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742 VOLUME 21 NUMBER 7 JULY 2003 NATURE BIOTECHNOLOGY

The US Food and Drug Administration(FDA; Rockville, MD) acts as an impor-

tant gatekeeper for controlling the intro-duction of novel medical products to theUS market. It is responsible for efficientlyreviewing submissions in a timely mannerand thereby facilitating their approval. Datafrom microarray technology promise toenhance decision-making on submissionsby providing the agency with additionalgenetic data related to toxicity and efficacyof a medicine or the molecular pathogene-sis of a disease or indication. For example,microarray data may enable not only theidentification of single nucleotide poly-morphisms (SNPs) and other DNA varia-tions associated with key drug metabolizingenzymes or targets, but also the detection inpatients of blood biomarkers (proteins orgene sequences) that are predictive ofadverse reactions. Similarly, in cancer,blood biomarkers may reveal ‘signatures’for cancer diagnosis or staging (for exam-ple, whether a cancer is local, regional ormetastatic). Indeed, each of the six FDAcenters has set up a laboratory to investigatethe application of microarrays within theareas they oversee— the Center for DrugEvaluation and Research (CDER) onhuman drugs, the Center for BiologicsEvaluation and Research (CBER) on bio-logics, the National Center for ToxicologicalResearch on toxicity of regulated products,the Center for Food Safety and AppliedNutrition on foods, the Center forVeterinary Medicine on animal feed anddrugs, and the Center for Devices andRadiological Health (CDRH) on medicaldevices—to better understand how thesedevices perform in the laboratory.

Although the FDA is committed toembracing microarray technology, it haslimited experience in reviewing data forproducts developed using microarrays.Many questions remain unanswered, inpart because drug manufacturers have notyet begun making submissions that includedata derived from these platforms.However, the FDA must develop or acquirethe scientific expertise needed to review

these submissions, and one way to addressthis is to reach out to industry and acade-mia for assistance.

Setting standardsOne of the main problems facing the FDA isa lack of standardization in microarraytechnology—both in the different microar-ray platforms used and in the statisticalprograms employed to analyze or mine thedata produced. There is also a lack of infor-mation regarding the reproducibility ofmicroarrays from different manufacturedlots (and even between chips within thesame lot) and from different laboratories.

To encourage the submission and dissemi-nation of genomic information, CDER hasproposed a regulatory mechanism, formerlycalled a ‘safe harbor,’ but now more appropri-ately termed ‘submission requirement.’According to this proposal, sponsors can sub-mit exploratory nonclinical and clinicalgenomic data based on microarrays to theagency. Exploratory data are usually not usedin decision-making by sponsors or theagency, and are not intended to be part ofclaims made in the usual core safety and effi-cacy data sets. Rather, they would becomepart of a knowledge database from which theagency would learn and which would also be

shared with the public. This mechanismwould be consistent with the interpretationof current regulations and guidances andwould enable pharmaceutical manufacturersto more freely generate and then submitexploratory genomic data on drugs under anInvestigational New Drug (IND)Application. The agency would establish anInterdisciplinary Review Group to examinethe results of exploratory genomic studiesthat would be submitted as part of an INDapplication (or New Drug Application) as a‘research information package.’ This reviewgroup would develop public and transparentprocesses with advisory committee oversight.Until such time that genomic data submittedin this way are considered predictive, reliableand relevant, the agency would not take anyinappropriate adverse regulatory action, suchas clinical review holds or requests for addi-tional studies, against a manufacturer thatsubmits these data. Until more is knownabout what questions microarrays can actu-ally address, the quality and reproducibilityof genomic measures and the ability to pre-dict adverse drug events and efficacy inpatients, this regulatory mechanism couldserve as an interim process to more freelyexchange data and develop and learn from agenomic database. The CDER is in theprocess of defining thresholds for determin-ing when genomic information representsvalid and relevant information, the scientificprinciples that characterize exploratory ver-sus valid genomic data and the regulatoryprocess by which a sponsor can take advan-tage of this mechanism. The FDA intends todevelop a draft guidance for industry todescribe this mechanism in more detail andis planning a public workshop to review thecomments about the draft guidance.

There has been a successful precedent foran exploratory mechanism in centers otherthan CBER and CDER. CDRH uses the pre-Investigational Device Exemption (pre-IDE) submission route to accomplish asimilar goal for in vitro diagnostics (IVDs).The pre-IDE is an investigational protocolused by the manufacturer to evaluate theperformance of their device. The manufac-turer submits the protocol to CDRH, andsubsequently meets with the center to get

Microarray data—the US FDA, industryand academiaJoseph L Hackett & Lawrence J Lesko

Joseph L. Hackett is in the Office of In VitroDiagnostic Device Evaluation and Safety,Center for Devices and Radiological Health, USFood and Drug Administration, Rockville,Maryland 20850, USA, and Lawrence J. Lesko isin the Office of Clinical Pharmacology andBiopharmaceutics, Center for Drug Evaluationand Research, US Food and DrugAdministration, Rockville, Maryland 20857,USA. e-mail: jlh@cdrh.fda.gov

Exploratory data are usually notused in decision-making bysponsors or the agency, andare not intended to be part ofclaims made in the usual coresafety and efficacy data sets.

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feedback that is nonbinding and does notobligate them to undertake any specificactivity. As in the CDER ‘submissionrequirement,’ CDRH will not take actionagainst a manufacturer after reviewing theprotocol. The pre-IDE serves to establish adialogue between the manufacturer and theFDA. If a drug were, for example, indicatedfor specific subpopulations of patients—only patients identified through evidenceabout drug safety and efficacy during thenew drug development process as poordrug metabolizers—CDER could mandatethe use of an IVD prior to approval, and theIVD would have to be cleared and approvedby CDRH. In those situations, collabora-tion among IVD manufacturers, drugdevelopers, and the FDA at an early stage inthe drug development process wouldincrease the likelihood that the IVD couldbe validated for performance and utility ina clinical setting to the agency’s satisfaction.

FDA reaching outThe FDA has initiated a major outreacheffort to tap the knowledge of experts inindustry and academia to better enable it tomake regulatory decisions. The agencyschedules presentations by speakers fromindustry and academia, and sponsors inter-nal invitation-only seminars and externalopen workshops with industry on a widerange of genomics issues. Efforts to obtainspeakers on genomics from industry and aca-demia continue. These activities occur at alllevels in the agency from a branch within adivision, to an office within a center, right upto the commissioner’s office. The agency alsouses several advisory committees composedof experts, primarily from academia, to pro-vide advice and recommendations on com-plex submissions containing genomicinformation. The agency can add new mem-bers with experience in genomics to its vari-ous advisory committees as the field matures.

An example of outreach activity was a two-day workshop jointly sponsored by the FDAand the pharmaceutical industry(Pharmacogenetics and Pharmacogenomicsin Drug Development and RegulatoryDecision-Making, University of Maryland,Shady Grove Conference Center, Rockville,MD, USA, May 2002). Participants at thisworkshop included agency officials, thePreclinical Safety Committee (DruSafe) of thePharmaceutical Research and Manufacturersof America (PhRMA; Washington, DC), andthe PhRMA Pharmacogenomics WorkingGroup, which consists of scientists activelyengaged in pharmacogenomics, with an equalnumber of attendees from the FDA and indus-

try. During the second day of the workshop,breakout discussion groups met to discussfour topics: first, genomic testing and dataquality; second, preclinical pharmacology andsafety; third, early clinical pharmacologydevelopment; and fourth, clinical trial safetyand efficacy1.

Both the FDA and the industry found theworkshop mutually beneficial. For example,the concept of a safe harbor (outlinedabove) was first proposed at the workshopby the FDA. One conclusion drawn fromthe conference was that at present little orno data demonstrate that any pharmacoge-nomic test would be completely reliable,have acceptable precision and accuracy andwould be clearly validated for patient selec-tion or predictions of clinical outcome. Thegeneral consensus was that neither drugcompanies nor the FDA are interested inreplacing more traditional toxicologicalstudies with toxicogenomic approaches asthe basis for assessment of toxicological riskfactors and regulatory decision-makingbecause the genomic approaches have notbeen scientifically validated. Rather, toxi-cogenomics will more likely be used to helpdesign better toxicology studies and selectthe best drug candidates. One recommen-dation was that scientists and regulatorybodies continue to hold open discussionsand dialogues as the science evolves.

In addition to pharmacogenetics/phar-macogenomics, the agency expects toreceive submissions for products incorpo-rating microarray data in other areas includ-ing antiviral therapeutics, and the diagnosisof cancer, infectious diseases and geneticdisorders. Although the agency has had con-siderable expertise in reviewing submissionswithin these subject areas, the challenge forthe future is to understand the relevance ofmicroarray data and evaluate productsincorporating the high-throughput datagenerated using microarrays. The agencyhas provided for comment a draft guidanceon preparation of submissions for devicesthat incorporate multiplex (microarray)testing (http://www.fda.gov/cdrh/oivd/guid-ance/html).

The agency sees continued interactionsbetween itself, industry and academia as acritical activity in its regulation of high-throughput microarray technology, ensur-ing that the FDA is able to bring microarraytechnology into the clinical and laboratorymarket in a timely and efficient manner2.

1. Lesko, L.J. et al. J. Clin. Pharmacol. 43, 342–358(2003).

2. Petricoin, E.F. et al. Nat. Genet. (suppl.) 32,474–479 (2002).

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