Letter from Editor - tbi Trends in Bio/Pharmaceutical Industry

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w w w . s a p a - w e s t . o r g

s u m m e r 

2 - 2 0 0 6 

letter from editor /2 

regulatory affair 

strategy to register a drug Product in the us /3 

Fang Li 

Trends In 

Bio/Pharmaceutical 

Industry 

official Journal of saPa-WesT 

Table of Content 

revisions of new drug registration Procedures by sFda /6 

Liang Kong 

new Tools to Protect the consumer: dsB and drug Watch /9 

Yanning Cui 

clinical Trails 

Ich e 4: a new Global regulatory Guideline on the clinical 

evaluation of cardiac safety for new drug development Programs / 2 

Rose Gao 

understanding cdIsc Basics / 6 

Jane Ma 

drug discovery and development 

Ion channels as Targets for Treatment of Type II diabetes mellitus /2 

Xiaozhou Yao 

Trends in stability Testing With emphasis on stability during Pharmaceutical 

Product development /25 

Daniel Liu 

diagnostics 

molecular Testing: clinical diagnostics and Beyond /33 

Wei Yu 

conference report 

From Bench to market: the successes, challenges and opportunities: 

-report on 8th saPa-WesT annual conference /39 

Leping Li 

company at Focus 

Vm discovery /44 

advertisement 

acea Biosystems /43 

cPc scientific /38 

millipore corporation /20 

mPI /46 

suzhou Industrial Park /32 

Regulatory Affair 

Trends In BIo/PharmaceuTIcal IndusTry | 2-2006

Trends in Bio/Pharmaceutical Industry 

Editor Board of 

Trend in 

Bio/Pharmaceutical 


Editor in Chief 

John Wang 

Novartis, USA 

Editors 

chengjun mo 

Medimmune, USA 

daniel liu 

Johnson and Johnson, USA 

deqian Wang 

Bayer, USA 

Jinzi Wu 

Ambrilia Biopharma Inc. 

Canada 

Jun han 

Novartis, USA 

leping li 

Amgen, USA 

li shi 

Merck, USA 

naibo yang 

Molecular Devices, USA 

Pei yang 

Nektar, USA 

yingfei Wei 

Elixirin, USA 

Guest Editor 

ruifang Wu 

Chief Executive Editor 

Chinese Journal of 

New Drugs, China 

Art Director 

Xiaojun li 

CA State, USA 

TBI online 

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Contact us: 

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2 Trends In BIo/PharmaceuTIcal IndusTry | 2-2006 

Letter from Editor 

Dear TBI readers, 

Although we are living in one of the 

most technologically advanced periods in 

history, we are reminded daily about the 

major challenges facing drug development 

such as the standardization of drug clinical 

R&D, the safety of drug development and 

understanding of complicated regulatory 

affairs. 

Over this last year, resolutions on how 

cardia safety of a new drug should be 

monitored during its clinical studies were 

published by International Conference on 

Harmonization (ICH). Meanwhile US FDA, while celebrating its 100 anniversary, 

also published several new guidelines regarding the drug safety surveillance. 

These new guidelines are their response to public and congressional criticisms 

subsequent to the NSAID and antidepressant controversies. With these changes in 

places, “real time information” from drug industries may be used to identify surrogate 

endpoints and to better predict product safety. 

Additional good news on the horizon is that the development of universal standards 

for clinical trials is getting its momentum with the establishment of CDISC 

(Clinical Data Interchange Standards Consortium) after 8-year comprehension. 

CDISC is assuming a key position in a process that will be helpful to develop and 

support global, platform-independent data standards to improve medical research 

and related areas of healthcare. In this issue, author provided extensive reviews 

from different angles. 

While providing pioneer overviews on these issues, we encourage you to afford 

your opinions, comments and letters to us. Without your participation and contribution, 

the goal to make the Journal being the top of critical and initiative opinions 

would never come true. All responses can be sent to tbi@sapa-west.org. 

Enjoy your reading! 

Daniel Liu 

Editor

Strategy to Register a Drug Product in the US 

Fang li 

About Author: Fang li, Phd. rac, is 

currently a manager of regulatory affairs 

at Warner chilcott, Inc. dr. li received 

her Bs degree in chemistry from Xiamen 

university, her ms degree in chemistry 

from Wuhan university and her Phd in 

medicinal chemistry from china Pharma- 

ceutical university in nanjing, Pr china. 

Previously, dr. li worked at ortho-clini- 

cal diagnostics, a Johnson and Johnson 

company as a Principal scientist, and 

at Thyreos corporation as director of 

chemistry and manufacturing. 

Abstract 


Globalization is not a one-way street. US used to be the major 

driving force in the innovation of pharmaceuticals but many other 

countries are playing catch-up. This article is intended to describe 

the necessary regulatory hurdles that need to be cleared before one 

can introduce a pharmaceutical product into US market. 

Introduction 

You have just successfully launched your new product in your 

country and it is selling like hot cakes. Your board of directors 

asked: “Hey, why don’t we try to make some money in the US 

market?” You decided that you are going to give it a try. So where 

do you start? 

First of all, to enter the US market, your product will need to get 

the approval from the US Food and Drug Administration (FDA). 

The sponsor (your company) files a market application with FDA. 

After reviewing your application, FDA will decide whether to grant 

the product approval. Selling your product without the approval 

would make you a felony under the US Federal Food, Drug and 

Cosmetic Act. 

Identify The Application You Would Need For the 

Regulatory Approval 

The application varies depending on the product. If it is a new 

drug that never has been approved in the US, whether it is a 

new chemical entity (NCE), a new molecular entity (NME), a 

new formulation of known drug substance(s), a new route of 

administration, or a different strength to an approved drug, you 

will need to file an New Drug Application (NDA). If it is a 

“me-too” product, also known as generics, then you can file an 

Abbreviated New Drug Application (ANDA). If it is a biologics, 

you will file a Biologics License Application (BLA). 

However, for a new product that intends to file an NDA, an 

Investigational New Drug Application (IND) is usually required 

when: 

• you need additional clinical data to support your application; 

• the clinical data generated outside of the US may be 

acceptable based on pre-IND discussion with FDA before you 

run the clinical studies oversea 

There are also cases that a company decides to file an IND in order 

to conduct a study for publication to help marketing a drug. 

IND is filed to start a clinical study (trial). Clinical trials are 

generally classified into three phases that may run concurrently: 

Trends In BIo/PharmaceuTIcal IndusTry | 2-2006 3


• Phase 1 includes single-dose studies, repeat- or multipledose 

studies, which usually last no more than 28 

days. These studies assess such things as: safety and 

tolerance (maximum tolerated dose); pharmacokinetics, 

pharmacodynamics, bioavailability and bioequivalence; 

drug interaction; and food effects. These studies are 

typically conducted in 20-80 healthy subjects or patients. 

• Phase 2 involves safety and efficacy studies conducted 

with as many as 200 patients who have a targeted disease 

or condition. It usually involves dose escalation study 

and safety and efficacy study. The term “early phase 2” 

or “phase 2a” is sometimes used to refer to pilot studies, 

and “late phase 2” or “phase 2b” is used to denote 

statistically powerful, placebo-controlled trials. In some 

rare cases, FDA has agreed that the sponsor could file 

an NDA application with Phase 2b data if the drug 

product showed significant benefit in treating serious or 

life-threatening disease for which there is no treatment 

available. At the end of phase 2, there is usually a 

conference between FDA and the sponsor to discuss 

phase 3 plans. 

• Phase 3, also known as pivotal trial(s), includes controlled 

safety and efficacy trials in large numbers (up to 

thousands) of patients. Depending upon the proposed 

indication, these may be longer-term studies that 

generate the data needed for NDA approval. Phase 3b 

studies are typically comparable studies run after NDA 

has been submitted. Other studies can be performed 

during phase 3, such as: dose-response, quality-of-life, 

pharmacoeconomics, special population, concomitant 

disease and formulation and withdrawal studies. The 

results from these studies address the labeling issues for 

the package insert. These clinical studies can last 2-6 

years and cost millions of dollars. 

• Sometimes, you will also see Phase 4 studies being 

mentioned in the press releases. It is usually required 

after the product approval to study special population 

(pediatric study, geriatric study etc). In the case of 

accelerated approval, the sponsor will have the obligation 

for additional Phase 4 studies to obtain extra data on 

broad population or to collect additional safety and 

efficacy data. 

How Much Money Is Needed? How Soon Will 

The Approval Be Coming? 

Once you are ready to file an NDA, the next question you 

may ask is how much it costs for the application, and how 

long the expected review time is. To answer them, let us 

mention the Prescription Drug User Fee Act (PDUFA). 

PDUFA was passed first on 1992 to accelerate FDA review 

of drug applications in response to complaints from the 

pharmaceutical industry. It required drug and biologics 

manufacturers to pay fees for drug and biologics applications 

and supplement. The legist ration was subsequently 

reauthorized in 1997 (PDUFAII) and 2002 (PDUFAIII). 


Under PDUFA, the target review time for standard application 

is 10 months. PDUFA fee for an application with clinical 

data in 2006 was $767,400; without clinical data was $383,700. 

The establishment fee was $264,000 and the product fee was 

$42,130. However, ANDA for generic drugs is not covered 

under the PDUFA. For medical devices, Medical Device User 

Fee and Modernization Act (MDUFMA) passed on 2002 that 

enables FDA to review Premarket Approval application at 

faster pace. 

Review time clock starts after your application is accepted 

for filing by FDA. The clock usually starts 60 days after FDA 

received your complete application and finished a primary 

review to determine that your application is complete in terms 

of contents and formats required by the regulation. You 

will get an acknowledge letter from the Agency regarding the 

acceptance of your application. 10 months from the date 

FDA accepted your filing is the PDUFA action date. In recent 

years, FDA is about 90% plus on time to let the sponsor 

know on or before the action date whether the application 

is approvable or not. However, the clock can be reset if you 

submit an amendment to the application containing important 

information such as a Chemistry, Manufacturing and Controls 

(CMC) amendment, or an amendment containing clinical study 

results which requires extra review time (the extension of 

review time for a major amendment could be up to 180 days). 

There are three outcomes from the review: approved; 

approvable (extra works needed), and not approvable. An 

approvable letter usually states what needs to be done and 

FDA will discuss with the sponsor in detail for the timelines, 

the scope and the expectations. The other two outcomes are 

self-explanatory. 

In certain cases, FDA may grant a product priority review. In 

1987, FDA created an “AA” priority category to classify all 

applications for potential AIDS therapies to ensure that these 

products receive the highest priority in the review process. 

Also, under 21 CFR 314.510, FDA may approve drugs based 

on surrogate end points that will reasonably predict clinical 

benefit, or on end points other than survival or irreversible 

morbidity. This regulation results in the accelerated approval 

of products that have unmet medical needs. Usually, drugs 

fall into these categories are for serious or life-threatening 

diseases. The PDUFA goal for priority NDA review time is 6 

months (4 months after accepted for filing). 

Submission, Going Electronic Or Not 

In recent years, the Agency has updated its computer system 

to accept submission electronically. Started from last October, 

FDA requires all product package insert (labeling) be submitted 

in Structured Product Labeling (SPL) format, signaling 

the commitment from the Agency towards electronic submission. 

It is generally recognized that electronic submissions 

will increase the review efficiency. It allows the reviewers to

access the application materials easily and cuts down paperclutter 

around the agency. There was one case that a biotech 

company submitted its NDA electronically that resulted in a 

speedy product approval (approved in 6 months after it was 

accepted for filing). In the future, rolling submission of an 

NDA should speed up the review process and allow better 

communications between and sponsor and the Agency. 

If an application has been approved in Europe, the Common 

Technical Document (CTD) format used in the European 

application is accepted by FDA. Otherwise, the application 

needs to be submitted at the format deemed by the Agency. 

NDA and ANDA content and format requirements can be 

found in Code of Federal Regulations (CFR) 21 CFR Part 314 

– Applications For FDA Approval to Market A New Drug. 

Appoint A US Regulatory Agent 

A foreign company should hire a US regulatory agent to 

submit its marketing application, unless it has a US subsidiary 

to handle the US regulatory affairs issues. The regulation 

requires the agent has a US address, telephone/fax in the US 

that FDA can reach during the business hours. It is advisable 

to hire a reputable company as your US regulatory agent 

to navigate through the complicated application processes 

and to get necessary help during the negotiation during the 

product review and to communicate effectively with the 

Agency. The regulatory agent also handles submissions and 

communications after the product approval. 

Obligations After Your Product Is Approved 

Although you get the approval letter, your job is not finished. 

You still need to comply with all the regulations and laws by 

the US government to market your product in the US. For 

instance, the advertisement and promotion of the product 

needs to comply with FDA’s and Federal Trade Commission 

(FTC)’s regulations. In recent years, many warning letters 

have been sent to the sponsors that violated the regulations 

when they made unsubstantiated or biased claims on their 

advertisements or their promotion materials. It is very 

important to adhere to what you have stated in your package 

insert for your product efficacy and safety information. 

Always be careful when your sales people disseminate sales 

aids and promotional materials to make sure your claims are 

backed by clinical data. For drugs approved under accelerated 

approval, after 120 days following the market approval, 

promotional materials must be submitted at least 30 days 

prior to dissemination. For other drugs, advertising and 

promotional labeling must be filed to the NDA at the time of 

initial dissemination/publication. 

The sponsor has the obligation to maintain the application 

by reporting any post-approval changes to the product, 


which include but not limit to submission of post-marketing 

adverse experience report periodically, reporting of death 

and life-threatening events to FDA within 15-days after initial 

notification, and submission of annual reports no later than 60 

days of the anniversary of the product approval. Every two 

year (schedule allows), FDA will inspect the manufacturing 

facilities to make sure the product is made in compliance of 

current Good Manufacturing Practice (cGMP). FDA also 

may inspect your contract testing laboratories, your clinical 

study sponsors, monitors and investigator sites. When you 

file a supplement towards an approved NDA, it could also 

trigger an inspection. Any lapse of compliance could bring 

serious consequences such as loss of marketing right, product 

injunction, plant closure, product seizure etc. Therefore, 

it is very important to understand the regulations and the 

applicable law to avoid unnecessary loss. 

There are numerous reports required to keep an NDA update 

and to ensure your market product is in compliance. The 

list below summarizes what we mentioned so far to keep the 

application in compliance: 

• Annual reports 

• Adverse event reports 

• Distribution reports 

• Field alerts 

• Status reports of post-marketing studies 

• Advertising and promotional labeling 

In the case when the product is found deviating from the 

approved specifications, a recall should be initiated. The recall 

can be initiated either by the company or by FDA. After the 

recall is completed, a status report is necessary to be submitted 

to FDA. 

Conclusion 

Generally speaking, the NDA approval in the US for your new 

product is exercisable once you have a careful preparation. 

You can find more comprehensive information at www. 

fda.gov and the links to the Agency’s centers and divisions. 

You can also find useful information at www.ich.org, and in 

Federal Register. Refer to 21CFR from Federal Register for 

the regulations covering drug, biologics and medical devices. 

Another useful website is the Regulatory Affairs Professionals 

Society website, www.raps.org . 

References 

1. 2005 Fundamentals of US Regulatory Affairs, RAPS, 2005 

2. 21CFR, some relevant parts--Part 300s (Drugs, IND/ 

NDA/ANDA); Part 600 (Biologics, BLA). Part 200s, 

Drugs, Labeling, GMP 

3. www.fda.gov/cder/guidance 



Revisions of New Drug Registration Procedures by SFDA 

liang Kong 

About Author: mr. liang Kong was 

graduated from china Pharmaceuti- 

cal university (cPu) in 200 , where he 

majored in International Pharmaceuti- 

cal Trade, and received ms in pharma- 

ceutical administration later. mr. Kong 

joined nanjiing yaxing marketing re- 

search company, a company special- 

ized in pharamceutical marketing in 

200 . he then joined shanghai dazhong 

Xuchang Pharmaceutical company as 

a sales manager from 2003 to 2004. 

mr. Kong is currently working in aPeX 

International clinical reseach co. ltd 

and is in charge of clinical trials in asian 

areas. mr. Kong has published several 

articles in the journals such as , 

> 

(German), > (uK) and consulted inter- 

national pharmaceutical companies and 

provincial government on china pharma- 

ceutical market and regulations. 


Abstract 

On 28 February 2005, the new “Drug Registration Procedure” 

was approved by the directors of China’s State Food and Drug 

Administration (SFDA). It came into effect on 1 May 2005, replacing 

the previouse temporary procedure, which had been in force since 

December 2002. The revised regulation comprises 16 chapters with 

212 articles, compared with 18 chapters and 208 articles of previouse 

Procedure. In total, 21 parts of the regulation have been revised. This 

article summarised a few key revisions included in the new Procedure. 

1. Application for new indications treated as “New 

Drug” 

Under the prevouse Procedure, application for a new indication for 

an approved drug was regarded as a “complementary application”. 

However, according to the definition by the , while there is no change to the substance, adding a new 

indication does affect a drug’s status. Therefore application for 

additional indication should be treated as New Drug submissions. 

Accordingly, the approval of additional indications will be treated as 

new drug approval. The new provision on that new states: “A new drug 

application refers to the application for registration of a drug that has 

not been marketed in the PRC. A drug that has been marketed in the 

PRC but is subject to a change in dosage form, administration route 

or added indication shall be administrated as a new drug.” However, 

due to different system used to assess traditional Chinese medicines 

(TCM) as opposed to chemical drugs or biologicals, the addition of an 

indication for a TCM will still be regarded as a complementary, rather 

than new, application. 

2. Intellectual property protection strenthened 

The previouse Procedure already carried a provision on IP protection. It 

stated that “an applicant for clinical study or production (importation) 

of a new drug shall submit documents showing patent status and 

ownership for the drug or its formulation, process, etc. and a letter of 

guarantee stating that the new drug does not infringe the patent rights 

of others. If the intellectual property dispute occurs after the drug 

registration approval, the two parties shall resolve through negotiation or 

legal proceedings such as filing a lawsuit.” Although Chinese regulartory 

authority has taken great effort to reinforce the Provision, many 

complaints still submitted by multi-national pharmaceutical companies 

in the recent years. As part of effort to further strengthen intellectual 

property rights protection, the new Procedure conducted wide-ranging 

revision of the laws related to pharmaceuticals. However, more severe 

protection has been added within the new procedure: “If the intellectual 

property dispute occurs after a drug is approved, the two parties shall

esolve that dispute via negotiation, communication with the 

Patent Office or legal proceedings such as filing a lawsuit. The 

patent owner can apply to the SFDA to cancel another approval 

number provided that there is a valid judgement from patent 

office or court. And the SFDA should cancel its approval 

number if the drug is proven to have infringed the patent”. 

As a result, the revised Procedure carries a much more severe 

provision, such that the patent owner can apply to the SFDA 

to cancel another approval number provided that there is a 

valid judgement from patent office or court. And the SFDA 

should cancel its approval number if the drug is proven to have 

infringed the patent. 

2. Accepting drug registration application by 

PFDA 

The significant difference between the previous procedure and 

the current procedure is that PFDAs are now authorized to 

accept new drug registration applications. This will streamline 

the SFDA approval process and shorten the approval time for 

the applicant. The procedure for accepting applications has 

been envolved from the three types under the old procedure to 

two types in the revised Procedure. 

Previously, a new drug application was only pre-examined by 

the PFDA and then had to be accepted by SFDA. PFDA was 

not authorized to acceprt submissions. Now, applications relating 

to drug complying with domestic standards are accepted 

by the PFDA; and imported drug applications are still accepted 

by the SFDA. Under the new Procedure, Provincial offices 

will be responsible both for initial reviewing and accepting 

new drug applications. A PFDA will first examinate if the application 

is complete and complys with correct formats. It will 

then carry out an on-site inspection to check the accuracy of 

the information provided. Examination of drug registration 

standard can be launched at the same time. Once satisfied with 

the initial investigation, PFDA will submit its conclusions and 

all application dossier to SFDA, allowing SFDA to organize 

a final technical examination and make decision to whether 

approve or reject the application. Shifting responsibility for accepting 

the drug registration applications helps to simplify the 

procedure and increase efficiency. Under the new procedure, 

feedback from the PFDA should be received within 5 days of 

submission, which was very much welcomed by the pharmaceutical 

industry. 

3. Procedure for OTC drug approval specified 

The old Procedure specified a number of situations where an 

application for an OTC form could be submitted. However, there 

was no specific procedure on how to handle such applications, 

nor any definition as to what information would be required in 

each instance. The new regulation corrected that. 


As in the previous Procedure, it is possible to apply for OTC 

status at the same time for new drug application in defined 

circumstances. For example, if national standards for the production 

and/or importation of OTC drugs of the same class 

already exists and the application is for a change in dosage 

form without any accompanying change in indications, dosage 

amount, or administration route; or if the application is for a 

new combination preparation developed from active ingredients 

already designated by the SFDA as OTC. Regarding 

specific procedure for handling such applications or defined 

requirements of what the application should include, the 

revised regulations detail the process more thoroughly. 

4. More requirements for repackaging imported 

drugs 

The revised Procedure stated several requirements for applications 

to repackage imported drugs. Among them, only the first 

two were included the previous regulation. 

• an Import Drug Certificate or Pharmaceutical Product 

Certificate should be obtained for the imported drugs 

before submission of the application; 

• the drug should not yet be manufactured in China or, if 

manufactured, not able to meet the clinical demand; 

• the drug of one pharmaceutical company shall only be 

repackaged for a period not exceeding the validity of 

the Import Drug Certificate or Pharmaceutical Product 

Certificate. 

• with the exception of tablet and capsule presentations, all 

roducts should be imported in their finished form and 

definitive inner packaging. 

• the domestic pharmaceutical production enterprise 

should hold a Drug Manufacturing Licence. If the tablet 

or capsule is to be repackaged in China, the drug must 

be within the production scope described in the Drug 

Manufacturing Licence and Good Manufacturing Practice 

(GMP) certificate. 

• any application to repackage an imported drug should be 

made one year prior to expiration of the Import Drug 

Certificate or Pharmaceutical Product Certificate. 

5. Supplemental application approved by PFDA 

The previouse Procedure stipulated that for a supplemental 

application relating to a change of enterprise name, the 

amendment of drug packaging and label as required by regulation, 

or the amendment of the insert sheet required by the 

SFDA, the application should be accepted and approved by 

the PFDA, and the SFDA and applicant notified. When there 

is no objection within 20 days after the SFDA receives the 



documents, the PFDA can inform the applicant to conduct 

the complementary application. With the latest revision, the 

process has been further simplified. The application will be 

accepted and approved by the PFDA. If the PFDA considers 

all the requirements to be met, approval of the Supplemental 

Drug Application will be issued and filed with the SFDA for 

record purposes only. If the requirements are not met, a Notification 

of Approval Opinion will be issued with explanation 

and recommendations of further action. 

6. Other Changes 

There are also some other revisions in the new Procedure. Fro 

example, Accelerated Approval process can now be applied 

to those drugs which address a defined public health need, as 

defined under the Chinese Emerging Public Health Regulation. 

Also the timeline for approval is much more specified than 

before. Under the new regulation, the approval authority must 

inform the pharmaceutical company whether its registration 

dossier is to be accepted within 5 working days of submission. 

The deadline for delivery of the approval letter has also been 

shortened to 10 days. In addition, as contract manufacturing 

comes under the jurisdiction of the Chinese Pharmaceutical 

Manufacturing Administration Procedure, related articles in 

the previouse procedure have been deleted from the new drug 

registration procedure to avoid the repetition and potential 

confusion. 

References 

1. China Drug Registration Procedure (temorary), issued on 

Oct 30, 2002 

2. China Drug Administration Law, issued Feb 28, 2001 

3. China Drug Registration Procedure, revised on Feb 28, 

2005 

8 Trends In BIo/PharmaceuTIcal IndusTry | 2-2006

New Tools to Protect the Consumer: DSB and Drug Watch 

yanning cui 

About author: yanning cui gradu- 

ated as an m.d. and received a 

master’s degree from Beijing’s 

capital university of medical sci- 

ence. she received postdoctoral 

training in new york medical col- 

lege and was a research fellow at 

harvard medical school for three 

years specializing in the cardiovas- 

cular system. she currently works 

at Pfizer, Inc. as a scientist. 

Abstract 


While celebrating its 100 anniversary, US FDA published several 

new guidelines regarding the drug safety surveillance. These new 

guidelines are results of FDA to response regulatory issues and 

public and congressional criticisms subsequent to the NSAID and 

antidepressant controversies. This paper overviews these FDA new 

tools that might impact the marketing efforts of pharmaceutical 

industry. 

The United States FDA (Food and Drug Administration) was created 

to enforce the first law in food and drug administration--the Pure 

Food and Drug Act of 1906. 1 2006 marks the 100th anniversary of 

the 1906 Food and Drug Act, and consequently the USFDA. To 

celebrate the centennial of this milestone event, the FDA has recently 

published a book titled, FDA: A Century of Consumer Protection. 2 

For a hundred years, the FDA passed legislative acts to the end 

of protecting consumers in food and pharmaceutical products 

consumption. However, in 2005 several high-profile controversies 

emerged over the FDA’s handling of drug safety issues, in particular 

discoveries that antidepressants may lead to suicidality in children 

and patients on COX-2 class nonsteroidal anti-inflammatory drugs 

(NSAIDS) faced higher risks or heart attack or stroke. In both 

cases, the FDA was slow to act and ignored or suppressed research 

results from its own reviewers in the Office of Drug Safety. In 

light of such controversies, the FDA announced in February 2005 

the establishment of an independent Drug Safety Oversight Board 

(DSB). The Board will be responsible for overseeing drug safety 

policies, resolving internal disputes regarding drug risks, and content 

approval for a new government website on drug safety information— 

Drug Watch. In addition, through the DSB the FDA created three 

new channels for communicating drug safety information to the 

general public: the Drug Watch website, Healthcare Professional 

Information Sheets, and Patient Information Sheets. 3 

To better understand the revised FDA regulatory framework in light 

of the 2005 controversies, main themes regarding FDA’s history and 

role, as well as recent drug safety developments in relation to the FDA 

are outlined below. 

Consumer Protection Through Standardizing 

Pharmaceuticals—the Federal Food and Drugs Act of 

1906 

The Federal Food and Drugs Act of 1906 prohibited the interstate 

transport of unlawful food and drugs under penalty of seizure of 

the questionable products and/or prosecution of responsible parties. 

The basis of the law rested on the product labeling regulation rather 



than pre-market approval. Drugs, defined in accordance with 

the standards of strength, quality, and purity in the United 

States Pharmacopoeia and the National Formulary, could not 

be sold in any other condition unless the specific variations 

from the applicable standards were plainly stated on the label. 

Foods were not defined according to analogous standards, 

but the law prohibited the addition of any ingredients that 

would substitute for the food, conceal damage, pose a health 

hazard, or constitute a filthy or decomposed substance. 

Interpretations of the food provisions in the law led to many 

court battles. If the manufacturer opted to list the weight or 

measure of a food, this had to be done accurately. Also, the 

food or drug label could not be false or misleading in any way, 

and the presence and amount of eleven dangerous ingredients, 

including alcohol, heroin, and cocaine, were required to be 

listed. 

COX-2 Selective (includes Bextra, Celebrex, and 

Vioxx) and Non-Selective Non-Steroidal Anti- 

Inflammatory Drugs (NSAIDs) 

Vioxx® is a non-steroidal anti-inflammatory drug prescribed 

for arthritis and menstrual cramps. Vioxx® was approved by 

the FDA in 1999. In September 2004, Vioxx manufacturer 

Merck announced the voluntary worldwide withdrawal of 

Vioxx®, after the drug was found to be linked to increased 

risk of heart attack and stroke among its users. More than 

10,000 lawsuits have been initiated against Merck regarding 

these serious side effects. 

In 2005, FDA issued supplemental request letters to sponsors 

of all non-steroidal anti-inflammatory drugs (NSAID) 

requesting labeling changes to their products. 4 

DSB 

The Drug Safety Oversight Board (DSB) is chaired by the 

Deputy Director of the Center for Drug Evaluation and 

Research (CDER) and is comprised of five members in 

total. DSB provides “independent oversight and advice to 

the CDER Director on the management of important drug 

safety issues and to manage the dissemination of certain 

safety information through FDA’s Web site to health care 

professionals and patients.” 5 

The DSB’s responsibilities include the following: 

• Identify, track, and oversee the management of important 

drug safety issues; 

• Adjudicate disputes among organizations concerning the 

management of drug safety issues; 


• Establish policies regarding the management of drug 

safety issues with CDER; 

• Select drugs to be placed on and removed from Drug 

Watch and update their status; 

• Track important emerging safety issues and ensure they are 

resolved in a timely manner; and 

• Ensure that CDER decisions about a drug’s safety benefit 

from the input and perspective of experts within and 

outside the FDA who have not conducted the primary 

review or served as a deciding official in the ongoing 

premarket evaluation or post market surveillance activities 

with respect to that drug. 6 

The Drug Watch Website 

In May 2005, the FDA issued a draft guidance outline of 

its proposed Drug Watch website for public comment. The 

website is not yet available; through the draft guidance the 

FDA hopes to solicit public input before implementing the 

website. Under the proposal, the DSB would serve as a 

new communication channel from the FDA to the public, 

identifying emerging safety signals under evaluation by the 

FDA before the agency has “fully determined its significance 

or taken final regulatory action.” 7 The objective behind 

Drug Watch is to “alert patients and healthcare providers 

of potential safety risks when the FDA is still evaluating the 

strength of the relationship between the drug and the adverse 

event”. 8 

Information in Drug Watch website would contain factual 

information about new potential side effects and/or risks 

that could be avoided by selecting patients appropriately, 

monitoring patients adequately, avoiding drug-drug 

interactions, or preventing medication errors. There would 

also be links to helpful patient information sheets and 

healthcare professional sheets containing emerging safety 

information and information in formats designed specifically 

for healthcare professionals and consumers. Under the FDA’s 

proposal, the Agency would conduct a preliminary review of 

the emerging information to determine which newly reported 

safety information warrants public dissemination while the 

FDA continues to scientifically evaluate the significance of 

the new data. The FDA would work as quickly as possible to 

resolve safety issues identified with drugs listed on the Drug 

Watch Web page. The FDA would also post information about 

the status of its analyses of emerging safety information. 

Conclusion 

In summary, the FDA took significant steps in 2005 to 

respond to regulatory issues and public and congressional

criticisms subsequent to the NSAID and antidepressant 

controversies. In 1993, the FDA initiated a new medical 

products reporting program, “MedWatch.” The Med Watch 

program makes it easy for healthcare professionals to report 

serious adverse events to the FDA. Once the proposed 

Drug Watch website is fully implemented, information 

from Drug Watch will link to MedWatch directly through email 

notifications to the MedWatch mailing list and the 160 

organizations that work with the FDA as MedWatch partners. 

Such information linkage between Drug Watch and MedWatch 

will serve to lever age and amplify the timely dissemination of 

drug safety data. 

References 

1. Adams, D.G.; Cooper, R. M., Kahan, J.S. Fundamentals of 

Law and Regulation Volume II 14-17. (1997) 

2. http://www.fdli.org/pubs/centennial/ 

3. New Release, Dep’t of Health and Human Services 

(HHS), Reforms Will Improve Oversight and Openness 

at FDA (Feb.15, 2005), available at: http://www.hhs.gov/ 

news/press/2005press 

4. http://www.fda.gov/cder/drug/infopage/cox2/ 

5. CDER manual of Policies and Procedures ch. 4151-3 

(May 5, 2005). 

6. McGrath W.: FDA’s New Drug Safety Initiative: One 

Year Later Update-Food and drug law, Regulation, and 

Education; January/February 4-7, 2006 

7. FDA Drug Watch Guidance, supra note 6, at 2. 

8. FDA Statement, FDA Acts to strengthen the Safety 

program for Marketed drugs (Nov. 5, 2004), available 

at http://www.fda.gov/bbs/topics/news/2004/ 

NEW01121.html 




Understanding CDISC Basics 

Jane ma 

About Author: Jane ma holds ms of 

health Informatics from university of min- 

nesota. she has 3 years software indus- 

try and 4 years pharmaceutical industry 

experience. she has been working as a 

clinical database analyst. 


Abstract 

Data standards can make data and its associated program more 

portable. The CDISC (Clinical Data Interchange Standards 

Consortium) is a standard for collection, analysis and submission 

of clinical data to regulatory authority in support of marketing 

applications. This paper presents an overview of the CDISC basics 

and the associated contexts, including ODM, SDTM, LAB and AdaM. 

Included will be the evolution of the standard, the current status, and 

strategic reasons to considering implementation of the CDISC. 

CDISC Overview 

It is widely recognized that standards improve process efficiency, 

regardless of the industry. Currently, clinical investigators, clinical 

study personnel, data managers and FDA reviewers must cope with a 

plethora of data formats and conventions. Some clinical investigators 

report the presence of many different computer systems for data 

entry at their sites for various trials, each of which uses different data 

conventions. Obviously, lack of standardization is not only inefficient 

and unnecessary expensive in the clinical trial data collection, analysis 

and submission; it multiplies the potential for error. Standardization 

of the look and feel of the data collection could reduce these 

inefficiencies and also help accelerate progress toward electronic data 

capture and submission. Therefore, the establishment of CDISC will 

be helpful to develop and support global, platform-independent data 

standards that enable information system interoperability to improve 

medical research and related areas of healthcare. 1 

CDISC plays a major role in today’s international clinical research data 

standards. It has been committed to the development of industry 

standards to support the processing of clinical trials data over the past 

8 years. Figure 1 shows the standardization of global clinical research 

model which was set up by ICH guideline. 

There are actually four CDISC models, each intended for different 

purposes and addressing different categories of data 1 . These models 

have recently been acknowledged by the FDA. Also, many companies 

are reengineering their internal processes to adopt them. 

Components of CDISC 

• Operational Data Model (ODM) 

The Operational Data Model (ODM) is designed first to enable archiving 

and reconstitution of clinical trial data and second to help transfer clinical 

trial data between sponsors and CROs. It is also possible to use ODM to 

exchange data between applicants and authority. This provides a format 

for representing the study metadata, study data and administrative data 

associated with a clinical trial. It represents only the data that would


between raw data and derived data. STDM covers delivering 

the raw clinical data to regulatory authorities for browing. 

ADaM is about delivering results from statistical analysis to 

the authorities. In the other words, ADaM is to not deliver 

analysis datasets per se to the authorities, but to deliver 

descriptions of the standard analysis methods used and allow 

the authorities to re-create the analysis based on data received 

via SDTM. 

Figure 2 shows how the CDISC standards relate in clinical 

trials. 

ePRO 

Lab 

ODM 

Lab 

Clinical 

Data 

Archive 

Figure 2. relationship of cdIsc components 

The most important of other new standards are currently 

being published for review or are being developed are: 

• The CRT-DDS (better known as define.xml) is a 

standard for providing data descriptions for Case Report 

Tabulations in an XML format for submission to a 

regulatory authority such as the U.S. Food and Drug 

Administration (FDA). The promise of this standard 

is that submissions done using the CRT-DDS can be 

processed considerable faster by the regulatory authorities. 

• The Protocol standard is in early development. It will 

however become an important standard as it will enable 

to describe a full clinical research protocol in machinereadable 

format. This will allow for automation of a 

number of now cumbersome tasks, like automated 

database setup, computer-based workflows, creation of 

dynamic eCRFs, etc. 

Table 1 summarizes the type of data each standard is intended 

to help transmit during the clinical research. While ODM is 

designed to help transfer CRF and audit trail data, it can also 


ODM 

Operational 

Clinical Data 

Sponsor 

SAS 

ODM 

SDM 

ADaM 

Operational 

clinical 

Data 

CRO 

Regulatory 

Authority 

be used to exchange data between IVRS and e-diary products 

and EDC solutions. 

DATA Coverage by CDISC Standard 

Data Type ODM LAB SDTM ADaM 

CRF x x x+ 

Audit x 

ePRO x- 

LAB x 

From the table, we can see that SDTM does not cover 

audit trail data, which is designed to transmit patient data to 

reviewers at the FDA for ad hoc analysis (e.g., identifying 

unexpected trends). ADaM is shown as containing more 

than the data included in CRFs, which is designed to transmit 

derived variables and descriptions of the programmed SAS 

analysis. 

Evolution of the CDISC 

Since its inception in the US in 1997, CDISC gained 

international traction and popularity. This is reflected in the 

mission statement:“Clinical Data Interchange Standards 

Consortium (CDISC) is an open, multidisciplinary, non-profit 

organization that has established worldwide industry standards 

to support the electronic acquisition, exchange, submission 

and archiving of clinical trials data and metadata for medical 

and biopharmaceutical product development.” 

1997 – Started as ‘grass roots’ group with 25 attendees at first 

meeting 3 

1998 – Invited to form DIA SIAC 3 

2000 – Independent, board-governed, non-profit 

organization. 3 

2001 – Joined as HL-7 associate 3 

2002 – First introduction in Japan 

2002 – EU representative added to CDISC board 

2004 – First Annual CDISC European Interchange 

Current Impacts of CDISC 

CDISC standards have a large impact on the clinical development 

process. Data standards are a critical component in the quest to 

improve global public health. CDISC provides more efficient 

and effective use of medical information by all members of the 

healthcare and life sciences ecosystem. 

Before CDSIC era, in the absence of industry standards, 

each biopharmaceutical company and CRO has developed 

their own. This has led to a plethora of standards within

the industry. In the absence of standards, each sponsor and 

project pair can require custom interface (Fig 3). 

In CDISC era, it is possible to collect, process, and analyze patient 

and health related information quickly, more cost- effectively 

and with greater accuracy under a standard. Each sponsor or 

project only needs to support one import format for clinical data. 

Conversely, each vendor can only develop one export format that 

can be used by all sponsors and projects. This example, finally, 

illustrates the value of most data exchange standards – reduce 

the effort to transfer data by agreeing on a common transfer 

format (Fig 4). 

diagram 3: Before cdIsc – In the absence of 

standard 2 

Biotech 

Pharma 1 

Pharma 2 Investigator 1 

Investigator 1 

Pharma N 

Investigator K 

Lab 1 

Lab 2 

CRO 1 

CRO 2 LAB L 

CRO M 

Labs 

Pharma 

CDISC 

Daat 

Standards 

CROs 

Tech / Software 

Regulatory Patients 

Regu latory 

Other Vendors 

diagram 4: after cdIsc – one standard for all 4 

Thus, CDISC improves the cost and quality of healthcare delivery 

for patients and consumers. In the other words, establishment of 

data standards and application of the standards across all studies 

and projects can be resource intensive. One of the key benefits to 

Clinical trails 

implement the standards is that the programs associated with this 

data become more portable. They can be moved from one study 

to the next with minor modifications. Not only are the programs 

more portable, the programmer and statistician working on 

one study can understand a new study with the same structure 

relatively quickly compared to learning a new set of programs, 

macro and data structures. The productivity gain is sometimes 

difficult to measure but, in the long run, it will outweigh the 

efforts invested in standardizing. 

Conclusion 

Based on the facts above, it can be concluded that CDISC 

implementation can cause: 

• Harmonization with HL-7 in the standard for data 

submission, including CRT datasets, analysis datasets and 

programs, and metadata. 

• Exchange of all clinical trial data between any two parties 

will be achieved by the application of the appropriate 

CDISC data models and standards. 2 

• Generation of a document that would benefit industry 

and FDA by providing recommendations for the use 

of CDISC standards with associated processes that can 

promote the enhanced use of electronic source data 

interchange within the context of the existing regulations 

for regulated clinical research. 

Since becoming the standard for collection, analysis and 

submission of clinical and preclinical trial data to the 

authorities in marketing application, the CDISC will become a 

tool to be used by the industries for their upstream processing 

to support Clinical Study Reports and Integrated Summaries. 

References 

1. http://www.cdisc.org 

2. Wayne R. Kubick; http://www.cdisc.org/pdf/CDIS- 

CBio0103x.pdf 

3. Wayne R. Kubick; www.lincolntechnologies.com/ 

Presentations/BarnettERSX.pdf 

4. Robert Weber; www.hl7.de/veranstaltungen/kongress/ 

xmlworkshop062002/Weber.PDF 


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Ion Channels as Targets for Treatment of Type II Diabetes Mellitus 

Xiaozhou yao 

About author: dr. Xiaozhou yao is a 

research Investigator at Galxosmith- 

Kline. his current focus is metabolic drug 

discovery specialized in ion channels 

and transporters. he received m.d. for 

northchina coal medical college, m.s. in 

cardiology from Tongji medical univer- 

sity and Ph.d. in electrophysiology from 

university of heidelberg, Germany. he 

completed his postdoctoral training at 

university of Texas medical Branch at 

Galveston. 

Abstract 

Ion channels have been successful targets for intervention of 

therapeutic agents for decades. As an example, the modulators of 

a particular potassium channel, ATP-sensitive potassium channel 

(KATP), have been the mainstay of oral treatment for type II 

diabetes mellitus. Increasing evidence has demonstrated that 

modulation of some of the voltage-gated potassium channels 

and the voltage-gated calcium channels may yield anti-diabetic 

indications. In recent years, the knowledge into ion channel 

structures and the technologies for ion channel functional 

screening have been significantly improved which provides us 

exciting opportunities of finding novel ion channel targets. In this 

review, the author has summarized the existing anti-diabetic ion 

channel targets, and the recent findings that support other ion 

channels as potential therapeutic targets for treatment of type II 

diabetes mellitus. 

Introduction 

Drug Discovery And Development 

Type II diabetes mellitus (previously called noninsulin-dependent 

diabetes) is widespread throughout Western society. It affects 

approximately 15 million people in the United States and 

accounts for about one sixth of all expenditures for health 

care. The mortality rate in patients with diabetes may be up to 

11 times higher than in persons without the disease (1) . From 

pathphysiological standpoint, type II diabetes mellitus causes 

abnormal carbohydrate, lipid and protein metabolism associated 

with insulin resistance and impaired insulin secretion. It usually 

begins as insulin resistance, a disorder in which the cells do not 

use insulin properly. As the need for insulin rises, the pancreas 

gradually loses its ability to produce it. Insulin resistance is a major 

contributor to progression of the disease and to complications 

of diabetes. Type II diabetes is a chronic, progressive disease that 

cannot be cured now. However, it can be treated using the nonpharmacological 

approaches including diet modification, weight 

control and regular exercise, and pharmacological approaches 

when the blood glucose levels can not be controlled with diet 

and exercise. There are five classes of diabetes medicines used 

in the United States: sulfonylureas, meglitinides, biguanides, 

thiazolidinediones, and α-glucosidase inhibitors which work 

in different ways to lower blood glucose levels via one of the 

following mechanisms: increase of insulin secretion, decrease of 

glucose absorption, improvement of insulin sensitivity or increase 

glucose clearance via kidneys. The blockade agents of KATP, 

for example, are mediated with increase of insulin secretion. 

The physiological importance of KATP channels in insulin 

secretion was established more than 20 years ago (2) . Many the 



anti-hyperglycemic agents, such as sulfonylureas, repaglinide, 

nateglinide are the modulators of KATP channels. Since 

last five years, increasing findings have demonstrated that 

modulation of other ion channels such as voltage-gated 

potassium (Kv) channels including Kv1.3, Kv1.4, Kv2.1, and 

voltage-gated calcium channels including Ca2.2 and L-type 

Ca channel showed antidiabetic indications which may lead 

to discovery of novel pharmacologic agents to treat type II 

diabetes mellitus. 

1. ATP-sensitive potassium (KATP) channels 

The KATP channel is a hetero-octamer consisting of 4 

subunits of sulfonylurea receptor (SUR) and 4 subunits of 

channel protein (Kir6). Kir6 is a member of the Kir channel 

family. SUR has three transmembrane domains (TMD0, 

TMD1, TMD2), and TMD2 is a member of the ATP-binding 

cassette (ABC) protein family. In the pancreatic β-cells, the 

KATP channels play an essential role in coupling membrane 

excitability with glucose-stimulated insulin secretion (3, 4) . 

As illustrated in Figure 1, 

K ATP Dependent Glucse -stimulated 

lnsulin Secretion 

G l u c s e 

K ATP/ADP 

APT blockers 

_ _ 

Kv blockers _ 

Kv channels 

K ATP channels 

Membrane depolarization 

Repolarization 

lnsulin secretion 

VGCa 2+ channels 

_ 

+ 

[ Ca2+]i 

increase of circulating glucose leads to increase of intracellular 

[ATP]/[ADP] ratio, producing changes in cytosolic nucleotide 

concentrations that cause KATP channel closure resulting 

in membrane depolarization. Consequent activation of 

voltage-dependent Ca2+ channels causes Ca2+ influx and a 

rise in [Ca2+]i, which triggers insulin release. Conversely, a 

decrease in the metabolic signal is to open KATP channels 

and suppress the electrical trigger of insulin secretion. Many 

currently marketed therapeutic agents, such as sulfonylureas, 

nateglinide and repaglinide promote insulin secretion by 

binding to the regulatory sulfonylurea receptor subunit (SUR1 

or SUR2) and inhibiting KATP channel currents (5) . Some 

other drugs act as potent stimulators of insulin secretion from 

direct closure of KATP channels mediated via Kir6.2 subunit (6, 7) . 


+ 

+ + 

_ 

+ 

There has been increasing evidence that excessive insulin 

release might be closely associated with development of type 

II diabetes, and relative insulin hypersecretion causes the β cell 

to become exhausted resulting in a reduced ability to respond 

to glucose stimuli and subsequent degeneration. Reduction of 

insulin secretion improves β cell function. (8) . Thus, inhibition 

of insulin secretion via activation of KATP channels has 

become a new approach for the treatment and prevention 

of type II diabetes. Although the relationship between 

hyperinsulinemia has been known for decades, only a few 

inhibitors of insulin release have been characterized in vitro 

and in vivo. KATP openers, such as diazoxide and NN414 

have been shown to protect β cells and preserve function of 

islets (9, 10, 11) 

2. Voltage-gated potassium (Kv) channels 

Kv channels belong to the six-transmembrane family of 

K+ channels consisting of Kv1 to Kv11 subfamilies (12) 

and regulate cell membrane potential by controlling the rate 

of K+ exit from the cell. Kv channel was found to be the 

dominant Kv current of β-cells (13) . Inhibition of the β-cell Kv 

current prolongs the action potentials, sustains the opening 

of voltage-dependent Ca2+ channels, and thereby enhances 

glucose-induced insulin release. Such a therapeutic strategy 

would be expected to pose a lower risk for hypoglycemic 

events comparison with sulphonylurea KATP channel 

blockers. Thus, the β cell Kv channel has attracted much 

attention as a potential therapeutic target for treatment of type 

II diabetes (14, 15) . 

2.1. Kv1.3 

Kv1.3 is expressed in a number of insulin sensitive tissues, 

including fat and skeletal muscle. Gene inactivation or 

pharmacological inhibition of Kv1.3 increases peripheral 

glucose homeostasis and insulin sensitivity by stimulating 

glucose uptake in adipose tissue and skeletal muscle (16) . The 

mechanism of this indication is thought that inhibition of 

Kv1.3 facilitates the translocation of the glucose transporter, 

GLUT4 to the plasma membrane which increases the amount 

of GLUT4 at the plasma membrane. It is well known that 

GLUT4 is the major insulin-responsive transporter that 

is predominantly restricted to adipose and skeletal muscle 

tissues. Insulin-stimulated glucose uptake in adipocytes and 

muscle is mediated with rapid movement of GLUT4 from 

intracellular storage sites to the plasma membrane (17) . In 

addition, studies have confirmed that mutations in the Kv1.3 

gene exist in humans which are associated with alterations of 

glucose homeostasis. Five single-nucleotide polymorphisms 

in the promoter region (T-548C, G-697T, A-845G, T-1645C, 

and G-2069A) were identified with allelic frequencies of

the minor allele of 26, 23, 9, 41, and 16%. A variant in the 

promoter of the Kv1.3 gene is associated with impaired 

glucose tolerance and lower insulin sensitivity (18) . Therefore, 

Kv1.3 is a promising target for the development of drugs 

for the improvement of insulin resistance that is a major 

contributor to progression of the disease and to complications 

of diabetes. 

2.2. Kv1.4 

A recent study has identified a link between Kv1.4 and GIP 

(glucose-dependent insulinotropic polypeptide). GIP is one of 

the major intestinal hormones involved in the stimulation of 

insulin secretion during a meal (19, 20) . GIP reduces A-type peak 

current amplitude of Kv1.4 via activation of protein kinase 

A (PKA). Using mutants of Kv1.4 with Ala-Ser/Thr substitutions 

in a potential PKA phosphorylation site, C-terminal 

phosphorylation was shown to be linked to GIP-mediated 

current amplitude decreases. GIP treatment results in similar 

decreases in A-type potassium current peak amplitude to those 

in HEK293 cells expressing Kv1.4 (20) . These results strongly 

support an important novel role for GIP in regulating Kv1.4 

cell surface expression and modulation of A-type potassium 

currents, which is likely to be critically important for its insulinotropic 

action. Therefore, Kv1.4 channel could represent a 

candidate gene as a therapeutic target for type II diabetes. 

2.3. Kv2.1 

It has been found that Kv2.1 forms the predominant component 

of repolarizing currents in mouse and human β cells. 

Dominant-negative “knockout” of Kv2.1 in islet decreases 

Kv2.1 current by 60-70%. Hanatoxin (HaTx), a specific 

Kv2.1 blocker (0.1 uM), inhibits total Kv currents by 65% 

in human islet (21, 22). Inhibition of Kv2.1 enhances first- and 

second-phase insulin secretion from perfused mouse pancreas. 

Hanatoxin induces slow intracellular Ca2+ concentration 

oscillations in human and mouse cells stimulated with glucose. 

A novel inhibitor of Kv2.1/Kv2.2 channels, guangxitoxin -1 

broadens the β cell action potential, enhances glucose-stimulated 

intracellular calcium oscillations, and enhances insulin 

secretion from mouse pancreatic islets in a glucose-dependent 

manner (23) . These data supports a mechanism for specific 

enhancement of glucose-dependent insulin secretion by Kv2.1 

blockers, which may provide a new opportunity for the treatment 

of type II diabetes. 

3. Voltage-gated calcium (Cav) channels 

Structurally, Cav channels are composed of at least three 

subunits, the α1, α2-δ, and β subunits. The α1-subunit is a 

pore-forming component, and is capable of generating Ca2+ 

Drug Discovery And Development 

channel activity (24) . Molecular cloning studies have revealed 

that CaV1.1, CaV1.2, CaV1.3, CaV2.1, CaV2.2, and CaV2.3 

genes encode the α1 subunits of L-, P/Q-, N-, R-, and T-type 

Ca2+ currents, respectively (25, 26, 27, 24) . As shown in Fig.1, Cav 

channels play crucial roles in stimulus-secretion coupling in 

pancreatic β cells. 

3.1. L-type Cav channels 

In the voltage-gated L type Ca2+ channel, β subunit is 

believed to play a key role in the assembly/expression of the 

channel complex and modulate Ca2+ currents through α1 

subunits (28, 29, 30) . It has been well documented that inhibition 

of L-type Cav channels reduces insulin secretion (31, 32, 33) . But, 

surprisingly, knock-out of L-type Cav channel β3 subunit 

showed an increase of glucose-stimulated insulin secretion. 

The β3 subunit knock-out mice appeared having a more 

efficient glucose homeostasis compared to wild-type mice (34) . 

The mechanism is thought that removal of Ca2+ channel β3 

subunit enhances Ca2+ oscillation frequency via a modulation 

of InsP3-induced Ca2+release. It is known that an oscillatory 

increase of free Ca2+ concentration [Ca2+]i in pancreatic β 

cell, , is a key feature in glucose-induced insulin release (34) . 

Since the increase in insulin release was manifested only at 

high glucose concentrations, blocking the β3 subunit in the 

beta cell may constitute the basis for a novel diabetes therapy. 

3.2. N-type Cav channels 

The voltage-gated N-type Ca2+ channel is localized in the 

plasma membrane of insulin-releasing β cells and glucagonreleasing 

α cells in the pancreatic islets. Electrophysiological 

and pharmacological studies have shown that glucagon 

secretion from α cells in the islets is a Ca2+-dependent 

process, and a N-type Ca2+channel blocker partially blocks 

the Ca2+ influx in alpha cells (35, 36) . Glucogan, a 29-aminoacid 

hormone activates the glycogenolytic and gluconeogenic 

pathways, thereby increasing hepatic glucose production. The 

actions of insulin and glucagon are thought to be essential in 

maintaining fasting and postprandial glucose homeostasis. The 

N-type Cav knock-out mice showed lower plasma glucagon 

and a higher glucose clearance rate in glucose tolerance test. 

These results suggested that N-type Cav channels play a role 

in glucagon release (37) . Thus, N-type Cav channel blockers 

might be candidate antidiabetic agents that could treat type II 

diabetic patients via decrease of glucose production. 

Summary 

Targeting ion channels has been a major approach for the 

treatment of type II diabetes. Blockers of KATP channels 

remain the main agents used to treat type II diabetic patients. 



Opening of KATP channels has been recognized as a 

new approach to preserve β cells in the islets. Blockers of 

Kv1.3, Kv1.4 and Kv2.1, N-type Cav channels and L-type 

Cav β subunit could become promising opportunity for the 

treatment of type-II diabetes in the future. Growing knowlage 

of ion channel structures and improvement of functional 

electrophysiological screening technologies will facilitate drug 

discovery in ion channels. 

References 

1. Diabetes statistics. Bethesda, MD.: U.S. Dept. of Health 

and Human Services, Public Health Service, National 

Institutes of Health, NIDDK, 1995; NIH publication no. 

96-3926 

2. Ashcroft FM, Harrison DE, Ashcroft SJ. Nature 

1984;312:446– 448. 

3. Bryan J, Vila-Carriles, WH, Zhao G, Babenko, AP, Aguilar- 

Bryan L. Diabetes 2004;53(Suppl. 3), S104–S112. 

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5. Aguilar-Bryan L, Bryan J. Endocr Rev 1999;20:101–135. 

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7. Proks P, Treinies I, Mest H, Trapp S. Eur J Pharmacol 

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9. Maedler K, Storling J, Sturis J, Zuellig RA, Spinas GA, 

Arkhammar PO, Mandrup-Poulsen T, Donath MY. 

Diabetes 2004;53:1706-13. 

10. Bjorklund A, Bondo Hansen J, Falkmer S, Grill V. 

Diabetologia 2004;47:885-91. 

11. Ritzel RA, Hansen JB, Veldhuis JD, Butler PC. J Clin 

Endocrinol Metab. 2004;89:795-805. 

12. Ottschytsch N, Raes A, Van Hoorick D, Snyders DJ. Proc. 

Natl. Acad. Sci. U. S. A. 2002;99:7986–7991 

13. MacDonald PE, Ha XF, Wang J, Smukler SR, Sun AM, 

Gaisano HY, Salapatek AM, Backx PH, Wheeler MB. 

Molecular Endocrinology 2001;15:1423–1435. 

14. Roe MW, Worley JF 3rd, Mittal AA, Kuznetsov A, 

DasGupta S, Mertz RJ, Witherspoon SM 3rd, Blair N, 

Lancaster ME, McIntyre MS, Shehee WR, Dukes ID, 

Philipson LH. J Biol Chem. 1996;271:32241-6. 

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Molecular Testing: Clinical Diagnostics and Beyond 

Wei yu, Ph.d. 

About Author: dr. Wei yu received B.s. 

from Fudan university, shanghai, china, 

before his graduate studies at shanghai 

Institute of Biochemistry, chinese 

academy of sciences. he obtained his 

Ph.d. in molecular biology from university 

of utah in 995 and then joined chiron 

for a postdoctoral training in cancer 

signaling pathway. he started working at 

field of molecular diagnostics at Roche 

diagnostics as a manager and a Principal 

scientist later the head of Technology 

Office for Asia/Pacific region,. Dr. Yu is 

currently a manager at cepheid, a fast- 

growing diagnostics company known for 

its anthrax system deployed in usPs. In 

addition to his interests in diagnostics, dr. 

yu is a registered patent agent to practice 

before usPTo on intellectual property 

issues and consulted for several biotech 

companies. 

Abstract 

In vitro diagnostics (IVD) using molecular methods are reaping 

the benefits of organism genome sequencing. In this review, the 

DNA/RNA based molecular testing paradigm will be discussed 

in details together with challenges that the molecular testing faces. 

Other aspects of molecular testing such as intellectual properties 

and applications outside of human diagnostics will also be 

explored. 

Today’s diagnostics have penetrated deeply into the healthcare 

Armageddon. A good percentage of fundamental medical 

achievements as better survival and better quality of life have to 

do with diagnostics. According to a study published by a health 

research firm, the Lewin Group (Falls Church, VA), diagnostics 

affect sixty percent or more of downstream decision-making in 

disease-management, resulting in improved health outcomes and 

net cost savings for the healthcare industry. The Lewin report 

documents a myriad of ways diagnostics influence patient care: 

assessing disease risk sooner; diagnosing disease earlier---long 

before symptoms occur; targeting disease more specifically, with 

often less invasive treatments; estimating prognosis more accurately 

and managing chronic disease more effectively, to name a few. 

Review Scope 

Diagnostics 

The scope of diagnostics as relevant to this review is in-vitro 

diagnostics (IVDs) as clinical diagnostics. Under the FDA’s 

definition, IVDs are medical devices or reagents that analyze 

human body fluids and specimens, such as blood or urine, to 

provide information for the diagnosis, prevention, or treatment of 

a disease. There are many segments in the IVD industry (Table1). 

One segment in IVD is molecular diagnostics that uses molecular 

methods to do in-vitro diagnosis. These methods could be nucleic 

acid or protein-based. The focus of the present review is on 

nucleic acid-based methods that detect either DNA or RNA. Any 

testing using the molecular method is a molecular testing, which 

includes molecular diagnostics if the testing subject is human. 

Molecular testing could also be applied to fields outside of human 

diagnostics. Developments and opportunities in these fields will 

also be discussed in this review. 



Table 1. Segments of In-vitro Diagnostics 

(IVD) 

Rapid immunoassays - infectious diseases, pregnancy, etc. 

Clinical Chemistries lab - cardiac markers, coagulation, 

gases, electrolytes, etc. 

Glucose monitoring systems 

Urinalysis strips and reader 

Immunochemistry reagents and test systems 

Hematology reagents and test systems 

Coagulation reagents and test systems 

Blood banking reagents 

Microbiology/virology tests and reagents 

Histology/cytology stains, HPV tests, etc. 

Molecular tests, genechips, arrays, reagents 

Segment of Molecular Diagnostics 

Diagnostics industry presumably is the picker of “lowhanging 

fruits” grown from the human genome sequence 

“tree”. Although the industry is moving at a steady pace, 

that clearly has not happened to a degree as heralded. Much 

has to do with the time that is needed to mine through the 

vast information and establish cause-and-effect relationships 

between genomics and disease. The frontier of such efforts 

remains to be the molecular diagnostics. Promising better 

sensitivity and specificity, it is the fastest growing segment of 

the IVD market, even though it accounts for just over 5%. It 

is anticipated to grow rapidly as a result of innovation of new 

technologies, maturation of existing platforms, and progress 

in sample preparation arena. By 2010, total revenues in the 

molecular diagnostics market are expected to reach 3.7 billion, 

with an annual growth rate of over 20%. 

The short-term drivers for this anticipated 20%-plus growth 

include blood donor screening, sexually-transmitted disease 

testing, cancer and cardiac marker monitoring, and testing 

for other infectious diseases including sudden-onset SARS, 

west nile virus, and potentially infective avian flu virus H5N1. 

Long term growth drivers are likely to be the identification 

and establishment of new genes associated with many diseases, 

the identification of single-nucleotide polymorphisms 

(SNPs) associated with adverse reactions or side effects to 

certain drugs, and the development of fully automated molecular 

testing platforms. Nucleic acid testing in areas outside 

of human diagnostics is also beginning to break ground in 

replacing or supplementing conventional methods that have 


long turnaround time and are sometimes unreliable. 

Main Technologies in Molecular Diagnostics 

Three major technology platforms dominate the landscape 

in molecular diagnostics: PCR-based, TMA-based, and 

GeneChip. 

With the advent of Polymerase Chain Reaction (PCR) in 1986 

by Kary Mullis at Cetus, a former biotech giant, molecular 

testing field has been dominated by technology platforms 

sprung from this basic invention which played a pivotal role in 

human genome sequencing. Later, the invention of real-time 

PCR by mainly Carl Wittwer of University of Utah and Idaho 

Technologies (both at Salt Lake, UT) catapulted PCR to frontier 

diagnostics tool due to improved precision and speed, and 

the homogeneousness of the assay. Attempts are constant in 

figuring out ways to molecularly test using alternatives to PCR. 

Such novel PCR-alternative methods include, but are not limited 

to, nucleic acid sequence-based amplification (NASBA), 

transcription-based amplification (TMA), branched DNA 

method, strand displacement amplification, and isothermal 

amplification methods. While these alternatives are functional, 

PCR still has an advantageous edge in terms of sensitivity and 

specificity. 

Roche Diagnostics (Basel, Switzerland) acquired intellectual 

property rights to PCR from Cetus in late 1980s, along with 

a team of original PCR developers. From hindsight, the 

acquisition contributed greatly to Roche’s current status as 

the world leader in diagnostics recording revenues of over $6 

billion in 2005. Roche developed PCR into the preeminent 

molecular diagnostics platform, in several cases, into gold 

standards, and has held that dominant position ever since. 

The position was eroded slightly when the foundational PCR 

process patents expired in the United States in March of 

2005. These patents will expire in March of 2006 the rest 

of the world. However, not all PCR patents have expired. 

Presently, Roche still holds more than 300 PCR-related patents 

that are often on improved processes or compositions of 

matter. Among those, only the followings have expired: 

process for amplifying, detecting, and/or cloning nucleic acid 

sequences; process for amplifying nucleic acid sequences; 

process for amplifying, detecting, and/or cloning nucleic acid 

sequences using a thermo-stable enzyme; kits for amplifying 

and detecting, and/or cloning nucleic acid sequences 

including a probe; kits for amplifying and detecting nucleic 

acid sequences; detecting AID-associated virus by PCR; and 

detecting viruses by amplification and hybridization. The 

expiration of fundamental patents, although a small number, 

will clearly open up the PCR diagnostics market since the 

commercial developers will no longer pay hefty royalties to 

use PCR. On the other hand, PCR in diagnostics has become

increasingly sophisticated unlike at the beginning of the 

invention a single reaction. It is now demanded in analyses 

of multiple analytes under very complex sequence contexts. 

For one, an original thermostable Taq polymerase probably 

will not fare well in multiplex reactions, which are often 

accomplished by HotStart or ColdStart enzymes nowadays. 

Exploiting expired PCR patents alone will not be competitive 

in marketplace. Waves in PCR technology innovation are 

somewhat similar to the linear progression of a Pentium chip 

speed in computer industry, often a sign of maturity for a 

technology. 

Between 2004 and 2005, GeneChip-based technology 

platforms represented by Affymetrix (Santa Clara, CA) went 

mainstream after first-ever FDA’s approval of GeneChip in 

diagnostics: the CYP450 AmpliChip developed by Roche 

and Affymetrix. The AmpliChip identifies variations in the 

CYP2D6 and CYP2C19 genes, which help break down drugs 

in the liver and can be used to gauge the metabolism of drugs 

such as antidepressants, antipsychotics, and beta-blockers. The 

test is designed to run on the GeneChip System 3000Dx, a 

microarray instrument platform manufactured by Affymetrix 

that also received FDA clearance for diagnostic use at the 

end of 2004. The dominant microarray IP position held 

by Affymetrix based on chip probe density makes it poised 

for significant growth over the coming years as GeneChip 

platforms flourish. 

Teaming up with Chiron for its paramount intellectual 

properties on HIV and HCV, Gen-Probe has found a fruitful 

collaboration using its own TMA technology platform. TMA 

is an RNA transcription amplification system using two 

enzymes to drive the reaction: RNA polymerase and reverse 

transcriptase. TMA is isothermal and can amplify either DNA 

or RNA, and produces RNA amplicon. TMA has very rapid 

kinetics resulting in dramatic amplification within 15-30 

minutes. A fully automated instrument platform Tigris was 

launched to handle the TMA assay. Although TMA platform 

has a reputation of being over-costly, with its uniqueness and 

automation, the tight grip of Chiron Gen-Probe on blood 

donor screening market will continue and prosper. A potential 

Novartis-Chiron merger could further expand their market 

share in blood testing, and possibly into other diagnostics 

areas. 

Diagnostics 

From an intellectual property perspective, for a full-scale 

molecular diagnostics business to operate, the platform 

is often the foundation including proprietary instrument, 

software, consumables, reagent technology and other 

pertinent components; Amplification/detection technologies 

and enabling chemistry (Figure 1), on the other hand, if not 

business-owned, often need licensing to secure the rights 

of commercial usage. At the top of the molecular testing 

paradigm pyramid is the sequence (Figure 1). As companies 

pursue molecular testing for, for example microorganisms, 

a heated area of competition and interest should be the 

freedom-to-operate of gene sequences. Similar to Chiron’s 

holding of HIV and HCV genome patents, Gen-Probe holds 

IP positions on 16S and 23S ribosomal RNA sequences of 

most microorganisms. The intergenic spacer sequences 

(IGSs) are patented by Innogenetics (Gent, Belgium). 

Although microorganisms could also be detected using 

genes that encode proteins, the above-mentioned sequences 

provide generally versatile regions in a genome to be screened 

along with, yet specific enough to be distinguished from, its 

close relatives. As more organism genome sequences are 

decoded, more conservative/divergent regions in genome will 

emerge. The IP position in these areas could have impact on 

operational freedom and profit in the long run. 

Tailored Medicine: Recent Progress and Outlook 

The combination of drugs (pharmacology) with genomics 

is known as pharmacogenomics, the science that allows 

researchers to predict the probability of a drug response based 

on a person’s genetic makeup. It is also known as tailored or 

personalized medicine. The science of pharmacogenomics 

has advanced significantly in the last five years, but it’s still in 

its infancy and is mostly used on a research basis, according 

to Larry Lesko, director of the FDA’s Office of Clinical 

Pharmacology and Biopharmaceutics. “There are three main 

ways that pharmacogenomics is applied,” Lesko says. “The 

first is to help predict the appropriate dose of a drug. The 

second is to target therapy to a subset of a disease. This means 

picking the most effective drug for the disease subset. And the 

third is to test viral genomics, such as in selecting treatment 

for HIV based on resistance”. 

One recent FDA approval lends great excitement over the 

coming of mainstream personalized medicine (Table 2). In 

Diagnostic Test Pharmaceutical Dx Manufacturer 

UGT1A1 Camptosar (Pfizer) Third Wave Technologies 

Her-2/neu Herceptin (Genentech) 

BioGenex, DakoCytomation, 

Vysis 

TRUGENE HIV HAART Therapy Visible Genetics 

Table 2. FDA-approved Pharmacogenomic Molecular Tests 



2005, Invader® assay of UGT1A1 by Third Wave Technologies 

Inc. (Madison, WI) was approved. 

The assay detects mutations in the UGT1A1 gene, which 

produces a drug-metabolizing enzyme, to screen for 

patients that could have adverse reactions to cancer drug 

Camptosar. This signals the FDA’s support of efforts 

to personalize medicine. According to FDA, more than 

100,000 Americans die each year from adverse drug reactions, 

and the annual cost of treating medicine misuse exceeds 

$130 billion. HerceptinTM was developed to treat HER- 

2/neu over-expressing breast cancer patient. Therefore 

the combination of FDA-approved Her-2/neu diagnostic 

testing in tissue with HerceptinTM treatment was a good 

example of tailored medicine (Table 2). The same is true 

for Novartis’ (Basel, Switzerland) GleevecTM treatment for 

chronic myelogenous leukemia (CML) caused by Bcr-Abl 

translocation. Although Roche’s RNA-based viral load tests 

were approved for monitoring HIV and HCV treatment 

regimen, the first pharmacogenomics approval was the Visible 

Genetics (Suwanee, GA) TRUGENE TM HIV-genotyping 

kit for mutations that confer resistance to HIV drugs. Other 

candidates are in the pipeline for pharmacogenomic tests 

including one by Third Wave to detect the risk of adverse 

reaction to the anticoagulant Coumadin (warfarin). 

The nature of tailored medicine calls more for nimble 

point-of-care device of rapid, walk-away molecular testing 

at doctor’s office, than for centralize lab tests. Presently, 

Cepheid’s GeneXpert® is a good candidate, although limited 

by the number of analytes it can test simultaneously when 

compared with GeneChip platform. It is a nimble, rapid, 

integrated, walk-away system based on real-time PCR and 

microfluidics, with small footprint. Another candidate is 

the GeneChip platforms. The improvement of speed and 

portability for GeneChip platform could also make it an 

ideal testing vehicle if pharmacogenomics warrants profiling 

pattern analysis of many genes rather than just a few. Like 

in the past, the pivotal driver of pharmacogenomics will 

continue to be the linkage establishment between genomic 

information and a medical condition. 

Two important prosperity “gate-keepers” for either drug or 

diagnostics industry are the policies and positions held by 

FDA, and the healthcare reimbursement policies stemming 

from Congress. In one promising development from 

FDA, it released a final guidance on pharmacogenomic 

data submissions and a preliminary concept paper on drugdiagnostic 

co-development. By publishing these documents, 

FDA has moved towards a position that it is setting the stage 

for anticipated advances in personalized medicine. Such a 

move lays the groundwork for greater collaborations between 

IVD and pharmaceutical companies. 


The Lewin report highlights the disproportion between 

the amount of healthcare decisions (over 60%) that rely on 

diagnostics and the percentage of diagnostics in total hospital 

(less than 5%) and Medicare (1.6%) costs. Although patients 

and physicians are increasingly relying on IVDs for critical 

medical decisions, significant access barriers exist according 

to the report. The little incentive to use newer diagnostic 

technologies is because both incremental and breakthrough 

advances are underpaid, which affect more than 40 million 

Medicare beneficiaries. IVD reimbursement reforms will be 

proposed in Congress to ensure that patients continue to have 

access to newer tests and IVD companies have incentives to 

invest in research and development. 

Diagnostics: Closer Ties with Pharmaceutical 


On one hand, it is likely that, in a not too distant future, pharmaceutical 

companies, under the intense needs of personalizing 

their medicines and targeting their clinical population 

for trials, start in waves of mergers and acquisitions gobbling 

up niche diagnostics companies with good IP positions, big 

market share, and unique platforms/technologies. On the 

other hand, pharmaceutical partners could be fearful of their 

market fragmentation or loss of sale if their blockbuster 

drugs are found to be only effective in smaller population 

of patients. The fine balance between these two propensities 

could be reached by the following proposition: Teaming 

up with a diagnostics partner on pharmacogenomics could 

resurrect previously failed drugs due to toxicities in wrong 

group of patients; could reduce development costs and risks 

by designing clinical trials that enroll only those patients who 

are likely to benefit, potentially reducing the size and length 

of costly development cycle. And progress is being made. 

For example, Roche Diagnostics and Eli Lilly (both in Indianapolis, 

IN) are working together to validate biomarkers that 

may help determine patient population that is likely to benefit 

from cancer drugs such as Gemzar. Although it is too early to 

predict whether the approval of a few pharmacogenomic tests 

is the coming of a wave, one landscape in the future could be: 

These closer ties will lead to more drug approval, more biotech 

survival, more confident and effective treatments marked 

with premium prices, but probably less blockbuster drugs yet 

still higher profits overall for drug industry. 

Challenges for Molecular Diagnostics 

Many challenges for molecular diagnostics on early days 

practically still exist today. The inherent high cost of 

molecular diagnostic tests is one of the acceptance barriers, 

especially when the outgoing method is inexpensive. It is also 

labor intensive, when non-automated, with sample-prep and 

reaction setup operations involving pippetting, centrifugation

and procedural intervention, together with high-requirement 

for operator’s skill sets. Also, the sensitivity of molecular 

tests could lead to potential cross-contamination or assay 

inhibition from sample-prep. For quantitative tests, the lack 

of standard that produces similar results across different 

platforms has also hindered acceptance, although FDA’s 

clearance or approval require equivalency with predicate 

devices. But the biggest hurdle has to do with lack of leap-offaith 

correlation of data derived from molecular tests to that 

from existing method. Additionally, patient access barrier is 

created by underpaid reimbursement policy for new diagnostic 

technologies in MediCare. Socially, the genetic profiling of 

pharmacogenomics also generated public anxiety over ethics 

concern of privacy and discrimination. 

Progresses have been made in recent years to address 

some of the above issues. First, ultimate convenience of 

reagent setup is now accomplished by bead technology. GE 

Healthcare (Piscataway, NJ), formerly Amersham Biosciences 

and Cepheid (Sunnyvale, CA) both developed freeze-dried 

bead format of reagents, namely Ready-To-Go beads and 

SmartBeads, respectively. Separate beads are for enzyme 

systems and primer/probe sets. This format of reagents 

eliminates many master mix reaction setup steps thus possible 

operator errors, providing more consistency, precision and 

stability. It is conceivable that many molecular diagnostics 

reagents can be converted to bead format. Cepheid has a 

customer-specified reagent program to accommodate such a 

market need. 

Secondly, several fully-automated instruments for molecular 

diagnostic testing have been developed and launched from 

steps of sample prep to results. Gen-Probe launched the 

Procleix Tigris system for TMA-based assays in blood 

screening. Roche launched the COBAS AmpliPrep 

Instrument to be combined with the COBAS TaqMan 48 

Analyzer or the COBAS TaqMan Analyzer for maximum 

throughput capacity, to simplify the workflow with automated 

sample preparation, amplification, and quantitation of RNA 

or DNAby PCR. Cepheid (Sunnyvale, CA) brought to market 

the oncology Bcr-Abl test in cartridge system for researchuse-only 

(RUO) in 2005, a fully-automated point-of-care 

integrated system capable of walk-away “sample in, answer 

out”. A similar system was deployed for routine Anthrax 

monitoring at mail handling centers of US Postal Services. 

An official launch of GeneXpert® in the IVD market 

could potentially make it the only such device in point-ofcare 

market. The hands-off, independent cartridge designs 

of GeneXpert® make it an attractive solution at doctor’s 

office. If combined with extensive menu and especially 

pharmacogenomic assays, it would be a powerful molecular 

diagnostics solution where actionable medical information 

Diagnostics 

could be obtained in a timely and nimble fashion. As to 

centralized lab testing, the recent market access by Beckman 

Coulter’s (Fullerton, CA) Vidiera NsP nucleic acid sample 

preparation platform could provide a solution. However, a 

seamless integration to various downstream molecular testing 

platforms may require custom efforts. 

Burgeoning Molecular Testing Markets for Non- 

Clinical Applications 

The gradual adoption of molecular testing paradigm is 

occurring not just in human diagnostics, it is also burgeoning 

in many other fields that demand rapid crystallization of 

actionable information. Presently, many of these fields 

are typically dominated by methods that require long 

turnaround time, leading to loss of opportunity for action, 

or irrelevance of information. Examples of these fields 

include: veterinary testing; environmental testing such as water 

testing; agricultural testing for plant diseases or geneticallymodified 

organisms; industrial microbiology in food testing 

for pathogens or food wine-making process monitoring; 

DNA fingerprinting for human and animal identity; testing 

for drug-abuse; and bioterrorism. The sheer volume of tests 

needed in some of these fields could make non-clinical testing 

a highly profitable operation. Meanwhile, it is expected that 

the pertinent user community be educated before a molecular 

testing would be accepted. For example, water testing 

of freshwater and beaches often relies on EPA-approved 

ColiAlert® and EnterolertTM from Idexx (Westbrook, 

ME), two colony counting-based colorimetric methods to 

monitor E. coli species and total Enterococcus counts in 

water samples, respectively. The time from sample to result is 

long, with often unreliable results. Molecular tests have been 

developed to substitute the Idexx methods, reducing reporting 

time from days to 3 hours. However, it will take time for new 

methods to be assimilated by water-testing community due 

to similar challenges encountered by clinical testing discussed 

above. Bioterrorism routine monitoring provides another rich 

“soil” where molecular testing could seed, grow and bloom. 

This notion was highlighted in the successful deployment of 

routine Anthrax monitoring using Cepheid’s GeneXpert BDS 

system in US Postal Services. The test accuracy has ensured 

zero false positive out of millions of tests. The allocation 

of guaranteed federal funds in antiterrorism will continue 

to be the impetus of growth for molecular testing in this 

field. Together, these areas create significant opportunities 

for niche companies to enter the market, since the regulatory 

restrictions are often less, and technology benefits of 

molecular testing are more obvious, generating attractive value 

proposition. 



Summary 

In conclusion, human clinical diagnostics and non-clinical 

testing for other living organisms are reaping the benefits from 

the genome sequencing. As the decoder of such sequence 

contents, molecular testing will continue to trail blaze the 

efforts in providing rapid and “digital” actionable information 

needed in a multitude of human decision-making processes, in 

replacement of often slow and vague “analog signal”. 

Recommended Readings: 

1. The Lewin Report (www.advamed.org/publicdocs/thevalueofdiagnostics.pdf) 


2. Pricewaterhousecoopers, T. Lefteroff “Personalized 

Medicine: The Emerging Pharmacogenomic Revolution,” 

(Feb 2005). 

3. CT Wittwer et al., “The lightCycler: a Microvolume multisample 

Fluorimeter with Rapid Temperature Control.” 

BioTechniques 22, 176-181 (1997) 

4. S. Little “Developments in PCR Detection Methods,” 

IVD Technology Nov. 2005 

5. J Kipp “Is Drug Companies Stalling the Pharmacogenomic 

Revolution?” Diagnostic Testing and Technology 

Report 5:10 (2005) 

6. KB Mullis et al. “Process for Amplifying, Detecting, and 

/or Cloning Nucleic Acid Sequences”, US Pat. 4,683,195 

(1986)

Conference Report 

From Bench to Market: the Successes, Challenges and Opportunities 

report on 8th saPa-WesT annual conference 

leping li 

The eighth SAPA-west annual conference was held on 

April 19 th , 2006 at the Crowne Plaza Hotel in Foster City, 

California. The all-day event brought together senior 

executives from biotech/pharmaceutical corporations, 

entrepreneurs of blooming startups and leading scientists 

at local biopharmaceutical companies and academic 

institutions. The theme of the conference was focused on 

the challenges facing the biotech/pharmaceutical industry 

and the great opportunities ahead toward globalization. The 

meeting programs featured plenary speeches that offered 

the attendants a high-level overview of the challenge and 

opportunity in our industry. The science-based lectures 

covering key aspects of the drug discovery and development 

processes were stimulating and educational to all attendants. 

As always, the challenges from a business opportunity point of 

view were vividly analyzed and discussed by business leaders, 

entrepreneurs and venture capitalists. A significant expansion 

in this year’s program was the presentations from several high 

profile incubators in China. The Annual Conference, with the 

great efforts of the organizing committee, the speakers and 

many SAPA-west members, cumulated a great success. 

In his keynote presentation, Dr. Robert Stein, President 

of Roche Biosciences at Palo Alto, gave his view of 

the pharmaceutical industry, the present and the future. 

He predicted that pharmaceutical industry would be 

transformed in significant ways in the next 15 years or so. 

The pharmaceutical industry, as we know today, with high 

profitable margin fueled by high prescription price, coexistence 

of multiple similar drugs made possible by forceful 

marketing muscle will cease to exist. In the challenging 

In order for the pharmaceutical sector to be competitive 

and profitable, the industry as a whole will need 

to take on new approaches to health maintenance 

and restoration and to conduct medical research for 

a better understanding of diseases and diagnoses 

to develop medicines to treat a subset of patient in 

order to achieve maximum effectiveness 

environment of healthcare cost pressure and potent 

competition from low price but efficacious generics, the 

pharmaceutical industry will have to be innovative to remain 

vibrant. Runaway cost and declining productivity have been an 

industry-wide issue. In order for the sector to be competitive 

and profitable, the industry as a whole will need to take on 

new approaches to health maintenance and restoration and 

to conduct medical research for a better understanding of 

diseases and diagnoses to develop medicines to treat a subset 

of patient in order to achieve maximum efficacy. While 

acknowledging the daunting tasks facing the industry, Dr. Stein 

offered an encouraging view about the future as well. He was 

particularly optimistic about Roche’s prospect with its leading 

position in several therapeutic areas and comprehensive 

medical diagnostic enterprise and its global research networks. 

Roche has five pharmaceutical research sites globally, including 

the recently established Roche R&D Center (China) LTD. 

He pointed out that by working on right projects, applying 

appropriate resources and organizing the workflow effectively 

a multi-international organization such as Roche will be able 

to take on the challenges and be successful. 

Mr. Mingde Yu delivered the second keynote speech. He 

is currently the Executive Chairman of China Worldbest 

Life Industry Co., Ltd. Mr. Yu gave a broad view on the 

status of Chinese pharmaceutical industry and the prospect 

of healthcare system in general. According to Mr. Yu, 

the pharmaceutical industry in China has been enjoying 

a rapid and healthy grow over the past decade. Sale of 

pharmaceuticals manufactured in China has been growing at 

18.8% over the five years between 1998-2003 while total net 

profit increased at an even higher annual rate of 28.8% for 

the same period. The high rate of growth will continue for 

some time in the near future. There is a large manufacturing 

In the next 15 years, innovation will be a high 

priority objective in China. A number of key 

projects have also been identified. Amongst 

them are the discovery and development of new 

medicines for the prevention, control of major 

infectious diseases. 

capacity in China with over 5000 manufacturers in compliance 

with GMP regulation. However, it is also well recognized 

that significant challenges are ahead of the Chinese biotech/ 

pharmaceutical industries, particularly in the areas of low 

innovation capacity, excessive manufacturing capacity and 

the lagging rural healthcare system. In the next 15 years, 

innovation will be a high priority objective in China. A number 

of key projects have also been identified. Amongst them are 

the discovery and development of new medicines for the 

prevention, control of major infectious diseases. Recognizing 

the issues, policy makers of the central government have 

outlined several important measures in the recent issued 



to set up the stage 

for building a healthy healthcare industry. Specific policies are 

being set and implemented to promote innovation by issuing 

favorable tax treatment and embracing competition. Many 

areas that are important to the healthcare industry were given 

particular priority. The huge healthcare market, the muchimproved 

infrastructure, and the favorable climate created 

by the policy makers of the central government have made 

China an attractive place for conducting innovative biomedical 

research and drug discovery and development. 

In these dynamic and evolving environments of the western 

world and in China, both speakers echoed the key points in 

how to be successful and thriving in the uncertain future. The 

other speakers further elaborated those important points. 

While focusing his presentation on the critical topic of 

drug target identification and lead selection, Dr. Jinlong 

Chen, VP of Biology at Amgen San Francisco, 

first shared with the audiences Amgen’s guiding principles 

in its research and development operation. These guiding 

principles, instituted by Dr. Roger Perlmutter, Amgen’s 

Executive Vice President of Research and Development, 

are to focus on grievous diseases, be modality independent, 

assess efficacy and safety in people, and ensure seamless 

integration from basic research to commercialization. Some, 

if not all, of those principles may seem obvious. However, 

the traditional pharmaceutical industry has spent much effort 

in engineering modest improvements to existing therapeutics 

as a means of supporting their established franchise. The 

traditional approach looks for a disease target that can be 

approached with a potent and selective molecule that can be 

manufactured in existing facility. Amgen has been building 

an interdisciplinary research and development organization 

Amgen has been building an interdisciplinary research 

and development organization that addresses the 

topics at the interfaces between chemistry, biology, 

molecular biology so as to make cutting edge 

discovery and to have the ability and capacity to 

evaluate the best modality for a good target. 

that addresses the topics at the interfaces between chemistry, 

biology, molecular biology so as to make cutting edge 

discovery and to have the ability and capacity to evaluate 

the best modality for a given target. Choosing a biological 

target is the anchoring step in a drug discovery process. 

Chen believed that a good drug target generally should have 

solid biological relevance to diseases, novelty, duggability 

and a strategic fit to the organization. He used the orphan 

G-protein coupled receptor and the orphan nuclear receptor 


platforms he helped to establish as examples to elucidate 

Amgen’s approaches toward identifying and selecting the best 

targets to work on. Genetic manipulation (gene knock in and 

knockout) enables the ready access to genetically modified 

animal models. Robust high throughput screening system 

accelerates the search for endogenous and synthetic ligands 

for the intended targets. The ready availability of these tools 

enables the early test of hypothesis and the determination of 

suitable modality. Central to any early discovery strategy is the 

ability to screen compound sets against the target of interest. 

Seamless screening operation ensures rapid and complete 

exploration of the chemical diversity of company’s collection. 

Lead optimization will then identify and select the potent, 

safe molecule to allow for expeditiously evaluation of the 

hypothesis in people with the validated biomarkers to bridge 

the preclinical and human studies. 

Once a lead molecule for modulating the biochemical pathway 

is identified, the next critical step is to optimize the activity 

and property of the lead molecule in order to find best 

molecule with the “developable” properties to advance to 

clinical evaluation. Optimizing a molecule’s pharmacokinetic 

properties often becomes the focal point of the process. 

Pharmacokinetics (PK) is a discipline dealing with the study of 

what would happen to a drug molecule when it is introduced 

to the body. Dr. David Lau , Senior Director at Scios, a 

Johnson and Johnson Company, covered this important topic 

in his presentation entitled “Picking the Pearl from Haystack 

Using Pharmacokinetic Principles”. Pharmacokinetics deals 

with the absorption, distribution, metabolism and excretion 

of a drug when it is introduced to the body. The study of 

pharmacokinetics plays at least two important roles in drug 

discovery: it assists in finding potent compounds that will 

achieve adequate exposure and thus in vivo efficacy; it also 

assists in choosing the developable clinical candidate. The 

study of a compound’s pharmacokinetics is intended to 

find out if the compound has adequate exposure for safety 

and efficacy testing, sufficient safety margin in preclinical 

species. The study is also to collect data to allow for accurate 

prediction of what the human PK might be and what the 

metabolism profile may look like. It is very important to gain 

insight about the molecule’s potential to interact with other 

drugs as well as the potential variability. In order to be able 

to collect sufficient amount of data to allow for a conclusive 

A combination of in vitro and in vivo PK and 

metabolism screening is important for advancement 

of drug candidates and development. Pharmacokinetic 

screening does not guarantee success in prediction 

of human pharmacokinetics. However, when 

appropriate in vivo and in vitro studies are performed, 

the odds should be significantly improved.

decision, one has to take many factors, including the types 

of assays and models to use, the timing of sequencing of 

experiments and the interpretation of data into considerations. 

A combination of in vitro and in vivo PK and metabolism 

screening is important for advancement of drug candidates 

and development. Pharmacokinetic screening does not 

guarantee success in prediction of human pharmacokinetics. 

However, when appropriate in vivo and in vitro studies are 

performed, the odds should be significantly improved. The 

ability to conduct these experiments, analyze data, and reach 

to conclusion in a timely and cost effective fashion is utterly 

important for the success of a drug discovery program. 

The sky-rocking cost of developing a new drug has forced 

the drug companies to invent and implement new ways to 

conduct preclinical and clinical studies intelligently to increase 

the likelihood of success. One of the many companies 

that provide services in these areas is MPI Research. At the 

SAPA-west annual meeting, Dr. William Harrison, President 

and Chief Operating Officer of MPI Research, gave a timely 

presentation entitled “Safety Assessment and Regulatory 

Affairs”. While touched on a various topics along the process 

of preclinical and clinical evaluations from both scientific 

and regulatory perspectives, he emphasized two important 

areas: the strategy of biomarker study and the concept of 

DxRx. A broad definition of a biomarker usually refers to any 

biological measurement that provides actionable information 

regarding disease progression, pharmacology, safety that can 

be used as basis for decision making in drug development. 

A broad definition of a biomarker usually refers to any 

biological measurement that provides actionable information 

regarding disease progression, pharmacology, safety that can 

be used as basis for decision making in drug development. 

Biomarkers represent tools to improve target identification 

and target validation, and identify beneficial and adverse 

drug effects and a way of segmenting patient populations for 

personalized medicine approaches. Integrating biomarkers 

across R&D programs improves quality and productivity by 

improving decision making and gaining greater insight into 

novel mechanisms in diseases processes, thereby addressing 

the declining number of new drug approvals. Biomark the 

new initiatives in industry and the regulatory. Perhaps the most 

ambitious attempt to find ways to modernize and improve 

drug R&D is the Critical Path Initiative, a FDA program 

that released its initial report and recommendations this 

March. According to the CPI report, the problem with drug 

R&D isn’t that drug companies are failing to come up with 

good drug candidates. Instead, the problem lies in getting 

them evaluated in the development stage, where new science 

has not been adequately applied. Critical Path Initiative is 

intended to stimulate efforts toward the goals of creating 

new opportunities to link biomarker development to drug 

Conference Report 

development and personalized care, through evidence-based 

medicine. 

In 2005, FDA issued a draft Concept Paper on Drug- 

Diagnostic Co-development. This document provides FDA’s 

Biomarkers represent tools to improve target 

identification and target validation, and identify 

beneficial and adverse drug effects and a way of 

segmenting patient populations for personalized 

medicine approaches 

initial views on co-developing and validating companion 

diagnostics for use with new (or existing) drugs. Dr. Harrison 

explained that the concept of combining a therapeutic entity 

with a corresponding diagnostic test is termed theranostics 

or Dx/Rx, and he believed that targeted therapeutics is the 

future of medicine. Other key technologies such molecular 

imaging, surrogate imaging biomarkers that can be used to 

diagnose disease and its prograssion and to quantify drugtarget 

interaction will be employed a lot more extensively in 

preclinical and clinical settings. 

Dr. John Patton, Chief Scientific Officer and cofounder 

of Nektar, formerly known as Inhale Therapeutics, 

told the successful story in the development of Exubera®. 

Exubera®. Exubera® is a fast-acting, powder formulation 

of human insulin that is inhaled into the lungs via the mouth 

before meals using a simple-to-use, hand-held device. Nektar 

developed the inhaler and the powdered insulin formulation 

for Exubera in partnership with Pfizer. In January 2006, 

Exubera was approved by the US FDA and the EMEA for the 

treatment of adult patients with diabetes mellitus. It is the first 

non-injectable insulin to be approved. Insulin plays a key role 

in the regulation of glucose metabolism, and defects in either 

insulin production and/or resistance to its action underlie all 

types of diabetes mellitus. Type II diabetics has reached to 

epidemic proportion worldwide. Diabetics is a serious disease, 

which is the leading causes of blindness, kidney failure among 

others. While administration of insulin by injection has helped 

many patients, the inconvenience and fear of injection has 

created a huge need for an alternative method of delivery. The 

idea of delivering insulin by pulmonary route was conceived 

in the 1920s, but remained elusive due to significant technical 

The idea of delivering insulin by inhalation was 

conceived in 1920s, but remained elusive due to 

significant technical challenges in delivering such 

a large molecule by this route until the recent 

technological breakthroughs achieved by Nektar. 



challenges in delivering such a large molecule by this route. 

Patton and fellow co-founder Bob Platz started Inhale 

Therapeutics in the 1990s and began their quest of developing 

of an inhalated form of insulin. Major technological 

breakthroughs were achieved by Inhale in the understanding 

of the relevance of aerosol dynamics to effective delivery. 

Factors now known to affect the amount and site of 

deposition of inhalated, aerosolized insulin include particle 

size, surface morphology, charge, solubility and hygroscopicity. 

In addition to developing a suitable insulin formulation for 

pulmonary delivery, the development of an inhalation device 

that can be easily and reliably operated by patients is a key 

technical obstacle that has to be overcome. Exbera, a product 

resulted from the effort of over 15 years by scientists from 

many disciplines, is approved in the FDA for the treatment 

of adult patients with diabetes mellitus for the control of 

hyperglycemia. In patients with Type I diabetes, it should be 

used in regimens that include longer-acting insulin. In patients 

with Type II diabetes, it can be used as monotherapy or in 

combination with oral agents or longer-acting insulin’s. The 

live demonstration on the operation of an Exubera Inhaler by 

Dr. Patton attracted the full the attention of audiences. The 

convenience in use should result in better patient compliance 

and translate into improvement in glycemia control. 

After sharing the difficulties and excitements during the 

development of Exubera, Dr. Patton offered valuable 

advise to these entrepreneurs who are ready to pursue their 

innovative ideas to successful therapeutic products –grab the 

opportunity and be persistent. 

The successful story of Gilead Sciences, headquartered in 

Foster City, is nothing short of remarkable. At the 8th SAPA- 

West annual conference, Dr. Gong-Xin He, a director of 

research at Gilead Sciences, shared the successful experiences 

in pursuing pro-drug strategy. The company was found largely 

based on nascent antisense technology platform back in 1987. 

With the appointment of Dr. John Martin as the CEO, the 

company reinvented itself and focused its effort largely on 

antiviral therapeutics including HIV and HBV and CMV, areas 

there are still significant unmet medical needs. Specifically, 

Gilead concentrated its effort on developing pro-drugs for 

the nucleotide-based antiviral agents. The nucleoside and 

nucleotide analogues exerted their antiviral efficacy primarily 

by the mechanism of inhibiting viral polymerase or reverse 

transcriptase activity. Advantages of drugs in this class such 

as AZT for HIV, Acyclovir for HSV, include low potential 

of resistance development or slow resistance generation, and 

long in vivo half-life. However, a major drawback is their lack 

of oral absorption, presumably due to the highly hydrophilic 

and ionic nature. Taking Adefovir, an anti HIV and anti- 

HBV agent, as an example, a pro-drug of Adefovir, called 

Adefovir dipivoaxil was designed and developed to improve 


the oral bioavailability. A once-daily 10-mg tablet formulation 

(Hepsera) was approved by FDA in 2002 for the treatment 

of human hepatitis B. A similar strategy was employed in the 

development of another pro-drug Tenofovir disoproxil. The 

There are still significant unmet medical needs in 

the area of antiviral therapeutics including HIV and 

HBV and CMV 

300-mg tablet, under the trade name of Viread®, has been the 

workhorse in HIV management treatment since its approval 

by FDA in 2001. Currently, three nucleotide antiviral drugs 

that generate a total of 1.5 billion dollar sales annually have 

made Gilead a sensational successful story. 

In addition to the presentations on global environments for 

the pharmaceutical and biotechnology industry the views of 

the directions we are heading to and the various important 

technological challenges we are facing, the conference was 

enriched with talks on market focus and product lunching and 

marketing strategies. 

The participations by several top rated Science/Technology 

and Business Industrial Parks such Nansa and Suzhou gave 

the meeting attendants another opportunity to see the much 

improvement in the infrastructures and the great opportunity 

for setting up companies and forging business partnerships in 

China. 

“Go East, Young biotech” was the key message of the final 

presentation of the all-day event, delivered by Dr. Charles 

Hsu, a venture partner at Pappas Venture, who has invested 

in several young biotechs with operations both in China 

and in the US. Hsu’s comments reiterated the theme of the 

8th SAPA-west conference and summarized the consensus: 

biotech/pharmaceutical industry will have to be innovative 

Biotech/pharmaceutical industry will have to 

be innovative to survive, the evitable trend of 

globalization already here with us. In addition to 

the considerably lower cost of doing business, the 

much-improved intellectual property protection 

enforcement and the large and still expanding 

consumer base are some of the advantages for going 

to China. 

to survive, the evitable trend of globalization already here 

with us. In addition to the considerably lower cost of doing 

business, the much-improved intellectual property protection 

enforcement and the large and still expanding consumer base 

are some of the advantages for going to China.


VM Discovery’s (VMD) is a venture capital backed company 

specialized in optimization of drug leads using proprietary 

drug design and optimization technology (the “VM OptimizerSM”) 

for drug development companies to produce superior 

medicines in a shorter time with fewer resources. VMD 

carries out comprehensive parallel multi-property (potency 

and over a dozen of ADME/Tox properties) molecular design/optimization/chemistry 

processes to identify novel, safer 

and optimized (best-in-class or first-in-class) small-molecule 

drug candidates. VMD has been developing a portfolio of 

optimized drug candidates, including new uses of old drugs, in 

the areas of cancer, diabetes, and neurological diseases. VMD 

has been providing these optimized drug candidates at various 

preclinical stages to pharmaceutical companies by means of 

out-licensing, sale or partnering. So far at least one of them 

is in Phase I/II human clinical trials for heart attack (first-inclass). 

VM Discovery’s Disruptive Core Technology 

The VM OptimizerSM consists of two proprietary molecular 

design and optimization engines, i.e. “AffinityOptimizer” 

and “AdmetOptimizer”. The former, which is drug target 

specific, is for designing and searching small-molecules to 

optimize their potency and selectivity through next generation 

structure- and ligand-based approaches. The protein target 

crystal structure is not pre-requisite. This discovery engine is 

particularly powerful to identify patentable compounds by 

searching through either commercially available compound 

databases (over 6 million synthetic small-molecules), “old” 

drug databases, partner’s corporate collection and virtual 

compound libraries. The later, AdmetOptimizer, which is 

independent of drug target, is a proprietary multi-property 

optimization engine for screening, evaluating and optimizing 

of multiple drug-able properties and toxicity of compounds. 

It consists of over a dozen, in-silico ADMET (absorption, 

distribution, metabolism and toxicity) models for virtually 

optimizing compounds for drug-ability, such as oral 

bioavailability, clearance, blood-brain barrier penetration, 

water solubility, metabolic stability, P450 3A4 inhibition and 

cardiotoxicity. The two Optimzers are utilized in parallel 

and are coupled with in-house medicinal chemistry and 

preclinical development to select novel, patentable and multiproperty 

optimized drug candidates in shorter time with fewer 

resources, and to “kill” the bad development candidates earlier 


V M D i s c o V e r y, i n c. 

New Safer Medicines Faster SM 

and faster, and to reduce both the time to market and the 

costs of a new major pharmaceutical product introduction and 

to increase management’s degree of confidence in the success 

of a drug development program. 

Product Pipeline 

Besides VMD-30283, one of most advanced clinical drug 

candidates designed by VMD for an US-based biopharmaceutical 

client and a first-in-class molecularly targeted compound 

for the treatment of heart attack, all following small-molecule 

drug candidates are either wholly owned by VMD or shared 

with our partners. Some of these optimized molecules are 

either highly selective “allosteric” inhibitors, or efficacious in 

animal disease models, or mechanism-based dual acting inhibitors 

of anti-apoptotic proteins, or have single-digital-nanomolar 

potency for disrupting protein-protein interactions, 

are in various stages of preclinical development for potential 

treatments of cancers, pain/CNS, diabetic and cardiovascular 

diseases, against validated and most sought-after drug targets. 

In addition to offering optimized drug leads, collaborative 

drug design, lead optimization and medicinal chemistry, 

VMD is entering into drug discovery joint-venture, license 

or “compound partnering” agreements relating to some 

of its projects. VMD has currently several drug discovery 

collaborations with both for-profit pharma/ biotech 

companies and non-profit top-US clinical research centers.

Some Recent Highlights: 

1) VMD has identified 7 compounds (from 6 scaffolds and 

over 2 million virtual molecules) for a US-based biopharmaceutical 

client, where 3 molecules are confirmed within low 

nanomolar activities against defined target. Within 18 months, 

the client moved one of them into combined Human clinical 

trials of Phase I/II for the treatment of Heart Attacks. No 

target crystal structure is available at the time. 

2) VMD has successfully identified a class of water-soluble, 

brain-penetrating small-molecules to selectively and reversibly 

inhibit PKCε (via allosteric binding) for potential treatment of 

alcoholism, pain and anxiety. This was accomplished by virtual 

screening over 4.5 million commercial available compound 

libraries and, identified and physically tested only about 250 

molecules. One of lead compounds is active in several animal 

disease models in Pain and Alcoholism. The project is accomplished 

within 6 months. No target crystal structure is available. 

3) VMD also helped a client to identify the specific (nanomolar) 

inhibitors (of an ion channel target) for potential treatment 

of pain and other diseases, from a virtual library. For our 

selected 17 molecules, one molecule and 5 others molecules 

have confirmed activities in nanomolar and sub micro molar 

ranges, respectively. The client finished the pre-clinical package 

and out-licensed to a big pharma for over $150 million. No 

target crystal structure is available. 

4) VMD-H880 series of compounds have been identified, in 

collaborating with a top US-based cancer research center, as 

novel, mechanism-based small-molecule inhibitors of Bcl- 

2 family (apoptosis pathway of disrupting protein-protein 

interactions) for potential breakthrough anti-cancer treatment. 

Unlike others known Bcl-2 inhibitors, our compounds of 

several scaffolds have shown cell-based activities in nanomolar 

Company at Focus 

Compound Clinical Indication(s) Target(s) Status Right(s) 

VMD-30283 Heart attack Undisclosed Phase I/II Client 

VMD-C620 Pain, alcoholism & alcohol abuse PKCε Preclinical Partner and VMD 

VMD-902 

Prostate, pancreatic & child cancers; 

Pain 

NGF/TrkA pathway In-vivo VMD 

VMD-H880 

series 

VMD-C300 

series 

VMD-8000 

series 

VMD-700 

series 

Breast, prostate & other solid tumor 

cancers 

Pain/CNS diseases; Cardiovascular 

diseases, and Cancers 

Bcl-2 family 

(apoptosis) 

Lead optimization 

Partner and VMD 

T-type Calcium channel In-vitro VMD 

Oncology & other diseases PI3K isoforms In-vitro VMD 

Type-II diabetes DPP4 In-vitro VMD 

range with novel dual-acting mechanisms: suppressing antiapoptotic 

proteins and cytotoxic to overexpressed cancer 

cells (first-in-class). The recent (March 2006) preclinical 

compounds license deal for the same target between Novartis 

and Infinity Pharmaceuticals valued at $400M ($30M upfront). 

Dr. Jay J.-Q. Wu, Ph.D. is Founder, President and ceo 

of Vm discovery, Inc. he has spent over years in 

developing computational algorithms for simulation and 

molecular design in chemical and biological systems and 

drug discovery, and so far (as Q 2006) at least two 

molecules he designed are in human clinical trials (I/II) 

for treatments of cancer and cardiovascular diseases. 

he was founding director of computational modeling at 

camitro (acquired by arQule), responsible for r&d of 

drug design and computational predictive models for the 

pharmacokinetics and adme/Tox properties. he previously 

held positions, as director, manager of molecular modeling 

at navicyte, acquired by Trega Biosciences (subsequently 

acquired by lion Biosciences), at simulations Plus, Inc. he 

earned his Ph.d. in Physical chemistry from the university 

of Konstanz, Germany, and m.s. and B.s. from Fudan 

university in shanghai, china. dr. Wu currently has also 

an appointment as adjunct Professor, Pharmaceuticals and 

Medicinal Chemistry at University of the Pacific, California, 

usa

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