FDA: Agency plans to issuea draft guidance eliminating50 types of manufacturingsupplements..............Page 2

Guidance: New draft guid-ance for manufacturers mak-ing biologics via spore-pro-ducing organisms.....Page 4

The FDA plans to start aquality by design pilot pro-gram for biotech applica-tion soon..................Page 6

Recalls: CDER clarifies170 percent increase indrug recalls..............Page 7

Warning Letter: Theagency cites Chinese APImanufacturer ...........Page 8

Congress: Lawmakers de-bate import safety bill; userfees for imports .......Page 9

Expert: Personal responsi-bility focus of GMP inspec-tions ......................Page 10

Issue No. 183October 2007

FDA Scrutinizing Data Integrity Issues In Applications: Training Investigators

The FDA is implementing specialized training courses instruct-ing agency inspectors on how to identify data integrity and fraud is-sues that have surfaced within the last two years, according to EdwinRivera-Martinez, branch chief for the Manufacturing Assessment andPreapproval Compliance Branch in the Office of Compliance.

“We recognize that this is either a growing problem, or lets justsay its a reoccurring problem,” Rivera-Martinez said during the2007 Parenteral Drug Association (PDA)/FDA Joint RegulatoryConference last month.

“One thing the Center for Drug Evaluation and Research Officeof Compliance is trying to do, in conjunction with the Office ofRegulatory Affairs, ... is developing specific training courses for ourinvestigators for uncovering … data manipulation” in the preap-proval inspections program, Rivera-Martinez said.

(See EMEA, Page 4)

(See Data Integrity, Page 2)

EMEA Recommends Viracept Reintroduction;Roche Sees Weak Uptake

The European Medicines Agency (EMEA) recommended themarket reintroduction of Roche’s HIV treatment Viracept after thecompany recalled all batches of the drug due to a manufacturing er-ror, but the firm does not anticipate sales of the product to reach pre-vious levels as patients have since switched to other treatments,Roche told DGR last month.

Viracept (nelfinavir mesylate) had $160 million in sales in 2006,the company said. Roche manufactures the drug for European marketswhile Pfizer produces the product for the U.S., Canada and Japan.

Roche recalled all Viracept batches earlier this year after a chemi-cal analysis of marketed product revealed the presence of ethylmethanesulphonate (EMS), a carcinogen believed to caus damage to

IINNSSIIDDEE TTHHIISS IISSSSUUEE

Page 2 DRUG GMP REPORT October 2007

In 2006, the FDA inspected 10 companiesfor data integrity issues and found that three wereengaged in questionable practices. This year,there were requests to inspect 10 to 12 firms forsimilar data-related issues, and inspection reportsfrom those audits are just now coming in, Rivera-Martinez said.

Data falsification, which is becoming an in-creasing focus in the FDA’s preapproval inspec-tions program, has been occurring in GMP opera-tions, contract laboratories, contract manufactur-ing facilities and clinical investigator sites andthe data manipulation is electronic-based, Rivera-Martinez said.

He indicated the agency often gets tipped-offto such infractions via employee complaints: “Youwon’t believe how many times we get calls on aweekly basis from informants in your companies.”

Rivera-Martinez recommended firms institute whistleblower programs so employeeshave an incentive to report fraud as mostwhistleblowers will report wrongdoing anyway,either to the FDA or the company. He said many whistleblowers were not just disgruntledemployees.

In addition, companies should audit materi-als suppliers and contract laboratories becausesome firms fail to conduct such reviews, Rivera-Martinez said. He highlighted a recent inspectionof a contract manufacturer that revealed a failureto report results of an out-of-specification (OOS)result for a degradent.

The original OOS result was based on anapproved analytical method, yet the contractorsubstituted the data with a result from an unap-proved analytical method, Rivera-Martinez said.— Christopher Hollis

Data Integrity, from Page 1

FDA Plans Draft Guidance ReducingManufacturing Supplements

The FDA will no longer accept submissionsfor approximately 50 types of manufacturingsupplements, according to a draft guidance theagency plans to release in the next few months,Helen Winkle, director of the Center for DrugEvaluation and Research’s Office of Pharmaceu-tical Science, said last month.

“We’re getting ready to put out a guidancewithin the next few months, which will list anumber of supplements that we no longer feellike we will require,” Winkle said at the 2007Parenteral Drug Association/FDA Joint Regulato-ry Conference in Washington, D.C.

The FDA told DGR that supplements filedwhen manufacturers change from one reliable rawmaterials vendor to another would no longer be re-quired. In addition, the guidance will list supple-ments that are not required by the FDA, yet arestill submitted to the agency. One such supplementincludes the testing site change submission.

In addition to the new draft guidance in de-velopment, the FDA intends to promulgate revi-

sions to 21 CFR 314.70, the regulation coveringthe types of manufacturing changes firms mustreceive FDA approval for prior to implementa-tion, Winkle said. She hopes the draft regulationwill be released by the end of the year.

“The most significant proposal is to allow fora category of changes that do not need to be report-ed to the application,” the FDA said. “These wouldbe handled through risk assessments specifiedwithin the companies’ internal change control sys-tems.” In connection with the revised rule, the FDA intends to issue a more extensive guidance on change control, which will likely be releasedbefore the draft rule is issued, Winkle said.

Changes to manufacturing requirements forbiologic drug products are also under considera-tion at the FDA. Chris Joneckis, senior advisorfor chemistry, manufacturing and control issuesat the Center for Biologics Evaluation and Re-search, said during the conference.

“We are internally upgrading and revising,both administratively and scientifically, how wedo our assessing of assays for those products thathave lot release … and looking at our lot releaseprocess.” — Christopher Hollis

October 2007 DRUG GMP REPORT Page 3

Page 4 DRUG GMP REPORT October 2007

DNA. Product complaints citing a strange odor em-anating from the drug triggered the investigation.

After the recall was initiated, the EMEA’sCommittee for Medicinal Products for HumanUse recommended suspension of Roche’s Vira-cept marketing authorization. The EuropeanCommission subsequently approved the action(DGR, September).

Following the EMEA recommendation,Roche submitted data to the agency for a revali-dated manufacturing process.

The root cause of the manufacturing errorwas related to the cleaning process of a holdingtank used in the active pharmaceutical ingredient(API) production process. When the API was re-moved from the tank, the vessel was then cleanedwith ethanol. Some ethanol was left in the vessel,and when new the API was introduced into thetank, a chemical reaction was triggered, creatingthe impurity, Roche said.

Roche was in supply discussions with Pfizeras it was correcting and revalidating its manufac-turing process. However, those discussions havesince concluded without an agreement, Roche said.

In response to the Roche recall, the FDAasked Pfizer to implement a new specification tolimit the presence of EMS in its batches of Vira-cept. However, the levels of EMS in Pfizer’sproduct were substantially lower than that ofRoche’s, Pfizer said last month in a Dear Health-care Professional letter warning physicians aboutEMS levels in Viracept.

Pfizer will now only release the drug to themarket if it meets new interim specifications agreedto by the company and the FDA. The firm is rec-ommending limitations on the use of the product.

The FDA told DGR it would release a guid-ance document “in the near future” that will ad-dress the appropriate levels of EMS in all prod-ucts. In addition, the guidance will address othertypes of impurities.

Both Pfizer’s and Roche’s processes for man-ufacturing Viracept API involve a step whereethanol comes into contact with methane sulfonic

acid, allowing EMS to form, Pfizer said. The pres-ence of EMS in Pfizer’s version of Viracept is notrelated to a cleaning process, the company said.

According to Peter Spargo, former Pfizer di-rector of European chemical R&D, many drugsare produced where an alcohol, such as ethanol,comes into contact with sulfonic acid to crystal-lize the active substance so it will have betterbioavailability and absorption properties. Spargois the managing director of UK-based consultingfirm Scientific Update.

The FDA told DGR that it is currently devel-oping a plan to assess the potential safety issuesfor all marketed products that may contain sul-fonate ester impurities. — Christopher Hollis

FDA Issues Guidance for BiologicsUsing Spore-Producing Organisms

Biologic drug manufacturers that rely onspore-bearing organisms such as bacteria to makeproducts such as vaccines may do so in either aseparate facility or a contained portion of a largerplant, according to a new guidance from the FDA.

Previously, regulations “required that allwork with spore-bearing microorganisms (spore-formers) be conducted in an entirely separatebuilding, or in a completely walled-off portion of a multiproduct building,” with equipment per-manently assigned to the spore-bearing organ-isms alone, the guidance notes. This will preventthe hazard posed by some spores that can causedisease.

Due to technical advances, new regulationscame into effect June 1, 2004, that “allow greatermanufacturing flexibility.” The final guidance de-tails what manufacturers that work with spore-bearing microorganisms are now advised to do.

However, the guidance encourages firms touse alternatives to spore-forming microorganisms.“Such alternatives could include the use of sporula-tion deficient strains, or recombinant proteins ex-pressed in nonspore-forming microorganisms.”

The guidance can be accessed at www.fda.gov/OHRMS/DOCKETS/98fr/03n-0528-gdl0002-vol1.pdf. — Martin Gidron

EMEA, from Page 1

October 2007 DRUG GMP REPORT Page 5

Page 6 DRUG GMP REPORT October 2007

Biotech QbD Pilot Program To Start Within Two Months

The FDA’s Office of Biotechnology Prod-ucts (OBP) plans to commence a quality by de-sign (QbD) pilot program within the next twomonths, Helen Winkle, director of the Office ofPharmaceutical Science (OPS), said last month atthe Parenteral Drug Association’s (PDA)/FDA2007 Joint Regulatory Conference.

QbD is when drugmakers establish a rangeof parameters in the manufacturing processknown as a design space, where changes withinthat range would preempt the need for firms tosubmit postapproval manufacturing supplements.

OBP is the biologics research arm for OPS,under the Center for Drug Evaluation and Research (CDER).

“In this particular pilot, instead of using theoriginal applications, as we’re not used to gettinga lot of [biologic license applications], they’re us-ing mainly comparability protocols,” Winkle said.The agency plans to announce the pilot programin a Federal Register notice.

During PDA’s QbD for Biopharmaceuticalsconference earlier this year, Barry Cherney,deputy director of OPB’s Division of TherapeuticProteins, said the pilot program could initially

extend review times for QbD applications due tothe increased amount of information required forthe submissions compared to traditional market-ing applications (DGR, June).

The agency’s QbD pilot program for smallmolecules has been ongoing for over a year. Theprogram has received 11 application review re-quests from manufacturers. The FDA has reviewedand approved five submissions, Winkle said.

She said the FDA is in the process of implementing postmarket regulatory agree-ments for companies that have submitted QbDapplications.

Regulatory Agreements

The agreements will list specifically whatmanufacturing supplements would and would notneed to be submitted to the agency.

Roger Nosal, a director with Pfizer’s regula-tory Chemistry, Manufacturing and Controls(CMC) unit, has called for the FDA to show regulatory flexibility with QbD CMC regulatoryagreements (DGR, June).

The decisions on what supplements will berequired would be based on risk assessments,Winkle said. The FDA is evaluating ways to ex-tend these regulatory agreements to firms thathave not submitted QbD applications, she added.

The Office of Generic Drugs (OGD) has itsown manufacturing initiative called question-based review (QbR). Janet Woodcock, the actingdirector for CDER, said last month during theGeneric Pharmaceutical Association’s 2007 An-nual Policy Conference that the QbR program hasbeen very successful, with over 90 percent, or416, of the submitted abbreviated new drug ap-plications (ANDAs) based on QbR.

QbR, which is based on risk assessments, in-tegrates the concepts of QbD into the ANDA re-view process. Woodcock said the agency wants tomove past QbR for generic drugs, establishingdesign spaces for ANDAs. — Christopher Hollis

Robert Schiff PresidentSchiff & CompanyWest Caldwell, NJMichael AnisfeldPresidentGlobepharmDeerfield, Ill.Ralph DillonDirectorCompliance Surety AssociatesMundelein, Ill.Troy FugateVice PresidentCompliance InsightHamilton, Ohio

EEDDIITTOORRIIAALL AADDVVIISSOORRYY BBOOAARRDD

October 2007 DRUG GMP REPORT Page 7

CDER Clarifies 170 Percent Increase in Recalls

Recalls for products regulated by the FDA’sCenter for Drug Evaluation and Research (CDER)were up 170 percent in fiscal 2007, according todata released by the agency last month.

However, when the recall data are adjustedto account for the incidents leading to specificproduct corrections, the number of recalls actual-ly declined.

Of the 977 recalls initiated in 2007, 672 re-sulted from one unidentified repackager, DeborahAutor, director of CDER’s Office of Compliance,said. The result was a massive spike in Class II re-calls, with 860 in 2007, compared with 188 duringfiscal 2006. In total, there were 361 recalls in 2006.

Class II recalls, which are less serious thanClass I recalls, represent a product correction whereuse of or exposure to the drug may cause tempo-rary or medically reversible adverse health conse-quences, or where the probability of serious ad-verse health consequences is remote, the FDA said.

Earlier this year, Omnicare’s former in-house repackaging arm initiated a recall of over500 million units of various drugs months after itclosed that part of its repackaging operation(DGR, June).

Adjusted Recall Data

When the recall data is adjusted to accountfor multiple recall incidents, there were only 306recalls in 2007, compared with 338 in 2006.There were 14 recalls categorized as Class I, 189as Class II and 103 as Class III, according to ad-justed 2007 data.

There were also fewer Class I recalls in2007 when comparing both adjusted and unad-justed data, Autor said.

She made the presentation on the recall datalast month at the 2007 Parenteral Drug Associa-tion/FDA Joint Regulatory Conference in Wash-ington, D.C.

In speaking about the annual recall data, Au-tor said the agency is continuing its effort to con-

duct root cause analyses to figure out how recallscan be minimized. “We will continue to performthose root-cause analyses and develop proactiveresponses, and we are using recall data as part ofour fiscal year 2007 risk-based site selectionmodel for GMP inspections.”

Sawyie Wang, a consumer safety officerwith CDER’s Office of Compliance, Division ofCompliance Risk Management and Surveillance(DCRMS), detailed the agency’s risk-based in-spections program during the conference. Ap-proximately 50 percent of FDA inspections werebased on the risk model, the FDA said.

She said the agency categorizes facilities in-to three tiers, with Tier I facilities representingthe highest risk and therefore having the highestpriority for an agency inspection.

The Risk Model

The risk model rates facilities by size, fre-quency of past inspections, number of FDA fieldaction reports and recalls for products originatingfrom facility, the types of products the facilitymanufactures (e.g., sterile vs. nonsterile), the riskof cross contamination with other drugs and afirm’s difficulty in controlling the manufacturingprocess, Wang said.

For example, in fiscal 2007, 60 percent of facilities with harder-to-control manufacturingprocesses were inspected, while 75 percent of facil-ities that posed a risk of cross contamination wereinspected. Almost 80 percent of facilities that hadhigh numbers of recalls were inspected, Wang said.

The duration since a site’s last FDA inspec-tion was apparently the strongest factor in the siteselection process, with over 90 percent of facili-ties that represented a high risk in that area beingaudited in 2007.

The biggest problem the FDA has in deter-mining which sites to inspect is actually obtain-ing data on facilities, John Gardner, director ofDCRMS, said during the conference. He antici-pates that the problem may be alleviated whenthe agency’s electronic drug listing rule takes ef-fect, hopefully by the end of the 2007, Gardnersaid. — Christopher Hollis

Page 8 DRUG GMP REPORT October 2007

FDA Cites Chinese API Supplier

The FDA has ordered that active pharmaceu-tical ingredients (APIs) manufactured at a Kun-shan Chemical & Pharmaceutical production facil-ity be denied entry into the U.S., according to aSept. 6 warning letter. Kunshan is based in China.

The agency cited two of Kunshan’s productionfacilities — one newer establishment for not docu-menting method validation to support proposedspecifications and one older site for not cleaningand maintaining production equipment in a goodstate of repair, according to the warning letter,which was posted on the FDA’s website Sept. 20.

Products made at the older site will be denied entry into the U.S.

Both sites were cited for a “lack of contem-poraneous documentation of production steps inbatch records, inadequate instructions in batchrecords and improper completion of productionsteps,” the FDA said. Inadequate documentationfor calibration of laboratory equipment was citedas well, although the agency said its concerns re-garding that issue have been addressed.

Kunshan has the following four API drugmaster files listed with the FDA:

l Antibiotics doxcycline hyclate and doxcyclineUSP (monohydrate), used to make tablet andcapsule formulations, respectively; and

l Two APIs for seizure medication phenytoin,which is the active ingredient in Pfizer’s Di-lantin (phenytoin sodium). There are severalapproved generic versions of the drug.

Connecticut-based chemwerth, a genericAPI development and supply firm, has an exclu-sive license to distribute Kunshan’s doxcyclineproducts in the U.S. Chemwerth President PeterWerth told DGR that the company has not im-ported doxcycline from Kunshan for quite sometime and has never imported doxcycline hyclateAPI produced by the firm, which is a high-vol-ume product compared with the other version.

However, doxcycline hyclate manufacturedby Kunshan has entered the country. According to

the warning letter, an unidentified product manu-factured at Kunshan’s older facility was made for consumption in non-U.S. markets, but FDArecords indicate the company has made severalshipments to U.S. firms.

Werth identified that product as doxcyclinehyclate API. He said large pharmacy compound-ing operations might be purchasing the APIthrough channels outside of his firm’s control.

The problems at the newer Kunshan facilitywill likely be resolved by spring 2008, althoughthe older site will not be the focus of Kunshan’scompliance priorities, Werth said. Until the warning letter is resolved, the FDA will not ap-prove any applications listing Kunshan as the APImanufacturer.

The letter can be accessed at www.fda.gov/cder/warn/2007/320-07-02.pdf. — Christopher Hollis

MedImmune Resolves FluMist Warning Letter

MedImmune said it has resolved the problemsthe FDA pointed out in a March warning letter con-cerning the company’s UK manufacturing facilityfor its influenza vaccine, FluMist.

The warning letter said MedImmune hadfailed to appropriately investigate excess biobur-den levels in bulk lots of FluMist, among otherviolations of current GMP (DGR, June).

Following the resolution of the warning let-ter, the FDA approved FluMist for use in childrenaged 2 through 5. FluMist’s (live influenza virusvaccine) indication was previously limited to patients aged 5 through 49.

Approval of the vaccine has been held upsince May. Originally, the FDA’s Vaccines andRelated Biological Products Advisory Committeeunanimously recommended approval of FluMistfor the new patient population.

It will cost $17.95 per treatment course, and the firm estimates 5 million doses have beenproduced for this season. — Martin Gidron,Christopher Hollis

October 2007 DRUG GMP REPORT Page 9

Lawmakers Debate Import Safety,How to Stop Counterfeit Drugs

The FDA needs to increase inspections andensure the safety of imported products over theirlife cycles to prevent counterfeit and substandarddrugs from entering the U.S. drug supply chain,witnesses and lawmakers said during a HouseSubcommittee on Health hearing last month.

Rep. John Dingell (D-Mich.) recently intro-duced H.R. 3610, the Food and Drug ImportSafety Act of 2007, which would create a user feeon imported food and drug shipments, funds fromwhich be used to hire additional inspectors.

The FDA has not yet taken a position on H.R.3610, but it will probably do so in the comingweeks, Randall Lutter, agency deputy commissionerfor policy, said at the hearing. He added that theagency is taking its own steps to enhance importedproduct safety, such as finding ways to increase in-formation sharing with other governments and hold-ing meetings with Chinese officials.

Lutter told the committee that the agencyshould be doing more inspections of importedproducts.

Lack of Oversight

Dingell grilled Lutter on the number ofpharmaceutical imports FDA inspectors examine,GMP requirements in foreign inspection facilitiesand the number of foreign inspections the agencyconducts each year.

Between 2,000 and 3,000 pharmaceuticalcompanies are registered with the U.S. and canship drugs to the country, Lutter confirmed. Hesaid some of the firms importing drugs have notbeen inspected in eight or 10 years.

The FDA’s underfunded importation safety sys-tem is “as full of holes as a block of Swiss cheese,”Dingell said. He said the lack of money and staffwas preventing the FDA from doing its job. “TheFDA that says it is being leaner and meaner is instead being leaner and weaker,” Dingell said,

adding, “I am going to get you folks, whether youlike or not, the resources and authorities you need.”

Reps. Henry Waxman (D-Calif.) and JanSchakowsky (D-Ill.) said they were wary of theuser fee H.R. 3610 would add because the agencyrelies too much on user fees. FDA AssistantCommissioner for Food Protection David Ache-son called user fees a double-edged sword, butagreed that resources needed to come from some-where to begin new programs.

Dingell defended the additional user fee asnecessary. “We cannot trust that kind of activityto an agency so poorly funded and so poorlystaffed,” he said.

Several lawmakers raised concerns with coun-terfeit drugs entering the country. Lutter said thereis a flood of counterfeit and unapproved foreigndrugs coming into the U.S. The FDA’s main strate-gy has been to communicate risks associated withthe products to the public, he added.

Destruction of Counterfeits

Rep. Steve Buyer (R-Ind.) noted that theFDA does not have the ability to destroy drugs itdiscovers to be counterfeit. Instead, the mostcommon procedure is for the FDA to return pack-ages with suspected counterfeit drugs to thesender. This policy means the government sendsbad goods back to “snake oil salesmen,” Buyersaid. The FDA is also concerned with the policy,Lutter said.

Agency Commissioner Andrew von Eschen-bach said the FDA would delay reforms to its Of-fice of Regulatory Affairs, including the plannedclosings of some laboratories, until an intera-gency working group investigating import safetycompletes its findings (DGR, August).

H.R. 3610 would prevent the HHS secretaryfrom closing or consolidating any of the 13 FDAfield laboratories or any of the 20 FDA districtoffices. More information on H.R. 3610 can beseen at thomas.loc.gov/cgi-bin/bdquery/z?d110:h.r.03610:. — Emily Ethridge

Page 10 DRUG GMP REPORT October 2007

FDA Inspectors Focus on PersonalResponsibility for GMP Violations

Company employees should be aware of theFDA’s focus on determining individuals responsiblefor GMP violations found during inspections,Parexel Consulting Vice President of StrategicCompliance Services David Chesney said at anFDAnews audioconference.

Recent enforcement actions reflect how theFDA places great importance on individual re-sponsibility for the company’s acts, Chesney said.For example, warning letters are typically ad-dressed to a company’s president and CEO, andcriminal prosecutions usually name individuals aswell as the corporation, he said.

Because of this focus, agency investigatorsare trained to look for and develop evidence onwhich person to charge in a regulatory action thatresults from an inspection, Chesney said. Headded that the Food, Drug and Cosmetic Act is astrict liability statute, which means that the FDAdoes not have to show a person intended to vio-late the law in order to charge the company or in-dividual with a violation.

Inspectors look at which employees have theduty and power to detect, prevent and correct theviolation, and which had the responsibility to doso, according to Chesney. To document each em-ployee’s responsibilities, duties and power, in-spectors may ask questions about an employee’sdirect reports, to whom they report and limits ontheir authority to act without higher approval.

The FDA Investigations Operations Manualinstructs investigators to consider questions suchas who knew of violative conditions, who shouldhave known of the conditions, who ordered is-sues to correct the conditions and who approvedor denied steps to correct the conditions, Chesneysaid.

In addition, inspectors look at what otheremployees say about who is in charge, whose ap-proval is necessary and who overrules whom, hesaid. Inspectors need to find out what the organi-zation chart says versus what real life in the of-fice is like, and can use the statements as leadsand will look for documented evidence to supportthem.

Observation of how employees work togeth-er in the firm during the inspection also helps in-vestigators determine who is responsible, accord-ing to Chesney. Investigators will look for em-ployees who issue orders, employees who reactto orders, employees who show understanding ofthe equipment and manufacturing issues, and em-ployees who supervise others.

Employees should avoid misrepresenting theextent of their authority, blaming others and giv-ing the FDA documents that are beyond the scopeof its inspection authority, Chesney advised. Employees should also make sure sensitive docu-ments are out of plain sight, he added.

To determine responsibility, investigatorscan talk to people outside the company, such ascontractors, consultants and pest control services,Chesney added. — Emily Ethridge

President: Cynthia Carter; Publisher: Matt Salt; Editorial Director: Christopher Changery; Executive Editor: Steve Brown

Copyright © 2007 by Washington Business Information Inc. All rights reserved. Drug GMP Report (ISSN 1061-2335), an executive briefingon FDA enforcement of quality requirements for pharmaceuticals, is published monthly, 12 issues, for $889. Photocopying or reproducing inany form, including electronic or facsimile transmission, scanning or electronic storage is a violation of federal copyright law and is strictlyprohibited without the publisher’s express written permission. Subscribers registered with the Copyright Clearance Center (CCC) may repro-duce articles for internal use only. For more information, contact CCC at www.copyright.com or call (978) 750-8400. For site licenses for multi-ple users or to purchase multiple copies, contact Content Sales Manager Alka Desai at (703) 538-7669.

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Adaptive Designs in Oncology

Depend on Electronic Reporting

Adaptive clinical trial designs derive much of the promise they hold for sponsors of oncology trials

from real-time reporting and analysis of the data, which can only be accomplished by electronic means, ac-

cording to an expert speaking at a recent conference sponsored by the Center for Business Intelligence.

Immediate and actionable data constitute the heart of an adaptive trial, Michael Rosenberg, president

and CEO of HealthDecisions, said at the conference. His company has conducted adaptive trials for nearly

20 years. “In the traditional trial cycle, there is some delay between when you get the data and when you

can access it,” he said. “With adaptive data, you can act as soon as you get the data.”

An important benefit of electronic data gathering and analysis, which is central to an adaptive trial de-

sign, is that it enables sponsors to collect metadata, including performance metrics such as the success of

individual sites in enrolling patients, Rosenberg said.

Such metadata “will profoundly change how the industry works,” he said. Collection of site enrollment

and other information in an adaptive trial makes distributed management possible, meaning that information

PDUFA Directs HHS to Develop

Electronic Track-and-Trace Standards

Under legislation President Bush signed into law Sept. 27 reauthorizing the Prescription Drug User

Fee Act (PDUFA), HHS is tasked with developing a standard numerical identifier for tracking drugs in the

supply chain.

The legislation, known as the FDA Amendments Act of 2007, was passed by the House Sept. 19 and

by the Senate Sept. 20. The president signed it into law just days before the Sept. 30 expiration of the pre-

vious PDUFA law.

The law gives HHS until March 2010 to develop a standard for numerical identifiers. The identifier

would be applied at the point of manufacturing or repackaging, either on the pallet or package level, and

should be “sufficient to facilitate the identification, validation, authentication and tracking and tracing of

the prescription drug,” according to the law.

In addition, the numerical identifiers should be harmonized with international consensus standards, if

practicable, the law says.

Although HHS has 30 months to develop the standard, EPCglobal — a nonprofit that promotes worldwide

adoption of electronic product codes — already has ratified its electronic track-and-trace, or epedigree, standards.

October 2007

(See PDUFA, Page 2)

(See Designs, Page 4)

PPHARMAHARMADEVICEEVICEPHARMADEVICETMTM

A monthly supplement to Drug GMP Report covering Part 11-related issues.IT REPORTIT REPORTIT REPORT

The new law requires HHS to consider radio

frequency identification technology, nanotechnol-

ogy, encryption technologies and other track-and-

trace authentication technologies in developing

its standard for the program.

In addition to considering new technologies

to track medicines, HHS must consult manufactur-

ers, distributors and pharmacies. It also should

seek input from the Departments of Justice, Home-

land Security and Commerce, according to the law.

The Healthcare Distribution Management

Association (HDMA), a trade group representing

wholesalers, commended the law. “HDMA is …

pleased that new authority has been provided to

the FDA to establish standards for numerical

identifiers that will facilitate the tracking of pre-

scription medicines,” the group said.

The FDA’s regulatory and criminal enforce-

ment resources will be expanded under the new

law, which gives the agency the authority not on-

ly to fight counterfeit medications but also to in-

terdict subpotent, substandard, adulterated, mis-

branded or expired drugs, including biologic drug

products and active pharmaceutical ingredients

originating from local and foreign sources.

“The [HHS] Secretary shall undertake en-

hanced and joint enforcement activities with oth-

er federal and state agencies and establish region-

al capacities for the validation of prescription

drugs and the inspection of the prescription drug

supply chain,” the law says.

Last year, the FDA lifted its long-standing

stay on the pedigree requirements stipulated in the

1987 version of PDUFA. However, the U.S. Dis-

trict Court for the Eastern District of New York re-

jected a requirement that secondary wholesalers

pass all the FDA-required information on a pedi-

gree document, specifically data tracing the prod-

uct back to its point of manufacture.

Under the new law, the FDA’s pedigree re-

quirements still do not mandate electronic track-and-

trace technologies. In addition, authorized distribu-

tors of record, wholesalers that have a written agree-

ment with manufacturers to distribute their drugs, re-

main exempt from passing a pedigree document.

As the federal government addresses issues

related to counterfeit medications, states are insti-

tuting their own pedigree requirements, some of

which mandate electronic systems. California, for

instance, will require firms to deploy epedigree

systems to track medications under a new law that

is set to take effect in January 2009. However, the

California State Board of Pharmacy (CSPB) has

the authority to delay implementing it until 2011.

The CSPB recently held an epedigree work-

group meeting to discuss the implementation of the

law and listen to presentations from manufacturers

on their progress in deploying the technology.

Virginia Herold, director of CSPB, told PIRthat manufacturers in general have concerns

about being able to fully deploy the technology

by 2009. However, Herold said the board is com-

mitted to the 2009 implementation timetable.

— Christopher Hollis

Page 2 PHARMADEVICE IT REPORT October 2007

PDUFA, from Page 1

eRecords: Quality

And Integrity Key

When it comes to records, whether print or

electronic, quality and integrity are key issues,

former FDA official Stan Woollen said at an Rx-

Trials Institute audioconference.

“I think it’s important to remember that the

concepts of data quality and integrity that apply to

paper records in clinical investigations also apply

to electronic records,” Woollen said in discussing

the FDA’s revised final guidance “Computerized

Systems Used in Clinical Investigations.”

In electronic recordkeeping, the computer

system used must be able to maintain the ele-

ments of data quality and integrity, he added.

(See eRecords, Page 3)

October 2007 PHARMADEVICE IT REPORT Page 3

Woollen used the acronym “ALCOA” to ex-

plain what he considers the quality elements of data:

� Attributable;

� Legible;

� Contemporaneous;

� Original; and

� Accurate.

As for integrity, Woollen said data must be

what he calls “The Three C’s” — credible, con-

sistent and corroborated.

With quality and integrity in mind, Woolen

said that when data are transferred directly into a

remote server, a copy of the data should be main-

tained at another location, and the copies should

be made contemporaneously.

Maintaining a credible, contemporaneous

backup copy of data is part of a company’s disas-

ter recovery plan. While the FDA does not re-

quire companies to have a backup or recovery

plan, Woollen said, it does require them to main-

tain adequate and accurate records.

“[I]f you didn’t have a recovery plan or a

disaster plan and your records were lost, the

agency could certainly cite you for failing to

maintain the required records,” Woollen ex-

plained during a question-and-answer time fol-

lowing his presentation, “New Part 11 Guidance

for Clinical Trials: What This Means for You.”

“[It] couldn’t cite you directly for not having

a backup plan or a recovery plan,” he added.

“But, it would go after citations regarding failure

to maintain the records.”

Responding to a question about when elec-

tronic recordkeeping systems fall under Part 11,

Woollen said it depends on how the systems are

used. “[I]f you’re using an electronic system to

print out data and you’re relying on that printed

data in your submission or your analysis or your

reporting, then … those records wouldn’t neces-

sarily come under Part 11,” he said.

“On the other hand … if you’re transmitting

this data electronically to other sites and if you’re

doing analysis on the electronic records and

you’re relying on that, then you’re really not rely-

ing on those paper records,” he added, “and the

Part 11 provisions the agency is still enforcing

would apply for your particular system.”

The audioconference can be accessed at

www.fdanews.com/conference/detail?eventId

=964. — Mari Serebrov

FDA Director Emphasizing

Electronic CTD Submissions

Pharmaceutical companies should be devel-

oping the capabilities to submit common techni-

cal document (CTD) applications electronically,

Gary Buehler, director of the FDA’s Office of

Generic Drugs (OGD), said.

“I can’t stress enough the importance of de-

veloping an electronic CTD format for your man-

ufacturing submissions — it’s critically impor-

tant,” Buehler said at the American Association

of Pharmaceutical Scientists’ Pharmaceutical Sta-

bility Testing to Support Global Markets work-

shop.

Although submitting both new drug applica-

tions (NDAs) and abbreviated NDAs in CTD for-

mat is recommended by the agency, the FDA

may start requiring manufacturers to send elec-

tronic versions when such applications are sub-

mitted, Buehler said.

“[OGD is] in a critical space crunch with re-

spect to our documents. We will receive 900 ap-

plications in fiscal year 2007 or somewhere

around there. And the 900 applications added to

the almost 800 we received last year and the 800

the year before have completely overwhelmed

our storage capabilities,” Buehler said.

The FDA issued a draft guidance on submit-

ting applications in CTD format earlier this year.

In 2008, the Center for Drug Evaluation and Re-

search will require that electronic applications

conform to CTD format. — Christopher Hollis

eRecords, from Page 2

Page 4 PHARMADEVICE IT REPORT October 2007

that used to filter up through a few layers to sen-

ior management can now reach the decisionmak-

ers directly. As a result, these managers can get a

continuous flow of data rather than receiving bul-

letins only at discrete points in time.

Distributed management enables sponsors to

identify issues before they become problems,

Rosenberg said. Sponsors can engage in constant

fine-tuning of patient enrollment, training and as-

sessing the performance of clinical research asso-

ciates, which in turn makes it possible to opti-

mize resources, he added.

One example of metadata collection in an

adaptive trial that resulted in unexpected side ben-

efits involved a screen failure rate that was appear-

ing among trial sites. “Normally, it wouldn’t have

been noticed till the end of the study,” Rosenberg

recalled. However, his firm determined the prob-

lem was traceable to those sites that had signed on

after the trial was under way. Among these sites,

the screen failure rate was twice that of the sites

that had been with the trial from the beginning.

Providing employee training at the late joining

sites soon lowered their screen failure rate so it

was equal to that of the early starters.

Rosenberg said the required components of

an adaptive trial include:

� A timely, continuous source of data and

metadata;

� Real-time reporting systems, which depend on

modern technologies, such as digital pens that

read responses entered on specially designed

grid-based case report forms and capture the

data directly through an optical sensor;

� Middleware, which he defined as a means of

integrating and summarizing data and meta-

data; and

� Integration with complementary systems.

Rosenberg cautioned that not all technolo-

gies are of equal value. He called web-based

electronic data capture a dead-end system with no

management capabilities. He said such systems

are expensive and do not produce much value at

the bottom line. — Martin Gidron

Designs, from Page 1

Fulcrum Pharma and Lorenz Form

Product Development Alliance

Fulcrum Pharma, a drug development and

regulatory services company, and Lorenz Life

Sciences have formed an alliance to develop

products and software for the drug development

process, Fulcrum announced.

Lorenz develops and markets software solu-

tions for the life sciences industry that are de-

signed to aid with submission assembly, review,

publishing, validation and management for regu-

lated environments, Fulcrum said.

The companies will establish a joint sales

and marketing campaign in North America and

Europe to provide electronic publishing solutions.

The product, Creative eRegulatory Solutions, will

provide a cost-effective, tailored approach to meet

the increasing demand for regulatory services, the

company said. — Jenn Batchelor

President: Cynthia Carter; Publisher: Matt Salt; Editorial Director: Christopher Changery; Executive Editor: Mari Serebrov

Copyright © 2007 by Washington Business Information Inc. All rights reserved. PharmaDevice IT Report (ISSN 1557-3516), an executive briefing onPart 11 compliance for the pharmaceutical and medical device industries, is published monthly as a supplement to Drug GMP Report. Photocopyingor reproducing in any form, including electronic or facsimile transmission, scanning or electronic storage is a violation of federal copyright law and isstrictly prohibited without the publisher’s express written permission. Subscribers registered with the Copyright Clearance Center (CCC) may reproducearticles for internal use only. For more information, contact CCC at www.copyright.com or call (978) 750-8400. For site licenses for multiple users or topurchase multiple copies, contact Content Sales Manager Alka Desai at (703) 538-7669.

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