fb clinical trials ebook 07

7/31/2019 Fb Clinical Trials eBook 07

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Once youve started the trial, you dont want it to

be shut down or delayed or any reason. Firstly, you

dont want to interere with patient care, especially i

your investigational drug is showing a clinical benet,

and secondly, i you cant keep the trial going, you cant

meet your drug-development goals. The quicker a trial

completes, the aster the drug can get to market, says

Gavin Choy, vice president o clinical operations at Astex

Pharmaceuticals.

These delays can be particularly costly or venture

capitalbacked companies, says Tom Woiwode, chie

operating ocer at Okairos, a European clinical-stage

biopharmaceutical company. This is because these com-

panies typically have a smaller margin or error than large

drugmakers.

Clinical trial supply isnt just an issue or investiga-

tional drugs. Some clinical trials compare the study drug

against a placebo; however, others, particularly those or

serious diseases or which it would be unethical to with-

draw active treatment, compare with a marketed drug

or another investigational drug. Other trials combine an

investigational drug with another drug in a combinatio

therapy. Its vital or these trials that there is a consta

supply o the comparator or combination drug as wel

the investigational drug.

Maintaining this kind o reliable clinical trials supply

needs a robust supply chain.

This requires complex planning to orchestrate the

various elements that need to be brought together to

have the right supplies ready in the right place at the

time, says Gerry Hepburn, chie operating ocer, vi

president and general manager, clinical supply service

Catalent Pharma Solutions. lB Sze Ege

Getting clinical trials right, and right the rst time,

is crucial or biopharma companies, especially as the

cost o getting a drug to market is skyrocketinga

piece in Forbes estimates drug development costs

have reached the eye-watering level o somewhere

between $4 billion and $11 billion (1). R&D returns

have thereore allen drastically and are around hal

what they were 10 years ago, explains Ian Shott,

managing director and principal consultant at Shott

Consulting: Attrition is the overriding driver o cost,

with a preclinical success rate o 0.01% and a success

rate in the clinic o 10% or less.

The larger part o the cost o clinical-stage drug devel-

opment comes rom clinical trials. According to Timothy

Scott, president o the U.S.-based pharmaceutical

chemistry development organization, Pharmatek Labo-

ratories, Phase II costs can range rom $4,000-$20,000

per patient. So, the last thing a drug developer wants

is any kind o interruption o a trial, or to have to start

a trial all over again, and this makes the reliable supply

o clinical trial material (CTM), whether manuactured

in-house or outsourced to a contract manuacturing

organization (CMO), absolutely critical.

An interruption in the provision o the clinical trial

material could require that trial to be conducted over

again, Scott says. And there is the cost o missed

opportunity in the marketplace. I the drug being devel-

oped has the potential o being a billion-dollar drug, that

is nearly $3 million in lost revenue every day the drug is

not on the market.

Drug developers need sucient supply; otherwise

there will be delays in development, says Anders

Fugelli, head o business development at Lytix Bio-

pharma. Its a step-by-step process; rst you need a

supply or animal testing or saety and toxicity, and then

you need to scale up or quantities or clinical trials.

Having a sucient drug supply or the clinical trial is

very important or the patient as well. Problems with

manuacturing can aect patients welare; clinical trials

can be vital stages in patients treatment, especially

those with advanced disease or with diseases or which

there are ew other available treatments.

April 2012 April

FierceBiotech.com FierceBiotechTHE BIOTECH INDUSTRYS DAILY MONITOR

thank you to our SponSor:

3When it all goes

wrong: Case study:

Clavis Pharma

5To outsource or not

to outsource, that

is the question

6Trimming Timelines

with Strategic Partner

Selection

*Sponsored Content*

9Picking the right

manuacturing partner

14Getting the regulatory

issues right

15Finding the

right time

16Looking to

the uture

Supplying globalclinical trialS:

KeyS to avoiding

coStly delayS


2/9

April 2012 Apri


Problems in the supply o

clinical trial materials rom

the manuacturers can cause

delays and cancellations o

trials, and these unortunate

outcomes can have a number

o dierent causes. Accord-

ing to the U.S. Government

Accountability Oce, short-ages o drugs, particularly

cancer and nutritional drugs,

have tripled since 2006, and

most o these are caused by

manuacturing shutdowns,

inadequate supplies o the

ingredients or the drugs, or

even communication break-

downs (2).

When a CMO shuts down

operations due to poor busi-

ness management or an FDA

[U.S. Food and Drug Admin-

istration] audit, this can have

a huge eect on the supply

o clinical trial material, Scott

says.

Other causes o plant

shutdowns include strikes; or

example, a strike at a Sigma

Pharmaceuticals warehouse

delayed shipping o drugs in

Australia (3). Any o these can

have an impact on supplies

o comparator drugs or drugs

used or standard o care.

Johnson & Johnsons

Doxil illustrates the impact

o drug shortages. Doxil is a

liposome-encapsulated orm

o doxorubicin used to treat

a wide range o cancers and oten

used as a comparator drug in clini-

cal trials. In November 2011, there

were around 30 clinical trials under

way that relied on Doxil (4).

Already in short supply, the

shortage o Doxil was worsened

by manuacturing problems at the

Bedord, OH, site o Ben Venue

Laboratories, a unit o Boehringer

Ingelheim and the sole manuac-

turer o the drug. The unit was

voluntarily shut down in Novem-

ber 2011 ater equipment ailures

thought to result rom a lack o

maintenance (5). Johnson & John-

son approved a single in-process

batch o Doxil or release in

December 2011, but Ben

Venue stated then that it did

not expect any urther batches

to leave the plant until the end

o 2012 (6; 7). The European

Medicines Agency (EMA)

issued a number o recalls o

oncology and antiviral drugs

produced at Ben Venue Labo-

ratories in November 2011, and

Canada has banned a number

o drugs rom the plant as well

(8; 9).

The lack o access to Doxil

slowed Eli Lillys trial o tasisulam

as a treatment o ovarian cancer

(4). It also threatened to aect

Endocytes recurrent, platinum-

resistant ovarian cancer trial, which

compared the combination o its

experimental drug EC145 and

Doxil with Doxil alone (10; 6). The

Ben Venue Laboratories plant also

manuactured methotrexate (9),

which is used as a comparator drug

in clinical trials. Suppliers Hospira

and Mylan have been asked by the

FDA to increase production to ll

the gap (11). In addition, Ben Venue

When it allgoes wrongBy Suzanne elvidge

Case study: Clavis PharmamanufaCturinissues Cause CliniCal trial delays

Bcg: Clavis Pharma is developing elacytarabine as a treatmen

late-stage acute myeloid leukemia, and a pivotal Phase III study, known

CLAVELA, started recruitment in June 2010. With its partner, Clovis O

ogy, Clavis Pharma also has a drug code-named CP-4126 in pivotal Pha

trials or the treatment o pancreatic cancer (12; 13).

Ceges & bsces: Clavis Pharmas Phase III trial or elacytarab

has been delayed because o manuacturing problems at Ben Venue L

ratories. These were actory-wide and not connected specically with

elacytarabine. This means that results rom the trial are now expected

rst quarter o 2013, which is a delay o around three months (12; 13).

oces: Clavis Pharma has dealt with this issue by managing its st

o elacytarabine very careully to make sure that patients already being

treated are not aected, and by timing its recruitment or when the nex

batch o drug becomes available. It has also ound an alternative suppli

Clavis Pharma has signed an agreement with Baxter Oncology to trans

manuacturing.

The rst approvals rom regulatory agencies to introduce clinical trial

rial rom the new contract manuacturer have been granted, and Baxte

released the rst batch o elacytarabine in March 2012 or clinical use.

nal batch rom Ben Venue Laboratories has also been released, and t

has allowed the company to lit its recruitment restrictions in most cou

The speed o recruitment into CLAVELA has been as planned, and w

are disappointed that the issues at Ben Venue Laboratories are now slo

down this progress, says Olav Helleb, Clavis Pharma CEO. We are

ing closely with Ben Venue Laboratories and Baxter so that we can res

ull-speed recruitment as quickly as possible, and we now expect to co

plete the recruitment in this important study during the second hal o 2

and to have data available in the rst quarter o 2013.

CP-4126 (also known as CO-101) has not been aected by this delay

is not manuactured by Ben Venue Laboratories. The drugs licensee, C

Oncology, is using two manuacturers or its clinical trials and potential

mercial supply and has sucient supplies in-house o both CP-4126 an

gemcitabine, the trials comparator drug or the pivotal Phase II trial, kn

as LEAP. Results are expected toward the end o 2012 (12; 13).

ke ews: While manuacturing issues are oten entirely unores

this shows how important it is to have a second supplier in hand (as C

Oncology has) to avoid delays in critical studies. Delays like this can ha

signicant eect on patients and could make the dierence between s

cess and ailure or a small biotech company. l

Laboratories manuactures inves-

tigational drugs, including Clavis

Pharmas elacytarabine, in Phase III

trials, and the manuacturing issues

have delayed development (see

case study).

One o the approaches that

Clavis Pharma used was to man-

age its stocks o elacytarabine very

careully and control recruitment.

Choy supports this as a mitiga-

tion approach: Having electronic

inventory solutions does help, as do

monthly meetings with our Chem-

istry, Manuacturing and Control[CMC] group with updates on

clinical trial usage and enrollment,

Choy says. There are always going

to be supply-chain issues, but we

always try to have contingency

plans in place, such as other suppli-

ers, or the ability to transer stocks

o drugs between clinical trial cen-

ters as a last resort.

CMOs also play a role in manag-

ing supply issues and will have

tools in place, such as comparator

sourcing, detailed project man-

agement, lean manuacturing

processes, streamlined packaging

and labeling operations, logistics

services, and enabling technology

or supply-chain and inventory man-

agement.

At Catalent, we make sure that

we plan contingency activities to

avoid a ailure in supply, Hepburn

says. This includes alternate, quali-

ed providers and internal backup

sites to ensure options are available

to complete work. Global events

in recent years, such as the Icelan-

dic volcano ash and severe winter

weather, tested our backup logistics

routes that allow us to continue to

deliver supplies to patients. l

There are always going to besupply-chain issues, but wealways try to have contingencyplans in place, such as othersuppliers, or the ability to

transer stocks o drugsbetween clinical trial centers asa last resort.

Gavin Choy, viCE prESidEnt o CliniCal

opErationS at aStEx pharmaCEutiCalS


3/9

April 2012


April

Sponsored Cont

Weve discussed how

important a reliable clinical

trial supply is, and weve

seen what happens when

it goes wrongnow, how

to plan to get it right. The

rst decision is whether

to keep manuacturing in-

house or to outsource it, or

whether to try to balanceboth approaches. The deci-

sion is actually a deault one

or many companies, because

they dont have the capacity

to manuacture in-house.

Ideally, a CMC director

would love to have everything

in-house, as he or she would

have better control o the

process. However, this is limited

by company size and resources,

says Al Gunduz, client services

manager at genetic testing labora-

tory Correlagen Diagnostics.

In general, many smaller biotech

companies contract out their sup-

ply chains, whereas larger pharma

companies tend to keep manuac-

turing capabilities in-house.The biggest advantage to

outsourcing or a small pharma

company is that they dont have to

build the inrastructure to support

development and manuacture o

their clinical trial material, Scott

says. They can ocus all o their

cash on answering the question

o whether their drug is sae and

ecacious. For large pharma

companies, 30 years ago, they pri-

marily worked to be FIPCOs [ully

integrated pharmaceutical compa-

nies] and kept all work in- house

or with large strategic partners.

Today, the large pharma industry

has evolved its business model to

integrate outsourcing. The com-

panies have capabilities in-house,

but they also rely on outsourcing

vendors or special capabilities

and overfow work. Not all large

pharma companies work this way,

but most now have project teamsthat work on each new com-

pound. The team looks at its plan

requirements, what resources it

has available in-house, and what

resources it has available outside

the company, and utilizes which-

ever resources help it achieve its

CTM supply goal.

OutsOurCing

Many o the big pharma compa-

nies are cutting manuacturing

and R&D around the world. For

example, Sano has cut a number

o acilities, including Genzymes

Cambridge (U.K.) R&D operation,

which is due to close by the end

o 2012, and Fawdon, a U.K. man-

uacturing plant that makes Plavix

and other drugs or the European

market, will be shutting up shop

by the end o 2015 (14).Most big pharma companies

are restructuring, cutting their

R&D and manuacturing capabili-

ties and cutting their pipelines,

Shott says. Over the last our

years, around 30% o the big

pharmaceutical company pipeline

has been cut. This has a knock-

Clinical trial planning or ast,

robust timelines involves many

aspects rom clinical development

to clinical manuacturing, patient

recruiting and clinical trial supply

chain management. Though clinical

trial supply is the last step, it is a

critical step in which many innova-

tors dont have in-house expertiseand are seeking strategic partners

to compensate. When selecting

partners, innovators nd the ol-

lowing traits crucial to success.

1. Gb sce ec

Dening an appropriate level o

global scale and reach is dicult.

But to assess i a clinical sup-

ply chain supplier is appropriate

or your needs, there are a ew

key questions that can help.

ae ee sfce -

be gb ses? Having

many geographically separated

sites provides advantages o

risk minimization against supply

interruption, local and diverse

regulatory knowledge, seam-

less multi-country supply, and

consistent quality and compli-

ance standards across sites. d e ses e e eces-

s eg s/

ceses? The lack o regulatory

approvals at a site can eectively

render it useless to your needs,

shrinking the true global ootprint.

Seek suppliers with excellent

regulatory compliance histories

and hard to get licenses to reduce

the risk o unoreseen

regulatory issues, as these

suppliers typically work very

closely with regulators.

hw bs s e ew

es? Selecting a sup-

plier with a robust network o

depots includes considering

their on-time shipping record,

volume o shipments, number

o countries served, the breadth

o their cold chain and controlled

drug capabilities, and requencyo depot audits as these items

can greatly reduce the risk o trial

delay rom depot shortcomings.

2. iege/cs seces

Choosing a partner that provides

multiple services creates ecien-

cies and reduced timelines by

1) reducing product handos, 2)

providing consistency in quality

and delivery and 3) simpliying

communication and project man-

agement. Depending on type o

clinical studies, the service capabili-

ties you may need to consider are:

dec C Sg

proo o established relationships

and ability to access the most

dicult drug products is key.

Cc mcg

the more dose orms

supported, the better. pcgg lbeg its all

about the volume and technology.

Wesg dsb

diverse locations, capacity, and

specialty handling capabilities

make a strong case.

oe Seces Regula-

tory consulting, ormulation

and analytical support.

3. Cc, eese

cs

Strategically, it is critical to work

with a company that continu-

ally invests in new technologies

automations and has industry

expertise. High-speed blinding

and labeling, automated syringe

plunger insertion, and many oth

technologies may have a positiv

impact to your timelines. Spe-

cic capacity and expertise in th

areas o controlled substances,cytotoxics/potents and cold cha

supply will also play an increas-

ing role as the market evolves.

4. re-e/-e s-

c s

Having real-time, secure inter-

net based access to your clinica

supplies data and electronically

linked sites can assist in many

ways rom orecasting to spot-

ting supply chain trouble beore

it happens. Many suppliers also

provide expanded insight that g

beyond nished goods to includ

complete inventory manageme

purchase order and invoicing

inormation, IVRS, label printing

shipment tracking, and global

quality systems to name a ew.

By selecting a clinical sup-

plier that meets these criteria,a drug developer can expect

to experience ewer delays,

reduced costs, greater service

and peace o mind throughout

their strategic partnership. l

Trimming Timelineswith StrategicPartner Selection

To outsource or not tooutsource, that is the questionBy Suzanne elvidge

cot o p 7


4/9

April 2012 Apri


April 2012 Apri

ormulation patents. This is partic-

ularly true o biologics, which are

more complex and where more

things can go wrong.

Keeping manuacturing in-

house does provide a comort

level or companies in that col-

leagues and capacity are available

close to hand to support the

development process, Hepburn

says. However, in-house manu-

acturing can also be seen as a

costly and underutilized resource

that has come under pressure in

recent years as the cost pressureon development has increased,

especially as third-party providers

have become more capable and

cost-eective.

While the trend has

generally been to sell o

manuacturing capabilities,

some companies are actu-

ally expanding to bring this

in-house, specically or

biologics. As an example, in

2009, Genentech Singapore

(Roche) opted to buy Lonzas

cell-culture biologic manuac-

turing acility in Singapore,

giving it bulk manuacturing

capabilities or monoclonal

antibodies (15).

We started by outsourc-

ing the manuacture o our

adenovirus vectors and

vaccines, but as we were

the only company working

in chimpanzee adenovirus

vectors and we know our

technology so well, it made

sense to bring the manu-

acturing back in -house,

Woiwode says. We used

a CMO or an earlier study

but ended up with a year-

long delay or an unoreseeable

problem. This was just an unor-

tunate situation and was not the

ault o the CMO.

Woiwode admits that Okairos

was in a unique position; as a spi-

no rom Merck, it had access to

the larger companys good manu-

acturing practices (GMP) acilities

in Rome, as well as to its experi-

ence and know-how.

the best Of bOth wOrlds

The in-house versus outsourc-

ing decision isnt one size tsalleven or companies that

have manuacturing capabilities,

choices still have to be made, as

these capabilities are still nite,

especially as the needs or clini-

cal trial supplies increase in later

stage and global clinical trials.

Large pharma companies such

as GlaxoSmithKline have the

in-house competencies and inra-

structure to manuacture drugs

or pilot scale and even or clinical

trials, and this is the ideal, as it

gives the company complete con-

trol, Fugelli says. However, by

the time the drug reaches Phase

III, even most big companies will

need to outsource because o the

quantities needed.

Its not a one-size-ts-all deci-

sion but one that needs to be

balanced according to the prod-

ucts in the pipeline and the

development timelines.

Individual investigational drugs

that are judged the most likely

to succeed by large inventor

companies are more likely to be

kept in-house or manuacture

and sometimes clinical trials

management, Shott says. Con-

versely, the high-risk products

more likely to be contracted o

by these companies to a CMO

Biologics and other complex

molecules and products are al

likely to remain in-house wher

possible.

CMOs may also be brought i

carry out part o the process, p

ticularly specialist stages, Hep

explains: Oten, biopharma co

panies have great expertise in

discovery phase or their produ

but require assistance to comp

the development. They are loo

ing or support rom the provid

particularly in the design, pack

ing and logistics o clinical trials

Know-how in the manuacture

handling o sterile vials or syrin

including rerigerated and cold-

chain experience, can be vital.

on eect; cutting the pipeline

reduces the demand or products

or clinical trials, and short-term

reduces the need or CMOs, as

companies try to use up inventory

and do as much as possible inter-

nally. However, in the long term,

this will increase the demand on

CMOs, as companies look to out-

source as much as possible.

The decision to outsource ver-

sus keep work in-house or clinical

trial supply is also driven by pres-

sures to reduce costs and get tomarket aster.

For much o the pharma

sector, it makes good sense to

partner with CMOs to manage

spending, avoid procuring

expensive equipment, improve

pipeline eciency, and to

access proprietary expertise,

says Paul Skultety, director o

pharmaceutical development

services at Xcelience, a U.S.-based

contract research organization

(CRO) providing services including

ormulation development, drug

preormulation, and clinical

supplies manuacturing.

Hepburn supports this: Out-

sourcing allows a company to ocuson core development. The scale o

the outsourcing providers is su-

cient to drive some economies.

However, the relationship does

require some investment to allow

the sponsor company to eel that

the provider is an extension o their

development process.

The outsourcing route is the one

taken by Astex, as Choy explains:

We decided that we didnt want

to build the supply chain in-house

but rather ocus on our core com-

petencies.

KeePing it in-hOuse

The advantage o keeping devel-

opment in-house is the levelo control that the company is

able to hold on to, including over

scale-up and product, process and

By the time the drugreaches Phase III, even mbig companies will need toutsource because o thequantities needed.

andErS uGElli, hEad o BuSin

dEvElopmEnt at lytix Biopha

cot from p 5


5/9

April 2012 Apri


I a company does decide to

outsource its manuacturing or

clinical trial supplies, the next

step o the process (and maybe

the hardest one) is to nd the

right partner.

Dierent types o company(segments) will have dierent

priorities and needs, Shott

says. Small biotechnology

startups are more driven by per-

son-to-person relationships and

have to depend on outsourc-

ing unctions and capabilities

downstream o discovery,

whereas midsize companies

will have a pipe-

line o drugs but

not the resources

o a big pharma

company. These

companies will tend

to make decisions

based on value

rather than just the

lowest cost. The

large companies

have very struc-

tured selection and

approval procedures

involving multi-unctional teams

and characterizing

the suppliers on a

scale rom tactical

through to strategic

or preerred.

There are all

kinds o CMOs,

rom small to large

and rom specialist

to one-stop shop,

and they are ound

worldwide. Which

one to choose

depends on the

stage o development o the drug

and the companys needs and avail-

able resources. The process starts

with dening the criteria: What do

you need to know about the CMO?

Is size an issue? What technical com-

petence is needed? Are there anyrequirements or location? Do you

want to stay with the same partner

throughout? Do you need a backup?

its bOth what yOu KnOw

and whO yOu KnOw

Beore making a decision, its impor-

tant to know what a company has

done beore and how it works, both

to conrm its quality and reputation,

and to make sure that its working

styles are a good t.

Price is important, but this is

a secondary issue, Fugelli says.

What I wish we had known beore

selecting a CMO was how it actually

worked on a day-to-day basis. Some

CMOs will just do exactly what they

are told and ocus on the manu-

acture, whereas others will oer

advice and support, make creative

suggestions, and even help with

documentation. They almost act as

a consultant, and this is what a smallbiotech company needs. I think this

would be an important thing or a

CMO to learn, that i they can sup-

port small companies, they will stick

with them through to Phase III.

Woiwode emphasizes the need to

look or the right experience, par-

ticularly or companies working with

biologics.

You need to nd a CMO that has

experience in the same or a related

system, Woiwode says. Com-

panies are developing ever more

complex therapeutic modalities,

such as personalized cancer vac-

cines, and manuacturers have to be

able to ollow this, so you are look-

ing or experience as close to yours

as possible. The partner must have

credibility, and you can oten nd out

about this through word o mouth,

and rom recommendations throughyour networks.

size isnt (always) everything

Sometimes using a small and low-

cost CMO is the right approach or

the early stage o development,

particularly or preclinical trials, as the

huge costs o clinical development

cot o p 11

Picking the rightmanuacturing partnerBy Suzanne elvidge

2

012CatalentPharmaSolutions.

Allrightsreserved.

clinical supply

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. .


6/9

April 2012 Apri


April 2012 Apri

continues to be a signicant driver o

the CMO choice.

staying all the way

The decision whether to use dier-

ent CMOs or early and late stages

o clinical development will dier

rom company to company and proj-

ect to project. The decisions may be

cost-driven, as a small CMO, or one

based in a developing market, can

be cheaper.

In Phase I and II, the costs o

CMC are around $2 million or a

small molecule, give or take, Scottsays. At those stages, the number

o decisions being made relative to

the chemistry and ormulation are

many and hypercritical, and this part

o the CMC can make or break the

program. In Phase III and commer-

cial stages o CMC development,

the ormulation is mostly established

and it is really a matter o scale-up.

At that point, the company will be

spending tens o millions o dollars

on CTM and commercial supply. In

the early stages, with lower overall

cost and many decisions, compa-

nies may opt to work with a local

company or a company that has

certain specialization, or particularly

good service or this early phase

work. In the later stages, with a lot

more budget in play, companies

many times will look or economies

o scale anywhere in the world.

The decisions will also vary based

on the companys internal resources.

Some companies want to main-

tain control and keep very early

phase work internal and outsource

the work at Phase IIb and beyond,

Hepburn says. Large pharma com-

panies may do the opposite to utilize

internal capacity at a later stage and

outsource their early phase

work to accelerate candidate

choice or elimination. Virtual

companies obviously need

to outsource the complete

process.

However, its important to

bear in mind that changing

CMOs partway through the

process can have certain

cost implications.

CMOs will charge or

development o process

(engineering runs) and devel-

opment o auxiliary testing,and changing CMOs will

mean duplication o these

services, Gunduz says.

I a drug developer is

going to change CMOs ater

Phase I or Phase II, they

need to work with a company that

can make the handover as smooth

and seamless as possible.

More oten than not these days,

we see emerging pharma ocused

on selecting a CMO partner that

can get them to Phase IIa or IIb, as

opposed to selecting a CMO pro-

vider that can take them all the way

to commercial, Skultety says. We

nd that or this segment, the ability

to remain fexible and responsive

to changes in product-development

strategy is crucial to program suc-

cess. We work with clients to

understand their overall product-

development goals and timelines,

help them overcome stage-specic

constraints such as amount o API,

poor solubility, bioavailability or PK

issues, and minimize handos by

coupling manuacturing, packaging

and distribution all at one site.

At the early stages o manu-

acturing, its important to have

absolute control, but as you get

know more about your drug and

manuacturing, it becomes easie

to transer its development acro

to an outsourced manuacturer,

Fugelli says.

One situation where it can be

important to have a CMO locked

place is or later stage developm

o biologics, because any chang

in manuacturing processes nee

to be made as early as possible

in the drug-development proces

and be fagged up to the regulat

authorities and documented in t

submission or approval (16).

To gain approval or a cell-bas

biologic, you have to use the sam

cell line or the marketed drug as

used in Phase III, Woiwode say

Altering the ormulation o bio

logics can have serious clinical

consequences, and it is importa

to be aware o this when chang

mean the tenet is wherever pos-

sible to ail ast and cheap. However,

a small CMO is unlikely to be able

to ollow through into later-stage

clinical trials, and so the drug devel-

oper needs to be prepared rom the

beginning to change source. How-

ever, sticking with the same CMO

throughout can also have its advan-

tages; see Staying all the way.

lOOKing at the KnOw-hOw

The right CMO has to have the right

competencies to be the perect t.Because I believe, where pos-

sible, that companies should use the

same CMO throughout the devel-

opment o the drug, its important

to look at scalability and capability

upront, Choy says.

A good approach is to create a

spreadsheet listing the require-

ments, and then rank the available

CMOs according to their capabili-

ties and other criteriaor example,

maximum or minimum batch sizes,

cost, ability to carry out ormulation

development or lling and packag-

ing, and their resources or clinical

distribution.

Scale is an important consider-

ation, but not as important as nding

a partner who meets your stage-

specic needs. Access to expertise,

scalable equipment, and respon-

siveness are key to early-stage

success, Skultety says.

lOCatiOn, lOCatiOn, lOCatiOn

By Phase III, most clinical trials are at

the very least being conducted in the

United States and Europe, and oten

are under way arther aeld as well,

especially as pharma markets are

growing in Asia and Latin America.

The need to align clinical sup-

ply with study demands that span

a global network o clinical sites

has driven changes in supply-chain

strategy, Skultety says. The right

documentation and permissions, as

well as the ability to ensure integrity

o clinical trial material under a wide

variety o transportation and storage

scenarios, are critical.

In this era o global communica-

tion and global clinical trials, the

location o a CMO isnt necessarily

the deal-breaker that it once was,

but its essential that it has beeninspected and approved by the

appropriate agencies or all countries

where the clinical trials will be car-

ried out.

Most reputable vendors have

experience with regulations or di-

erent areas o the world and have

the logistics in place to ship to those

locations, Scott says.

Woiwode recommends manuac-

turing using the same CMO or all

trials globally: Stick with who you

know, i you have a good relation-

ship with them, wherever they are

located.

The requirements are dierent in

the United States and Europe, and

its important to be aware o these

(and be satised that the CMO o

choice is aware o them, too).

Typically, the location o the

clinical trials and the location o the

CMOs are not dependent upon one

another within the United States.

Clinical trials to be perormed in the

E.U. need to be compliant with the

needs o the EMA, Gunduz says.

Typically, or these, a CMC direc-

tor will choose a CMO in the E.U.,

as it will be aligned or EMA regu-

lationsor example, even basic

requirements such as the produc-

tion o water or injection can vary

between FDA-regulated and EMA-

regulated acilities. The better CMOs

within the U.S. should be compliant

or both the U.S. and Europe, but

this is not a statutory requirement. A

CMC director will have to visit those

API production and CMO locations

requently, so he or she may want

them to be as local as possible.

However, there are situations in

which a local CMO is more impor-

tant, Hepburn explains: Particularly

in trials that use comparators whichcan be region- or market-specic,

the need to manuacture and pack-

age locally can be critical. This

cot o p

cot from p 9

Most reputable vendorshave experience withregulations or dierentareas o the world and have

the logistics in place to shipto those locations.

timothy SCott, prESidEnt o

pharmatEk laBoratoriES


7/9

April 2012 Apri


o development, e.g., beore Phase

IIb, the GMP requirements have

traditionally been less arduous than

ater, but the trend is now toward

increasing rigor, particularly where

Phase III trials or chronic diseases

are concerned.

Pharmaceutical companies are

looking or the most eective and

ecient low-cost and astest way

to develop a drug, but the regula-

tors are getting more cautious,

asking or bigger trials, which need

more clinical material, adding more

cost and time, Shott says.This caution over requirements

or clinical trials may stem rom the

case o Vioxx (roecoxib), which

was used to treat arthritis. The

drug was linked with an estimated

27,785 heart attacks and sudden

cardiac deaths in the 5 years it was

on the market between its launch

in 1999 and September 2004,

when it was pulled (19). Problems

were rst detected in 2000, but

Merck did not react immediate

and the drug remained on sale

late 2004. This incident led reg

lators and the public to questio

the rigor and appropriateness o

clinical trial design and executio

in chronic drugs, and by extens

the manuacturing and supply o

products or clinical trials. l

To get a drug approved or

market, its vital that compa-

nies (or their CMOs) comply

with current GMPs and ensure

that the documentation is in

place. I regulatory bodies

dont believe a company is

complying, they can reuse togrant approval, and i a acil-

ity isnt ready or inspection,

this can delay approval. As an

example o this, approval o

Cialis (tadalal) and a number

o other drugs was delayed

because o manuacturing

concerns at Eli Lillys plants

in Indianapolis (16). In some

cases, regulatory rigor has

varied depending on the stage

Getting theregulatoryissues rightBy Suzanne elvidge

CMOs. For example, a change in

the ormulation o Eprex (recombi-

nant erythropoietin) in 1998 led to

the ormation o neutralizing anti-

bodies against both the native and

recombinant erythropoietin, causing

a number o cases o pure red cell

aplasia, a orm o anemia (17).

Changing the cell line or the manu-

acturing site can cause variations in

glycosylation patterns on the protein

surace or changes in the protein

olding. While this might not change

the activity or saety o the resultingtherapeutic, it can aect its regula-

tory approval (17). An example o

this is Genzymes Myozyme (aglu-

cosidase ala), which is approved

or the treatment o the genetic

disorder Pompe disease. When

Genzyme moved its production to

a larger bioreactor at another site,

the FDA asked the company to le

or approval a second time, because

the dierences in the glycosylation

meant that the FDA regarded it as a

dierent molecule (18).

Keeping to the same CMO does

maintain consistency between

phases, between trials, and even

simply between batches o drugs.

Variations in clinical trial outcomes

are to be expected due to biological

variability in the humans taking part

in the trials, and the variability o

the drugs, which could be due to arange o parameters, including varia-

tions in process conditions during

drug substance and drug product

manuacture or indeed variations in

minor impurities, which can have

unexpected eects. Because o

this its important to have faw-

less process control and complete

consistency.

Processes and specications

need to be rigorously and com-

prehensively dened, and its

important to have security o sup-

ply rom a properly inspected and

approved supplier, Shott says.

baCKuPs arent just

fOr COmPuters

Its important to select a lead

supplier and a backup. This dual

sourcing strategy saves problems

like those experienced by Clavis

Pharma (see case study), but its

vitally important that both suppliersare properly validated.

By the time a drug reaches

global Phase III trials, most trials

will need more than one supplier

because o the scale and to reduce

the risk o issues with any one sup-

plier, Fugelli says.

Maintaining a portolio o potential

CMO partnersrom high-cost

top-tier partners to lower tier, aswell as spot suppliers or emergen-

ciesallows drug developers to

choose partners according to the

importance o a project, or its level

o risk. For companies taking this

approach, its a good idea to main-

tain good connections with all the

partners, keeping projects going

with as many as possible to keep

the relationships strong and active.

Given the high cost and potential

value o the work and outcomes,

many companies tend to identiy a

narrow group o CMO partners they

trust and have built a relationship

with, Hepburn says. A limited

number o companies are more

tactical in their selection o provider

and move around between CMOs.

According to Skultety, the deci-

sion to adopt a one-stop-shop

model versus a portolio approach

to contract development and manu-

acturing services is a subject oongoing debate.

Early phase work can be sus-

ceptible to signicant fuctuation in

project requirements, and CMOs

must have the ability to respond

rapidly in order to ensure on-time

delivery and receipt o clinical

materials, Skultety

adds. Responsive-

ness, willingness to

customize and the

ability to react within

short lead times are

critical success ac-

tors or early stage

providers. Later

stage work is driven

by increasing clini-

cal trial complexity

and an expanding global network

o depots, investigators, and

countries. In addition to oeringstage-appropriate manuactur-

ing capacity and scale, eective

late-stage CMOs employ technol-

ogy-driven solutions or clinical

orecast modeling and simulation

and cold-chain supply manage-

ment to protect the integrity and

timeliness o global clinical trials

supply. l

Given the high cost and potentialvalue o the work and outcomes, manycompanies tend to identiy a narrowgroup o CMO partners they trust andhave built a relat ionship with.

GErry hEpBurn, ChiE opEratinG oiCEr, viCE

prESidEnt and GEnEral manaGEr, CliniCal

Supply SErviCES, CatalEnt pharma SolutionS.

Pharmaceutical companiare looking or the mosteective and efcient lowcost and astest way todevelop a drug, but theregulators are getting mocautious, asking or bigge

trials, which need moreclinical material, addingmore cost and time.

ian Shott, manaGinG dirECto

prinCipal ConSultant,

Shott ConSultinG

cot from p 12


8/9

April 2012 Apri


Looking tothe uture

By Suzanne elvidge

The trend across the

biotech and pharmaceutical

industries is generally toward

outsourcing, and the manu-

acture o supplies or clinical

trials seems to be no excep-

tion.

As the costs o drug devel-

opment increase, there will bea bigger push or both CROs

and CMOs to provide services

to ll these needs at a more

cost-eective price than doing

the work in-house. I believe

the role o CROs and CMOs

will become more important in

the development o upcoming

drugs and generics, Gunduz

says. Shott agrees: The trend

or the uture will be towards

increased outsourcing, includ-

ing manuacturing. By 2020,

we will see signicant out-

sourcing o manuacturing and

support unctions.

While this reduces the pres-

sure on companies overall,

it is still very important that

people within the drug-inno-

vator company work directly

with the CMOs and keep aclose eye on the process.

Companies are outsourcing

more and more throughout

drug development, even as

ar as early-stage R&D, and

this is a big responsibility or

those who have to manage

the process and relationship

in-house, Fugelli says.

As CMO capabilities grow world-

wide and competition becomes

more heated, providing a value-

added service or those companies

that want or need it will become

increasingly important (see Its

both what you know and who you

know).

In the uture, companies all over

the globe will be able to provide

the level o GMP services required

and all at about the same price,

especially given the increases in

costs in China and India, Scottsays. It will come down to hav-

ing the required capabilities, but

more importantly, it will be about

the quality o the service provided.

Is the vendor responsive? Do they

communicate well with the client

and in a timely manner? Does the

client eel that the vendor is truly

client-centric?

The key to improved reliabilit

o clinical drug supply is better

collaboration, between teams

within companies, Shott says:

Companies need to look at th

options or manuacturing right

the beginning and need to imp

collaboration between dieren

departments and specialist gro

Traditionally, work has been do

in silos, with the research team

getting the cheapest source o

drug candidates prior to clinica

trials, and then development teneeding a more reliable source

later stage trials involving muc

larger patient populations in th

clinic. This approach is under-

standable, as the attrition rate

drugs in R&D is around 95%, b

it is important to have somethi

locked in place by Phase II e

and dose trials. l

Finding theright timeBy Suzanne elvidge

Speaking with a CMO at

the right time is just as impor-

tant as picking the right CMO,

as i the manuacturing is not

put in place in time, it can

cause delays to clinical trials

that are as limiting as those

caused by manuacturing

problems.Companies that are going

to outsource need to start

nding a CMO as soon as

they have selected their lead

candidate, or even a couple

o years beore the prod-

uct goes into clinical trials,

Fugelli says. For one o our

products, we selected what

we thought would be our clini-

cal candidate rom three potential

molecules, but we asked the CMO

to scale up all three to 10 grams,

and this helped us in our nal

selection o the candidate. These

kinds o practical tests could also

help in choosing a CMO.

Finding a CMO this early means

looking at the idea o manuac-

turing when companies are at

preormulation and API character-

ization stages. However, its easy

to get caught up in moving drug

development orward, ocusing on

the clinical questions, and losingsight o the ormulation and manu-

acturing issues. This can be the

downall o companies and trials,

because they dont pay enough

attention, and Choy has seen the

impact o this. He reports a bio-

tech company that had completed

its clinical package and submitted

its NDA, but the drug showed

long-term stability issues when the

active ingredient came out o solu-

tion. The company had to retract

the NDA and its stock ell by 40%.

Drug developers need to be

ully prepared or discussions with

CMOs, to support them in making

the right decision.

Some items that pharma com-

panies must have in place prior to

partnering: quality audit, quality

agreement, manuacturing service

agreement, environment, health

& saety audit, equipment require-

ments, acility requirements,

personnel training requirements,

Scott says.

Partnering or licensing can

change any decisions made about

manuacturing, particularly or

small pharma or biotech compa-nies signing agreements with large

pharmaceutical companies.

The norm or biotechs is to

partner with a large pharma com-

pany or the market, Woiwode

says. This is the point where deci-

sions may have to be made about

changing CMOs, or about bringing

manuacturing in-house. l

Some items that pharmacompanies must have inplace prior to partnering:quality audit, qualityagreement, manuacturing

service agreement,environment, health &saety audit, equipmentrequirements, acilityrequirements, personnel

training requirements,

timothy SCott, prESidEnt o

pharmatEk laBoratoriES


9/917 April 2012

1. Herper, Mahew. The Truly Staggering Cost Of

Invenng New Drugs. Forbes. [Online] February 10, 2012.[Cited: March 24, 2012.] hp://www.forbes.com/sites/mahewherper/2012/02/10/the-truly-staggering-cost-of-

invenng-new-drugs/.

2. Burton, Thomas M. GAO Report Blames Drug ShortagesOn Manufacturing Problems. Wall Street Journal Health Blog.[Online] December 14, 2011. [Cited: March 24, 2012.]hp://blogs.wsj.com/health/2011/12/14/gao-report-blames-drug-shortages-on-manufacturing-problems/.

3. Palmer, Eric. Warehouse strike creates drug shortages

in Australia. FiercePharma Manufacturing. [Online]

March 19, 2012. [Cited: March 24, 2012.] hp://www.ercepharmamanufacturing.com/story/warehouse-strike-creates-drug-shortages-australia/2012-03-19.

4. McBride, Ryan. J&Js chemo drug shortage hits Amgen,Lilly, Endocyte trials. FierceBiotech. [Online] November 1,2011. [Cited: March 23, 2012.] hp://www.ercebiotech.com/story/jjs-chemo-drug-shortage-hits-amgen-lilly-endocyte-trials/2011-11-01.

5. Miller, George. Ben Venue shutdown strains J&J drugsupply. FiercePharma Manufacturing. [Online] November 21,2011. hp://www.ercepharmamanufacturing.com/story/ben-venue-shutdown-strains-jj-drug-supply/2011-11-21.

6. Duval, Amy. The current shortage of Doxil across the

major markets. Decision Resources: Drugwatch Blog.[Online] January 17, 2012. [Cited: March 23, 2012.] hp://decisionresources.com/The-Decision-Resources-Blog/January-2012/Doxil-Shortage-011712.

7. Miller, George. J&J releases Doxil batch; Ben Venuetroubles detailed in FDA report. FiercePharma Manufacturing.[Online] December 14, 2011. [Cited: March 24, 2012.] hp://www.ercepharmamanufacturing.com/story/jj-releases-doxil-batch-ben-venue-troubles-detailed-fda-report/2011-12-14.

8. . Europe takes precauons with Ben Venue drugs.FiercePharma Manufacturing. [Online] November

28, 2011. [Cited: March 24, 2012.] hp://www.ercepharmamanufacturing.com/story/europe-takes-precauons-ben-venue-drugs/2011-11-28.

9. Palmer, Eric. Ben Venue cant say when crucial cancerdrug will be available. FiercePharma Manufacturing. [Online]February 12, 2012. [Cited: March 23, 2012.] hp://www.ercepharmamanufacturing.com/story/ben-venue-cant-say-when-crucial-cancer-drug-will-be-available/2012-02-12.

10. Wall, J. K. Drug shortages hit Lilly, Endocyte. IBJ.com.[Online] November 7, 2011. [Cited: March 23, 2012.] hpwww.ibj.com/drug-shortages-hit-lilly-endocyte/PARAMS/arcle/30590.

11. Dooren, Jennifer Corbe. Sebelius Says Leukemia-DruShortage Will Be Resolved Within Two Weeks. Wall StreetJournal Health Blog. [Online] February 16, 2012. [Cited:

March 24, 2012.] hp://blogs.wsj.com/health/2012/02/1sebelius-says-leukemia-drug-shortage-will-be-resolved-within-two-weeks/.

12. Clavis Pharma. Clavis Pharma Update on Phase IIICLAVELA Study. Clavis Pharma. [Online] March 26, 2012.[Cited: March 26, 2012.]hp://www.clavispharma.com/news-events/2012-press-releases/clavis-pharma-update-ophase-iii-clavela-study.

13. Clavis Pharma Update regarding Phase III CLAVELA tClavis Pharma. [Online] January 17, 2012. [Cited: March 2

2012.] hp://www.clavispharma.com/news-events/2012press-releases/clavis-pharma-update-regarding-phase-iii-clavela-trial.

14. Palmer, Eric. Sano cuts connue with closing ofmanufacturing plant in U.K. FiercePharma Manufacturing[Online] March 15, 2012. [Cited: March 24, 2012.] hp://www.ercepharmamanufacturing.com/story/sano-cuts-connue-closing-manufacturing-plant-uk/2012-03-15.

15. MacDonald, Gareth. Roche buys Lonzas Singaporebiologics plant. in-Pharma Technologist. [Online] August31, 2009. [Cited: March 24, 2012.] hp://www.in-pharmatechnologist.com/Industry-Drivers/Roche-buys-Los-Singapore-biologics-plant.

16. Boersig, Charles. Why NDAs Fail - 15 pialls and howto avoid them. R&D Direcons. February 2003, Vol. 9, 2.hp://65.17.196.124/pdf/nda.pdf

17. Elvidge, Suzanne.Biosimilar drugs in Europe: Threat o

opportunity to innovaon. s.l. : FirstWord Dossier, 2011.

18. Taylor, Phil. Genzyme knockback has implicaons forbiosimilars. in-Pharma Technologist. [Online] April 23, 200[Cited: March 24, 2012.] hp://www.in-pharmatechnologcom/Industry-Drivers/Genzyme-knockback-has-implicaofor-biosimilars .

19. msnbc.comsta. Report: Vioxx linked to thousandsof deaths.Arthris on msnbc.com. [Online] October 6,

2004. [Cited: March 24, 2012.] hp://www.msnbc.msn.com/id/6192603/ns/health-arthris/t/report-vioxx-linkedthousands-deaths/#.T29GjdldORM.

Bibliography
http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/http://blogs.wsj.com/health/2011/12/14/gao-report-blames-drug-shortages-on-manufacturing-problems/http://blogs.wsj.com/health/2011/12/14/gao-report-blames-drug-shortages-on-manufacturing-problems/http://blogs.wsj.com/health/2011/12/14/gao-report-blames-drug-shortages-on-manufacturing-problems/http://www.fiercepharmamanufacturing.com/story/warehouse-strike-creates-drug-shortages-australia/2012-03-19http://www.fiercepharmamanufacturing.com/story/warehouse-strike-creates-drug-shortages-australia/2012-03-19http://www.fiercepharmamanufacturing.com/story/warehouse-strike-creates-drug-shortages-australia/2012-03-19http://www.fiercebiotech.com/story/jjs-chemo-drug-shortage-hits-amgen-lilly-endocyte-trials/2011-11-01http://www.fiercebiotech.com/story/jjs-chemo-drug-shortage-hits-amgen-lilly-endocyte-trials/2011-11-01http://www.fiercebiotech.com/story/jjs-chemo-drug-shortage-hits-amgen-lilly-endocyte-trials/2011-11-01http://www.fiercepharmamanufacturing.com/story/ben-venue-shutdown-strains-jj-drug-supply/2011-11-21.http://www.fiercepharmamanufacturing.com/story/ben-venue-shutdown-strains-jj-drug-supply/2011-11-21.http://decisionresources.com/The-Decision-Resources-Blog/January-2012/Doxil-Shortage-011712http://decisionresources.com/The-Decision-Resources-Blog/January-2012/Doxil-Shortage-011712http://decisionresources.com/The-Decision-Resources-Blog/January-2012/Doxil-Shortage-011712http://www.fiercepharmamanufacturing.com/story/jj-releases-doxil-batch-ben-venue-troubles-detailed-fda-report/2011http://www.fiercepharmamanufacturing.com/story/jj-releases-doxil-batch-ben-venue-troubles-detailed-fda-report/2011http://www.fiercepharmamanufacturing.com/story/jj-releases-doxil-batch-ben-venue-troubles-detailed-fda-report/2011http://www.fiercepharmamanufacturing.com/story/europe-takes-precautions-ben-venue-drugs/2011http://www.fiercepharmamanufacturing.com/story/europe-takes-precautions-ben-venue-drugs/2011http://www.fiercepharmamanufacturing.com/story/europe-takes-precautions-ben-venue-drugs/2011http://www.fiercepharmamanufacturing.com/story/ben-venue-cant-say-when-crucial-cancer-drug-will-be-available/2012http://www.fiercepharmamanufacturing.com/story/ben-venue-cant-say-when-crucial-cancer-drug-will-be-available/2012http://www.fiercepharmamanufacturing.com/story/ben-venue-cant-say-when-crucial-cancer-drug-will-be-available/2012http://ibj.com/http://www.ibj.com/drug-shortages-hit-lilly-endocyte/PARAMS/article/30590http://www.ibj.com/drug-shortages-hit-lilly-endocyte/PARAMS/article/30590http://www.ibj.com/drug-shortages-hit-lilly-endocyte/PARAMS/article/30590http://blogs.wsj.com/health/2012/02/16/sebeliushttp://blogs.wsj.com/health/2012/02/16/sebeliushttp://www.clavispharma.com/news-events/2012-press-releases/clavishttp://www.clavispharma.com/news-events/2012-press-releases/clavishttp://www.clavispharma.com/news-events/2012-press-releases/clavis-pharma-update-regarding-phase-iii-clavela-trialhttp://www.clavispharma.com/news-events/2012-press-releases/clavis-pharma-update-regarding-phase-iii-clavela-trialhttp://www.fiercepharmamanufacturing.com/story/sanofi-cuts-continue-closing-manufacturing-plant-uk/2012http://www.fiercepharmamanufacturing.com/story/sanofi-cuts-continue-closing-manufacturing-plant-uk/2012http://www.fiercepharmamanufacturing.com/story/sanofi-cuts-continue-closing-manufacturing-plant-uk/2012http://www.in-pharmatechnologist.com/Industry-Drivers/Rochehttp://www.in-pharmatechnologist.com/Industry-Drivers/Rochehttp://65.17.196.124/pdf/nda.pdfhttp://www.in-pharmatechnologist.com/Industry-Drivers/Genzymehttp://www.in-pharmatechnologist.com/Industry-Drivers/Genzymehttp://msnbc.com/http://msnbc.com/http://msnbc.com/http://www.msnbc.msn.com/id/6192603/ns/health-arthritis/t/report-vioxx-linked-thousands-deaths/#.T29GjdldORMhttp://www.msnbc.msn.com/id/6192603/ns/health-arthritis/t/report-vioxx-linked-thousands-deaths/#.T29GjdldORMhttp://www.msnbc.msn.com/id/6192603/ns/health-arthritis/t/report-vioxx-linked-thousands-deaths/#.T29GjdldORMhttp://www.msnbc.msn.com/id/6192603/ns/health-arthritis/t/report-vioxx-linked-thousands-deaths/#.T29GjdldORMhttp://msnbc.com/http://msnbc.com/http://www.in-pharmatechnologist.com/Industry-Drivers/Genzymehttp://www.in-pharmatechnologist.com/Industry-Drivers/Genzymehttp://65.17.196.124/pdf/nda.pdfhttp://www.in-pharmatechnologist.com/Industry-Drivers/Rochehttp://www.in-pharmatechnologist.com/Industry-Drivers/Rochehttp://www.fiercepharmamanufacturing.com/story/sanofi-cuts-continue-closing-manufacturing-plant-uk/2012http://www.fiercepharmamanufacturing.com/story/sanofi-cuts-continue-closing-manufacturing-plant-uk/2012http://www.fiercepharmamanufacturing.com/story/sanofi-cuts-continue-closing-manufacturing-plant-uk/2012http://www.clavispharma.com/news-events/2012-press-releases/clavis-pharma-update-regarding-phase-iii-clavela-trialhttp://www.clavispharma.com/news-events/2012-press-releases/clavis-pharma-update-regarding-phase-iii-clavela-trialhttp://www.clavispharma.com/news-events/2012-press-releases/clavishttp://www.clavispharma.com/news-events/2012-press-releases/clavishttp://blogs.wsj.com/health/2012/02/16/sebeliushttp://blogs.wsj.com/health/2012/02/16/sebeliushttp://www.ibj.com/drug-shortages-hit-lilly-endocyte/PARAMS/article/30590http://www.ibj.com/drug-shortages-hit-lilly-endocyte/PARAMS/article/30590http://www.ibj.com/drug-shortages-hit-lilly-endocyte/PARAMS/article/30590http://ibj.com/http://www.fiercepharmamanufacturing.com/story/ben-venue-cant-say-when-crucial-cancer-drug-will-be-available/2012http://www.fiercepharmamanufacturing.com/story/ben-venue-cant-say-when-crucial-cancer-drug-will-be-available/2012http://www.fiercepharmamanufacturing.com/story/ben-venue-cant-say-when-crucial-cancer-drug-will-be-available/2012http://www.fiercepharmamanufacturing.com/story/europe-takes-precautions-ben-venue-drugs/2011http://www.fiercepharmamanufacturing.com/story/europe-takes-precautions-ben-venue-drugs/2011http://www.fiercepharmamanufacturing.com/story/europe-takes-precautions-ben-venue-drugs/2011http://www.fiercepharmamanufacturing.com/story/jj-releases-doxil-batch-ben-venue-troubles-detailed-fda-report/2011http://www.fiercepharmamanufacturing.com/story/jj-releases-doxil-batch-ben-venue-troubles-detailed-fda-report/2011http://www.fiercepharmamanufacturing.com/story/jj-releases-doxil-batch-ben-venue-troubles-detailed-fda-report/2011http://decisionresources.com/The-Decision-Resources-Blog/January-2012/Doxil-Shortage-011712http://decisionresources.com/The-Decision-Resources-Blog/January-2012/Doxil-Shortage-011712http://decisionresources.com/The-Decision-Resources-Blog/January-2012/Doxil-Shortage-011712http://www.fiercepharmamanufacturing.com/story/ben-venue-shutdown-strains-jj-drug-supply/2011-11-21.http://www.fiercepharmamanufacturing.com/story/ben-venue-shutdown-strains-jj-drug-supply/2011-11-21.http://www.fiercebiotech.com/story/jjs-chemo-drug-shortage-hits-amgen-lilly-endocyte-trials/2011-11-01http://www.fiercebiotech.com/story/jjs-chemo-drug-shortage-hits-amgen-lilly-endocyte-trials/2011-11-01http://www.fiercebiotech.com/story/jjs-chemo-drug-shortage-hits-amgen-lilly-endocyte-trials/2011-11-01http://www.fiercepharmamanufacturing.com/story/warehouse-strike-creates-drug-shortages-australia/2012-03-19http://www.fiercepharmamanufacturing.com/story/warehouse-strike-creates-drug-shortages-australia/2012-03-19http://www.fiercepharmamanufacturing.com/story/warehouse-strike-creates-drug-shortages-australia/2012-03-19http://blogs.wsj.com/health/2011/12/14/gao-report-blames-drug-shortages-on-manufacturing-problems/http://blogs.wsj.com/health/2011/12/14/gao-report-blames-drug-shortages-on-manufacturing-problems/http://blogs.wsj.com/health/2011/12/14/gao-report-blames-drug-shortages-on-manufacturing-problems/http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/

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