www.elsevier.com/locate/addr

Advanced Drug Delivery Revi

Regulatory aspects of drug approval for macular degenerationi

Lewis Gryziewicz *

Global Regulatory Affairs, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612-1599, USA

Received 26 August 2005; accepted 13 September 2005

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries with approximately 15

million people with the disease in the United States. AMD is characterized as a progressive degenerative disease of the

macula. There are two forms of AMD: neovascular and non-neovascular. The non-neovascular form of AMD is more

common and leads to a slow deterioration of the macula with a gradual loss of vision over a period of years. The neovascular

form of the disease is responsible for the majority of cases of severe vision loss and is due to proliferation of abnormal blood

vessels behind the retina. These blood vessels leak blood and fluid into the retina, which results in visual abnormalities. The

development of these abnormal blood vessels is due in part to the activity of VEGF (vascular endothelial growth factor) and

its inhibition is expected to impact on the onset and/or severity of vision loss associated with the proliferation of abnormal

blood vessels.

Age-related macular degeneration is an underserved treatment population. Visudyne (verteporfin for injection), Novartis

Ophthalmics, is FDA approved for the treatment of patients with predominantly classic subfoveal choroidal neovascularization

due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis. Pegaptanib sodium (Macugen,

Eyetech Pharmaceuticals, Inc. and Pfizer, Inc.) is indicated for the treatment of neovascular (wet) age-related macular

degeneration. This article will review the approval pathway for these two products and that required of future products

indicated for macular degeneration.

D 2005 Elsevier B.V. All rights reserved.

Keywords: Macular degeneration; AMD; Neovascular form

Contents

. . . . . 2093

. . . . . 2093

1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2. Visudyne (verteporfin for injection) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

0169-409X/$ - s

doi:10.1016/j.ad

i This review

DegenerationQ, V* Tel.: +1 714

E-mail addre

ews 57 (2005) 2092–2098

ee front matter D 2005 Elsevier B.V. All rights reserved.

dr.2005.09.009

is part of the Advanced Drug Delivery Reviews theme issue on bDrug Delivery Strategies to Treat Age-Related Macular

ol. 57/14, 2005.

246 6088; fax: +1 714 246 4272.

ss: Gryziewicz_Lewis@allergan.com.

. . . . . 2095

. . . . . 2096

L. Gryziewicz / Advanced Drug Delivery Reviews 57 (2005) 2092–2098 2093

3. Macugen (pegaptanib sodium) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. Future efforts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . 2097

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2097

1. Overview

In order for a drug product to be marketed in the

United States, it must be approved by the U.S. Food

and Drug Administration (FDA). The authority for the

FDA was established by the Federal Food Drug and

Cosmetic Act (FD&C Act). The Act requires FDA to

approve new drug products that are the subject of a

New Drug Application (NDA) containing adequate

data and information on the drug’s safety and sub-

stantial evidence of the product’s effectiveness.

The FD&C Act leaves it to the interpretive and

discretionary power of the FDA to determine the

legal requirement that a sponsor presents substantial

evidence of effectiveness prior to a drug’s approval.

Pharmaceutical companies work closely with the FDA

to assure that the development program they are pur-

suing will meet FDA’s expectations and criteria.

FDA has promulgated regulations based on the

FD&C Act and its amendments. These are found in

Title 21 of the Code of Federal Regulations. The

regulations establish the basic requirements for receiv-

ing approval of an NDA. Greater detail is provided in

Guidelines and Guidances that represent the FDA’s

current thinking on a given topic. Information specific

to the development of an individual new drug product

can be obtained from meetings and correspondence

with FDA [5,6].

Most drug products are not developed for a single

market such as the United States, but with the intent of

marketing the product worldwide. A difficulty for

pharmaceutical companies has been the differing

requirements from Health Authorities around the

world. In an effort to harmonize worldwide require-

ments for the approval of drug products, the Interna-

tional Conference on Harmonization was established.

The International Conference on Harmonization

(ICH) is a project involving regulatory and industry

representatives of the major pharmaceutical market-

places in the world; the European Union, Japan, and

the United States. The purpose of ICH is to make

recommendations on ways to achieve greater harmo-

nization in the interpretation and application of tech-

nical guidelines and requirements for product

registration in order to reduce or obviate the need to

duplicate the testing carried out during the research

and development of new medicines. The objective of

such harmonization is a more economical use of

human, animal and material resources, and the elim-

ination of unnecessary delay in the global development

and availability of new medicines while maintaining

safeguards on quality, safety and efficacy, and regula-

tory obligations to protect public health [7].

The ICH has published a collection of guidelines

attempting to standardize the requirements for estab-

lishing the safety, efficacy, and quality of pharmaceu-

tical products. These guidelines currently have been

adopted not only by the ICH participating countries;

the European Union, Japan, and the United States; but

also by countries that are monitoring the ICH process

including Canada and Australia.

While neither the FDA nor the European Medi-

cines Agency (EMEA) have established a formal

guidance for the development of drugs for macular

degeneration, reviewing summary documents of pro-

ducts FDA and EMEA have evaluated gives insight

into the requirements for approval for a drug to treat

macular degeneration.

2. Visudyne (verteporfin for injection)

Verteporfin therapy is a two-step process consist-

ing of drug and light treatment. The drug verteporfin

is a photosensitizer. In other words, it is a light-

activated drug. The first step is the intravenous injec-

tion of verteporfin, after which it is preferentially

retained in the proliferative new blood vessels relative

to the normal blood vessels. Verteporfin has been

shown to be retained in the choroidal neovascular

membrane. Verteporfin is inactive without light, so

the second step involves light activation of vertepor-

fin by shining nonthermal laser light at the neovas-

cular lesion via a slit lamp and a contact lens. When

L. Gryziewicz / Advanced Drug Delivery Reviews 57 (2005) 2092–20982094

verteporfin is activated by light, it reacts with oxygen

producing reactive singlet oxygen and other free radi-

cals locally. These free radicals damage the endothe-

lial cells, ultimately resulting in localized vascular

occlusion of the CNV. It is believed that this selective

damage of leaking blood vessels results in stabiliza-

tion of vision or reduction in the rate of vision

decline. So, verteporfin therapy provides a dual selec-

tivity for the choroidal neovascularization, firstly, by

its selective retention in the tissue and, secondly, by

shining the light only on the area where the treatment

effect is required [8].

The goal of drug development is to bring to mar-

ket the lowest effective dose of the drug product.

Typical drug development would include a phase 2

dose-ranging study assessing several dosage levels of

the drug in the disease. Photodynamic therapy is

composed of two therapies, the drug verteporfin and

the activation by light requiring use of a laser. Thus in

phase 2 development of verteporfin therapy there are

two variables that must be determined, the dose of the

drug and the wavelength and intensity of the light

to achieve the best efficacy at the most appropriate

dose.

This was accomplished in a multicenter, open-

label, non-controlled, dose-escalation study evaluating

the safety and dose-response characteristics of five

regimens of varying verteporfin doses and light para-

meters [9]. The study enrolled 142 patients with the

primary assessment of efficacy the extent of fluores-

cein leakage from CNV. Visual acuity was used as a

secondary assessment of efficacy, as well as for asses-

sing ocular safety. Patients underwent assessments

within 1 week before treatment and 1, 4, and 12

weeks after treatment [8].

Based on the phase I/II data, the phase III regimen

was chosen to use the minimum effective dose of both

verteporfin and light that caused complete closure of

classic CNV 1 week after treatment. The regimen was

also associated with the lowest percentage of lesions

with classic CNV progression beyond the borders of

the original lesion by 12 weeks. Also, the chosen

regimen had the most favorable mean changes in

visual acuity from baseline [8].

The main objective of the phase III program

was to determine if verteporfin therapy in patients

who have subfoveal choroidal neovascularization sec-

ondary to AMD would safely reduce the risk of

vision loss compared to a placebo given as a sham

treatment [8].

For approval, FDA suggested that a minimum of a

2-year follow-up be performed for any of the macu-

lar degeneration studies, however, they expressed a

willingness to accept results at a 1-year time point

for submission of a new drug application with the

feeling that if a visual acuity benefit was demon-

strated at 1 year, that that would be sufficient benefit

for patients and that therapy might be deemed appro-

vable at that particular point in time. Recognizing

that the disease will continue for the lifetime of the

individual patients and that additional data would be

needed, FDA requested that anyone pursuing these

indications pursue trials that went for at least 2 years

and that that information from the 2-year follow-up

and subsequent, if performed, would be included in

the labeling of the product at the time that that

information became available (p. 89). FDA also

indicated that 1-year and 2-year data are the critical

analysis timepoints. In the FDA’s experience, time to

effect is not an indicator of long term efficacy for

AMD [8].

The prospectively defined primary efficacy end-

point was the percent of responders. The responders

were defined then as the proportion of patients who

lost less than 15 letters of visual acuity on the ETDRS

chart at the month 12 examination compared to base-

line (p. 46). A loss of 15 letters can be equivalent to 3

lines on the ETDRS vision chart. A loss of 3 lines or

worse represents a clinically relevant vision change

with respect to the visual function of a patient (p. 45).

FDA indicated that an alternate method of performing

the analysis was the percentage of people with a 15

letter loss [8].

FDA approved Visudyne for the treatment of

patients with predominantly classic subfoveal choroi-

dal neovascularization due to age-related macular

degeneration, pathologic myopia or presumed ocular

histoplasmosis based on the 2-year data from 2 pivotal

phase 3 studies [9]. A total of 609 patients (VISU-

DYNE 402, placebo 207) were enrolled in these two

studies. During these studies, retreatment was allowed

every 3 months if fluorescein angiograms showed any

recurrence or persistence of leakage. The placebo

control (sham treatment) consisted of intravenous

administration of Dextrose 5% in water, followed by

light application identical to that used for VISUDYNE

L. Gryziewicz / Advanced Drug Delivery Reviews 57 (2005) 2092–2098 2095

therapy [2]. While there was a continued decrease in

visual acuity in all treatment groups over the 2-year

period, the verteporfin groups had better visual acuity

than the placebo group at all timepoints [9].

In Europe Visudyne is approved for the treatment

of patients with age-related macular degeneration with

predominantly classic subfoveal choroidal neovascu-

larization, occult subfoveal neovascularization with

evidence of recent or ongoing disease progression,

or patients with subfoveal choroidal neovasculariza-

tion secondary to pathologic myopia [10].

The different indications represent different inter-

pretations of the data by two different sets of

reviewers. The United States package insert for Visu-

dyne states that there is insufficient evidence to indi-

cate Visudyne for the treatment of predominantly

occult subfoveal choroidal neovascularization while

the European review of the same study report deter-

mined that a statistically significant result at the 2-year

time point justified the indication. FDA did not allow

the indication due to the failure to demonstrate statis-

tical significance at the 1-year time point [9,11].

FDA approved the indication for predominantly

classic subfoveal choroidal neovascularization due to

presumed ocular histoplasmosis based on a study with

a historical control. FDA reasoned that the indication

represents a relatively small addition to the patient

population with minimal risk. The EMEA did not

accept the concept of using a historical control and

classified the study as an uncontrolled study, thereby

not justifying inclusion in the label [9,11].

3. Macugen (pegaptanib sodium)

Pegaptanib is a pegylated synthetic oligonucleotide

that acts as an antagonist of vascular endothelial

growth factor isoform 165 (VEGF165), the VEGF

isoform most associated with ocular disease. Pegapta-

nib has been developed to treat the pathological chor-

oidal neovascularization associated with neovascular

AMD and prevent deterioration of visual acuity.

As the different angiographic lesion subtypes of neo-

vascular AMD (i.e., classic and occult) share common

pathophysiological features, most importantly ab-

normal neovascularization and increased vascular

permeability, the anti-angiogenic and anti-permea-

bility activity of pegaptanib would be expected to

benefit all angiographic lesion subtypes of neovascu-

lar AMD [1,4].

It is difficult to deliver an effective concentration of

a drug to the retina. Topical ocular delivery is unable

to achieve sufficient penetration to the retina. Many

diseases of the retina, such as macular degeneration,

affect an older population, making systemic delivery

of these drugs limited by tolerance to side effects.

Pegaptanib is injected into the vitreous every 6

weeks in order to deliver the drug to the site of action.

Three phase 1/2 clinical studies with pegaptanib

were without dose-limiting toxicities. Based on these

findings the drug was taken into two large phase

2/3 efficacy studies powered to detect a clinically

meaningful treatment benefit (the proportion of

patients losing less than 15 letters of visual acuity)

between active treatment and sham after 54 weeks of

treatment [4].

Patients in each study were randomized to one of

four treatment groups (0.3 mg pegaptanib, 1 mg

pegaptanib, 3 mg pegaptanib or sham injections once

every 6 weeks) and were scheduled to receive 9 intra-

vitreous or sham injections for 48 weeks with a follow-

up period to 54 weeks. At 54 weeks, patients in the

pegaptanib arms were re-randomized (1:1) to either

discontinue or continue on treatment for a further 48

weeks (8 injections) primarily to assess the safety and

need for longer term therapy [4]. In both studies, the

primary efficacy endpoint was the proportion of

Responders, defined as patients losing less than 15

letters of best-corrected VA in the study eye from

baseline up to 54 weeks, using the ETDRS chart.

Study results showed pegaptanib 0.3 mg achieved

statistical significance for a clinically meaningful pri-

mary efficacy endpoint (percent of patients losing less

than 15 letters of VA) in two replicate, well-controlled

clinical trials. Pegaptanib 1 mg also showed a statis-

tically significant treatment benefit for the primary

efficacy endpoint compared with sham in the first

study and was near to significance in the second

study. Also, patients receiving 0.3 mg or 1 mg pegap-

tanib were more likely to maintain or gain VA than

sham patients at 54 weeks in the combined analysis.

Patients receiving 0.3 mg or 1 mg pegaptanib were

also more likely to gain three lines of VA than sham

( p =0.0401 for 0.3 mg and p=0.0238 for 1 mg versus

sham for three line gain) at 54 weeks (Macugen AC p.

26). Based on this analysis the 0.3 mg dose adminis-

L. Gryziewicz / Advanced Drug Delivery Reviews 57 (2005) 2092–20982096

tered once every 6 weeks represents the lowest-effec-

tive dose [4,12].

4. Future efforts

Although many diseases of the anterior segment of

the eye can be effectively treated with topical applica-

tion of medications, it is more difficult to deliver

therapeutic levels of drugs to the back of the eye

with topical administration. Since diseases such as

macular degeneration that affect the retina affect

older patients, side effects may limit the systemic

administration of drugs.

One issue with pegaptanib is its need to be injected

intravitreally every 6 weeks. Most agree that local

drug delivery to the back of the eye is desirable for

the treatment of retinal diseases; however, the devel-

opment and regulatory approval of a medication in a

sustained-release drug delivery system present a num-

ber of challenges. At Allergan we are working on

extended release drug delivery systems that can be

injected into the eye less frequently to deliver drug to

the retina. Of note is our drug delivery system that

implants a drug delivery system in the vitreous to

slowly release drug over an extended time period;

anywhere from 1 to 12 months.

A number of the drug delivery systems deliver

medications for a very long period of time; sometimes

over a number of years. Rather than launching into

large, expensive, and resource consuming trials with

implants that deliver the drug for many years, it is

often prudent to prove that the drug is effective over a

shorter period of time. Although an implant can be

filled with drug and deliver the compound for several

years, it may make sense to start studies with implants

that last for less time. Similarly, this will also demon-

strate that the drug is active when administered to a

specific location. For example, just because a drug

works when delivered systemically does not mean that

it will work equally as well or not have additional side

effects if the drug is delivered into the vitreous, even if

similar intravitreal levels are achieved with both sys-

temic and intravitreal drug delivery.

Pharmacokinetic studies are important in the

development of local ocular drug delivery. Although

a benefit of ocular drug delivery is the ability to

achieve higher intraocular drug concentrations by

avoiding the blood–retinal and blood–aqueous bar-

riers, intraocular drug levels will vary depending on

clearance from the vitreous and whether the com-

pound concentrates in tissues like the retinal pigment

epithelium. It is also important to determine which

tissue level is most critical for the drugs activity. For

retinal diseases like macular degeneration, the drug

concentration at the retinal pigment epithelium or

choroids is important while for retinal diseases like

proliferative vitreoretinopathy, vitreous levels may be

the target. Finally, some compounds are so potent that

even small levels in the blood may lead to systemic

side effects. It is a mistake to assume that intravitreal

drug delivery completely eliminates the risk of sys-

temic adverse events.

In the development of an implantable drug delivery

system, it is critical to demonstrate consistent release

rates from the device. The FDA has stated that release

rates should be within F10%. These release rates can

be checked in vitro; however, some in vivo data

confirming the release rates are desirable, since the

human vitreous has unique characteristics that can

affect drug release from many drug delivery devices.

If one embarked on a clinical development plan,

demonstrated preclinical safety, and clinical safety

and efficacy with an implant later shown to release

drug outside of the specifications, the initial studies

could be invalid.

Combination products of a drug and a device, such

as our technology, offer special regulatory challenges

to companies. A product of this type is typically devel-

oped by a company that possesses an expertise in either

the development of drugs or devices, not both.Working

in the new area; i.e. device development for a drug

company, offers significant challenges.

A combination product can be a device that con-

tains a drug product or a drug product that relies on a

device for administration. FDA will make a determi-

nation if the product will be regulated by the Center

for Devices and Radiological Health (CDRH) or the

Center for Drug Evaluation and Research (CDER).

FDA makes this determination based on the properties

of the product. A drug that is delivered to the retina

via an implantable device would be regulated as a

drug since the intended outcome of therapy is depen-

dent on the pharmacologic action of the drug. The

implant is used solely to deliver the drug to the back

of the eye. The injector that delivers the drug delivery

L. Gryziewicz / Advanced Drug Delivery Reviews 57 (2005) 2092–2098 2097

system to the eye is also regulated by FDA as a

device.

Regulatory oversight of products that combine a

drug and a device requires coordination within the

FDA Divisions responsible for each aspect of the

product. This causes increased difficulty for the spon-

sor company in determining who is primarily respon-

sible for the review of their application. The sponsor

finds themselves in a position of encouraging the two

Center’s reviewers within FDA to communicate and

share information on their review and the status of

their review. Reviews that involve coordination

between FDA Review Divisions and reviewers who

do not usually work together can add significant time

to the FDA review and approval process. The recent

requirement for medical devices to pay user fees to

FDA in exchange for CDRH adhering to strict review

timelines may help in overcoming this issue.

FDA has established a Request for Designation

process that allows a Sponsor company to request

FDA to designate the lead Review Division for the

product early in the development process. Thereafter

communication with FDA on the product will go

primarily to the lead Center; however, it is important

to assure that reviewers from both Centers are

involved in the development process and all concerns

and comments are incorporated into the product

development strategy.

Often a device company will work closely with

CDRH staff to develop and submit a combination

device-drug product, only to find out during the appli-

cation review that upon consultation by the CDRH

reviewer with CDER, new issues are brought up that

could have been incorporated into the clinical study

design. This points out the importance of early com-

munication with all involved parties at FDA during

product development. Assuring that representatives

from both Review Divisions are present at FDA

Sponsor meetings allows for identification and discus-

sion of issues early in the process [13,14].

5. Conclusion

Age-related macular degeneration is a devastating

condition with limited treatment options for patients.

Once therapy is initiated it is continued chronically,

thus the FDA requires data from long term studies to

assess drugs for approval for this indication. Visudyne

was the first drug approved for this indication based

on a slower degradation in visual acuity at 1 and 2

years compared to placebo. Pegaptanib appears to not

only slow the progression of visual acuity deteriora-

tion, but to maintain and potentially improve visual

acuity in some patients.

The two therapies discussed were evaluated in

clinical trials in an environment where patients had

no or limited options. They were reviewed as priority

review drugs by the FDA. FDA defines priority

review drugs as those providing a significant improve-

ment compared to marketed products including non-

drug products/therapies in the treatment, diagnosis, or

prevention of a disease. Future therapies for AMD

will be required to conduct long term studies in AMD

patients who have the option of using FDA approved

therapies. It will be harder to enroll patients in trials

with experimental, unproven treatments. FDA may

also expect stronger clinical and statistical signifi-

cance from these studies in order to bring additional

products to market.

References

[1] FDA Briefing Package for August 27, 2004 FDA Advisory

Committee Meeting. Available at: http://www.fda.gov/ohrms/

dockets/ac/04/briefing/2004-4053B1_02_FDA-Backgrounder.htm.

[2] Visudyne Package Insert. Seattle, WA: QLT PhotoTherapeu-

tics, Inc., 2003.

[4] Eyetech Pharmaceuticals, Inc. Briefing Package for August 27,

2004 FDA Advisory Committee Meeting. Available at: http://

www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4053b1.htm.

[5] M. Matthieu, New Drug Development: A Regulatory Over-

view, Sixth edition, Parexel International Corporation, Wal-

tham, MA, 2000.

[6] R.A. Guarino, New Drug Approval Process, Third edition,

Marcel Dekker, Inc., New York, NY, 2000.

[7] ICH Harmonized Tripartite Guidance, Guideline for Good

Clinical Practice, E6, May 1, 1996. Available at: http://www.

ich.org/cache/compo/276-254-1.html.

[8] Visudyne Advisory Committee meeting transcript. Avail-

able at: http://www/fda.gov/ohrms/dockets/ac/cder99t.htm#

Dermatologic%20and%20Ophthalmic%20Drugs%20Advisory%

20Committee.

[9] FDA Visudyne Summary Basis of Approval. Available at:

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?

fuseaction=Search.Label_ApprovalHistory#apphist.

[10] Visudyne Summary of Product Characteristics. Available at:

http://www.emea.eu.int/humandocs/Humans/EPAR/visudyne/

visudyneM.htm.

L. Gryziewicz / Advanced Drug Delivery Reviews 57 (2005) 2092–20982098

[11] Visudyne CPMP Review. Available at: http://www.emea.eu.

int/humandocs/Humans/EPAR/visudyne/visudyneM.htm.

[12] FDA Macugen Summary Basis of Approval. Available at:

http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.

cfm?fuseaction=Search.Label_ApprovalHistory#apphist.

[13] FDA Manual of Standard Oprating Procedures and Policies,

Intercenter Consultative/Collaborative Review Process, June

18, 2004. Available at: http://www.fda.gov/oc/combination/

intercentersop.html.

[14] Assignment of Agency Component for Review of Premarket

Applications, Federal Register, Vol. 68, No. 120, June 23,

2003. Available at: http://www.fda.gov/OHRMS/DOCKETS/

98fr/03-15698.html.