Cardiology & Oncology Drug Development & Regulation

March 2009 Vol 9 No 3 www.drugdeliverytech.com

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TherapeuticFocus

Cardiology & Oncology Drug Development& Regulation

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IntroductionHeart disease and cancer are still the

two leading causes of mortality in the

world. Recent data show that in the US,

the total direct and indirect costs

associated with treating cardiovascular

diseases and stroke are estimated to be

$449 billion, by comparison, the

estimated costs for all types of cancer

was $219 billion.1 Sales of drugs treating

cardiovascular disorders, hypertension,

and cancer accounted for roughly 31% of

the $287 billion prescription

pharmaceutical market in 2007; these

drugs continue to be the largest therapy

classes in the US (Figure 1).2 In the

cardiology sector, Pfizer’s Lipitor®

amassed sales revenues of $12.7 billion

in 2007, making it the best selling drug

in pharmaceutical history. Not to be

outdone, the biotech industry has

likewise developed a number of

successful blockbuster cancer therapies

as intravenous solutions or vaccines,

including Herceptin® and Avastin®,

monoclonal antibody-based therapies to

treat breast and colon cancer,

respectively, and Gardasil®, a vaccine

against cervical cancer.3 Sales of cancer

drugs are projected to double and could

reach $80 billion by 2012, according to

IMS Health.

There are several reasons for this

increased sales growth, which include

extended lifespan, increases in obesity

and hypertension in the US population,

an increasing number of patients on

chemotherapy in major markets, longer

treatment periods for a growing number

of patients, and the

greater availability

of more expensive

and modern

targeted therapies

to treat these

diseases. However,

hotly debated

issues have risen

over the long-term

safety of coronary

drug-eluting stents

(DES), efficacy of

beta-blockers in

treating

hypertension, and

the long-term

safety of statins. In

the oncology

sector, there has

been an increase in

the development of highly potent,

hydrophobic compounds, and difficulty

in ensuring their solubility as well as

specificity to target the tumor site.

Because oncology drugs are cytotoxic,

maintaining containment facilities during

the developmental phase for these actives

can become expensive. Furthermore,

with both of these drug classes,

Figure 1.

By: Stuart L. Cantor, PhD, Senior Scientist, and Kadriye Ciftci, PhD, Senior Director Drug Delivery,ICON Development Solutions

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difficulties proving efficacy or

unexpected safety concerns, particularly

during later-stage development amid

Phase III trials, can be particularly

challenging.

The increased number of

blockbuster drugs that are scheduled to

lose patent protection in the coming

years (Figure 2), coupled with the FDA’s

Amendments Act of 2007 granting

sweeping new powers to the agency for

such tasks as requiring drug makers to

do post-marketing clinical trials, are

making the regulatory climate more

expensive and time-consuming for the

pharmaceutical industry. Furthermore,

because drug safety issues are

paramount due to highly publicized

cases like Vioxx®, the FDA is closely

scrutinizing safety data while improving

its management of safety signals.

Drug DevelopmentOncology drugs in development are

generally highly potent as well as

cytotoxic; some may even have narrow

therapeutic windows. It is important to

assess the safety of these compounds

early on to determine that they are

effective in treating the disease process

while not damaging healthy tissue.

According to the M3 Guidance for

Industry, single-dose acute toxicity

studies are required to be performed for

pharmaceuticals and should be

evaluated in two small mammalian

model species before the first human

exposure.4

The ratio of time for animal to

human testing is 1:1, meaning that the

FDA will allow a company to conduct

human clinical trials for only the same

time period in which animal data has

been supplied. Sometimes, the agency

can also request that safety and/or

toxicity data in a non-human primate

also be supplied before an

Investigational New Drug (IND) can be

approved. A contract research

organization

(CRO) can assist a

company with

developing a

game plan for the

extent of both

preclinical animal

testing and future

clinical trials;

such services can

be outsourced by

start-up or virtual

companies with

limited in-house

drug development

resources. The

CRO can also

help the company

in its

correspondence

with the FDA and

offer guidance

during the critical pre-IND meeting.

Under current regulations, a sponsor is

permitted to start their clinical trials 30

days after filing its IND with the FDA

unless notified earlier that there are

issues with the application.

Recent reports from the

Pharmaceutical Research and

Manufacturers of America (PhRMA)

noted that 750 new medicines are being

tested in the fight against cancer, and

256 new medicines are in development

to treat cardiovascular diseases.5,6 While

there have been a number of successful

anti-neoplastic small molecules

launched over the years, such as 5-

fluorouracil, paclitaxel, and

doxorubicin, the focus has shifted away

from broad-acting cytotoxic drugs

toward the development of new

therapies directed against specific

molecular targets. Although biologics

and vaccines derived from larger protein

molecules offer promise in these

therapeutic areas due to their high

disease specificity and activity at

relatively low concentrations as

compared with small molecules,

physicochemical stability and potential

immunologic issues need to be closely

monitored and controlled to ensure a

drug product’s beneficial effects.

“In contrast to most drugs that are

chemically synthesized and with a

known structure, most biologics are

complex mixtures that are not easily

identified or characterized. Biological

products, including those manufactured

by biotechnology, tend to be heat

sensitive and susceptible to microbial

contamination,” says Paul Richards,

FDA Spokesperson at CBER.

“Therefore, it is necessary to use aseptic

principles from initial manufacturing

steps in order to ensure sterility of the

finished products, which is also in

contrast to most conventional drugs.”

Furthermore, vaccine clinical

development follows the same general

pathway as for drugs and other

biologics. However, due to the complex

nature of many vaccines, each lot must

be thoroughly tested for safety, sterility,

and potency by the manufacturer. These

tests, as well as many others that

manufacturers must perform, are

Table 2.


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specified in their biologic license

applications (BLAs). If the product is

subject to official release by the FDA’s

Center for Biologics Evaluation and

Research (CBER), the manufacturer

must submit samples of each production

lot to the Agency together with a release

protocol showing a summary of the lot

manufacturing history and the results of

all the manufacturer’s tests performed on

that lot, says Mr. Richards.

“The most challenging aspects to

developing these biologic drugs is the

design of efficient and robust

fermentation and purification processes

and the production of a stable

formulation,” says Peter Ihnat, PhD, Sr.

Principal Scientist, Protein Therapeutics,

Bristol-Myers Squibb.

Protein formulations can be

developed using either lyophilized

powders or liquid parenterals; however,

freeze-drying is not as popular an option

nowadays due to the increased cost and

longer development time required to

produce a successful formulation.

“Typically, the target level for

protein impurities for liquid formulations

is < 5%, and these are usually due to

oligomers or aggregates; however, due to

the immunogenic potential of these

compounds, impurity levels are

evaluated on a case-by-case basis.

Moreover, long-term protein stability is

monitored using at least two to three

orthogonal methods in addition to an in

vitro bioassay to assess biological

activity,” says Mr. Ihnat.

RegulatorySubmissions

The CTD or Common Technical

Document was developed to be used for

regulatory submissions and finalized as

the M4 Guidance for Industry in 2004.7,8

This table of contents format is highly

recommended for INDs, New Drug

Applications (NDAs), and Abbreviated

NDAs (ANDAs) from the US and

required for European and Japanese

submissions. Canadian INDs must also

be in CTD format; however, these are

referred to as CTAs or Clinical Trial

Applications for Phases I-III. The CTD

contains several modules with Modules 2

and 3 containing critical Chemistry,

Manufacturing, and Control (CMC)

information.

While Module 2 deals with both

non-clinical and clinical overviews and

summaries, the quality section or

Module 3 deals only with CMC issues

and provides information on the

physicochemical properties and control

of the drug substance as well as the

development, manufacture, and control

of the finished drug product. Modules 4

and 5 address non-clinical and clinical

study reports, respectively. Updates to

the IND data following Phase I-II trials

can be provided in information

amendments and annual reports;

however, the emphasis should be on

reporting significant changes that can

have a safety-related impact. CMC

development will continue in parallel

with the clinical development during

Phase III studies.9,10

If the CMC section will be written

for an already approved drug but a new

dosage form, the Drug Master File

(DMF) number, if available, can be

referenced for some of the pertinent

manufacturing information for the drug

substance. For all scientific data, the

FDA is particularly concerned that the

experimental study design and statistical

analysis be sound and free from flaws,

and requires a rationale and justification

used for final specifications selected as

well as the use of novel excipients and

any unusual tests performed.

Two other regulatory submission

pathways available are the 505(b)(2) and

combination product options. The

505(b)(2) route offers companies the

advantage of not having to supply the

safety and efficacy data on an already

approved drug product, and such filings

can be used to support new and

innovative drug delivery forms. Data

from published studies can even be

submitted to the FDA. However, the

company would need to provide

additional clinical data necessary to

demonstrate any safety and efficacy

differences between the original drug

and the 505(b)(2) drug. Some of the

different types of applications covered by

the section 505(b)(2) are:

• change in an active ingredient (ie,

different salt, ester, complex,

chelate, clathrate, racemate, or

enantiomer) for a listed drug

containing the same active

moiety;

• change in dosage form, strength,

formulation, dosing regimen, or

route of administration; and/or

• change from a prescription

indication to an over-the-counter

indication.

The important benefits of using the

505(b)(2) filing route are a faster

pathway toward regulatory approval

without giving the sponsor the burden of

supplying duplicate safety and efficacy

data on an already existing compound.

However, the FDA does still require that

a sponsor provide additional clinical

data, termed bridging studies, which are

necessary to support any changes or

modifications from the listed drug(s) to

the 505(b)(2) drug(s), and these studies

will allow extrapolation of the efficacy

and safety data. Furthermore, a

505(b)(2) applicant may qualify for 3 or

5 years of Hatch-Waxman marketing

exclusivity.11

The other non-traditional route for

regulatory approval deals with

combination products, such as coronary

DES, which are considered a drug-

device combination product under the


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Code of Federal Regulations (CFR) 21

CFR 3.2(e)(1). The Office of

Combination Products (OCP) at the FDA

assigns such products to a lead agency

center, based upon the product’s primary

mode of action. OCP ensures timely,

consistent pre-market review and

appropriate post-market regulation of

combination products by facilitating the

review process involving more than one

agency center. In this case, the

investigational device exemption (IDE)

application would be sent to the FDA’s

Center for Devices and Radiological

Health (CDRH) with significant

consultation by the Office of New Drug

Quality Assessment (ONDQA)/Division

of Cardiovascular and Renal Products.

Many scientific and regulatory issues

will arise due to the complex nature of a

coronary DES. Some important concerns

that would need to be evaluated and

discussed in a submission include acute

and chronic stent biocompatibility,

polymeric coating characterization (ie,

thickness, uniformity, integrity, adhesion

to stent), and drug release profile. The

predominant percentage composition of a

combination product does not dictate the

Agency center(s) where it is regulated,

rather, it is the primary mode of action or

the “most important therapeutic action of

a combination product” that determines

where a combination product will be

regulated. For example, DES submissions

are assigned to CDRH because the

device’s role in physically maintaining

vessel lumen patency provides the most

important therapeutic action of the

combination product. The drug plays only

a secondary role in reducing restenosis or

re-narrowing of the coronary arteries, a

phenomenon which is caused by the

body’s formation of scar tissue in

response to stent implantation.12

While the agency currently does not

require the use of Process Analytical

Technologies (PAT) for their submissions,

the use of PAT for CMC documentation

is looked upon favorably. PAT uses tools,

such as near-infrared (NIR) or Raman

spectroscopy, to provide real-time process

data. PAT finds wide applicability in the

pharmaceutical industry and can be used

to assess blend and content uniformity,

prediction of dissolution time, and can

determine the end-point of a coating or

drying operation. Not only can end-

product testing be reduced, which can

save a company money, but the FDA can

also provide some regulatory flexibility

for any process changes that could occur

in the future, provided that they are

accompanied by scientific justification.13

“The Agency considers PAT to be a

tool for designing, analyzing, and

controlling manufacturing through timely

measurements (ie, during processing) of

critical quality and performance attributes

of raw and in-process materials and

processes, with the goal of ensuring final

product quality. The goal of PAT is to

enhance understanding and control of the

manufacturing process and to facilitate

innovation in development,

manufacturing, and quality assurance by

focusing on process understanding. These

concepts are applicable to all

manufacturing situations,” says Jon E.

Clark, MS, Associate Director for the

Office of Pharmaceutical Science (OPS)

Policy Development at the FDA CDER.

Due to the serious nature of the

diseases they treat, both cardiology and

oncology drugs qualify under the fast-

track drug development program

classification. The three designations

given by the FDA are accelerated

approval, fast-track, and priority

review.14,15 In 1992, accelerated approval

for oncology drugs was codified into law

under Subpart H (21 CFR part 314.530)

and added to the new drug application

regulations. Accelerated approvals are

granted for the treatment of serious or

life-threatening conditions and a benefit

over available therapy exists.

This designation requires using a

surrogate endpoint for efficacy, ie, an

evaluation intended to substitute for a

clinical endpoint such as survival or

morbidity, and which is reasonably likely

to predict clinical benefit. Examples of

tumor assessment endpoints are response

rate to drug therapy or time to tumor

progression, measured using anatomic

imaging techniques. Once accelerated

approval has been granted, continued

marketing of the product will be

contingent on the sponsor’s providing

timely and conclusive evidence from

validation trials that establishes that the

experimental drug is safe and provides

tangible clinical benefit. The product

approval can be withdrawn if

confirmatory studies fail to show clinical

benefits, or if the drug sponsor fails to

conduct the confirmatory studies.

A fast-track status is granted by the

Agency for those drugs also developed to

treat life-threatening diseases and that

demonstrate the potential to address an

unmet medical need. In this instance, a

rolling NDA can be approved that allows

for completed sections of the NDA to be

submitted to the FDA on an ongoing

basis. The FDA strongly recommends

several meetings, including a pre-IND

consultation, meetings following Phases

I-II, and a pre-NDA meeting to expedite

the approval process. The other

designation, priority review, is for drugs

showing a significant therapeutic benefit

compared to the standard of care. In this

case, the FDA would review a NDA

within 6 months as opposed to the

standard review completion timeline of

10 months.

Outsourcing KeyCapabilities

In addition to hearing the term CRO

as a common buzzword these days, the

fact is that both small and large

pharmaceutical companies can benefit

from utilizing the added services and

expertise of a global CRO while focusing

on their core competencies. The CRO


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market size is currently estimated at about $15 billion in revenue per year and is

growing at a healthy annual rate of 14.8%. By 2010, the market is forecast to be in

the vicinity of $22.9 billion, according to Frost & Sullivan. A CRO should be chosen

carefully at the outset of a project after considering the budget, timelines, the range

of services provided, and the resources offered. A CRO can assist with the review and

editing of the regulatory submissions and can either represent the company as their

sole agent or accompany their client in meetings with the FDA. For smaller

companies with limited resources, limited regulatory expertise, and tight timelines,

meetings with the FDA early in the development process can alert the company if

they are going down the wrong pathway.

Meetings with the FDA can be arranged at both the pre-IND stage, where the

company can ask questions to see if they have done enough work to prove a drug’s

safety, and also before going through the time and expense for Phase III clinical trials

(an after Phase II meeting). These meetings are invaluable in identifying additional

safety, toxicity, or efficacy issues pertinent to cardiology and oncology IND/NDA

filings. More frequent interaction with the FDA would be recommended (ie, end of

Phase I meeting) if the drug would be marketed to a small patient population with a

rare disease or condition, ie, orphan drug classification for a disease affecting less

than 200,000 people in the US. Orphan drugs would also be granted accelerated

approval status, and NDAs are given a priority review timeline of 6 months.

A CRO can act as a regulatory resource for a company to guide them as to what

the minimum agency requirements are to prove safety and efficacy and which tests

would be superfluous. Another key advantage of using a CRO is that they have the

capability to offer their clients a strategic viewpoint on risk assessment and

management, and can additionally shoulder some of that risk in interactions with the

FDA. The Agency will take a global view of the scientific data to assess the risk-

benefit ratio, ie, the benefits of the drug substance and final drug product must far

outweigh any complications or potential risks to human health. The Agency also

examines what therapeutic advantages the new product has over therapies currently in

the market. Sometimes there is no information available on comparator products as

the regulatory submission is for a first-in-class therapy. In such instances, a CRO can

provide key information as it can draw from a wide knowledge base from past client

experiences with a variety of dosage forms. �

References1. Rosamond W, et al. Heart Disease and Stroke Statistics 2008 Update: A Report from the American Heart Association Statistics Committee and Stroke Statistics

Subcommittee. Circulation. [Available at: http://circ.ahajournals.org/cgi/content/full/117/4/e25 (DOI: 10.1161/circulationaha.107.187998); Accessed August 6, 2008].

2. Buono D. IMS study finds decline in prescription drug market growth. Drug Store News. (April 21, 2008) [Available at:

http://findarticles.com/p/articles/mi_m3374/is_5_30/ai_n25407255; Accessed July 30, 2008].

3. Lawrence S. Billion dollar babies-biotech drugs as blockbusters. Nature Biotechnol. 2007;25(4):380-382. [Available at: http://www.nature.com/naturebiotechnology ;

Accessed August 6, 2008].

4. FDA Guidance for Industry M3: Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals. Center for Drug Evaluation and Research

(CDER) & Center for Biologics Evaluation and Research (CBER), (July 1997).

5. 2008 Report: Medicines in Development for Cancer. [Available at: http://www.phrma.org/files/meds_in_dev/Cancer2008.pdf; Accessed July 27, 2008].

6. 2007 Report: Medicines in Development for Heart Disease and Stroke. [Available at: http://www.phrma.org/files/Heart2007.pdf; Accessed July 27, 2008]

7. FDA Guidance for Industry M4: The CTD- Quality Questions and Answers/Location Issues. CDER & CBER, (June 2004).

8. FDA Guidance for Industry M4: The CTD- General Questions and Answers. CDER & CBER, (December 2004).

9. FDA Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized,

Therapeutic, Biotechnology-derived Products. CDER & CBER, (November 1995).

10. FDA Guidance for Industry: INDs for Phase 2 and Phase 3 Studies. Chemistry, Manufacturing, and Controls Information. CDER, (May 2003).

11. FDA Guidance for Industry: Applications covered by Section 505(b)(2). CDER (October 1999).

12. FDA Guidance for Industry: Coronary Drug-eluting stents- Nonclinical and clinical studies. Center for Devices and Radiological Health (CDRH) and CDER (March

2008).

13. FDA Guidance for Industry: Q8 Pharmaceutical Development. CDER & CBER (May 2006).

14. FDA Guidance for Industry: Fast Track Development Programs- Designation, Development, and Application Review. CDER & CBER (January 2006).

15. Dagher R, Johnson J, Williams G, Keegan P, Pazdur R. Accelerated Approval of Oncology Products: A Decade of Experience. J Natl Cancer Inst. 2004;96(20):1500-

1509.

Stuart Cantor,PhD

Senior ScientistICON DevelopmentSolutions

Dr. Stuart Cantor graduated from the University of

Maryland Pharmacy School and is a Senior Scientist

for ICON. Dr. Cantor currently assists global clients

with their CMC sections of regulatory documents for

solid dosage forms and biologics, and also handles

clinical supply chain management issues. He has 7

pharmaceutical publications online/in-process, and

has published a book chapter on wet granulation.

He interned at Wyeth and Bristol Myers Squibb

(BMS) and studied different granulation processes

and their mechanical properties. His research

covered preformulation, formulation, analytical

method validation, blend segregation, and chemical

imaging. His expertise is in extrusion-

spheronization, wet granulation, and NIR

spectroscopy. Dr. Cantor previously developed the

sugarless fiber chews for diabetics launched by

BMS under the Choice® DM brand.

Dr. Kadriye Çiftci is Senior Director of Drug

Delivery/Formulations at ICON Development

Solutions. She has more than 15 years of

experience in academia and pharmaceutical R&D.

Dr. Ciftci completed her training at the University of

Illinois at Chicago and the University of Michigan

Medical School. She previously worked as a Tenure-

track Assistant Professor at Temple University and a

Research Fellow at the Schering Plough Research

Institute. Her special interests include cancer

research, gene therapy, and the development of

novel drug delivery systems, particularly biotech

products and vaccines.

Kadriye Ciftci,PhD

Senior Director DrugDeliveryICON DevelopmentSolutions


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