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REGULATORY
COMPLIANCE
2021

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TABLE OF CONTENTS
The Alzheimer’s Approval Maze  4
Navigating one of the FDA’s biggest decisions of the decade

Winning the drug development relay  18

Six ways to complete handoffs and speed your company’s race
to the development finish line

Keys to submitting a successful IND  23

Steps to help your company understand, prepare and master the
FDA’s IND application

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The Alzheimer’s
Approval Maze
Navigating one of the FDA’s biggest decisions of the decade
Meagan Parrish, Senior Editor
W
hen the news broke in March
2019 that Biogen, a biopharma
titan, was abandoning devel-
opment for a drug targeting Alzheimer’s
disease, the reaction was one of predictable
disappointment — but not surprise. Another
heart-sinking data readout. Another blow
to millions of Alzheimer’s patients. Another
company’s fortunes sunk by a single
press release. Another day in Alzheimer’s
drug development.
Although failure is the norm in pharma,
for no other indication is that fact quite as
harsh as it is with Alzheimer’s disease where
the common calculation is that 99 percent
of drugs tested ultimately falter.
And perhaps for no other indication are
the stakes quite as high. To date, no
www.PharmaManufacturing.com
disease-modifying drug has ever been
approved to treat Alzheimer’s, leaving
patients with only a handful of medications
to potentially alleviate symptoms. If just one
could be shown to arrest the slowly advanc-
ing disease that robs patients of their
cognitive functions and independence, the
potential payoff for the company holding
that holy grail would be astronomical.
“A new Alzheimer’s treatment would easily
become a blockbuster,” says Pamela Spicer,
senior analyst at Informa Pharma Intelli-
gence. “The market is wide open.”
But although Biogen had decided to halt
two late-stage trials of its drug, adu-
canumab, after a futility analysis concluded
it was unlikely to provide benefit, the com-
pany didn’t toss the data into the dumpster
eBOOK: Regulatory compliance 2021 4

fire. Instead, Biogen hunkered down, reeval-
uating its results and ultimately coming to
a startling conclusion: The March analysis
had been wrong, and one of the studies had
trended in the right direction.
That October, in a move that sent shock-
waves through the pharma world, Biogen
announced that it would in fact file for
approval of aducanumab with
the U.S. Food and Drug Admin-
istration (FDA) — a decision
that could tee up the first new
drug approval for Alzheimer’s
in 18 years.
Confusion, controversy and
conflicting beliefs have been swirling
around the drug ever since.
Is aducanumab actually effective enough
to warrant an FDA approval? Does it finally
prove that drugs that help clear amyloid
plaques in the brain slow the progression of
Alzheimer’s?
Or would a regulatory approval offer false
hope to millions of Alzheimer’s patients? And
is Biogen, whose financial future is strongly
tied to the drug, collaborating too closely
with regulators to push through an OK?
Throughout the roller coaster ride adu-
canumab has since taken, critics and
advocates have sprung up on both sides
and remained sharply divided.
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This June, the FDA is scheduled to finally
render a verdict on aducanumab — a deci-
sion with major ramifications for patients,
the industry’s wider pipeline for Alzheimer’s
treatments, Biogen, and the science behind
the drug. And as the June action date nears,
the agency is navigating a complicated
maze towards what will be one of its most
consequential decisions of the decade.
Advocacy groups are screaming
for this drug. Right now,
it is their only hope.
—Pamela Spicer
LOOMING AMYLOID
Rooted within the debate about adu-
canumab is the idea that Alzheimer’s is
linked to the build-up of beta-amyloid, a
sticky protein that can collect in plaques in
the brain along with tangles of tau, another
protein that’s involved in transporting nutri-
ents within nerve cells. What is known is
that when beta-amyloid and tau clump up
in patients with Alzheimer’s, it can trigger
a cascade of brain cell degeneration and
death, and ultimately, the hallmark symp-
toms of dementia.
What isn’t agreed upon is whether or not
decreasing the amount of amyloid or tau
can slow or reverse this progression of
neuron destruction. Yet, for more than
two decades, that idea — known as the
eBOOK: Regulatory compliance 2021 5

“amyloid hypothesis“— has dominated
Alzheimer’s drug research. And ultimately,
the approach has led several major pharma
companies including AstraZeneca, Roche
and Pfizer, to drive head-first into an
R&D ditch. The problem? Multiple drugs
have been shown to help clear the brain
of amyloid but haven’t improved clinical
dementia symptoms.
It’s a situation that led one researcher to
notoriously quip that by the time drugs
clear amyloid, it’s too late, and the process
is like removing tombstones from a grave-
yard — it won’t make the people buried
there “any less dead.”
“Everyone thought that if you stopped
these plaques, you could reverse Alzhei-
mer’s,” says John LaMattina, the former
president of Global Research and Devel-
opment at Pfizer and the author of several
books on the pharma industry. “But this
is a great lesson in what can go wrong in
drug development.”
Although the amyloid theory is now teeter-
ing on the edge of a scientific cliff — many
believe that drugmakers should abandon
the target all together — today’s pipeline for
Alzheimer’s is still filled with drugs targeting
amyloid in different ways and, increasingly,
tau. However, researchers are also fine-tun-
ing their approach to amyloid while casting
a wider net towards other targets.
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“Right now there are over 120 Alzheimer’s
drugs in clinical development and for the
first time, over half are non-amyloid and
non-tau drugs,” explains Dr. Howard Fillit,
a neurologist and the founding executive
director and chief scientific officer at the
Alzheimer’s Drug Discovery Foundation
(ADDF), an organization that helps fund
Alzheimer’s drug development.
While some of the non-amyloid and non-
tau drugs are aimed at new approaches
to stopping Alzheimer’s disease, such as
epigenetics, neuroinflammation and neu-
roprotection, Fillit says about half of the
pipeline is devoted to testing repurposed
drugs for Parkinson’s, hypertension, diabe-
tes and more.
“We are trying to advance the field by
taking risks on these repurposed drugs
because we know the mechanism of action
and there’s good evidence that they might
be neuroprotective,” he says.
Yet, for those still in the amyloid game, such
as Biogen, the goal has been to improve the
odds of their drug’s success.
“All of these lessons have kept amyloid at
the forefront because it is a hallmark of
the disease, so it makes sense as a target,”
Spicer says. “Despite the failures, pharma
companies have learned and have refined
their approach.”
eBOOK: Regulatory compliance 2021 6
 www.PharmaManufacturing.com

Specifically, pharma companies have
shifted to trialing amyloid drugs earlier in
the disease progression — an approach
they’ve been able to achieve thanks to the
development of positron emission tomog-
raphy (PET) imaging, which can reveal the
presence of amyloid and tau long before a
patient begins exhibiting symptoms. PET
imaging, in fact, came into play in a big way
during Biogen’s trials of aducanumab.
“It was a revolutionary aspect of the adu-
canumab studies because it was one of the
first times everyone in the trial was proven
to have Alzheimer’s through a biomarker
test,” Fillit says. “Then the same PET amy-
loid test was used to test pharmacological
efficacy by seeing the removal of amyloid
plaques as measured by the scan. So this
has become the first real rigorous tests of
the beta-amyloid hypothesis.”
“Even though the amyloid approach is con-
troversial,” Spicer says, “as we’ve seen [with
aducanumab]…it’s on the cusp of potentially
paying off.”
ALL THOSE IN FAVOR
“Of the two studies … 302 was a positive
study. We can’t argue about that,” Dr. Ali-
reza Atri, a neurologist and the director of
Banner Sun Health Research Institute, said
during his introductory comments for a
recent webinar Biogen gave on the results
of its two late-stage studies of aducanumab.
Organized by Alzheimer’s Disease Interna-
tional (ADI), the presentation by Samantha
Budd Haeberlein, the head of Biogen’s
Neurodegeneration Development Unit,
was used to walk the audience through
the results of its two key trials — dubbed
ENGAGE (aka 301) and EMERGE (302).

Alzheimer’s fast facts

6+
MILLION
$ 355
BILLION
$ 1.1
TRILLION

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Alzheimer’s disease and other forms of Alzheimer’s and dementia to
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—Alzheimer’s Association

eBOOK: Regulatory compliance 2021 7


There’s no doubting the scans. In patients
with amyloid and tau present, brain scans
using PET imaging are lit up in red and
yellow where the plaques are growing. But
follow-up scans from one year later of some
of the nearly 3,300 patients involved in
the studies revealed how those colors had
faded as the amyloid cleared.
What’s more, Haeberlein said that patients
given a high dose of aducanumab (10 mg)
in study 302 showed improvement on their
Clinical Dementia Rating (CDR) scores, a
global tool used in Alzheimer’s patients that
measures memory, orientation, judgement
and problem solving, personal care and more.
When compared to a placebo, Haeberlein
said patients on the high dose regimen of
aducanumab fared 22 percent better on their
CDR scores, while the lower-dose group had
an intermediate effect of 15 percent.
Patients on the high dose of aducanumab in
302 also showed an 87 percent reduction in
the clinical decline of neuropsychiatric scores
that measure depression, anxiety and more.
Caregivers of patients on the high dose also
reported 84 percent less burden compared to
caregivers of patients on a placebo.
There’s a caveat though — patients in 301
did not show the same level of improve-
ment. Why the difference?
According to Atri, who worked as a site
investigator on one of the aducanumab
www.PharmaManufacturing.com
trials and consulted Biogen on the drug,
the largest contributing factor to the dis-
crepancy was related to a difference in
total exposure to the higher 10 mg dose.
Although the two trials were identical in
design, Atri says they started at different
times. That distinction, coupled with a pro-
gram amendment to give patients with the
APOE4+ gene the higher dose, changed
the dose exposure and the duration of dose
exposure for patients between the two
studies — ultimately leading to the diverg-
ing outcomes.
When patients in 301 had the opportunity
for full dosing, Haeberlein said the results
were similar to the positive outcomes
observed in 302. She also pointed to a small
group of patients with a rapidly progressing
form of the disease who may have skewed
the result.
In a recent interview, Atri spelled out why
he believes that, despite the diverging
results from 301 and 302, the bottom line is
that the drug works to some degree.
“The data, though complex, is really clear
and very consistent in critical respects,”
he says. “The drug clears amyloid from the
brain on average, and on a group level,
there is a correlation between washing it
out and having slower cognitive decline.
When you look at CDR, the results are pos-
itive. Daily function? Same thing. Behavior?
Same thing. We have all these different
eBOOK: Regulatory compliance 2021 8

components we measure and they all went
in the same direction.”
As for the futility analysis that caused
Biogen to halt the late-stage trials in March
2019 because it predicted that they would
not meet their primary endpoints? Accord-
ing to an update on aducanumab given by
Biogen in October 2019, the analysis was
flawed because it only considered
patients who enrolled in the stud-
ies early and were not exposed to
a higher dose for a long enough
period of time.
Atri also says that aducanumab
was a “victim of a miscalculation and a
flawed futility analysis.”
Ultimately, Biogen has argued, the “totality
of these data support a regulatory filing.”
Yet, Atri cautions that if approved, guard-
rails will have to be put into place when
administering aducanumab. Although the
safety profile of aducanumab is generally
favorable, it can cause a potentially dan-
gerous side-effect called amyloid related
imaging abnormalities (ARIA).
“ARIA could potentially lead to hemor-
rhage or strokes if left unchecked,” he
explains. “So in a real-world setting you
don’t want an untrained doctor to select,
infuse and manage a patient, and then that
patient develops ARIA. We’ll need a lot of
www.PharmaManufacturing.com
education, including for neuro-radiologists,
to detect ARIA.”
Atri also admits that aducanumab shouldn’t
be overhyped and that it’s not a cure. Addi-
tionally, there are several key questions
hovering over the drug, such as whom the
drug works best for, what dose is best and
what other side effects could develop from
This did not rise to the level of
approval on a single pivotal trial.
—Dr. Scott Emerson
long-term use. It is also still unclear what
exactly the 22 percent improvement in CDR
could mean for patients in the long-run.
“Theoretically, if you have 22 percent less
decline over a year and a half, you’re going
to have the equivalent of about four months
additional benefit over that 18 month
period,” Atri explains. “But if someone is
diagnosed early, they may have 10-15 years
of life left and a 20-25 percent slowing of
disease progression could mean two to
three years of additional benefit.
“We’ll learn more about that over time,
which is probably going to take a decade,”
he says.
Even with those lingering questions, major
patient groups are pushing for approval.
eBOOK: Regulatory compliance 2021 9

“Advocacy groups are screaming for this
drug,” Spicer says. “Right now, it is their
only hope. Otherwise, there are only drugs
that mask symptoms.”
But the mismatched results from 301 and
302 make it difficult to justify approving
aducanumab. So groups like the Alzheimer’s
Association have reasoned that instead of
denying the drug, a good compromise by
the FDA would be to offer a conditional
approval that mandates a follow-up study.
We’re still in the early days of
understanding this disease.
—John LaMattina
Atri also argues that because of the large
unmet need hanging in the balance, Alz-
heimer’s patients shouldn’t have to wait for
Biogen to conduct another study before an
approval is given.
“Are we really going to make people wait
another five years for this?” he says. “I don’t
think that’s right. People should have the
choice to make an informed decision and
have appropriate access to this.”
ALL THOSE OPPOSED
Ideally, data is meant to provide crisp,
irrefutable evidence to help scientists
avoid subjective interpretations. But as
the situation with aducanumab shows,
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circumstances surrounding data can
sometimes muddy what should be a clear-
cut picture.
To some extent, the debate about adu-
canumab has been less about what Biogen
presented — and more about how Biogen
has made those presentations.
These concerns came to light on Nov.
6, 2020, when the FDA’s Peripheral and
Central Nervous System Drugs Advisory
Committee held a public meeting to vote
on whether or not aducanumab should
win approval. Minutes into the virtual
meeting, it was clear that the feedback
from the 11 scientists pooled to offer
opinions on the aducanumab studies
was not only going to be disapproving —
it was going to be scathing opposition.
Right out of the gate, committee members
took issue with a briefing document that
the FDA put together ahead of the meeting.
Rather than presenting its own separate
information, committee members called out
the FDA for taking the extraordinary step of
collaborating with Biogen on a single docu-
ment instead.
“Usually there is a sponsor’s briefing book
and then a separate one from the FDA,” Dr.
Scott Emerson, an emeritus professor of
biostatistics at the University of Washing-
ton who served on the advisory committee,
says. “But this one merged them.”
eBOOK: Regulatory compliance 2021 10

After learning that Biogen co-authored
the FDA’s pre-meeting briefing docu-
ment, Public Citizen, a consumer advocacy
group known for not pulling punches
with pharma, sent a letter to the agency’s
Office of Inspector General demanding
an investigation.
“We’ve been looking at pre-briefing doc-
uments for 20 years and have never seen
anything like this,” says Michael Carome, the
director of Public Citizen’s Health Research
Group. “This is what can go wrong with the
FDA — the agency can be too biased with
the industry’s interest. That can result in
drugs coming to market that are not shown
to be safe.”
Although Emerson, who has been serving
on FDA advisory committees for about
20 years, says this wasn’t the first time he
had seen a merged briefing document, he
admonished the FDA clinical reviewers for
presenting information on aducanumab that
was “abnormally imbalanced” in its support
for the drug.
“They didn’t present results — just conclu-
sions,” he says.
The committee also expressed concerns
about how many members of the FDA
and Biogen have sought to explain away
the negative results from the 301 study
by focusing on the positive trends in 302.
Emerson likened Biogen’s analysis to the
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Texas “sharp shooter fallacy,” a reference
to a marksman who fires a shotgun at a
barn and then draws circles around the
bullet holes.
Caleb Alexander, a professor of epide-
miology and medicine at Johns Hopkins
Bloomberg School of Public Health, who
also sat on the advisory committee for adu-
canumab, offered his own colorful take on
why the FDA’s glowing support for adu-
canumab didn’t jive with Biogen’s data.
“It just seems to me like the audio and video
on the TV are out of sync,” Alexander said
during the committee meeting. “There are
literally a dozen different red threads that
suggest concerns about the consistency
of evidence.”
Typically, the gold standard for winning
approval from the FDA is two positive late-
stage trials. And even if the FDA were to
consider data from a single phase 3 trial,
as it sometimes does, Emerson and others
on the committee argued that the posi-
tive results from 302 alone are not robust
enough to warrant approval.
When asked if 302 should be used as a
benchmark to support FDA approval, the
feelings of the committee were clear — 10
voted “no,” while one voted “uncertain.”
“This did not rise to the level of approval
on a single pivotal trial and there were too
eBOOK: Regulatory compliance 2021 11

many issues that were questionable,” Emer-
son says.
According to Emerson, Biogen took a
number of other missteps on its path to
seeking approval. The company, he says,
rushed into the phase 3 trials, did not do
a good job modifying the design of the
studies, and because of the side effects
associated with ARIA, many believe that
the trials could not have been truly blinded.
But most suspiciously, Emerson says that
Biogen has yet to publish its results in a
peer-reviewed journal.
“In this case, the peer-reviewed process
would have made their presentation better,”
The aducanumab studies
STUDIES:
Two 18-month, randomized, double-blind, placebo-
controlled phase 3 trials
SIZE:
3,285 patients at 348 sites in 20 countries
POPULATION:
Early Alzheimer’s disease (mild cognitive
impairment) with confirmed amyloid/tau biomarker
PRIMARY ENDPOINT:
Clinical dementia rating (CDR-SB) at 18 months
www.PharmaManufacturing.com
he says. “Without that, I worry that they are
trying to suppress the correct result.”
When asked if his opinion on aducanumab
has changed in the months since the
advisory committee meeting, Emerson
is unequivocal: His concerns about adu-
canumab’s effectiveness have only gotten
stronger. In fact, after digging through the
available literature from the long list of
other amyloid-targeting drugs that failed,
Emerson came away with the conclusion
that Biogen likely doesn’t have a positive
study at all. Instead, Emerson believes
Biogen generated the kind of “false posi-
tive” result that can happen from years of
repeating similar studies.
“The more trials you do, eventually you find
one that’s positive,” Emerson says. “But
sooner or later we probably need to say
that amyloid’s not the problem, because it is
only a sign of the disease and not necessar-
ily the root cause of cognitive decline.”
THE FDA UNDER PRESSURE
In theory, FDA advisory committees are
designed to provide the agency with scien-
tific input from a group of outside experts.
But according to David Gortler, who served
as senior advisor to the FDA commissioner
and was a member of the senior executive
leadership team under former Commis-
sioner Stephen Hahn, advisory committees
typically back up the agency for decisions
that have already been made.
eBOOK: Regulatory compliance 2021 12

“The FDA is looking for someone to validate
what they already know,” Gortler says.
So what happens when the committee
throws a curve ball at the FDA and votes
against a drug the agency supports?
Although the committee’s vote is non-bind-
ing — the FDA is not required to follow its
advice — the agency usually does. Making
any other move is certain to raise eyebrows.
The FDA had originally planned to render
its verdict on aducanumab this March, but
recently, the agency reset the action date
to June 7 and asked Biogen for more data.
Several analysts have speculated that the
decision to delay is a good indication the
FDA plans to give it the go-ahead.
“The agency could have denied approval by
now but instead they received more data and
analysis that would not have been available
to the advisory committee,” Spicer says. “And
the additional requested time may be a signal
that they could go through with approval.”
Either way, the agency is undoubtedly
moving carefully towards its final decision
and there are several emerging factors that
could come into play as the deadline nears.
Chief among them is the lingering question
of who will become the FDA’s permanent
acting commissioner.
After the Biden administration took over
in January, Hahn left his top spot at the
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agency and was quickly replaced by Janet
Woodcock, the director of the Center for
Drug Evaluation and Research (CDER), who
is now acting as the interim commissioner.
In a recent op-ed penned for Forbes,
LaMattina wrote that Biogen has the most
at stake when it comes to the impact of
Biden’s final pick for commissioner.
Woodcock, who has worked at the FDA
since 1986 and who Gortler calls a “land-
mark” figure with a “huge presence,” is the
clear front-runner. Her storied history at
the agency also offers insights into how she
might view the aducanumab decision.
In particular, many have pointed to her deci-
sion in 2016 to support eteplirsen, a drug
for Duchenne muscular dystrophy, a rare
and deadly condition that primarily impacts
young boys. The drug barely performed
better than a placebo in trials and the FDA’s
advisory committee voted against approval.
But with a chorus of patient groups demand-
ing help, the FDA made the controversial call
to give it the green light.
“[Woodcock] tends to be sympathetic to
approving new drugs where there is tre-
mendous medical need, but where the
efficacy is not fully demonstrated,” LaMat-
tina wrote in Forbes.
The decision-making mindset of the other
candidate under consideration — Dr.
eBOOK: Regulatory compliance 2021 13

Joshua Sharfstein — might be a little harder
to predict.
According to LaMattina, Sharfstein, a vice
dean at the Johns Hopkins Bloomberg
School of Public Health, who held a top
position at the FDA under President Barack
Obama, might be more concerned with
maintaining public trust in the agency than
appeasing patient groups.
“He is thought of as someone who would be
tougher on the biopharmaceutical industry,
particularly on the need for greater trans-
parency with respect to the interactions
that the FDA has with companies,” LaMat-
tina wrote.
The Biden administration’s delay in naming
a new FDA chief has left the door open for
more public debate about the matter. Most
recently, Woodcock critics have emerged
among Democrats in the Senate, who
The Alzheimer’s pipeline
373
Total number of Alzheimer’s
drugs currently in preclinical
and clinical development
—Informa Pharma Intelligence
www.PharmaManufacturing.com
accuse her of not doing enough to combat
the opioid epidemic.
Now, reports have surfaced that the Biden
team is looking beyond Woodcock or
Sharfstein for the job. Either way, once the
incoming chief is seated, there’s a good
chance that person could have the final say
about aducanumab.
“The approval process inside the FDA
depends on the drug. Many will weigh in on
the decision,” Gortler explains. “And if the
drug fails down the line with one medical
officer, someone else could appeal it up the
chain. But the commissioner will have the
ultimate authority.”
The conundrum for the incoming commis-
sioner could not be much worse. No matter
which way the agency sides, the decision
will kick up a firestorm of backlash, either
from patient groups who want the drug
45 40
Beta amyloid protein Tau aggregation inhibitors
antagonist drugs in in clinical and preclinical
preclinical and clinical development in 2020, up
development in 2020, from 30 in 2016
down from 60 in 2016
eBOOK: Regulatory compliance 2021 14

approved or from watchdogs who think the
agency is too cozy with Biogen and want
it rejected.
“It’s a no-win situation for the FDA,” LaMat-
tina says.
BRACING FOR THE FALLOUT
Whatever fate awaits aducanumab, the
FDA’s decision is going to impact a number
of stakeholders. Here’s what the final word
means for industry players.
Biogen
The exact estimates of how much revenue
aducanumab could bring in vary, but its
status as a sure-fire blockbuster is not in
question. On the low end, analysts have
predicted that its sales could reach $5
billion a year — others shoot as high as
$34 billion, a number that would easily
breeze past Humira, the world’s top-selling
drug that is expected to rake in $20 billion
this year.
For Biogen, who has been developing the
drug with Japan’s Eisai, aducanumab would
be a giant springboard out of its growing
sales slump. Wall Street analysts believe
that if aducanumab wins approval, Biogen’s
shares could soar by 70 percent. But if
not? The sales hole the company is already
struggling with is likely to get much deeper.
Tecfidera, Biogen’s top seller, is now
competing with a generic that hit the
www.PharmaManufacturing.com
market last spring. Analysts predict that
the new competition will cleave close to
$3 billion off of Tecfidera’s sales this year,
which pulled in $4.4 billion in 2019 and
comprised 31 percent of the company’s
total sales. Meanwhile, the company is
also in a rut with Rituxan, a blockbuster
autoimmune and cancer treatment, which
is facing biosimilar competition and Biogen
says will experience “significant erosion”
this year.
All told, Biogen’s revenue slid by about 6
percent in 2020 to $13.45 billion.
Clearly, the company needs a boost and is
counting on aducanumab to breathe new
life into its financial forecasts. According to
a recent Biogen earnings call, the company
is planning to drop $600 million on launch-
ing aducanumab this year and has already
allocated a “significant portion of its manu-
facturing capacity” to the drug.
The Alzheimer’s pipeline
According to Fillit, approving aducanumab
would signal to drug developers and inves-
tors that amyloid-targeting drugs are worth
the gamble.
“A lot of big companies have dropped neu-
rosciences,” Fillit says. “But I think once we
get some proof of concepts out there and if
aducanumab is approved, I think you’ll see
more interest in neurosciences in general,
but in particular with Alzheimer’s disease.”
eBOOK: Regulatory compliance 2021 15

I think it’s a false argument that approving aducanumab will
somehow stop the field from advancing
—Dr. Alireza Atri
Aducanumab’s fate could also become
entangled with an amyloid-clearing drug
called donanemab being developed by Eli
Lilly and Co. In January, Lilly reported pos-
itive top line results from a phase 2 trial
that showed donanemab slowed decline on
the Alzheimer’s Disease Rating Scale by 32
percent compared to a placebo. The poten-
tial success of another amyloid drug could
give the FDA more scientific justification for
approving aducanumab.
But because these successes in efficacy
are still modest, others argue that an adu-
canumab approval could continue to focus
too much R&D on amyloid — potentially
steering investment dollars away from
better treatments.
Atri, however, waves those concerns away.
“I think it’s a false argument that approving
aducanumab will somehow stop the field
from advancing,” Atri says. “It would be a
first-generation drug…but later we’ll have
second generation drugs that work better
and may have less potential for side effects,
just like we’ve seen with other drug classes
for other indications.”
www.PharmaManufacturing.com
The FDA’s bar for success
What will the FDA’s ruling on aducanumab
say about how it measures success with
Alzheimer’s treatments?
According to Spicer, approving adu-
canumab could signal to the industry that
the agency is willing to wave through a
drug with lower efficacy.
“What happens with aducanumab could
raise or lower the bar for regulatory
approval,” Spicer says.
Biogen has also filed for approval in Japan
and the EU, but Spicer says those countries
are likely to wait on the FDA before making
their decisions.
And because Biogen fell short of having
two positive late-stage studies, giving the
drug an approval but mandating post-mar-
ket analysis may be the direction the FDA
chooses to go.
Who’s going to pay for it?
“In the old days, you just had to worry
about the FDA approval,” LaMattina says.
“Now you have to worry about payers
eBOOK: Regulatory compliance 2021 16

putting your drug on their formularies.
So, this is going to be a dicey situation
for aducanumab.”
Analysts estimate that aducanumab could
cost as much as $50,000 a year, raising the
critical question of patient affordability. Can
America’s health care economy withstand
the weight of aducanumab, given the mil-
lions of Americans who might be eligible to
receive the drug?
It’s a piece of the puzzle that would need to
be solved quickly, Fillit says, given the over-
whelming patient demand that could follow
an approval.
“If it’s approved I think there’s going to be
a lot of patient demand for it,” Fillit says.
Even with the various concerns surrounding
aducanumab — such as efficacy and price
— Fillit, who has been treating Alzheimer’s
patients since 1980, says that doctors are
still likely to get on board with a new drug
that’s been approved.
“There may be doubters, but for most of us,
there’ll be good reason to at least try the
drug for our patients and get some clinical
experience with it,” Fillit says.
LIFE WITHOUT A CURE
“This is far from a perfect drug,” Atri says.
“It has modest efficacy. But this is going to
be the tip of the iceberg for a new genera-
tion of Alzheimer’s drugs.”
www.PharmaManufacturing.com
Despite its flaws, many argue that approv-
ing aducanumab is critical to building
what caregivers are going to need for
Alzheimer’s in the long-run: an arsenal of
multiple treatments.
“If we look at other diseases of aging like
cancer or hypertension — none of these are
treated by just one drug,” Fillit says. “There
are so many pathways with cancer and the
same is probably true for Alzheimer’s.”
In the meantime, prevention remains the
best medicine for Alzheimer’s. Get good
sleep, eat healthy and stay fit — mentally
and physically.
“A recent report in Lancet estimated that
40 percent of Alzheimer’s cases could be
prevented by lifestyle and co-morbidity
management,” Fillit says, explaining how, if
people used prevention methods to delay
the onset of Alzheimer’s by five years, it
could potentially reduce the number of
patients by 50 percent — an achievable
goal that could lower the globe’s Alzhei-
mer’s burden.
Prevention will also remain important
because when it comes to unlocking the
secrets of Alzheimer’s, drugmakers still
have a long way to go.
“We’re still in the early days of understand-
ing this disease,” LaMattina says. 
eBOOK: Regulatory compliance 2021 17

Winning the drug
development relay
Six ways to complete handoffs and speed your
company’s race to the development finish line
Xiaoxia Li, Executive Technical Director, WuXi AppTec Laboratory Testing Division
T
he drug development process is a
long and winding road with oppor-
tunities and pitfalls alike. Drug
developers navigating their compound’s
preclinical testing, clinical trials and man-
ufacturing are frequently under pressure
to progress more efficiently and meet
tight timelines. Additionally, when one
step unexpectedly falters, the impacts are
far-reaching across the planned develop-
ment process.
Drug development can feel like a relay race
at times, and if companies don’t coordinate
each handoff precisely, they can fall behind.
As companies make hypothetical strides
around the track, they are always searching
for ways to carefully compress and coor-
dinate timelines to hit key financial and
regulatory benchmarks.
www.PharmaManufacturing.com
Here are six ways drug development teams
can keep programs on track and even
accelerate the process.
DEFINE GOALS BEFORE
ENTERING PRECLINICAL WORK
When beginning the preclinical phase, it is
common to work with up to 10,000 com-
pounds, which can be overwhelming and
lead to distractions. Committing to a more
detailed approach and keeping goals in
mind with every decision can help teams
gain momentum and stay laser-focused
from the start. Setting goals and expecta-
tions at the program’s onset is critical to
streamlining the process and advancing to
first-in-human (FIH) trials.
Developers must set long-term goals to
avoid unknowingly creating limitations, like
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Proactivity and proper planning can help minimize the risk
of delays during handoffs and even accelerate the drug
development process.
insufficiently saving and archiving data that
may not seem relevant at the time. The
long-term application of data is central to
successful drug development programs.
Focusing solely on the task at hand, at
whatever stage of the process, can keep
a team from understanding how the new
data will impact the next step. Every pre-
clinical insight must be well documented
to leverage results during other studies or
clinical trials.
To ensure alignment, define and
communicate goals with teams and
partners. Having clear-cut goals in terms
of regulatory pathways and target
populations sets the stage for the rest
of the development process, and any
ambiguity can result in excess work and
budget variances.
CONSIDER DUAL FILING EARLY
If a company is considering entering
additional markets shortly after commer-
cialization and manufacturing, explore dual
filing as an option. Although it might seem
overwhelming to factor in multiple regions’
regulatory requirements, dual filing offers
many efficiencies.
www.PharmaManufacturing.com
Submitting a global Investigational New
Drug (IND) package to the U.S. Food and
Drug Administration can minimize the need
to conduct repeat studies, enable faster
expansion into foreign markets and broaden
the investigation of multi-ethnic populations.
To capitalize on these benefits, companies
should make this decision at the onset of a
program. This choice allows laboratories to
plan studies in adherence to the global Good
Laboratory Practices (GLPs) and follow rele-
vant regulatory body requirements. Beyond
study conduct, each regulatory body has
different reporting and archival standards.
Recognizing and preparing for these differ-
ences can reduce the number of additional
follow-ups and requests for information
during or after submissions.
FOCUS ON STUDY PREPARATION
Proving the safety and efficacy of a drug
requires numerous studies, which are critical
to capturing the data necessary for support-
ing an IND application. However, the value of
the resulting data is contingent on the proper
study set up. Often, laboratories cannot
adjust study parameters after the fact, and
any mid-study shifting could lead to retesting
or data loss. Thorough planning is essential.
eBOOK: Regulatory compliance 2021 19
 www.PharmaManufacturing.com

Companies should begin their planning

and study program by running the test Proper study plans
article through pre-formulation. This step
focuses on selecting the right drug sub- Once a plan is set in place and thor-

stance, excipients and packaging material oughly reviewed, companies should be

for product development to ensure data sure the plan answers and accounts for

demonstrates the materials’ stability under these questions:

varied conditions. The next step is securing

all necessary supplies, such as reagents or 1. Are the test systems selected for

test systems for upcoming evaluations. A safety testing to develop that spe-

laboratory testing partner typically com- cific compound?

pletes this portion of the preparation. It’s

crucial to ensure that partners can meet 2. What adverse effects could be induced

these criteria without delays. by the drug in the selected system?

Because a study is only as strong as its 3. At what dose level and treatment dura-

documentation, drug developers must pro- tion does the toxicity occur?

actively identify the reporting and format

needs for IND applications. For exam- 4. Are the compound’s adverse effects

ple, each regulatory body has different reversible if the administration

in vivo testing requirements. Accommo- is stopped?

dating the applicable reporting standards

will help ensure that applications pro- 5. Has the concordance of the toxicity

vide enough detail to justify each study in human and in the selected species

during submission. been considered?

At this stage, development teams should 6. Will the compound’s toxicity in human

document their findings and share this (if any) be detectable, monitorable and

background information with their team and manageable in a clinical trial?

any testing partners. It can also be helpful

to define descriptive terms and peer review 7. Do the compound’s adverse effects

requirements before beginning a study. differ between genders?

Study preparation establishes a foundation 8. Is the compound genotoxic?

for studies, working relationships and the

overall chance of a compound’s success.

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Meticulous study preparation can propel a
program forward — or stop it in its tracks.
IDENTIFY KEY
REPORTING CRITERIA
Developing thorough reports is essential
to minimizing delays and ensuring all the
correct components are available when
filing a submission. Reviewers will expect
thoughtful and comprehensive reporting,
so being aware and up to date on the latest
requirements is essential. Here are a few
key reporting components to consider:
Monitor schedules: Clearly define all time-
lines and ensure all parties are working
towards the same deadline. If there are any
changes to the submission schedule, com-
municate them immediately.
Scientist reports: When working with mul-
tiple laboratory testing partners, there may
be varying approaches to documentation
that should be synchronized. Companies
may also consider submitting a Q&A state-
ment with all contributing scientist reports.
Define descriptive terms: When reporting
materials, minimize all ambiguity by defin-
ing all necessary terms, such as clinical
signs and pathology.
Peer review requirements: Ensure that any
peer review requirements are factored into
the study timeline to avoid surprise set-
backs when preparing the final reports.
www.PharmaManufacturing.com
SEND compliance: If submitting data to
the FDA, companies must ensure their for-
matting complies with the Standard for
Exchange of Nonclinical Data (SEND) pro-
cedures. Laboratory testing partners should
be well versed in compiling SEND data
packages, but it’s essential to inquire about
their expertise in this area.
PICK THE RIGHT PARTNER
Kicking off the drug development process
might feel overwhelming, but a laboratory
testing partner can support and even serve
as an extension of the team. A committed
and reliable testing partner can keep a pro-
gram on track by offering companies access
to specialized methodologies, equipment
and dedicated personnel. Additionally,
leveraging a laboratory testing partner can
introduce a third-party into the mix and
eliminate the assumption of any bias in the
studies and results.
However, testing partners can operate
in highly unique ways. Before selecting a
laboratory, be sure to ask the right ques-
tions and determine their competencies.
Companies should investigate the labora-
tory testing partner’s familiarity with each
region’s different expectations when con-
sidering global applications and their access
to testing systems.
If a development team is spread thin,
consider finding a laboratory testing part-
ner that can provide the full spectrum of
eBOOK: Regulatory compliance 2021 21

support, including translation services,
regulatory planning/strategy, dossier
preparation, communications with regu-
latory agencies and submissions on your
behalf. Allowing a laboratory testing part-
ner to focus on these details can free up
your staff to handle other pressing items.
Companies that take time identifying a
laboratory that fits their program’s unique
needs set themselves up for successful
partnerships and IND applications.
MEET WITH REGULATORS
Developers can reduce testing errors and
ensure clear requirements by scheduling
a pre-submission meeting with governing
officials. These meetings can help identify
what is important to each regulatory body
when developing applications, potentially
saving time by reducing regulatory feed-
back and the possibility of retesting. With
the ever-changing regulatory guidelines,
a pre-submission meeting can keep a pro-
gram on track and allow teams to adapt to
new expectations early on.
www.PharmaManufacturing.com
To get the most value out of these meet-
ings, come prepared with specific questions
that pertain to the compound’s intended
testing plan. Including a testing partner in
the conversation can help developers who
want increased clarity on testing parame-
ters and potential issues. Partners can help
guide a compound and adjust plans based
on regulators’ feedback.
SUCCESSFULLY COMPLETING
THE RELAY
The drug development process is com-
plex, and each step in the process requires
preparation, attention and expertise. Pro-
activity and proper planning can help
minimize the risk of delays during handoffs
and even accelerate the drug develop-
ment process.
When a team broadens its perspective,
invests in planning, remains curious and
leans on the right partnerships, it can more
seamlessly reach key benchmarks and move
toward a medical solution. 
eBOOK: Regulatory compliance 2021 22

Keys to submitting a
successful IND application
Steps to help your company understand, prepare and master the FDA’s
IND application
Xiaoxia Li, Executive Technical Director at WuXi AppTec Laboratory Testing Division
T
he Investigational New Drug (IND)
application is the first sizeable
regulatory assessment that drug
sponsors face in the development process,
and it can be quite daunting. With the goal
of beginning clinical trials and scaling-up
drug manufacturing, it’s critical to under-
stand the requirements for this necessary
regulatory milestone.
A thorough understanding of the IND
application will make it easier to navigate
this process. Drug sponsors with a strong,
detailed background can prepare for unan-
ticipated barriers, save valuable time and
minimize spending.
WHAT IS THE IND?
Before drug sponsors can dive into First
in Human (FIH) studies, they first have to
www.PharmaManufacturing.com
demonstrate the safety and efficacy of the
proposed drug in their IND application. The
application should give a full synopsis of the
drug, including all salient data collected from
the development and testing phases, along
with manufacturing information.
All new drugs must have the U.S. Food and
Drug Administration’s (FDA) permission
before starting a clinical investigation
in the United States. It also applies to
existing drugs that have experienced
a change in composition. In the FDA’s
view, the primary concern for an initial
IND application is to ensure the safety of
clinical trial participants. This regulatory
stage is no small feat, and for many
smaller biotech and biopharma companies,
it may be their first exposure to a
regulatory agency.
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Early discovery Preclinical proof
& development of principle
THE ROAD TO THE IND
A helpful starting point to better grasp
the IND application is to review the typical
path to a successful application filing. The
development and screening process varies
for large molecules, small molecules and
cell therapies, as they each have distinct
characteristics and challenges. Although
large molecule submissions have grown in
popularity over the years, small molecules
still account for the highest volume of prod-
ucts in this space. A typical path for the
development of a small molecule is illus-
trated below:
The standard process for a small molecule
starts with the research component, what
the industry calls “early discovery and
development,” where a therapeutic target
(e.g. gene or protein) is first identified (i.e.
target identification). A target is selected
by the sponsor because it is believed to
play a significant role in the disease of
interest. The sponsor would then conduct
a series of screening assays consisting
of target validation, hit discovery, assay
development and screening, hit to lead and
lead optimization. As such, sponsors would
advance to conduct the first synthesizing
www.PharmaManufacturing.com
Preclinical Clinical
IND-enabling research
and relationship screening to decipher
which compounds could have a future as a
potential treatment as they interact with the
target. Based on the desirable pharmaco-
kinetic and physiochemical properties, the
sponsor can then select one, or sometimes
several, compounds to move forward into
the next stage.
Following the initial discovery and screen-
ing stages mentioned above, work can
finally begin on the manufacturing pro-
cess and preclinical testing plans. All the
information gathered from this point and
moving forward is necessary for the IND
application and contributes to the success
of approval.
THE CONTENTS OF AN
EFFECTIVE IND
Regulators expect IND applications to be a
highly detailed and all-encompassing data
package relating to the safety and efficacy
of the compound. When compiling all of
the necessary information, it’s imperative to
thoroughly vet the three main components
to the application: the chemistry, manufac-
turing and control, the preclinical animal
data and the clinical trial information.
eBOOK: Regulatory compliance 2021 24

Chemistry, manufacturing and control:
The CMC information is the first compo-
nent of the IND application, providing
regulators with a detailed analysis of the
inner workings of the drug itself. The CMC
can break down into two parts: substance
and methods.
The substance of the drug refers to its
identity, purity, potency and stability. A
successful IND application has thorough
information on the biological, physical and
chemical characteristics of the drug, includ-
ing all of the ingredients and their purpose.
It’s critical to support the stability of the
drug in this section and provide information
that proves the compound’s intended effect
materializes. To avoid the risk of informa-
tion gaps, manufacturers should have all of
the supporting molecule data before they
begin to compile the application.
The second part of the CMC, or the meth-
ods, relates specifically to the manufacturer.
The sponsor is required to disclose all the
substances that may be present in the man-
ufacturing process. The most successful
applications contain descriptions of the
manufacturing processes and methods
used to help understand how the drug is
made and the sponsor’s plan to proceed
with production.
Preclinical studies:
Preclinical study data is the second
component of an IND application. During
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this step, the sponsor’s primary goal is to
determine if the drug is safe for initial use
in humans and the compound exhibits
pharmacological activity to support
commercial development. Sponsors can
only begin the application when they
have experienced success with their
preclinical studies, including pharmacology,
pharmacokinetics (PK), absorption,
distribution, metabolism, excretion (ADME)
and toxicology studies.
This preclinical data can break down into
1
two pillars: initial preclinical, what the
industry calls “Proof of Principle,” and
IND-enabling studies. The initial preclinical
studies include in vitro and in vivo pharma-
cology, PK and pilot non-Good Laboratory
Practice (GLP) toxicology studies.
If the compound reports encouraging
results during initial preclinical evalua-
tions, then the compound can advance to
IND-enabling studies which can include GLP
toxicology and safety pharmacology stud-
ies. Whether testing is completed in-house
or with a lab testing partner, it’s crucial to
conduct IND-enabling studies in compli-
ance with GLP regulations. This regulation
assures regulatory bodies of the applica-
tion’s quality when reviewing the study
data. These IND-enabling studies provide
essential information about the safety pro-
file of that compound and will help the FDA
determine whether first in human clinical
trials can proceed.
eBOOK: Regulatory compliance 2021 25

The best practices for IND submission success can often get lost
in the chaos of preparation.
Technical competency and expertise in
these testing areas are vital to critically
assess and collect results. It’s a common
practice for sponsors to outsource these
studies to a lab testing partner, which can
streamline the process, ensure accuracy and
save valuable internal resources. Experts
in regulatory affairs, available for consul-
tation, can assist with the compilation of
the IND materials, such as organizing and
drafting the actual application package. If a
sponsor’s team doesn’t have the necessary
background or experience to support this
step, vet a contract research organization
for IND support capabilities to provide cus-
tomized help for your program.
Preclinical study data needs to be reliable
and demonstrate intended clinical usage,
which is easier said than done. While it’s
easy to summarize these procedures, in
reality, the process is extensive and can
take years to complete conducive studies
and detailed data collection — leaving room
for reporting errors and roadblocks.
Keep in mind that the purpose of compiling
this data is to establish reasonable safety
of the drug for its initial use in humans and
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describing the compound’s pharmacologi-
cal activity. By leading with this goal at the
forefront, sponsors can focus on developing
a comprehensive application.
Clinical trials:
Clinical trial information is the final stage of
the IND application and often regarded as
the centerpiece to the application. Spon-
sors need to demonstrate that the proper
clinical trial protocols are in place to safely
and successfully execute the studies while
mitigating potential risks to the study sub-
jects. These protocols should be detailed,
step-by-step plans with comprehensive
supporting data. Laying this out in an
organized manner is critical to creating an
exemplary application.
It’s also essential to include data on the
clinical investigators, the professionals that
will manage the clinical trials and record
the compound’s potential effects. These
investigators are responsible for the admin-
istration of the drug, so it is important to
prove to the regulatory agency that these
individuals have been thoughtfully selected
and are well qualified to fulfill their clinical
trial duties.
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Sponsors must have their study reviewed
by an institutional review board (IRB) under
FDA regulations, who can then require
changes for the purpose of protecting
human research subjects. There are many
components they will look for, such as
an Investigator’s Brochure, to educate the
investigators of the significant facts of the
drug. The investigators need to have all the
information and data in order to conduct
their clinical trial on a course that is least
hazardous to the subjects or patients. Infor-
mation as to the subjects taking part in the
study, the safety plan and dosage amounts
are also essential factors to include. Pre-
clinical summaries should support this
evidence and explain the reasoning behind
these choices.
Before sending the IND package off to
the FDA, thoroughly vet and scrutinize
the chemistry, manufacturing and control
(CMC), preclinical animal data and
clinical trial information to achieve the
best results.
CONSIDERATIONS FOR A
SUCCESSFUL SUBMISSION
The path to a successful IND application
depends on a variety of factors, and the
best practices for IND submission success
can often get lost in the chaos of prepara-
tion. Before jumping into the next project,
consider these key points to ease the strain
of the process and increase the chances
for approval.
www.PharmaManufacturing.com
Start with the end goal and work back-
ward: Think about the most direct route for
supporting the initiation of human studies
and map out what studies are needed to
achieve the goal. Working backward can
help identify potential pressure points in
your plan and timeline miscalculations.
Work with competent development part-
ners or consult with appropriate experts:
Expertise is required to have the studies
and activities conducted successfully that
meet the regulatory agency’s require-
ments. Don’t underestimate the challenges
and wear the team too thin.For example,
if a sponsor doesn’t have the expertise
to summarize the preclinical study data
correctly, it is critical to consider partner-
ing with a credible consultant or contract
research organization.
Know the molecule: This background will
determine the study design, necessary tests
and ultimately, make it easier to assemble
data for the IND application. Then apply this
to the understanding of the common path-
ways for small molecules, large molecules
and cellular therapies.
Build a robust and practical plan: If it feels
like the planning is complete, there is usu-
ally room to finesse and improve its clarity.
Disorganization of the preclinical program
or the overall development plan is one of
the most frequent causes of delays in time-
lines and submission.
eBOOK: Regulatory compliance 2021 27

Build a relationship with the regulatory
agency: They are willing to answer ques-
tions and provide guidance. Establishing
trust with the agency early on can help
sponsors better understand the process and
build credibility.
A successful IND submission is a significant
milestone for sponsors. Ensuring that drug
sponsors and manufacturers have a viable
understanding of the process, the contents
of an effective application and predictable
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challenges can make the IND application
more approachable. Reach out to a lab test-
ing partner for additional background on
this process within their organization. 
REFERENCES
1. The United State Food and Drug
Administration. (2020). IND Applications
for Clinical Investigations: Chemistry,
Manufacturing, and Control (CMC) Information
| FDA. Retrieved July 10, 2020.
eBOOK: Regulatory compliance 2021 28