacterial gyrase
and/or topoisomerase IV. Specific terms for
both were not disclosed.
“The first [strategy] is to combine ‘741
with generic partners that already have
physician experience but couldn’t get
through that outer membrane,” Mahade-
via said.“We’ve also found very interesting
combinations with novel agents that other
pharmas designed originally for Gram-
positive applications but as Gram-positive
applications largely had been met, these
molecules had limited commercial value
until we were sort of able to reinvigorate
them and add spectrum.”
The latter strategy was applied in the
Vertex transaction, where combination
with a Potentiator dramatically increased
the in-licensed agents’ spectrum, he add-
ed. Spero continues to assess other pos-
sible collaborations with companies that
have approved antibacterials, or candi-
dates nearing approval and even earlier in
development, he said.
R e i m b urs e m e n t
Photocredit:DavidPeterlin/shutterstock.com

R e i m b u r s e m e n t
the Clinton campaign – but it isn’t “new,” and it may not actually
offer much point of differentiation from the Trump campaign. At
least during the primaries,Trump declared support for“price nego-
tiation”– and set some very aggressive savings targets.
But one section of Obama’s article jumped out to us: in a dis-
cussion of“Lessons for Future Policy Makers”to be drawn from the
ACA debate and implementation, Obama warns of the power of
“special interests”to protect the status quo:
The second lesson is that special interests pose a continued ob-
stacle to change. We worked successfully with some health care
organizations and groups, such as major hospital associations, to
redirect excessive Medicare payments to federal subsidies for the
uninsured. Yet others, like the pharmaceutical industry, oppose
any change to drug pricing, no matter how justifiable and mod-
est, because they believe it threatens their profits. We need to con-
tinue to tackle special interest dollars in politics. But we also need
to reinforce the sense of mission in health care that brought us an
affordable polio vaccine and widely available penicillin.
Now, it is true that hospitals cut a deal with the Administration
to accept reimbursement cuts as part of the overall health care
expansion in the ACA. But it is also true that hospitals weren’t the
only – or even the first – “special interest” to come to the table
and make a deal.
That role, of course, was played by the pharmaceutical compa-
nies, which negotiated the“donut hole”discount deal that helped
bring the ACA debate forward in 2009.
Obama’s article duly notes the benefit to seniors from the closing
of the donut hole in Part D as part of the ACA, but does not mention
thattheideacamefromanindustryproposal.Obamaalsonotestwo
otherwaysthattheACAaddresseddrugprices–viaenhancedMed-
icaid rebates and the creation of a“biosimilar”pathway – but again
without noting that the pharmaceutical industry actually agreed to
those steps as part of industry support for the law.
Now, it is true that the pharma industry deal was never broadly
popular with the industry itself, and that any cooperation with
the Administration ended almost as soon as the law was signed.
Obama includes a footnote noting the industry’s opposition to
the proposed Medicare Part B demonstration project to test alter-
nate payment structures as evidence that industry opposes “any
change to drug pricing.”
But the fact remains: the pharmaceutical industry supported the
ACA and agreed to a significant contribution (including a market
share“fee”not noted in Obama’s article) to help make it happen.
And there is danger to the industry in the narrative that the ACA
was enacted over the objections of pharma, when the truth is that
pharma’s support was critical to its passage (and continues to be
critical to its overall affordability).
Perhaps someone should send a letter to the editor of JAMA?
From the editors of the RPM Report. Published online July 12, 2016.
KoreanPro-InnovationPricingStepsDrawMixedResponses
Jung Won Shin jungwon.shin@informa.com
S
EOUL - South Korea will raise the
prices of “global innovative novel
drugs” and biomedicines, and short-
en the period before national health insur-
ance listing, to provide incentives for RD
spending and the development of local
origin drugs aimed at global markets.
In another part of new measures to im-
prove the country’s medicine pricing sys-
tem, the Ministry of Health andWelfare has
lengthened the interval between regular
drug price cuts based on market surveys of
actual transaction prices (ATPs).
The announcements come amid the
pharma industry’s repeated demands to
properly reflect the value of South Korea-
originated novel drugs to encourage in-
novation and original RD and appear to
reflect some of the key requests made by
manufacturers, including raising the start-
ing reimbursement prices of biosimilars
relative to their reference drugs.
The industry has long been complaining
that South Korea’s drug pricing system –
which focuses on improving the national
health insurance scheme’s financial stand-
ing and budget – is an obstacle to domes-
tic pharmas’entry into global markets.
Following Hanmi Pharmaceutical Co.
Ltd.’s series of major out-licensing deals,
which showcased the country’s potential
for innovation, and the government’s policy
to nurture the biopharma industry as a new
growth engine, the ministry has been draw-
ing up the new measures since January.
Discussions were held by a consultative
body comprising industry and other ex-
perts with the aim of accelerating South
Korea originated global drugs and beefing
up the international competitiveness of
the domestic pharma industry. The latest
steps will be implemented in October after
revisions to the relevant regulations.
Pricing Revisions
Under the new measures, prices of desig-
nated “global innovative novel drugs” will
be set 10% higher than the current ceiling
reimbursement price of alternative drugs,
or existing drugs or treatments used for
the same indications.
There is danger to the industry in the
narrative that the ACA was enacted
over the objections of pharma, when
the truth is that pharma’s support
was critical to its passage.

R e i m b u r s e m e n t
The definition refers to products that
have improved clinical utility and highly
contribute to the national health and med-
ical system by way of clinical trials and RD
investment in South Korea.
Oncology or orphan drugs that have re-
ceived the world’s first approval in South
Korea but for which there is no relevant
evidential data will be exempted from
economic evaluation during the reim-
bursement review. Such evaluation is
usually conducted to assess the product’s
cost versus improved clinical usability.
For defined global innovative novel
drugs, the government will also shorten
the Health Insurance Review Assessment
Service’s evaluation period of reimburse-
ment appropriateness to 100 days from 120
days currently, and the drug price negotia-
tion period to 30 days from 60 days, both to
speed up the reimbursement process.
Also for designated drugs, the govern-
ment will postpone lowering their prices
(through the normal regular price reduc-
tion system) until their patent expiry.
Biosimilars, Designations
The government has also improved the
reimbursement pricing system for biosimi-
lars and biobetters to provide new incen-
tives for development.
Under the measures, the prices of bio-
similars that contribute to the national
health and medical system will be raised to
80% of the reference original drug’s price,
from 70% currently. Prices of biobetters
will be set at 100%-120% of reference drug
prices, higher than the 90-110% now for
incrementally modified drugs.
The government will change the interval
of regular drug price cuts based on actual
transaction prices in the market to two
years, from one year at present.
The government has also designated six
additional innovative pharmas that will re-
ceive incentives such as preferential drug
prices and tax benefits.
The six companies are Dong-A ST Co. Ltd.,
Dong Wha Pharm. Co. Ltd., Yungjin Pharma-
ceutical Co. Ltd., PharmaResearch Products
Co.Ltd.,PharmicellCo.Ltd.andCorestemInc.
The new designation has boosted the
total number of firms considered to be in-
novative to 46, including 37 pharma com-
panies, seven bioventures and two foreign
firms (Sanofi-Aventis Korea and Korea Ot-
suka Pharmaceutical Co. Ltd.).
Through these steps, the government
expects the number of South Korea-orig-
inated global drugs that will receive ap-
provals in the US or EU to rise to 12 by 2018
from just two last year, two South Korean
pharmas to be ranked in the top 50 global
pharmas by 2018, and eight biosimilars to
be developed by 2018 from five as of 2015.
The health ministry said it would contin-
ue to pursue policies to improve the drug
pricing system taking into consideration
strengthening of reimbursement cover-
age and the global competitiveness of the
pharma industry. It will also continue to ex-
pand support for innovative pharma firms
given that they are playing the leading role
in new drug development and entry into
global markets.
The new measures also include several
steps to speed up the commercialization
of selected medical devices.
The government will shorten the period
to determine national health insurance
reimbursement listing for designated de-
vices to 100 days from 150 days currently,
and will allow new devices to be used at
certain medical institutions for three years,
without NHI coverage, if they lack clinical
data for technology evaluation.
For medical activities using cell therapies,
the government is aiming to shorten the
market entry period to nine months from 13
byconductingapprovalandevaluationpro-
cesses at the same time.
The government will also set up a one-
stop support body for all cycles - devel-
opment, approval, evaluation, listing and
exports.
Through the measures, it aims to in-
crease the market entry rate of promising
medical devices, while raising the number
of companies with an annual production
value of KRW100bn ($87.2m) or above to
five in 2018 from just three last year.
Foreign Concerns
The latest measures drew a mixed re-
sponse from domestic and foreign pharma
firms in South Korea.
The Korea Pharmaceutical Manufac-
turers Association (KPMA) welcomed the
government moves, saying the changes
are “reasonable”and will help the industry
“expand investments in RD and speed up
entry into global markets.”
The KPMA also called for the govern-
ment to support and nurture the industry
via measures that can properly value novel
drugs, expand RD-related tax incentives
and give pharma companies freedom to
decide on export prices.
However, Korean Research-based Phar-
maceutical Industry Association (KRPIA),
which represents foreign firms operating in
South Korea, raised concerns over the mea-
sures, saying they focus mainly on domes-
tically developed novel drugs and raised
doubtsovertheireffectivenessandfairness.
“We positively evaluate the govern-
ment’s will to nurture the pharma industry
and welcome the steps to improve bio-
medicine drug prices and ATP-based price
cuts,” said the KRPIA. “But we regret that
the measures on global innovative novel
drug prices are leading to discrimination
of innovative novel drugs.”
The announced steps will be solely ap-
plied to domestically developed drugs,
while less than half of the new medicines
developed by foreign firms are expected
to meet the other qualifications which are
set irrelevant to innovation, it noted.
From the editors of PharmAsia News.
For defined global
innovative novel drugs,
the government will also
shorten the evaluation
period of reimbursement
appropriateness to 100
days from 120 days
currently, and the drug
price negotiation period to
30 days from 60 days.

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Biosimilar Sponsors May Be Going Overboard
On Clinical Data, FDA Says
Sue Sutter sue.sutter@informa.com
S
tudying multiple indications ‘not the right way to approach
biosimilars,’ agency says; Amgen conducted more studies
than needed for its proposed Humira biosimilar to enhance
patient and physician confidence.
Some biosimilar product sponsors are doing more clinical stud-
ies than FDA believes necessary to support licensure.
“We are seeing biosimilar sponsors proposing to do multiple
studies in multiple indications, which to us is not the right way
to approach biosimilars,” FDA Division of Pulmonary, Allergy and
Rheumatology Products ClinicalTeam Leader Nikolay Nikolov said.
Nikolov’s remarks came during the Arthritis Advisory Commit-
tee’s July 12 review of Amgen Inc.’s ABP 501, a proposed biosimilar
to AbbVie Inc.’s Humira (adalimumab). Amgen is seeking approval
for seven indications on the Humira label spanning arthritic, der-
matologic and inflammatory bowel disease conditions.
Remarks by FDA and Amgen suggest sponsors may be taking a
cautious approach with their clinical development programs to en-
sure public confidence in the efficacy and safety data underlying
products approved on the abbreviated regulatory pathway.
Three Clinical Studies
The clinical package for ABP 501 included data from a three-way
pharmacokinetic study to support a scientific bridge between the
Amgen product, EU-approved Humira and US-licensed Humira.
The BLA also included comparative clinical efficacy studies in two
indications conducted as part of a global development program.
A study in rheumatoid arthritis patients was designed with
FDA input and used US-licensed Humira as a comparator. A
second study in plaque psoriasis used the European reference
product and was conducted entirely outside the US without any
design input from FDA. The latter also included a single-transi-
tion component in which patients on EU Humira were switched
to ABP 501 (see table).
FDA concluded that both studies demonstrated similar efficacy
between ABP 501 and the Humira comparator, with no clinically
meaningful differences.
Under the Biologics Price Competition and Innovation Act, a
351(k) application must include information demonstrating bio-
similarity based upon data derived from analytical studies, animal
studies and a clinical study or studies, although the agency has
discretion to determine that one of these elements is unnecessary.
In FDA’s view, clinical data in a biosimilar development program
should address residual uncertainties about similarity following
extensive analytical structure and function characterization and,
where relevant, animal studies.This concept of clinical data playing
only a supporting role to analytical similarity data is one that the
committee members struggled with during the ABP 501 review,
although they ultimately voted 26-0 to recommend licensure as a
biosimilar for all requested indications.
‘Added Confidence For Physicians, Patients’
Panelists asked Amgen why it conducted two comparative clinical
studies and how it selected the conditions studied.
“We could have done one study to satisfy regulatory purposes,
ABP 501 Clinical Studies To Support Biosimilarity
Study Study Population Objectives Design/Duration Comparator
PK Similarity Study
20110217 203 Healthy Subjects Three-way PK bridging
comparison, safety,
immunogenicity
Randomized,
double-blind, parallel
group; single dose
US Humira
EU Humira
Comparative Clinical Studies
20120262 526 rheumatoid arthritis
patients
Efficacy, safety,
immunogenicity, PK
Randomized, double-blind,
parallel group; 26 weeks
US Humira
20120263 350 plaque psoriasis
patients
Efficacy, safety,
immunogenicity, PK
Randomized, double-blind,
parallel group; 16 weeks
EU Humira
156 patients on EU Humira
arm re-randomized to EU
Humira or ABP 301
Safety, immunogenicity, PK Single transition from
EU Humira to ABP 501;
32 weeks
EU Humira
Source: FDA, Amgen advisory committee briefing documents and slides
Bi o si m il a rs

Bi o si m il a rs
but we did two studies to provide added confidence for physicians
and patients,”Richard Markus, Amgen VP-global biosimilars devel-
opment, said.
Efficacy in rheumatoid arthritis and psoriasis is well measured,
with good response rates forTNF inhibitors, Markus said.While the
RA study examined immunogenicity of ABP 501 and US Humira in
a patient population on background methotrexate, the psoriasis
study was conducted in a population that was not immune-sup-
pressed, he noted.
“There is no expectation from the FDA at least that there will be
studies in all indications,”FDA’s Nikolov said.“We have not specifical-
ly recommended one indication or one population versus another.”
Nikolov proceeded to share FDA’s thinking about biosimilar de-
velopment and the role of clinical data relative to analytical data.
“In general, the clinical endpoints that are used for these clinical
studies are far less sensitive than anything else before we get to the
clinical studies,”he said.“When we talk about comparing differences
between two molecules with products that are potentially very simi-
lar,it’salmostimpossibletodesignastudytodetectthesedifferences.”
“This is one of the reasons we don’t think that the clinical efficacy
is a key of determining biosimilarity,” Nikolov continued. “Biosimi-
larity is determined based on the analytical similarity, which is re-
ally a cornerstone in the assessment of biosimilars, and that sup-
portive data are the clinical exposure, clinical PK and potentially
clinical efficacy. And in some cases it might be a pharmacodynam-
ics endpoint, not a clinical endpoint for efficacy.”
Although FDA acknowledges“the community’s nervousness and
need for additional reassurance or confidence that these products
would work in different indications,”Nikolov suggested some spon-
sors are going overboard in their clinical development plans under
the abbreviated pathway.
Other Biosimilar Clinical Data Packages
Nikolov has been the clinical team leader for the first three TNF-
inhibitor biosimilar applications to reach the advisory committee
stage.
CelltrionInc.’sapplicationforInflectra(infliximab-dyyb),abiosimilar
to Janssen Biotech Inc.’s Remicade (infliximab), included data from a
total of nine clinical trials, including efficacy studies in RA and anky-
losing spondylitis patients. Only one study, a three-way PK bridging
study in healthy subjects, was conducted specifically to support US
licensure.The agency approved Inflectra in April, but the biosimilar’s
launch has been held up by patent dispute issues.
On July 13, the Arthritis Advisory Committee endorsed licensure
of Sandoz Inc.’s GP2015 as a biosimilar to Amgen’s Enbrel (etaner-
cept). The Sandoz application contained data from four PK studies
in healthy subjects and a confirmatory efficacy and safety study in
plaque psoriasis patients.
The first biosimilar application to win FDA approval, Sandoz’s
Zarxio (filgrastim-sndz), a biosimilar to Amgen’s Neupogen (fil-
grastim), included data from a total of eight clinical studies. Two
of these were conducted to support US licensure: a PK study in
healthy subjects, and an efficacy and safety study in 218 breast
cancer patients.
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Amgen’s Humira Biosimilar Gains Nod From Panel
Perplexed By Regulatory Pathway
Sue Sutter sue.sutter@informa.com
T
ime and again, FDA officials had to explain the importance
of the analytical characterization data in the biosimilar de-
velopment paradigm.
An FDA advisory committee’s overwhelming endorsement of
Amgen Inc.’s ABP 501 as a biosimilar to AbbVie Inc.’s TNF-inhibitor
Humira (adalimumab) belied the struggle that many of the agen-
cy’s external experts faced in understanding the basic concepts
underlying the 351(k) regulatory pathway.
At its July 12 meeting, the Arthritis Advisory Committee voted 26-0
that the totality of evidence supports licensure of ABP 501 for seven in-
dicationsontheHumiralabelthatarenotprotectedbyexclusivity:rheu-
matoid arthritis, juvenile idiopathic arthritis (ages four years and older),
psoriaticarthritis,ankylosingspondylitis,Crohn’sdisease,ulcerativecoli-
tisandplaquepsoriasis.
The vote further solidifies the view that when it comes to the na-
scent biosimilar pathway, any application that makes it to advisory
committee stage stands a good chance of panel endorsement and
FDA licensure.
Yet, the unanimous vote was surprising given the tenor of the
discussion that preceded it.
More than half the panelists were clinicians, many of whom said
they were unsure how to interpret the analytical data, concerned
about the strength of the clinical data and uncomfortable with the
concept of extrapolation to indications that had not been clinically
studied, particular in inflammatory bowel disease.
In the end, the panelists were sufficiently persuaded as to the
importance and strength of Amgen’s analytical characterization of
structural and functional similarity between ABP 501 and Humira,
with data from a three-way pharmacokinetic
studyandcomparativeclinicaltrialsinrheuma-
toid arthritis and plaque psoriasis playing only
a supporting role.
“The FDA team attempted, I’m not sure they
succeeded, to educate the rest of us about
the importance of the analytic data and the
framework that [they’ve] been thinking about
longer and more deeply than some of us who
are assembled,” said the panel’s acting chair-
man, Daniel Solomon, a rheumatologist at
Brigham and Women’s Hospital.
Heightened Post-Marketing
Requirements Urged
Still, some panelists wanted more reassurance
about the wisdom of licensure based on data
extrapolation.
They caveated their approval recommenda-
tions with a call for enhanced pharmacovigilance and post-market-
ing studies in the conditions licensed based on extrapolation, even
though FDA officials said biosimilars would be expected to face the
same standard pharmacovigilance requirements as other products.
“Ifeltthattheanalyticstudieswereextremelystrong,”saidTherese
Wolpaw,arheumatologistatPennStateCollegeofMedicine.“Icame
to understand that one can take that kind of strength of analytic evi-
dence and use that for extrapolation. I do think … that we should
engage in continuous quality improvement,”and through post-mar-
keting studies“learn how the extrapolation worked.”
University of Pennsylvania biostatistician Warren Bilker said he
thought the clinical studies clearly demonstrated biosimilarity in
RA and psoriasis.
“I am however concerned about extrapolation and feel it’s criti-
cal to mandate post-marketing surveillance and active surveillance
studies on safety and efficacy of all the extrapolated indications for
this and other biosimilars,”he said.
Twelve of the 26 advisory committee members also participated
in the Feb. 9 review of Celltrion Inc.’s Inflectra (infliximab-dyyb), a
biosimilar to Janssen Biotech Inc.’s Remicade (infliximab). At that
meeting, FDA similarly rejected the notion of unique post-market-
ing requirements for biosimilars with extrapolated indications.
Third Time’s Not The Charm For Easing
Confusion
The committee’s review of ABP 501 marked the third time that FDA
has brought a biosimilar application to its external advisors.
At the panel reviews for Inflectra and Sandoz Inc.’s Zarxio (filgrastim-
sndz), a biosimilar of Amgen’s Neupogen (fil-
grastim), the agency’s external experts strug-
gled to understand the abbreviated pathway’s
heavy emphasis on analytical characterization
data rather than clinical data, and use of ex-
trapolation to support licensing of indications
that have not been clinically studied.
This struggle was evident again at the
meeting on ABP 501, which if licensed would
become the first US biosimilar to Humira.
Panelists generally agreed with FDA re-
viewers that the evidence from analytical
studies supported a demonstration that ABP
501 is highly similar to US-licensed Humira,
notwithstanding minor differences in clinical-
ly inactive components. They also generally
agreed there were no clinically meaningful
differences between ABP 501 and Humira in
RA and psoriasis.
Bi o si m il a rs
“The FDA team
attempted, I’m not
sure they succeeded,
to educate the rest
of us about the
importance of the
analytic data,”
acting chairman
Solomon said.

However, they were unsure how far the analytic and limited
clinical data could take them, particularly when it came to uses for
which the biosimilar was not studied.
Clinical pharmacologist ScottWaldman,Thomas Jefferson Univer-
sity, questioned whether enough was known about adalimumab’s
mechanism of action in inflammatory bowel disease to make the
jumpfromanalyticalcomparisonstolicensing,absentaclinicalcom-
parison in such patients.
“What’s not clear to me is the unknown mechanism of action for
inflammatory bowel disease and the fact that we don’t have … the
bridge to clinical activity in that indication,”Waldman said.“For me,
the residual uncertainties were not reduced based on mechanism of
action in a clinically meaningful way.”
Panelists also raised concerns about extrapolation to pediatric
populations.
Despite the analytical and structural similarity of ABP 501 to Hu-
mira, the absence of pharmacokinetic or other clinical data in chil-
dren makes extrapolation to pediatric patients“a huge leap of faith,”
saidJeremyAdler,apediatricIBDspecialistatUniversityofMichigan.
Analytical Data Drive The Decision
Time and again, FDA officials found themselves having to explain
the importance of the analytical characterization data in the bio-
similar development paradigm, with nonclinical, clinical pharma-
cology and comparative clinical studies aimed at addressing re-
sidual uncertainties.
“Why does the FDA feel justified in making that leap” from the
analytical, PK and limited clinical data to extrapolation, Wolpaw
asked.“That’s a fundamental question for me.”
“We have reviewed the data and we have confidence in the data
that the two molecules are so similar that we can rely on the safe-
ty and effectiveness of the reference product,” FDA Clinical Team
Leader Nikolay Nikolov said.
“This is really the premise of our approach to bisoimilars,”he con-
tinued.“These are not new molecules that we don’t know anything
about. We know a lot. This proposed biosimilar for discussion, we
think it’s highly similar or similar enough to give us confidence that
the mechanisms of action will be the same for all the indications …
and this is supported by the clinical pharmacology exposure data
and again the clinical data in these additional clinical studies.”
“It’s not the clinical data that drives our decision,”Nikolov added.
“I think that is the crux of the problem is that you have people that
are clinicians and you’re asking us to make a judgment that is out of
our comfort zone,”Wolpaw replied.
Nikolovreiteratedearliercommentsthattheagencytriedtoinvite
panelists with diverse expertise, including product quality, clinical
pharmacology, rheumatology, gastroenterology and dermatology.
Office of Biotechnology Products Director Steven Kozlowski
pointed to the experience with comparability protocols in explain-
ing that analytical data have long been used to support manufac-
turing changes in biologic products.
“It is a hard challenge for you to think about the analytical data
when you come from clinical backgrounds, but the reality is again
[with] manufacturing changes and other things, you’ve been in
some sense unknowingly depending on analytical tools and
comparability for decades,”Kozlowski said.
In their votes, some committee members said their struggles
to understand the biosimilar paradigm reflected the need for a
strong educational campaign directed at the general public.
“You see how difficult it was for us to come to grips with un-
derstanding the purpose and the pathway for biosimilarity,”
Mara Becker, a pediatric rheumatologist at Children’s Mercy in
Kansas City, pointed out. “Try[ing] to disseminate that to the
public so that they understand it is going to be really important
moving forward.”
After the meeting, Leah Christl, FDA associate director for thera-
peutic biologics, acknowledged that the biosimilar pathway has
been a learning curve for the early advisory committees. “Over
time it will be different, but right now it’s a new place for everyone,”
she said.
Thearthritiscommitteewillquicklygetanotherdoseofexperience
when it reviews Sandoz’s GP2015, a proposed biosimilar to Amgen’s
Enbrel (entanercept), on July 13.
The user fee goal date for Amgen’s ABP 501 is Sept. 25.
Bi o si m il a rs
Clinical Trial Landscape Whitepaper
By Christine Blazynski
Reviewing the landscape of clinical trials
that completed in 2015, the disease areas
with successful outcomes, and the
companies that backed them.
Download your copy now!
citeline.com/category/whitepapers/

Biosimilar Advisory Committee Features Actual Debate
About Biosimilarity
Derrick Gingery derrick.gingery@informa.com
F
DA says problem with protein misfold-
ing with Sandoz’ Enbrel biosimilar can-
didate unlikely to generate unique tox-
icity issues in extrapolated indications.
The path down the biosimilar approval
pathway has been a bumpy one for FDA’s
advisory committees, with many advisors
expressing discomfort with the very idea
of relying on analytic similarity as the basis
of approval even as FDA has worked to en-
sure that only the most robust applications
reach the panel review stage.
But the Arthritis Advisory Committee’s July
13 review of Sandoz Inc.’s GP2015, which ref-
erences Amgen Inc.’s tumor necrosis factor
blocker Enbrel (etanercept), was in many ways
a watershed because the agency’s outside
experts not only embraced the biosimilarity
concept but also debated the technical merits
of the application in depth.
Uncertainty about the analytical charac-
terization of Sandoz’s proposed biosimilar
etanercept product nearly created an ex-
trapolation problem for the firm as the com-
mittee discussed whether protein misfold-
ing questions were enough uncertainty to
think twice about approving the product for
all of Enbrel’s indications.
Sandoz’s GP2015, which references Am-
gen Inc.’s tumor necrosis factor blocker
Enbrel (etanercept), is seeking all of the in-
dications approved for Enbrel: rheumatoid
arthritis, polyarticular juvenile idiopathic arthritis in patients
two years and older, psoriatic arthritis, ankylosing spondylitis,
and plaque psoriasis in patients 18 and older.
Sandoz only conducted a clinical study of the product in
plaque psoriasis.
It was one of only a few issues that loomed during what was a
mostly smooth advisory committee session.
Yihong Ye, a senior investigator at the National Institute of
Diabetes, Digestive and Kidney Diseases, who’s expertise was in
protein quality control, said it is unclear whether the misfolded
protein in GP2015 will cause toxicity problems.
“The question here is whether the long-term administration
of the products into patients with that kind of misfolding is go-
ing to have any adverse effects in disease situations that have
not been tested,”Ye said.
“I think there’s a gap there as to if we want
to extrapolate the applications into other
diseases. I think we should be more cau-
tious with that.”
Indication extrapolation is an important
concept for biosimilar sponsors, in part be-
cause it limits the necessary clinical studies
for approval.
But it remains a concern for some patient
groups and other stakeholders, who want
more information about whether a biosimi-
lar will behave like its reference product in
the indications that are not studied.
Committee members still voted unani-
mously, 20-0, that the totality of the evi-
dence supported approval of the product
for all of Enbrel’s indications.
The GP2015 meeting was the second
consecutive day the advisory committee
considered a biosimilar application. On July
12, it unanimously recommended that the
totality of evidence supported approval of
Amgen’s ABP 501, a proposed biosimilar of
AbbVie Inc.’s TNF-inhibitor Humira (adalim-
umab), despite confusion about some as-
pects of biosimilar development.
FDA had noted in its committee briefing
documents that initial testing of GP2015
raised a characterization issue due to a find-
ing that it was not statistically equivalent to
US-approved Enbrel. Sandoz had to design
another model to resolve the issue and es-
tablished that its product was in fact equivalent.
GP2015-Only Toxicity Issue Unlikely,
FDA Says
Similar protein misfolding problems also have been seen with
Enbrel, FDA said. But Ye countered that Amgen confirmed that
related adverse events did not emerge with Enbrel.
“The reference product used in all those diseases has been
tested for each of the cases, whereas Sandoz is trying to extrap-
olate the [indications] based on testing in one clinical situation
and they want to extrapolate that into other situations,”Ye said.
“They don’t have data on that.”
FDA used Enbrel’s history to argue that Sandoz did not need
to repeat that testing with GP2015.
Steven Kozlowski, director of the Office of Pharmaceuti-
Bi o si m il a rs
The Arthritis Advisory
Committee’s July 13
review of Sandoz’
GP2015, which
references Amgen’s
tumor necrosis factor
blocker Enbrel,
was in many ways a
watershed because
FDA’s outside experts
not only embraced the
biosimilarity concept
but also debated the
technical merits of the
application in depth.

Sandoz Climbs‘Pyramid’To Reach Biosimilar Success
Donna Young donna.young@informa.com
B
iosimilarshaveturneddrugdevelopment‘upsidedown,’where
analytical confirmation outweighs clinical – a paradigm shift
that must not only be embraced by the biopharmaceutical in-
dustry, but the prescribing community if US market for those prod-
ucts is going to be successful.
For companies seeking to put a new biosimilar on the US market,
Novartis AG unit Sandoz Inc. suggests using a pyramid scheme.
No, not the type scammers use to dupe unsuspecting investors
into dubious deals.
An approach Sandoz has used to demonstrate biosimilarity of
products intended to emulate the innova-
tor biologics on which they were based – a
strategy that was wholeheartedly endorsed
on July 13 by an FDA advisory panel, which
unanimously backed the licensure of the
company’s GP2015, a version of Amgen Inc.’s
Enbrel (etanercept).
Mark McCamish, global head of develop-
ment at Sandoz, said the company’s pyra-
mid strategy has been successfully used for
other RD programs, including for Zarxio(fil-
grastim-sndz) – the first biosimilar licensed
by the FDA and currently the only one on
the US market.
The program takes a comprehensive ap-
proach of comparing the biosimilar with
the innovator at the analytical, non-clinical,
pharmacokinetics (PK) and clinical levels,
McCamish explained.
“The development of a biosimilar requires
a paradigm shift,” he argued, adding that
fundamental change must not only be embraced by the biophar-
maceutical industry, but also by the prescribing community, if
the US market for those products is going to be successful.
Typically, McCamish said, doctors focus on the clinical aspects
of medicines: How they are used, the diseases for which they are
indicated, the recommended dosages and the adverse events
– all of which are defined by clinical trials, often two studies for
each indication.
But with biosimilars, the goal isn’t to establish safety and efficacy
– since the licensed innovator already has done that – but to dem-
onstrate biosimilarity, he noted.
“The development of biosimilars turns the
world upside down,”McCamish declared.
With biosimilar development, the analytical is
at the base of the pyramid – the foundation for
judging the product’s similarity to the innova-
tor biologic – while the clinical confirmation as-
pects sit at the top, with the PK and non-clinical
in the middle, he said.
But that concept, McCamish said, “will be
an ongoing challenge for us in communicat-
ing this to clinicians.”
Last-Minute Refinements To
Presentation
Indeed, he noted how even several members
of the FDA’s Arthritis Advisory Committee a
day earlier had difficulty grasping the concept
of how biosimilarity is determined, while they
were reviewing Amgen’s application for its
investigational biosimilar version of AbbVie
cal Quality’s Office of Biotechnology Products, said the many
production lots that Sandoz analyzed found the issue and that it
occurred in similar ways between the two products.
He also said that expecting a different result unique to an in-
dication for which GP2015 was not studied is unlikely.
“I understand the point that maybe this is misfolded a little
differently than that even though there’s less and that might be
disease-specific, but that seems very unlikely to sort of be mis-
folded in a different way that wasn’t detected by all these assays
and would only play out in other indications,”Kozlowski said.
Ye ultimately agreed that the data was robust and that toxic-
ity was less likely.
The exchange is the type of conversation FDA has been hoping
to see more of during biosimilar advisory committee meetings.
Kozlowski said previously that the agency want to direct com-
mittee discussions more toward analytical characterization is-
sues rather than clinical data.
Sandoz On Track For Second 351(k) Win
The GP2015 review appears to be behind. The goal date was in
June, based on the application filing date.
Despite the apparent delay, Sandoz still is on track to become
the first sponsor with two approved biosimilars in the US.
Its Zarxio (filgrastim-sndz), a biosimilar of Amgen’s Neupo-
gen (filgrastim) was the first biosimilar to be approved in the
US and is the only one currently on the market.
Sandoz also has a pending biosimilar application for pegfil-
grastim, which references Amgen’s Neulasta, but it also appears
to be delayed.
Bi o si m il a rs
Sandoz exec Mark
McCamish said the
pyramid strategy has
been successfully
used for other RD
programs, including
for Zarxio (filgrastim-
sndz) – the first
biosimilar licensed
by the FDA.

Inc.’s tumor necrosis factor (TNF) blocker Humira (adalimumab).
So McCamish said Sandoz modified its presentation to make
the details clearer after watching the committee “struggle with
the concepts”at the Amgen biosimilar meeting.
Under the biosimilar development approach Sandoz “pio-
neered,” McCamish explained that his company first defines its
development target, which involves thoroughly understanding
the innovator molecule and its quality or physicochemical at-
tributes and their variability from batch to batch.
He said Sandoz then maps the significant variability and criti-
cality in quality attributes and defines the“goal posts.”
After that, it systematically engineers its biosimilar product to
match the branded biologic across the cell line, the bioprocess
and drug development, McCamish said. It then establishes the
similarity based on physicochemical, biological and functional
characterization.
Atthatpoint,SandozseekstointeractwiththeFDA,atwhichpoint
it hopes to reach consensus on the appropriate clinical programs re-
quired to confirm biosimilarity and then conducts those trials.
Extrapolating Products, Not Indications
Given the FDA has urged companies not to study each indication
– declaring pursuing individual uses is not the right approach for
biosimilars, because it adds to the time and costs of development,
defeating a key purpose of those products – McCamish said San-
doz’s approach is not to extrapolate from one indication to anoth-
er, but from one product to another.
He pointed out that with Amgen’s Enbrel, a TNF-alpha blocker,
the anti-inflammatory mechanism of action is identical across all
approved indications.
So, McCamish said, Sandoz argued that extrapolating GP2015’s
clinical data in plaque psoriasis to all of Enbrel’s other approved
indications – rheumatoid arthritis, polyarticular juvenile idiopathic
arthritis, psoriatic arthritis, ankylosing spondylitis – was scientifi-
cally justified.
The FDA’s advisory committee agreed – backing up what drug
reviewers had earlier said in briefing documents ahead of the July
13 meeting.
In fact, the extrapolation issue led to one of the panel’s livelier
exchanges.
“All of these indications are TNF-alpha mediated. The mecha-
nism of action is the same,” said panelist Scott Waldman, director
of gastrointestinal cancer at Thomas Jefferson University Medical
College.“So given the substantial data that we’ve heard, the highly
similar nature of the molecules analytically and their clinical per-
formance, it seems to me that based on their similarity and iden-
tical mechanism of action, that extrapolation will be reasonable.”
“You’ve convinced me,” added panelist Donald Miller, profes-
sor of pharmacy practice at North Dakota State University, who
praised the“education”he got at the meeting on why data should
be extrapolated between products and not indications.
“I’m totally comfortable with that,”Miller said.
Bi o si m il a rs
Comprehensive Comparative Evaluation of GP2015 and Enbrel
Clinical
Confirmation
Pharmacokinetics
Non-clinical
Analytical
Confirmatory efficacy, safety and
immunogenicity study in patients with
moderate-to-severe plaque psoriasis
PK bioequivalence studies in
healty volunteers
Animal PD, PK, toxicology
Structural and functional comparison using
state-of-the-art technology
Comprehensive Comparative Evaluation of GP2015 and Enbrel

FDA’s ANDA Approvals
Sponsor Active Ingredient Dosage; Formulation Approval Date
Fera Levythyroxine sodium 100 mcg/vial and 500 mcg/vial; powder for intravenous 6/29/2016
Edenbridge Ethacrynic aci 25 mg; tablet 6/30/2016
Aurobindo Methenamine hippurate 1 gm; tablet 7/5/2016
Aurobindo Granisetron HCl EQ 1 mg base/mL and EQ 4 mg base/4 mL; injectable 7/6/2016
Zydus Nateglinide 60 mg and 120 mg; tablet 7/6/2016
Aurobindo Tri-Mili (ethinyl estradiol/
norgestimate)
0.035 mg/0.18 mg, 0.035 mg/0.215 mg, 0.035 mg/0.25
mg; oral-28 tablet
7/6/2016
Teligent Triamcinolone acetonide 0.1%; topical lotion 7/7/2016
Teligent Triamcinolone acetonide 0.1%; topical lotion 7/7/2016
Aurobindo Mili (ethinyl estradiol/norgestimate) 0.035 mg/0.25 mg; oral-28 tablet 7/7/2016
Osmotica Hydromorphone HCl 8 mg, 12 mg, 16 mg and 32 mg; extended-release tablet 7/7/2016
Alcon Gatifloxacin 0.5%; ophthalmic solution/drops 7/11/2016
CSPC Ouyi Metformin HCl 500 mg, 850 mg and 1 gm; tablet 7/11/2016
Polygen Amlodipine besylate EQ 2.5 mg base, EQ 5 mg base and EQ 10 mg base; tablet 7/12/2016
Hetero Fenofibrate 48 mg and 145 mg; tablet 7/12/2106
Aurobindo Ropivacaine HCl 40 mg/20 mL, 200 mg/100 mL, 100 mg/20 mL, 150 mg/30
mL, 150 mg/20 mL, 100 mg/10 mL and 200 mg/20 mL;
solution for injection
7/13/2016
Rhodes Morphine sulfate 20 mg/5 mL; oral solution 7/13/2016
Tentative Approvals
Hetero Labs Eltrombopag 12.5 mg, 25 mg, 50 mg and 75 mg; tablet 7/6/2011
Teva Vilazodone HCL 10 mg, 20 mg and 30 mg; tablet 7/11/2016
@PharmAsiaNews
Pharmasia News
Pharma intelligence |

Galderma Pioneers NDA Path Into OTC
AcneTreatment Market
Malcolm Spicer malcolm.spicer@informa.com
F
DA on July 8 announces approval for Galderma Laboratories
to market Differin Gel 0.1% (adapalene) as an OTC, once-daily
topicalfortreatmentofacnebyconsumers12yearsoldandup.
The first OTC acne treatment proposed in a new drug applica-
tion, Differin Gel 0.1%, will compete in a market that has included
only monograph-ingredient products, led by the Neutrogena and
Clearasil brands.
FDA’s Center for Drug Evaluation and Research on July 8 an-
nounced approval for Galderma Laboratories L.P. to market Differin
Gel 0.1% (adapalene) as an OTC, once-daily topical for treatment of
acne by consumers 12 years old and up.
CDER also notes that Differin Gel labels will advise women who
are pregnant, planning to become pregnant, or breast-feeding to
ask a doctor before using the first OTC in the retinoid class of drugs
for the treatment of acne. An image of the approved label was not
made available.
The center pointed out concerns about adapalene safety for
pregnant women in its evaluation of Galderma Lab’s supplemen-
tal NDA and during an April meeting of the Nonprescription Drugs
Advisory Committee, which voted unanimously to recommend
approval of the application.
However, the approval announcement notes general concerns
about the retinoid class of drugs.
“While there have been no adequate and well-controlled stud-
ies of Differin Gel 0.1% in pregnant women, there is no specific
evidence that Differin Gel 0.1%, when used topically as directed,
causes birth defects in humans. Some other retinoid drugs have
been shown to cause birth defects,”according to CDER.
Health care providers and medical experts generally are con-
cerned about any drug ingredient’s safety for pregnant woman or
other vulnerable populations, but FDA particularly questioned Dif-
ferin Gel because adapalene reaches within the dermis to treat the
inflammation caused by acne lesions.
Other OTC acne ingredients act on acne at the surface of the
skin. The other OTC ingredients are all in the acne monograph –
benzoyl peroxide, salicylic acid and sulfur.
According to Galderma Lab’s briefing material for the NDAC
meeting, salicylic acid products accounted for 69% of the US OTC
acne treatment market in 2015, benzoyl peroxide products 30%
and sulfur, which is not recommended by the American Academy
of Dermatologists, less than 1%.
BenzoylperoxidewasaddedtotheOTCacnemonographin2010,
theonlychangesinceFDAfinalizedthemonographin1991,andthe
most recent change in the Rx acne ingredient market was in 1994.
Differin Gel’s approval could prompt other OTC switch applica-
tions for acne ingredients, with Valeant Pharmaceuticals Interna-
tional Inc.’s Retin-A/Renova (tretinoin) line a likely candidate.
With three separate brands, Johnson Johnson is the dominant
firm in the OTC acne product space, with $306.1m in US sales at su-
permarket, drugstore and mass-merchandise retail chains, military
commissaries and some club and discount retail chains for the 52
weeks ending March 20, according to IRI, a Chicago-based market
research firm.
In addition to the Johnson Johnson Clean Clear brand con-
taining benzoyl peroxide 5% or 2.5%, the firm also owns the mar-
ket-leading Neutrogena brand, which uses Salicylic Acid 2% or 0.5
or benzoyl peroxide 5%, 3% or 2.5%, and the Aveeno line, with sali-
cylic acid at 0.5% or 2%, of OTC acne treatments.
Clearasil products, made with salicylic acid 2% and marketed by
RB – formerly Reckitt Benckiser Group PLC – are No. 2 in the space,
with $73m in sales in the period, according to IRI. Private label
products accounted for nearly $67m sales in the category.
Exclusivity Question Open
Galderma Labs, the Fort Worth,Texas-based US subsidiary of Swiss
firm Galderma SA, declined to comment on marketing plans for
the product or a planned launch date. Galderma, owned by Swiss
firm Nestle SA’s Nestle Health Science SA business, has marketed
Rx adapalene oral and topical formulations since 1994 in Europe
and since 1996 in the US.
The firm stated in an email that Differin Gel contains a prescrip-
tion-strength retinoid“clinically proven to treat current and future
breakouts.”Adapalene has been prescribed to more than 40 million
people globally for more than 20 years, according to Galderma.
FDA explained that Differin Gel’s safety and efficacy for Rx were
initially established in five clinical trials with subjects with mild to
moderate acne. For the OTC switch, Galderma submitted data ac-
crued from 1996-2016 on post-marketing safety; from a label com-
prehension and self-selection studies and an actual use trial; and
from a maximal use trial.
The agency said the results from the label comprehension and
self-selection studies and actual use trial showed consumers can
understand information on the OTC label, and appropriately select
and use the product. The maximal use trial, a study of absorption
of the drug through acne-affected skin when applied daily over a
large surface area, demonstrated that absorption is limited.
According to CDER, whether Differin Gel will have market exclu-
sivity has not been determined.
As a first-in-class OTC, the product likely will be a significant non-
prescription sales driver for Galderma and its market performance
would be even stronger with private label or other branded ada-
palene acne treatment competition precluded by exclusivity.
The Hatch-Waxman Amendments to the Food, Drug and Cos-
metic Act, the 1984 law designed to promote generics while leav-
C o nsu m e r d ru g s

ing intact a financial incentive for research and development, al-
lows sponsors up to three years’ exclusivity if additional clinical
studies are needed to support a switch.
CDER officials who evaluate NDAs for nonprescription or Rx
drugs do not determine whether the product will launch with
periods of market exclusivity allowed under Hatch-Waxman. In-
stead, following FDA’s approval of an NDA, an exclusivity board
determines whether clinical trials were required for the approval
and the application merits an award of exclusivity for a product.
05140811008
The Hatch-Waxman Amendments allow FDA to grant three-year
market exclusivity for OTC drug NDAs when clinical trials are re-
quired. While FDA could consider giving whether studies such as
actual use trials qualify as clinical and would support exclusivity for
a product, the agency has not diverted from allowing only clinical
trials to qualify.
From the editors of Tan Sheet. Published online July 10, 2016.
SecondTime Around:
EU GMP Guideline For ATMPs Out For Consultation Again
Vibha Sharma vibha.sharma@informa.com
T
he European Commission’s latest
draft guideline on GMP require-
ments for ATMPs might make
things easier for ATMP producers who are
not engaged in mainstream pharmaceuti-
cal production.
The European Commission has re-is-
sued for consultation its draft guidance
on good manufacturing practices for ad-
vanced therapy medicinal products, after
modifying the document to address com-
ments raised during a 2015 consultation
of the guideline.
The new draft is more extensive than
the previous document, Barbara Freisch-
em, executive director of the European
Biopharmaceutical Enterprises (EBE) told
the Pink Sheet.
The fact that it has been released for a
second round of consultation“addresses a
key comment from our industry” that the
previous draft was not detailed enough to
be a stand-alone document, but was too
detailed for an annex, Freischem said.
“The new draft is more extensive, as
would be appropriate for a stand-alone
guideline,” she explained, adding that
the EBE was willing to support either a
stand-alone guideline or an annex to ex-
isting GMP guidelines. “In our view, this
type of stand-alone guideline is likely to
make it easier for producers of ATMPs
that are not engaged in mainstream
pharmaceutical production to meet ap-
plicable GMP requirement for ATMPs.”
Some industry respondents to the first
consultation had objected to the devel-
opment of a stand-alone ATMP guideline.
The commission’s summary of responses
stated that around 20% of the contribu-
tors had a negative perception about the
development of a self-standing guide-
line. “These objections were more com-
mon in the industry sector and some ap-
pear to be grounded on the perception
that the intention of the Guideline is to
create double standards depending on
whether ATMPs are manufactured by in-
dustry or academia/hospitals,” the com-
mission said.
In the latest guideline, the commission
says that “the quality, safety and efficacy
attributes of the ATMPs and compliance
with GMP should be ensured for all ATMPs
(including investigational ATMPs), regard-
less of whether they are developed in a
hospital, academic or industrial setting”.
The EBE is currently reviewing the new
draft to formulate its comments, Freisch-
em said.
Among other things, it will examine
whether the latest version of the guide-
line will also apply to ATMPs covered by
the hospital exemption scheme, given
that the ATMP Regulation (Regulation
(EC) no 1394/2007) stipulates that hospi-
tal exempted products should meet qual-
ity standards equivalent to community-
level standards.
According to the commission, that the
latest document takes into account com-
ments received during the 2015 consulta-
tion, as well as input from consultation with
the European Medicines Agency and com-
petent authorities in EU member states.
With the second round of consultation,
the commission said it wanted to give
concerned stakeholders more opportu-
nity to express their views on the GMP
requirements that should apply to ATMPs.
Stakeholders have until Sept. 26 to submit
feedback on the revised draft guideline.
The EBE said it would like the guideline
to be finalized by the end of this year, and
to come into force as soon as possible.
From the editors of Scrip Regulatory Affairs.
C o nsu m e r d ru g s
M a nu fac t urin g
The latest might make things easier for ATMP
producers who are not engaged in mainstream
pharmaceutical production.

FDA Backs Off From Early Citations Of Compounder
Sterility Issues
Bowman Cox bowman.cox@informa.com
A
month after compounding phar-
macists’ latest annual visit to Con-
gress, FDA has acted on one of
their chief complaints – investigators cit-
ing them for GMP violations even in cases
where the agency later acknowledged
they were exempt.
Compounding pharmacists July 13 won
a partial reprieve from the FDA crackdown
on sterility assurance that has continued in
the wake of the fall 2012 fungal meningi-
tis outbreak in which contaminated phar-
macy-compounded drug products were
linked to more 750 infection cases includ-
ing 60 deaths.
Starting Aug. 1, FDA investigators will
cite pharmacies for any violations of cur-
rent good manufacturing practices (cGMPs)
only if they first find in a “preliminary as-
sessment”during their inspections that the
pharmacies don’t qualify for an exemption
from current good manufacturing practice
requirements for traditional compounding,
regulated under Section 503A of the Food
Drug and Cosmetic Act.
The exemption does not apply to regis-
tered outsourcing pharmacies regulated
under Section 503B, which operate more
like drug manufacturers.
The agency said it also will conduct thor-
ough post-inspection reviews to make
sure the firms qualify as Section 503A com-
pounders. If they don’t, FDA says it“intends
to consider citing cGMP violations in any
regulatory action it decides to pursue,”such
as a warning letter.
The agency noted that it has cited com-
pounders that weren’t registered as out-
sourcers for cGMP violations – but only
when it had evidence“that at least some of
their drugs were not compounded in accor-
dance with the conditions of Section 503A.”
Such evidence has been so common,
FDA said,“that in the substantial majority of
cases,inspectedhumandrugcompounders
not registered as outsourcing facilities were
compounding at least some of their drugs
not in accordance with Section 503A, sub-
jecting their drugs to cGMP requirements.”
The agency said it changed its policy in
response to “input from stakeholders that
they would like inspectional evidence re-
garding Section 503A to be reviewed ear-
lier, prior to the close of an inspection, and
to be taken into consideration in decisions
aboutwhattoincludeinanyFormFDA483.”
The agency stressed that despite Section
503A, traditional compounders are still sub-
jecttonon-cGMPFDCActprovisions,includ-
ing the prohibition on preparing, packing or
holding drugs under insanitary conditions.
FDApostedthepolicyonitswebsiteinan
unusual unsigned and undated notice that
appeared under a Health and Human Ser-
vices Department letterhead.
It’s the second compounding-related
pronouncementfromtheagencyinaweek.
The first was a pair of draft guidances that
seemed aimed at discouraging compound-
ing of commercially available products.
Compounders Pressed Case
On Hill
The new FDA inspection policy responds
to concerns members of the International
Academy of Compounding Pharmacists
(IACP) raised June 14 during visits with
members of Congress during IACP’s latest
annual Compounders on Capitol Hill event.
One of the academy’s “primary asks” at
this year’s event was for FDA to inspect
Section 503A compounding pharmacies
for compliance with US Pharmacopeia
standards or other standards established
by state pharmacy laws and regulations
rather than cGMP standards, IACP’s com-
munications VP, Dagmar Anderson, wrote
in a post on IACP’s website.
USP is revising its General Chapter 797
for sterile compounding. The pharmaco-
peia’s Compounding Expert Committee is
reviewing more than 8,000 comments on
the proposed revisions from more than
2,500 stakeholders that USP received by a
Jan. 31 deadline, and it is possible there
may be another round of comments.
Other IACP requests included an effort
to obtain relief from a prohibition against
office-use compounding by Section 503A
pharmacies that IACP said Congress
didn’t intend to establish when it passed
the Drug Quality and Security Act in 2013.
Anderson wrote that IACP questioned
why “records of inspections (483s) based
on cGMPs were published to the FDA’s
website publicly, for all to see, even when
FDA later determined the pharmacy was
in compliance with section 503A and
handed the pharmacy investigation back
to the state board of pharmacy.”
She added that “although IACP is cer-
tainly encouraged by today’s notice, we
are working to obtain clarification on
what FDA will use to determine what
constitutes a 503A pharmacy.”
And she stressed that “we rarely see a
Federal agency publish this type of noti-
fication where they outline a course cor-
rection in their procedures without some
sort of influence.”
From the editors of Gold Sheet. Published
online July 10, 2016.
M a nu fac t urin g
Former IACP President Michael Leake,
Louisville, Ky., meets with Senate Majority
Leader Mitch McConnell, R-Ky., as part of
IACP’s Compounders on Capitol Hill Day
Photocredit:InternationalAcademyofCompoundingPharmacists

Upcoming ICH Q11 GuideTo ClarifyWhat Constitutes
Starting Materials
Joanne S. Eglovitch joanne.eglovitch@informa.com
T
here will be no easy answers on
starting materials for drug sub-
stance manufacture, an ICH work-
ing group is finding. Draft guidance that
could come later this year will explain the
differences between chemicals that are
custom-made and those that are commer-
cially available and is expected to outline
in more detail the information needed in
submissions for starting materials.
A question-and-answer guide the In-
ternational Council for Harmonization of
Technical Requirements for Pharmaceuti-
cals for Human Use, or ICH, is developing
on the topic of starting materials for drug
substance manufacture will provide more
detail on just what information applicants
need to provide regulators on starting ma-
terials and is expected to better clarify the
differencesbetweencustom-manufactured
chemicals and those that are commercially
available.
However, the ICH Q11 QA guide will
stop short of saying how many synthesis
steps must occur after chemicals have been
designated as starting materials, which
is when good manufacturing practice re-
quirements begin to apply. The answer to
that question will have to be determined
case by case, based on the science.
Pfizer Global CMC Research Fellow Tim
Watson, who is serving as the industry rap-
porteur for the ICH Q11 Implementation
Working Group (IWG) discussed the status
of the upcoming QA guide on starting
materials at the annual meeting of the Drug
InformationAssociationonJune 28inPhila-
delphia. Watson was one of the IWG team
members who met in Lisbon, Portugal, in
mid-June to work on the QA document.
Watson said that a draft guide is being cir-
culatedamongtheteammembersandthat
the goal is to have a document ready to
deliver to the ICH when it meets in Osaka,
Japan, in November.
Hesaidthat“decisionsabouttheproposed
starting materials are very important; they
set the expectations for what quality infor-
mation should be filed in the CTD (Common
Technical Document) and what both pre-
marketassessmentandpostmarketchanges
can be applied. … If we get this wrong there
can be added risk of patient access” as well
as commercial supplies not being available.
The ICH Q11 guideline, adopted in May
2012, provides a set of general principles
for selecting starting materials. Watson said
that ICH Q11“has been implemented quite
successfully except for the starting materi-
als area.This has been quite challenging.”
The API industry has complained that the
guidanceistoohighleveltobeusefulinthat
itdoesnotprescribethenumberofstepsbe-
fore a chemical becomes a starting material.
This lack of clarity is reflected in the high
number of rejections of drug master files,
or DMFs, because of inadequate informa-
tion on starting materials. In the US and
the EU roughly one third to one half of all
DMFs and certificates of suitability (CEPs)
are rejected due to either inadequate iden-
tification of starting materials or insufficient
information about them.
ICH announced in October 2014 that the
IWG was developing a question-and-answer
document to clarify the necessary informa-
tion for selecting and justifying starting ma-
terials in drug master files. ICH also issued
a final business plan in October 2014 that
described the need for the QA. The plan
stated that “regulator resources are impact-
ed because regulators spend considerable
time confirming acceptability of a proposed
starting material, especially if inadequate in-
formationisprovidedinthemarketingappli-
cations.Theneedforextensivedialoguedur-
ing review of marketing applications would
be considerably reduced or eliminated if the
expectationsofregulatorsandindustrywere
more closely aligned.”
Watson told the DIA meeting that he so-
licited the input from another IWG group
member, Robert Bream of the European
MedicinesAgency,attheLisbonmeetingto
getaregulatoryperspectiveonstartingma-
terials. Bream said that regulators are con-
cerned about the risk to quality posed by
impurities.Therearealsoconcernsthatsup-
ply chains are much more complex than in
the past and there is greater lack of visibility
now on the synthesis of starting materials.
Industry on the other hand is concerned
about the economics and cost of validating
starting materials.
Complexity Led To Delay
Watson said that IWG’s original plan after its
September 2015 meeting in Ottawa was for
the regulatory members to issue the docu-
ment as draft guidance for comment in their
respective regions by December 2015. How-
ever, this was“an aggressive goal”and a date
that the IWG was not able to meet. Watson
said that the complexity of the starting mate-
rialissueandthevoluminousnumberofcom-
mentsreceivedfromindustrygroupspreclud-
edtheteamfrommeetingthetargetdate.
Watson said that“we had 60 spreadsheet
pages of comments.” The team, he said
“needed to step back and focus on a quality
document and not to rush this through.”
A crucial issue that the guide will resolve
is how much information sponsors should
provide on starting materials.“How much in-
formation is enough?”said Watson.“It is the
elephant in the room question; how many
steps are important or what is important for
GMPs? We want to make sure that we get
that right.”
“Weareseeingsomebadbehaviorswhere
companies are implementing crystallization
prior to their starting materials so they can
saythatnoknownimpuritiesimpacttheAPI.”
Watson said that the QA will not, how-
ever, specify the number of steps before a
chemical becomes a starting material. “We
have had a lot of debate and discussion
aboutthenumberofsteps.Wehavecometo
the conclusion that we do not want to spec-
ify a certain number of steps,We think that it
will distract from the science.We want to get
M a nu fac t urin g

away from specifying 15 to 20 steps.”
Elaborating on this point,Watson said that
the number of synthesis steps needed for a
robust process is different than the number
of steps required for a less robust one.
“We thought it would distract from cases
where you have a very robust process that
wouldcrystallizeandremoveanyimpurityin
the product. Does this mean by default that
this is a five-step [synthesis]? No. it does not
make sense to focus on step numbers. We
think you should focus on what the prod-
uct needs. If it is a less robust process and it
cannot purge impurities then maybe you
don’t have enough knowledge, then maybe
something like this will produce more steps.
… So we backed down from a specific num-
ber.We expect to get comments on that.”
Commercial And Custom
The QA will also clarify the differences
between starting materials that are ob-
tained by custom synthesis and those that
are commercially available. Under ICH Q11
manufacturers do not have to define the
synthetic steps for commercially made
materials. However, if a chemical from a
custom synthesis is proposed, its use as a
starting material should be justified.
Watson said that “there is a big discus-
sion around commercially available and
the custom starting materials. As it stands
right now there seems to be a line drawn
in the sand on whether it is custom or
when it is commercially available.”
There have been situations where man-
ufacturers develop APIs in-house as a cus-
tom chemical and then qualify three or
four vendors to make the substance and
then say it is commercially available so
they don’t have to document the synthesis
steps to regulators.Watson said that this“is
not an appropriate mechanism to deter-
mine whether it is commercially available.”
The final QA, he said, will also connect
or“build bridges”from ICH Q11 to ICH Q7,
ICH Q10 and ICH Q12.
Watson said that “we hope to improve
global harmonization regarding the selec-
tion and justification of starting materials
and we hope to clarify that connectivity
back to ICH Q7 and the importance of GMP.
We also hope to give better information on
the type and level of information needed
to justify starting materials. As it stands
today it is a thesis to justify your starting
material. We also want to put connectivity
back to quality oversight and ICH Q10 and
the importance of suppler management
and change [under ICH Q12]. We have had
a healthy discussion on the importance
of quality system change management.
We think it is very important and we have
positioned this as a foundational aspect in
selecting starting materials.”
The draft guide is undergoing a second
round of internal review. Watson said that
“we will assess the feedback from constit-
uent comments and we hope to finalize
the QA. … Our goal in November is to
deliver a step 2b to the assembly so it can
go out for public consultation.”
The goal is to have is to have a final doc-
ument approved for implementation in
November 2017.
From the editors of Gold Sheet. Published
online July 10, 2016.
M a nu fac t urin g
FDA’s NDA And BLA Approvals
Below are FDA’s original approvals of NDAs and BLAs issued in the past week. Please see key below chart for a guide to frequently
used abbreviations
Sponsor Product INDICATION CODE Approval Date
New Drugs
St. Renatus
Kovanaze (tetracaine HCl/
oxymetazoline HCl)
Nasal spray for regional anesthesia when performing a
restorative procedure on teeth 4-13 and A-J in adults and
children who weigh 40 kg or more
4, S 6/29/2016
Shire
Xiidra (lifitegrast 5%
solution/drops
Use of the integrin inhibitor for treatment of signs and
symptoms of dry eye disease
1, P 7/11/2016
Fresenius Kabi
Smoflipid (soybean, MCT,
olive and fish)
Injectable complex lipid emulsion for adults as a source of calo-
ries and essential fatty acids for parenteral nutrition when oral or
enteral nutrition is not possible, insufficient, or contraindicated
4 7/13/2016
Key to Abbreviations
Review Classifications NDA Chemical Types
P: Priority review
S: Standard review
O: Orphan Drug
1: New molecular entity (NME); 2: New active ingredient; 3: New dosage form;
4: New Combination; 5: New formulation or new manufacturer; 6: New indication;
7: Drug already marketed without an approved NDA; 8: OTC (over-the-counter) switch;
9: New indication submitted as distinct NDA – consolidated with original NDA;
10: New indication submitted as distinct NDA – not consolidated with original NDA
N e w P ro d u c t s

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