Personalized Medicine’s Perception Gaps. A new report released this week by the biopharmaceuticals company Quintiles (pdf) examines the perspectives of four key stakeholder groups – biopharma executives (n=200), managed care executives (n=153), physicians (n=503) and patients (n=1,000) – across a wide range of personalized medicine issues.

The report contains a number of interesting statistical nuggets about how these groups perceive their strengths, weaknesses and future role in the advancement of personalized medicine. These include the following:

• Only 44% of biopharmaceutical executives believe that their organization provides “readily available” outcomes data to demonstrate the value of medications;
• Healthcare professionals generally agree (65%) that patients who seek out information on their own achieve better health outcomes, but more than a third (36%) believe that patients are more frequently misinformed than they were five years ago;
• Fewer than half (44%) of doctors surveyed are optimistic that the quality of healthcare will be significantly improved over the coming decade; and
• At least a third of payers (33%) and biopharma execs (38%) believe that personalized medicine will have a negative effect on job and healthcare discrimination (this despite the passage of 2008 legislation (GINA) designed to prevent discrimination on the basis of genetic information in both cases).

Perhaps the most surprising finding of all is that patients appear to be largely unfamiliar with the entire concept of personalized medicine. Only 24% of patients surveyed had previously even heard of “personalized medicine,” indicating that healthcare companies and providers alike have considerable work remaining in order to bring personalized medicine into the mainstream.

The report concludes that there is “considerable misalignment among healthcare stakeholders on various aspects of the healthcare universe.” According to the report, physicians are frustrated by payers, payers are frustrated by a complex and ill-suited regulatory regime, biopharma executives are torn between maximizing health outcomes and maximizing value to shareholders and patients are “viewed by all groups as not doing enough to improve their own healthcare.”

Clinical Trial Innovations. One major barrier to the development of increasingly personalized therapies is clinical trial recruitment. The more personalized the therapeutic or diagnostic tool in development, the more difficult it is to locate patients who satisfy the trial’s enrollment criteria.

Enter PatientsLikeMe, the patient-driven health platform, which this week announced a new feature to help match patients with clinical trials more effectively. PatientsLikeMe’s new tool will query a government database of ongoing clinical trials (ClinicalTrials.gov) and “automatically match up members of the website with every clinical trial they may be eligible for based on their conditions and location.”

Also this week, pharmaceutical giant Pfizer announced a new form of “virtual” clinical trial which, according to NatureNews, will lower barriers to clinical trial enrollment by allowing “participants to receive medication, video-conference with clinicians, and report symptoms in the comfort of their own home.”

The announcements from Pfizer and PatientsLikeMe are just the latest in a serious of innovations seeking to leverage digital and social media tools to encourage more widespread and efficient personalized medicine research.

Personalized Medicine and Cancer. Despite the many challenges it faces – from scientific complexity to regulatory, reimbursement and intellectual property regimes ill-equipped to accommodate innovation – the present and future of personalized medicine was on display this past week as thousands gathered in Chicago for the annual American Society of Clinical Oncology (ASCO) meeting (see previous news).

To help us keep up with the latest developments in oncology, Luke Timmerman of Xconomy offered a detailed wrap-up of the major developments announced at ASCO by U.S. companies. In addition, at the Consumer Genetics Conference in Boston this past week, Illumina CEO Jay Flatley announced cuts in the company’s pricing for individual whole-genome sequencing, including an attractive $10,000 price point for tumor-normal pair sequencing of cancer patients. Finally, Matthew Herper of Forbes elegantly recapped outgoing ASCO president George Sledge’s big-picture perspective on “cancer’s new era of promise and chaos.”

Whatever the challenges, it remains clear that opportunities abound for personalized medicine companies and investors. A new survey from PwC’s Health Research Institute found that consumers are willing to spend approximately $13.6 billion per year of their own money on healthcare services. It found further that more than three-quarters (76%) of the Fortune 50 is comprised of either healthcare companies or companies with a health division.

Roundup of tweets from the intersection of genomics, personalized medicine and the law:

• Troubling: 1/3 of managed care execs think personalized medicine will have negative effect on job/healthcare discrimination #quintiles
• Sad that more than 56% of MDs think that quality of healthcare will improve over next decade #quintiles
• MDs agree (65%) that patients who seek out information achieve better health outcomes, but 36% worry about patient misinformation #quintiles
• Also, managed care execs appear to have a dramatically inflated view of the value they add in educating/understanding patients #quintiles
• Note that only 44% of biopharma execs say outcomes data readily available to support value of new medications #quintiles cc @wilbanks
• Quintiles healthcare report is goldmine of data on MD, pharma, managed care & patient views http://bit.ly/jBNzx5 HT @cwhogg
• 76% of Fortune 50 companies are in healthcare or have a health division: http://bit.ly/iZaw6x HT @FierceHealth
• Re: last tweet, HIPAA as a floor, & not preemptive, will make compliance/sharing more difficult cc @wilbanks @danielg280
• Michigan court rules state law trumps HIPAA data disclosure/privacy provisions: http://bit.ly/jmeCkE
• The @Forbes NGS piece is garbage, but @matthewherper’s piece on genomic medicine & cancer remains a #mustread: http://onforb.es/iuOHrX
• Glad to see it. Hopefully would-be investors read to bottom. RT @matthewherper: I added my thoughts on the post. We agree (not surprising.)
• Health app accelerator @Rock_Health funds 11 startups, including @genomera: http://bit.ly/jWoJcI HT @InVivoBlogEllen
• Includes this gem: “[NGS] will also open door to creating superhumans w/ unusual intelligence or physical skills.” Really? @matthewherper?
• Unimpressed by @Forbes NGS article which amounts to advert for two cos ($ILMN, $LIFE) in which author holds shares: http://onforb.es/mr2jpx
• HHS releases add’l details on NIH reorg needed to produce NCATS, incl. proposed budget of $722M: http://bit.ly/makQKQ
• More clinical trial innovation: $PFE’s online-only trial aims to lower participation barriers: http://bit.ly/kX5P7B HT @bmahersciwriter
• Cont. innovation from @patientslikeme, using ClinicalTrials.gov to improve patient recruitment: http://bit.ly/joJuiP by @RyanMFierce
• My #sonyc slides from last night are online: http://bit.ly/ldIXMO Did my best to cover personal genomics in 5 slides.
• MT @LouWoodley: If you missed last night’s #sonyc on Science+Law it is now online: http://bit.ly/l4QCsO HT @science3point0
• RT @BiotechPatent: SCOTUS affirms clear & convincing standard for invalidity defense in #patent challenge http://tinyurl.com/44ga9b8
• Belated update re: House hearing on FDA med device approvals, feat. testy exchange with Shuren: http://bit.ly/m6TrhL HT @dgmacarthur
• Prev article on AUS nobel / genome publication mistakenly implies US law (GINA) prohibits life insurers from using genetic info. It doesn’t.
• RT @dgmacarthur: Awesome – Australian Nobel Laureate announces plan to publish his complete genome on the internet: http://bit.ly/j8yJyi
• Agenda here: http://bit.ly/jRmhfd Anybody live-tweeting? RT @FierceMedDev: Hatch, Hamburg, Shuren speaking at MDMA.
• Interesting. 63% (n=2137) said “yes” to FMR1. RT @PHGFoundation: Should babies be screened for untreatable disorders? http://bit.ly/k50xx8
• RT @DailyNewsGW: Roche, Merck Partner on Cancer Therapy Diagnostics: http://bit.ly/kRaB7o
• Genetic privacy may be doomed, as @razibkhan argues (http://bit.ly/jKKUY0). Question is, will that matter and, if so, what are our options?
• “Suggests online collection of self-reported data in recontactable cohort may be viable method for broad & deep phenotyping in large pop’n”
• MT @mary_carmichael: Just read @23andMe GWAS replications paper-in-progress. Neat stuff there. Congrats, @nkeriks! http://bit.ly/m0YJwb
• RT @dgmacarthur: Post on the wondrous Cambridge BioResource by @elainewestwick: http://bit.ly/ljKGjp (I’m in there too!)
• Wonderful time at #sonyc event on science & law w/ @SLSingh et al. Thx to @LouWoodley @JeanneGarb @j_timmer & rest of @S_O_NYC for invite.
• Although, to be fair, $10K for tumor/normal pair does represent a more significant price drop for $ILMN. #cgc2011
• Wonder how much extra $ILMN capacity is due to emergence of $GNOM, which is targeting $4K by 2nd half of ’11: http://bit.ly/iNrqo3 #cgc2011
• The fact that the WGS floor only dropped $2K (non-clinical drop is $10K) may be better indicator of ILMN capacity #cgc2011
• Here’s today’s $ILMN presser on WGS pricing: http://bit.ly/l9IPmB Compare to last June: http://bit.ly/j8KLeu #cgc2011
• Wish I could be at (or at least following along) #cgc2011. Follow @wimufi @davidpendletonk @RDGene & others for live tweets
• Ready for the $1K genome? 3 great posts @genomesunzipped: http://bit.ly/l7kQYEhttp://bit.ly/iqnH6vhttp://bit.ly/jfYNj1
• Pfizer ($PFE) investing $100m in Boston research collab; another attempt to bridge “valley of death”: http://bo.st/iFUcip by @Globecarolynyj
• Done panicking cell phone users, WHO shifts focus to genomic “grand challenges” for developing world: http://bit.ly/mfucTd
• Another NGS play: “sequencing by expansion” RT @DailyNewsGW: Stratos Genomics Raises $2.1M: http://bit.ly/jCzLXX
• Looking forward to participating in tonight’s #sonyc panel on Science & the Law w/ @SLSingh et al. http://bit.ly/koLQ6c
• Sen. Sanders introduces legislation (again) to reward new drugs with cash prizes, not patents: http://bit.ly/lcgm5S
• Updating the DTC Debate: Trial by PR, More FDA Letters, the Problem of Pleiotropy & New RUO Guidance http://bit.ly/jXJzHh
• RT @EdwardWinstead: RT @matthewherper: Cancer’s new era of promise and chaos. #ASCO11 #genomics http://onforb.es/jNZVtr
• Chicago for #ASCO11 to discuss current state of DTC genetic testing. For those not here, an update: http://bit.ly/jXJzHh
• RT @Sagebio: disclose full results and data to address epidemic of false claims; J. Ioannidis in SciAm http://bit.ly/jsaxDZ
• Rescheduled House committee hearing on FDA/medical devices to be held tomorrow: http://bit.ly/iDRdzz
• Follow @DNAlawyer for #UVAGEL tweets http://bit.ly/jcnHFv Muin Khoury arguing “no sci foundation” for personal genomics, incl. PGx?
• RT @dgmacarthur: More press-release scare-mongering about personal genomics – my response: http://bit.ly/j0VWxf
• NYU opening Center for Genomics and Systems Biology tomorrow: http://bit.ly/jnYIbB HT @DailyNewsGW cc @S_O_NYC
• Looks like a great program. RT @DNAlawyer: UVA GEL symposium is tomorrow and Thursday. I’ll be there. http://bit.ly/jcnHFv
• Interesting GINA proposed as a model. Focus on use makes sense; outright ban doesn’t. Health & genetic data must be used, just used properly
• NYT examines health data privacy, re-identification & control. http://nyti.ms/jlgEeu HT @FierceHealth
• MT @mary_carmichael: Study: “strong link b/w happiness & 5-HTT:” http://bit.ly/mHXjP3 More news, green jelly beans cause acne: xkcd.com/882/
• ESHG annual conf starts today, incl. plenty of anti-DTC genetic testing sentiment: http://bit.ly/iZ7fnd HT @shwu
• FDA mtg to nominally focus on analytical validity for NGS. But that’s only one part of broader debate re: FDA & next gen of clinical tools.
• More FDA: on 6/23, FDA holding public meeting on use of NGS platforms in clinical setting: http://1.usa.gov/liUKNg
• Summary of April’s FDA strategic priorities plan by@GENbio: http://bit.ly/iRhcZa Very high level, funding a challenge.
• amednews on the coming regulation of FDA medical apps: http://bit.ly/lshHTQ HT @GeneSherpas cc @mobilehealth
• Asked as an aside: how would FDA regulate Dr. Watson? (Not as far off as it appears. WGS Dx software coming soon, poses similar challenge.)
• For more on Dr. Watson, highly recommend this Feb piece from @PGxReporter: http://bit.ly/iF3VNC Major need: better data collection, sharing
• IBM’s Watson now “as good as smartest second year med student”; widespread use still 8-10 yrs out http://onforb.es/llIAO2
• 1st issue (& t-shirts) already out. RT @wilbanks: Citizen Science Quarterly, a CC licensed journal. via @doctorow http://bit.ly/lLGYjw
• British Columbia court rules against anonymous sperm & egg donation. Will rest of Canada follow suit? Will US be next? http://bit.ly/jTJADw
• Here’s the link to the survey on “the informational aspects of genetic tests” (takes ~5 min): http://bit.ly/kZjjdD
• Genetics of CF severity, a survey of DTC customers and the value of a genetic diagnosis from @genomesunzipped: http://bit.ly/mTYMQi
• Telomeres predicting lifespan? Blackburn: “that’s just silly, isn’t it?” Interview w/ @NatureNews on future of field: http://bit.ly/kEmbwp
• Update on Patent Reform Act progress in Congress from @GENbio: http://bit.ly/jZHH0l
• Poor job by NYT failing to link DNA fish fraud story to earlier teen citizen scientists http://nyti.ms/jh49yA @matthewherper @leonidkruglyak
• RT @DailyNewsGW: $MYGN Teams with Topin to Market OnDose to Oncologists: http://bit.ly/merPqJ
• $GNOM continues to raise more $, talk expansion: http://bit.ly/mwUb06
• Facebook & pharma seeking to sort out social medial policy: http://bit.ly/lek4cG
• RT @wilbanks: Bob Cook-Deegan, a living legend in the gene wars, talks about gene patents. Read. http://bit.ly/lT2n3O
• And on a Friday to boot. RT @Duncande: With my full genome sequenced (by PGP at Harvard & $GNOM), I’ve been designated “PGP 13″ – lucky 13!
• Good question MT @blaine_5: DTC ELSI issue: why aren’t bone marrow donors informed of risk of genomic analysis by bone marrow recipients?
• Authors: “to delay policy-making decisions until all poss qs answered wrt DTC unrealistic given state of field.” I agree. HT @eurogene
• Good NEJM back-&-forth re: Bloss, @EricTopol, et al.’s Feb article on effect of DTC genetic testing: http://bit.ly/lhhqbj
• Genetic Technologies Sues 10 Firms for Infringement on a Method to Determine Haplotype: http://bit.ly/imgHmE HT @blaine_5
• Inspection, Compliance Data Disclosure to Be Widened by U.S. FDA: http://bloom.bg/mJEyCi
• Survey: 2/3 of small med device & Dx firms prefer EU in seeking 1st regulatory approval. Shuren: “we’re on it”: http://bit.ly/kIjqkD
• RT @PGxReporter: In latest PGx pact w/ Population Genetics, Quintiles aims to save Pharma money & time http://bit.ly/lFbogm
• RT @PHGFoundation: Retention of cleared suspects’ DNA by police ruled unlawful http://bit.ly/lRfyIN
• +1 RT @genetics_blog: neat RT @moorejh: Topic map of all grants awarded by the #NIH in 2010 http://is.gd/IfzuzG
• Good, but won’t WGS soon obviate need for mult tests? RT @westr @DivaBiotech: New Genetic Testing Tech for IVF Embryos http://bit.ly/iHNBPc
• Nuffield launches public consultation on ethical/social issues arising from emerging biotechnologies: http://bit.ly/lf07df
• RT @rzeiger: Interesting Google job to run internal health + wellness programs. Ping me if u want to learn more http://goo.gl/ULPvF
• RT @girlscientist @ClinSeqNews: HudsonAlpha Researchers to Sequence Immune Repertoires of 10K Indiv. for 100 Diseases http://bit.ly/kQmHH3
• From Toll House cookies to gastrointestinal diagnostics. RT @DailyNewsGW: Nestle Health Science Buying Prometheus Labs: http://bit.ly/kp1IkI
• RT @InSequence: Life Tech, Gen-Probe to Collaborate on FDA Clearance for Dx Assays on CE Sequencer: http://bit.ly/jH9YiK
• The license out as the biotech end game? MT @ldtimmerman: How to make $ in biotech beyond IPO, M&A http://bit.ly/kczVun
• A new model for @23andMe? @ldtimmerman reports it is rebranding itself as “a research company”? http://bit.ly/k8ImME
• RT @matthewherper: Biopharm execs: We want to focus on the future, but investors won’t let us. http://ow.ly/51GRS
• The challenge of therapeutic success. Or “Innovations of today increase cost of innovations tomorrow”: http://bit.ly/ltLLoj HT @MishaAngrist
• GLR Post: Patent Update: Looking Beyond Section 101 & Continued Murkiness of Method Patents: http://bit.ly/ii5arT
• Precision Quality DNA (recent FDA letter: http://1.usa.gov/mgciWO) has strong feelings re: DTC reg: http://fda.pqdna.com
• Looking forward to some great brainstorming at “The Future of Pathology in Personalized Medicine”: http://bit.ly/ll5LqQ
• Great @DanielSolove column: “Why Privacy Matters Even if You Have ‘Nothing to Hide’”: http://bit.ly/lXG6O7 HT @MishaAngrist
• “The Privacy Challenge in Online Prize Contests” in NYT http://nyti.ms/kFVVgt w/ a HT to @23andMe’s consent form.
• What does the future hold for biotech & VCs? Interesting Q&A in Nature’s bioentrepreneur: http://bit.ly/ki35i3
• First VT, now CA. RT @FierceHealth: Another state considers single-payer #health system http://bit.ly/lTvRec
• RT @FierceBiotech @ScottKirsner: VCs on boards of directors: 1 not enough but > 2 is dangerous. Like martinis. -Bob Higgins @HighlandCapital
• Good. incls dedicated investment to improving reimbursement. RT @DailyNewsGW: UK Groups Investing in Pers Med Projects: http://bit.ly/lbORVW
• +1 RT @matthewherper: Should we just let athletes use performance-enhancers? Why we’re dopes about doping: http://ow.ly/4Zqc9
• Yes, re: NIH budget cuts RT @drjonboyg: the @Battelle & UMR reports show how short sighted that is given huge economic impact of NIH funding
• Collins comments on BGI at end of article also interesting. Maybe NIH funding bump if China viewed as more of a threat?
• Looming NIH budget cuts “sobering”; may drive grant success rate to “lowest in history”: http://bit.ly/jt14vo
• RT @WSJHealthBlog: The CDC’s zombie apocalypse juggernaut: next up, a video contest…..http://on.wsj.com/kShypJ cc @kashhill
• My anecdotal data similarly bleak. RT @DNAlawyer: Anecdotal data: only 2 of my undergrad students @ Duke heard of GINA before I covered it.
• Two comments: 1) pre-06/07 DTC surveys tough to compare to post-07 DTC surveys (diff products). 2) wish some actual data on GINA awareness.
• Oregon has collected data on state-led pop’n surveys of genetic testing use/awareness: http://1.usa.gov/mTMmRj HT @ewencallaway
• RT @dgmacarthur: Joe Pickrell’s discusses potential artefacts in the Science RNA-editing paper at @genomesunzipped: http://bit.ly/jUVz6t
• Note $MYGN’s planned EU expansion to begin in Germany. New Gene/Myriad headed for conflict? Prev GLR: http://bit.ly/fylYeL
• NewGene’s NGS-Based BRCA1 & BRCA2 test coming to France, Germany http://bit.ly/lXZmxk HT @MattMealiffeMD @BRCAscoop
• Missed ind. research results (IRR) & incidental findings (IF) conf (http://bit.ly/epMlQm)? Great live tweets by @genome_gov et al. #ifirr
• RT @bigs: keep liking NIH’s Kathy Hudson more & more. ‘what we want is for every (person) to be a (research participant) as well’ #IRBreform
• RT @Erika_Check: Pickrell will be posting more on possible artifacts in DNA/RNA mismatch study tomorrow @GenomesUnzipped.
• RT @Erika_Check: DNA/RNA mismatch story getting more interesting. Joe Pickrell: “many of the results reported are potentially artifactual”
• Surprised? RT @GENbio: Pres bioethics panels sometimes choose topics driven by political pressure than scientific need http://bit.ly/iIYhdN
• NIDS Eyes Next-Gen Sequencing Needs: http://bit.ly/mRQohw
• Looking forward to @crossborderbio ongoing series on “Valuation and Other Biotech Mysteries”: http://bit.ly/j8Sb5R
• RT @matthewherper: @BiotechPatent This Forbes writer thinks the idea that medical prices are closely connected to dev costs is wrong.
• Forbes columnist takes aim at impending medical device tax: http://onforb.es/jJdYIb HT @BiotechPatent
• Stem Cells: The growing pains of pluripotency: http://bit.ly/m077oj Excellent, comprehensive piece by @Erika_Check
• RT @LifeSciVC: Good to see positive trend. RT @nvca: Venture Capital Performance Continues to Improve http://bit.ly/klA8fi cc @JCainHart
• Intrigued by @HelicosUnveiled (http://bit.ly/iqLNz5) which appears to be unsanctioned PR for Helicos. Other exs of this?
• RT @EdwardWinstead: Timely… Eric Lander at NIH 5/20 11:30 a.m.: From the ‘Genetic Code’ to the ‘Genetic Code’ webcast
• Enough frustration to actually produce change? RT @NatureNews: US panel calls for reform in human subject protection http://goo.gl/fb/kS28S
• RT @MattMealiffeMD: RT @adamfeuerstein: The thing you will mostly notice about #ASCO11 abstracts is that there isn’t a ton of new data.
• RT @genome_gov: Joseph Thankuria – Informed Consent, Biobanking, and Data distribution in the Personal Genome Project #ifirr
• I look fwd to “intense criticism” forecast by @dgmacarthur. MT @Erika_Check: DNA/RNA mismatches challenge central dogma http://bit.ly/ijeWvd
• A personal genomics challenge from @blaine_5 to @genomesunzipped readers (& the rest of you as well): http://bit.ly/jUeXqB
• Telome Health suggesting monthly telomere checkups? http://bit.ly/ldvZpD (see sidebar) Great business model if you can sell it.
• Yes. Life, disability & long-term not covered by GINA (state rules vary) RT @drjonboyg: @genomicslawyer except for long term life insurance!
• Also, I don’t understand the confusion/concern about telomere testing (DTC or otherwise) & discrimination. Clearly covered by GINA.
• On DTC telomeres, #1 I would not be surprised to see another round of “come meet with us” letters from the FDA.
• While the Post tackles DTC athletics, the NYT is featuring an even newer DTC fad: telomere testing: http://nyti.ms/kKtk77
• Canada pursuing its own version of GINA (genetic nondiscrimination legislation): http://bit.ly/iA8bjC HT @mikesgene
• Medco Drug Trend Report predicts cancer drug spending could rise up to 15%/year through 2013: http://bit.ly/ioLIPn
• RT @MichelleNMeyer: @drjonboyg & @genome_gov live tweeting conf on return indiv research results (IRRs) & incidental findings (IFs) #ifirr
• HT to CDC for realizing that best way to teach emergency preparedness is via zombie apocalypse: http://on.wsj.com/kkAD0W
• Rob Stein tackles DTC genetic testing for child athletes in today’s Post: http://wapo.st/lsrkpH AIBS just received FDA ltr
• PGP-1K continues progress. MT @Duncande: It’s official, my complete genome has been sequenced! Thx to PGP (@PGorg) & $GNOM
• Chinese biotechs wrestle with transparency, cultural hurdles (NBT): http://bit.ly/jw3zcU (And you think it’s tough here)
• Interesting post on @23andMe, data sharing and “the altruism instinct”: http://bit.ly/jHfkG1
• More med companies adopting social media (& policies), but 52% say lack of FDA guidance impeding uptake: http://bit.ly/jC1tE0
• RT @MishaAngrist: ENCODE gets ENGORGED http://bit.ly/kvs7S7
• 1K genomes project update from @InSequence: http://bit.ly/lesrH3 WGS & exomes for 1K ppl, another 1K+ on the way
• Genomic Health repaid $800K in royalties due to Incyte’s failure to maintain IP: http://bit.ly/j3H1PN Lesson: pay the PTO on time
• U of Washington, Pharmigene resolve IP dispute around warfarin dosing, agree to license: http://bit.ly/joZucZ
• RT @ldtimmerman: Hood: I despair whether in US we can sequence enough ppl, families. China will. IRBs too much of an obstacle here isb2011p4
• RT @ldtimmerman: Schadt talked all about PacBio machine, not Mt. Sinai, or Sage, to this high-science audience #isb2011p4
• Good overview in NBT of NGS providers & why they are eying clinical seq as their next market opp: http://bit.ly/lYUGRS
• RT @PGxReporter: Medco to Evaluate Clinical Utility of AssureRx’s PGx Test in Guiding Psychiatric Treatment: http://bit.ly/lWZWvL
• RT @dgmacarthur: How a @23andMe test profoundly changed a woman’s life in two very different ways: http://bit.ly/jbO7Yq
• #ASCO11 abstracts come out today. @brianreid has a modest proposal to ‘socialize’ the process for 4,000+ abstracts: http://bit.ly/lZMCzy
• Upcoming debate b/w Phil Sharp & Stephen Friend (moderated by @ldtimmerman) on pro/con of open source biology: http://bit.ly/jshQ77
• European Society of Cardiology says Europe needs a “single, coordinated” system for regulating medical devices: http://bit.ly/iCelNF
• Some candid advice from @LifeSciVC on how to pitch a biotech startup to VCs: http://onforb.es/jwO8LP
• Genetics as Culture in a Consumerist Age: http://bit.ly/kPvgiX Submit a poster/presentation & come join me in Innsbruck.
• Some good talks over the weekend at #ISB2011P4, tweeting supplied by @ldtimmerman, @finchtalk, etc.
• RT @MishaAngrist: Does Pac-Bio have a PR problem? http://bit.ly/jUAFar $PACB
• Here’s @ldtimmerman detailed take to the Schadt/$PACB/Mt. Sinai move: http://bit.ly/k2xjI8 Good to see more genomics $/talent coming to NYC
• AMP position statement recommends against using brand names in companion Dx labeling: http://bit.ly/mjbpPi by @SampleGW
• RT @Sagebio: “a brilliant rebel in the field of genomics” A. Pollack on Eric Schadt move to Mnt Sinai http://nyti.ms/lIwJ7S
• RT @RyanMFierce: More buyouts to come? RT @FierceBiotech: PerkinElmer acquires Labtronics, buyouts pile up. http://bit.ly/l5owst
• Short @techreview piece on another nanopore-based seq play, Noblegen: http://bit.ly/kqAs25 Gaudy goal: 30 genomes, 15 min
• Lumigenix FDA/DTC letter (http://1.usa.gov/jxBtS6) far more conciliatory in tone than similar letters last summer (http://bit.ly/aGpLU0)
• Australian DTC company @Lumigenix receives FDA inquiry letter: http://1.usa.gov/jxBtS6
• Health Insurers Making Record Profits as Many Postpone Care: http://nyti.ms/k1jwBs via @twilli2861
• Summary of Battelle report on economic impact from Human Genome Project from @drjonboyg / @genome_gov: http://1.usa.gov/itBVMr
• RT @JohnCFierce: In-depth article from Forbes on the development of India’s biotech hubs. http://onforb.es/iesQxC
• Verghese op-ed (http://nyti.ms/mD8twZ) led to post on ‘iPatient’ (http://bit.ly/lqqR5M). Lots of work to do redefining what “patient” means.
• Hah RT @bmahersciwriter: I’m so tempted to buy plush microbes from the CSHL gift shop. Wife: What did you bring me? Me: Chlamydia. bg2011
• Detailed summary of FutureMed Day 1 from @Medgadget http://bit.ly/kq1XIc HT @daniel_kraft & congrats to @tgoetz on his new company, 1+1 Labs
• RT @matthewherper: Beating Moore’s Law Since January 2008! My post on bg2011 http://ow.ly/4U4u8
• In context, this is incredible. MT @lukejostins: GM on 1000 Genomes Project. Now have 1094 whole-genome, 977 exomes, 1542 2.5M chips BG2011
• MT @dgmacarthur: GM: Feb 2000, 98% of SNPs in sequenced individual were novel. Now # is down to ~1%. bg2011 (Gabor Marth on 1K Genomes proj)
• 41yo woman w/ BRCA mutation & recent history of Breast Cancer (NEJM): http://bit.ly/isJG0O Interesting patient perspective on testing, risks
• How to calculate your own Alzheimer’s risk, based on genetic and environmental data http://bit.ly/jZ5Dlh @genomesunzipped by @lukejostins
• RT @dgmacarthur: Key message from the meeting so far: we are assigning function to non-coding variation at an astonishing rate. bg2011
• Great idea. See @matthewherper’s latest for related. RT @bigs: Teller proposes ‘sequencing the human lifestyle’ in add. to genome #futuremed
• RT @matthewherper: What should we sequence after the genome? Mark Changizi has an interesting answer: http://onforb.es/iqmBu6
• Also includes working catalog of other public genomic data RT @razibkhan: Ashkenazi 23andMe v3 genotype for the taking: http://bit.ly/iCiKPE
• RT @genome_gov: Watch NHGRI’s Advisory Council meeting May 16, 8:30 a.m. Webcast: http://bit.ly/jsFeIA. Agenda: http://1.usa.gov/mvmMTs.
• GLR Post: New Diagnostic Guidelines & DTC Testing for Alzheimer’s Disease: http://bit.ly/mHDi6Y
• SAS forming “think tank” to look at how healthcare & life sciences cos use its analytics software: http://bit.ly/ldjJeW via @RyanMFierce
• Latest on Fabrazyme dispute: patients allege Genzyme diverting ltd drug supply to European patients: http://bit.ly/kMs3nG
• Good q. Payors have leverage, GH knows it. RT @MattMealiffeMD: can you be both payors “agent” & “neutral arbiter”? http://bit.ly/jpt0KB
• CardioDx closes out Series E to the tune of $60M, will focus on expanding reimbursement coverage: http://bit.ly/k2uvyp
• Generation Health program tackles two key challenges: lack of transparency (runs in both directions) & lack of data. Here’s hoping it works.
• Generation Health launches ambitious pilot program to bridge the gap b/w Dx providers & payors: http://bit.ly/jpt0KB
• MT @dgmacarthur: analyses of early @iontorrent data by @pathogenomenick (http://bit.ly/miHnoj) & Keith Robison (http://bit.ly/jYemtG)
• Interesting @NatureNews piece on Anil Potti & how scientists view & manage their online reputations: http://bit.ly/iHFAx8
• $GNOM update: a backlog of genomes (>2k) & plans for aggressive pricing, new machines & ~1K genomes/month by year end: http://bit.ly/mCeeJC
• RT @PGxReporter: Continuing Push to Diversify Offerings, Myriad Licenses Chronix’s Early Cancer Detection Technology: http://bit.ly/ijzK1t
• Is public’s (not scientists’) reluctance to question Bin Laden DNA ID evid. of genetic exceptionalism? http://bit.ly/jCG7me by @Erika_Check
• VA db a great potential resource. Too bad it’s relatively closed & researcher-only (i.e., no EHR linking or participant data return)
• Veterans Affairs to create genomic research database with 1M vets: http://bit.ly/m6zWSg via @PGxReporter
• RT @MishaAngrist: Of 113 med devices recalled from 05-09, 80 (71%) fast-tracked by FDA: http://bit.ly/jLNN2s (via journalistsresource.org)
• $800B or not, Jim Evans says expectations for personalized genomic info remain too high: http://bit.ly/e0eBdA HT @MishaAngrist
• RT @bmahersciwriter: Great piece dissecting the logic of an $800bn return on investment for the human genome http://bit.ly/jW0pAO
• $LIFE-funded study: $800bn = economic impact of human genome project http://on.wsj.com/lnmQkL Report http://bit.ly/mAXixa
• CDER chief Woodcock says FDA expects to issue biosimilar guidance this year: http://reut.rs/j5nlCi
• RT @lukejostins: A conversation with @elainewestwick about sharing data, newborn screening and carrying cystic fibrosis http://bit.ly/mQjdBa
• Settlement in MA wrongful birth case: http://bit.ly/jZSXBt For past GLR coverage: http://bit.ly/9u060V
• RT @InSequence: Granting PacBio’s Reexamination Request, USPTO Invalidates All Four Helicos Patents: http://bit.ly/mT4fZF
• Study on how info affects DTC genetic testing decision: http://bit.ly/ki7QqR Anybody read/have the underlying study?
• RT @dgmacarthur: Have a burning question to ask genome visionary George Church (@geochurch)? Ask away: http://bit.ly/kHX0bF (via @ianholmes)
• PerkinElmer acquires Geospiza (@finchtalk), beefing up software for DNA analysis http://bit.ly/jGYiiM by @ldtimmerman
• Recent case further evid Fed Cir may leave 101 open, tighten other patentability criteria. See: http://bit.ly/gba0FI
• Fed Cir recently invalidated pair of DNA diagnostic patents: http://bit.ly/l411JS Will try to get analysis on GLR nxt wk
• The latest PGM vs. MiSeq ad from @iontorrent is out: http://youtu.be/gStCvyGpnRU Prev discussion here: http://bit.ly/fTkxlD
• Second rd of #FDADTC comments now appearing on regulations.gov (search FDA-20111-N-0066). Expect more in coming days.
• ZyGem, Lockheed developing portable forensic DNA platform: http://bit.ly/kha4Nj Goal: ID next Bin Laden in field in < 1 hr.
• GLR Post: News Roundup: Biotech Funding & LDT Regulation: http://bit.ly/jYTzWz
• This piece on Sulston, the human genome project & the Wellcome Trust by @markgfh is simply fantastic: http://bit.ly/miiX4X
• RT @dgmacarthur: .@nilshomer has joined the genome sharing gang – his @23andMe data are publicly available under CC0: http://bit.ly/lfLM22
• GLR Post: The Next Social Media Revolution Will Occur In…Personalized Medicine? http://bit.ly/lMimh7
• BRACAnalysis drives $MYGN revenues higher; company expects Euro launch in ’12: http://bit.ly/jyQ5Yj
• Supreme Court Case on Script Data Sale Presents ‘Gray Area’ for PBM Personalized Rx Efforts: http://bit.ly/lygTKo
• FTC continues fight against pay-for-delay drug deals, chairman calls them “outrageous”: http://bloom.bg/msSVrG
• RT @crossborderbio: Based on survey of clinical research site pros RT @JohnCFierce: top 10 CROs in CenterWatch survey: http://bit.ly/moqDGu

This will, I believe, mark direct-to-consumer (DTC) genetic testing’s formal debut at ASCO. It should also serve as another reminder that, despite its relatively small numbers (both in terms of dollars and customers), DTC genetic testing continues to exert an outsized influence when it comes to conversations about the future of genomic medicine. This is particularly true when the discussion turns to appropriate policy and regulatory oversight.

In advance of ASCO, here are several items of interest from the past few weeks in DTC genetic testing.

“Trial by Press Release.” That’s exactly what Daniel MacArthur of Genetic Future termed this week’s press release from the European Society of Human Genetics (ESHG) highlighting two presentations on DTC genetic testing at the recent ESHG annual meeting.

The studies themselves have yet to be published, but preliminary findings were meant to provide new evidence that (a) the risk prediction models employed by personal genomics companies are neither perfect nor consistent and (b) clinical geneticists are skeptical of the value of DTC genetic tests.

Neither finding is surprising, although, as MacArthur points out, the first study – from Rachel Kalf of Erasmus University – will need to be published in full before its claims, including the claim that one DTC company (deCODEme) utilizes fundamentally flawed risk prediction models, can be fully vetted.

The desire to encourage greater transparency and consistency among the risk prediction models employed by DTC genetic testing companies has been expressed numerous times in the past (higher-profile examples include current NIH Director Francis Collins, genomic pioneer Craig Venter and colleagues and last summer’s GAO report) and repeatedly embraced by DTC companies themselves (see, e.g., here and here).

When it comes to debating the future of the DTC genetic testing industry there are plenty of areas of legitimate disagreement. For example, should different types of DTC tests (e.g., carrier screening vs. pharmacogenomic testing vs. genetic ancestry testing) which make different types of claims be regulated differently? And how, if at all, should the concept of utility, whether clinical or personal, be incorporated into a genetic test evaluation?

But the need to improve transparency and consistency in DTC risk prediction models already appears to be shared nearly universally among DTC stakeholders.

The second study included in the ESHG release, conducted by Heidi Howard of the University of Leuven, Belgium, includes the finding that 63% of a “representative sample of clinical geneticists” from across Europe “wanted to proscribe whole genome scans carried out by DTC companies.”

That statistic has bounced around the internet echo chamber the past few days, but, again, is it offering us anything we did not already know (or at least strongly suspect)? As MacArthur points out, asking the current cohort of genetic testing gatekeepers how they feel about being sidestepped by genetic testing companies seeking to engage directly with individuals feels slightly rhetorical:

While it is important that personal genomics companies consult with medical professionals in devising their risk prediction algorithms and interfaces, regulation of genetic testing should not be based on the views of the traditional gatekeepers of genetic information.

As both MacArthur and Razib Khan of Gene Expression note, the appropriate question to ask is not whether clinicians believe genetic tests are harmful in the hands of consumers, but whether genetic tests are actually harmful in the hands of consumers.

Thankfully, a growing list of researchers is asking that very question, including Bloss et al. (see also a recent back-and-forth in the NEJM), Kauffman et al. and the recently launched Impact of Personal Genomic Services (IPeG) study (some details here), about which my co-presenter Stacy Gray will be providing more details during today’s panel.

As the Food and Drug Administration (FDA) and others continue to wrestle with the difficult job of shaping DTC regulatory policy, the data generated by these and other studies will be critical in ensuring that any policy which eventually emerges responds to the demonstrated challenges of DTC genetic testing, and not merely to hypothesized harms.

The FDA Sends Three More DTC Letters. Speaking of the FDA, nearly a year to the day after it sent its first letter of concern to a DTC genetic testing company (Pathway Genomics), the agency sent out its latest batch of DTC letters. The recipients this time: Lumigenix, American International Biotechnology Services and Precision Quality DNA.

Much has transpired since that first FDA letter – including many more DTC letters, a Congressional hearing last summer and a closely watched advisory panel meeting earlier this spring – but for now, at least in public, the FDA is continuing to employ the same case-by-case approach to DTC genetic testing oversight it has utilized from the outset.

Not everyone is happy with the FDA’s current approach. One of the most recent companies to receive a letter, Precision Quality DNA, has devoted a section of its company website to the FDA’s handling of DTC regulation, and has published its strongly worded reply to the agency’s most recent letter.

While it would be inaccurate to characterize Precision Quality DNA’s response as representative of the views held throughout the DTC industry, several of the points the company raises – including the need for greater transparency surrounding the FDA’s review and oversight of DTC genetic testing products – seem likely to resonate with other companies, whether they are currently in dialogue with the FDA or anxiously awaiting their own letter from the agency. (A good bet for a future FDA letter: companies offering direct-to-consumer telomere measurement tests, several of which drew criticism in recent weeks for over-inflating the ability of telomere length to predict individual longevity.)

The Latest in DTC Offerings. American International Biotechnology Services (AIBioTech), another company to receive a recent DTC letter from the FDA, found itself under the FDA’s microscope thanks to its Sports X Factor Genetic Athletic Assessment Test. The test purports to “reveal a person’s genetic athletic performance indicators as well as the potential for several risk factors,” including the risk of “negative results after an injury to an individual, such as a concussion,” or the possibility of an “undiagnosed heart condition.”

AIBioTech is not the first company to attempt to combine genetic testing and athletics – we dissected offerings from Athleticode and Atlas Sports Genetics back in 2009 – but the company’s test has received additional scrutiny due to its inclusion of markers for the apolipoprotein E (APOE) gene. The APOE gene, which comes in at least three different versions or alleles (ε2, ε3 and ε4), has been shown to affect an individual’s risk of coronary heart disease, as well as for developing late-onset Alzheimer’s disease.

Providing APOE results directly to consumers raises a host of delicate ethical and legal issues, as we discussed last month when DTC veteran 23andMe unveiled APOE reporting as part of its standard service. AIBioTech has drawn criticism for largely ignoring these issues in offering its athletics-focused test. (This in addition to criticism of the scientific validity of the claims offered up by AIBioTech and other athletic genetic testing companies.)

The inclusion of APOE in the AIBioTech test also highlights one of the frequently discussed challenges of trying to regulate any genetic test – whether DTC or otherwise – on the basis of its claims or intended use. As the proliferation of genomic data continues and our collective genomic understanding grows, the number of genetic markers which exert influence upon multiple traits of varying significance is likely to rise.

APOE’s implication in both heart disease and Alzheimer’s is a classic illustration of the phenomenon of pleiotropy – the ability of a single gene to influence multiple phenotypic traits – although it is hardly the only pleiotropic gene (genes responsible for sickle-cell disease, PKU and albinism, among others, also exert pleiotropic effects). As additional pleiotropic biomarkers are identified, the notion that genetic tests should be evaluated based on their intended use is likely to come under increasing pressure. How, for instance, will regulators address a genetic ancestry test when one or more of the biomarkers employed by the test could be used to predict an individual’s genetic risk for a serious disease? While this dilemma is not a conceptually new one, as the regulatory framework for genetic testing evolves, the nonlinearity of gene-trait relationships seems likely to pose a significant challenge for regulators, clinicians and companies who would prefer the ability to provide precisely targeted genetic test results to individuals.

Regardless, the issue seems likely to be mooted in large part at the point in the not-too-distant future where individuals have routine and early access to complete whole-genome sequences. Then the issue will no longer be whether or how to provide data with the potential to help predict multiple phenotypic effects, but how to exert any control whatsoever on the interpretative tools available (including, perhaps, IBM’s Dr. Watson, which is now reportedly “as good as the smartest second year med student”) to individuals who have access to complete and portable personal genomic data.

Are You Ready for RUO? Finally, one very recent development of potential significance to the DTC industry is the applicability of the just-released FDA draft guidance for research-use-only (RUO) and investigational-use-only (IUO) in vitro diagnostic products.

Published earlier this week, the RUO/IUO guidance clarifies the rules for marketing and commercializing diagnostic products under the widely used RUO and IUO exemptions, which allow device manufacturers to avoid submitting their products under the FDA’s rigorous medical device approval pathway. (For more see this article in Pharmacogenomics Reporter.)

The draft guidance, which is open for public comment for the next 90 days, is a significant event for manufacturers of laboratory developed tests (LDTs), many of which are thought to incorporate RUO/IUO components despite being offered for clinical or diagnostic purposes. Expect LDT manufacturers and industry groups, such as the Association of Molecular Pathology and American Clinical Laboratory Association, to have plenty to say on the RUO/IUO draft guidance before the comment period expires at the end of the summer.

Less clear is what impact the RUO/IUO guidance might have on the DTC industry. As with LDTs, it is not known exactly how many DTC genetic test providers utilize RUO/IUO components in their products. However, the pairing of an RUO or IUO device with a DTC product certainly occurs. For instance, 23andMe utilizes the Illumina OmniExpress Plus in its popular DTC service. The OmniExpress is part of a family of popular DNA microarray products offered by Illumina and labeled for research use only (pdf).

This exact issue appeared last summer when the FDA included Illumina in its first batch of DTC letters following the Pathway/Walgreens dust-up. From our coverage last June:

Of all the companies receiving letters, Illumina is the only one not to offer at least one product directly to consumers (the company does offer a commercial whole-genome sequencing service, although that product requires the participation of a healthcare professional). Illumina’s letter notes that the company has “received FDA clearance or approval for several of its devices,” but not for the HumanHap550 array. “Yet Illumina is knowingly providing the HumanHap550 array to 23andMe and deCODE Genetics for clinical diagnostic use without FDA clearance or approval” despite its being labeled “For Research Use Only.” As Gutierrez notes, “…Illumina has to follow the law, and they are aware that the chips are not being used for research only.”

Although the specific product has changed over the past year, the fundamental issue has not. The new RUO/IUO guidance, if approved in its current form, places a heavier burden on providers of RUO/IUO devices to “not sell such products to laboratories they know use the product for clinical diagnostic use.”

Which brings us back to one of the fundamental tensions concerning DTC genetic testing services: whether such services are intended, at least in the eyes of the FDA, for clinical diagnostic use. While the FDA and DTC genetic testing companies may not agree on the reasonably intended uses of these services, the FDA’s draft RUO/IUO guidance threatens to insert another key player – platform technology providers, like Illumina – squarely into the middle of the DTC debate.

If the FDA continues to maintain that the genetic testing services offered by 23andMe, Lumigenix and other DTC providers are intended for use in clinical and/or diagnostic testing, the Illuminas of the world will find themselves with a difficult choice to make. They will likely be forced to (a) defy the FDA’s RUO/IUO guidance, (b) stop selling their RUO/IUO devices to DTC companies or (c) attempt to shepherd their RUO/IUO devices through the FDA’s resource-intensive medical device approval process.

Or as the FDA puts it:

FDA is aware that laboratories sometimes use IVD products labeled RUO in clinical diagnosis and that many manufacturers, importers, and distributors of IVD products labeled RUO are also aware of such use. Manufacturers who label their IVD products: “For Research Use Only. Not for use in diagnostic procedures,” should not sell such products to laboratories that they know use the product for clinical diagnostic use. If a manufacturer learns that a laboratory to which it sells its RUO-labeled IVD product is using it in clinical diagnosis, it should halt such sales or comply with FDA requirements for IVD products, including premarket review requirements, if applicable.

If it were only DTC companies utilizing RUO/IUO devices, manufacturers like Illumina might simply stop selling those devices in light of the small (current) size of the DTC industry. But because those same devices also appear to be used by a number of LDT manufacturers, who represent a much larger market, there is a strong possibility that RUO/IUO device suppliers like Illumina will seek to obtain FDA approval for those devices, hopefully while working with the FDA to keep those devices on the market in the interim to avoid interruptions to patient care (or, in the case of their DTC customers, consumer product supply).

Regardless, the next few months will bear close watching to see whether the FDA’s attempt to more strictly enforce RUO/IUO labeling results in any significant shift in the relationships between DTC genetic testing companies and their technology suppliers.

What’s Next for DTC? Remember that it was roughly this time last year when Pathway Genomics’ failed partnership with Walgreens kicked off a busy summer of DTC (and related) activities at the FDA and on Capitol Hill. Up until this week, Washington had been relatively quiet since the end of last summer, at least in public. While the RUO/IUO situation bears watching, there are some who expect this summer to bring further fireworks on a par with last year.

While several important initiatives continue to loom as possibilities – including the FDA’s long-anticipated LDT guidance and new diagnostic-focused legislation from Congress – with 2011 nearly halfway gone I continue to think that the prospects for industry-wide regulation of DTC genetic testing in 2011 remain dim.

As the size of the NGS sequencing market grows and an increasing number of NGS purchasers evaluate an expanding array of providers and technologies (see William Blair’s Next-Generation Sequencing Survey), NGS companies are beginning to look beyond price points and product specs in an attempt to stand out.

Ion Torrent on the Offensive. Consider Ion Torrent, an NGS newcomer recently acquired by Life Technologies, which launched its first product (the Personal Genome Machine) a scant four months ago. Since then, Ion Torrent has announced improvements to the PGM’s output, read length and sample prep (coverage from Matthew Herper of Forbes here and here).

As it seeks to distinguish the PGM from its competitors’ products, particularly Illumina’s offerings (see J.P. Morgan’s Next Gen Sequencing Survey), Ion Torrent has added a new dimension to its PGM campaign. Ion Torrent recently launched several creative online advertisements, with its side-by-side comparison of the PGM and Illumina’s MiSeq system—modeled after Apple’s popular “I’m a Mac/I’m a PC” campaign—raising the most eyebrows.

Read the rest of this entry at Genomes Unzipped »

In hindsight, it might have been ill-advised to offer predictions about the near-term future of genome sequencing during the same week in which one of the year’s major industry conferences (the JP Morgan annual Healthcare Conference) is taking place.

There have been a number of high-profile announcements from genome providers over the past two days. Life Technologies disclosed it had booked 60 orders for the recently unveiled Personal Genome Machine (PGM) and, more importantly, announced that the PGM’s output would be increased by an order of magnitude (10 megabases to 100 megabases) in Q1. Not to be outdone, Illumina, the current market leader in genome sequencing technology, responded later the same day by unveiling its new MiSeq machine. As both Matthew Herper and Keith Robison explain in detail, the MiSeq is a direct and formidable challenger to the Personal Gene Machine as a result of its price, speed and utilization of Illumina’s established sequencing platform.

But the biggest stories, at least by one metric, belong to sequencing newcomer Complete Genomics and Illumina (again). Complete Genomics announced this week that the Institute for Systems Biology (ISB) has ordered a whopping 615 whole-genomes as part of the ISB’s ongoing research into the genetics of neurodegenerative diseases, including Huntington’s. Meanwhile Illumina, at the same time it was launching the MiSeq machine, disclosed that it “currently has a 1,000-genomes backlog” for its own whole-genome sequencing service.

Let’s forget, for a moment, about how much these whole-genome sequences cost and reflect on simply how many of them there are. Just over a decade ago, Bill Clinton and Tony Blair were lauding the first draft human genome sequence; and the Human Genome Project would not declare the first genome “complete” until the spring of 2003.

Again, seven and a half years ago, there was only one single genome sequence to be had anywhere in the world. And it took 13 years and $3 billion dollars to get just the one. Today? We casually discuss hundreds and even thousands of genomes to be sequenced in a matter of months and for thousands of dollars apiece (not $1,000, but likely less than $10,000).

Even if the $1,000 genome does not arrive this year, 2011 will almost certainly see 1,000 genomes sequenced. And in many ways, that may be the worthier milestone to celebrate. Every significant increase in the number of sequenced genomes means a corresponding increase in the amount of genomic data available to elucidate the genetic bases of human traits and disease. There is still a tremendous amount of work to be done to make sense of all that data (and a tremendous amount of environmental, trait and other data that must also be correlated), but sequencing thousands of genomes is a significant step in that process.

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The past few weeks have also seen strong third quarter earnings reports from market leaders Illumina (earnings recap) and Life Technologies (earnings recap), with both companies touting double-digit growth in their next-generation sequencing businesses. Illumina and Life Technologies (Life) are also hard at work on their next generation of products which are intended to compete more directly with the offerings from PacBio and CGI (Oxford Nanopore for Illumina, Ion Torrent and Starlight for Life). Meanwhile, China’s own sequencing entrant, BGI, continues to buy up sequencers (first from Illumina, more recently from Life), and what will soon become the world’s largest provider of genomic sequencing has its own ambitious plans.

These recent positive commercial developments reflect increasing demand for next-gen sequencing, for both platforms and services. While today’s New York Times puts the cost of a complete human genome at $20,000, the retail price is actually much lower in many instances. For instance, Illumina recently announced price cuts to $14,500 for groups of five or more genomes and to $9,500 for sequencing with “potential direct clinical value,” and several companies are offering genomes in the $5,000 to $10,000 range, particularly for new, large orders.² As the next-gen sequencing market continues to expand (pdf) from traditional research applications to encompass more pharmaceutical R&D and, ultimately, clinical diagnostic applications, prices will continue to fall. A “$1,000 genome” by the end of 2011 or early 2012 remains a strong possibility, although keep in mind that what matters is “not how much a genome sequence costs, but what you can (or cannot) do with that sequence.”

As Prices Fall and Profits Rise, Lawsuits Abound. In addition to strong earnings and successful IPOs, another recent trend in the sequencing space has been an uptick in litigation. One of the movement’s most enthusiastic adopters has been Helicos Biosciences, one of the first companies to attempt to commercialize a next-gen sequencing platform.

First, Helicos Biosciences (Helicos) announced this past spring that it was “repositioning” itself from a (largely unsuccessful) provider of sequencing tools to a (hopefully more successful) developer of molecular diagnostics tests utilizing its HeliScope technology. Then in August, shortly after PacBio filed for its IPO, Helicos responded with a lawsuit alleging PacBio’s infringement of four patents protecting its single-molecule sequencing technology. Most recently, Helicos amended its complaint to bring in most of the rest of the sequencing industry – in the form of Illumina and Life – as additional defendants.

According to Helicos’ new CEO, Ivan Trifunovich, the company’s litigation activities:

…further support our recently announced strategic initiative to maximize the return to our shareholders on the technology investments that we have made by vigorously protecting our seminal next-generation sequencing intellectual property rights.

PacBio has already denied Helicos’ infringement claims and we can expect both Illumina and Life to follow suit. In the meantime, Helicos will continue its efforts to avoid a NASDAQ delisting.

In case you were concerned that CGI might be left out of the patent infringement litigation fun, fear not. CGI is currently engaged in its own legal wrangling with Illumina (and Illumina’s predecessor, Solexa). Following a familiar narrative, Illumina filed a patent infringement lawsuit against the company in August, shortly after CGI filed for its IPO. CGI then countersued, denying infringement, alleging Illumina’s patents are themselves invalid or unenforceable and including a Sherman Act (antitrust) claim against Illumina for good measure. Those patents, by the way, are themselves the subject of protracted litigation between Illumina, Life and one of Life’s predecessors, Applied Biosystems.

And it is not just patents that have the sequencing companies squabbling. The most recent piece of litigation comes courtesy of microarray manufacturer Affymetrix, a company that does not appear to have embraced whole-genome sequencing in its business model but is nevertheless suing PacBio for allegedly pilfering both employees and trade secrets.

What’s Next for Next-Gen Sequencing. It is not surprising to see commercial success beget corporate litigation. Litigation, particularly patent infringement litigation, is generally time-consuming, expensive and risky. But as the sequencing space continues to expand, those companies that succeed commercially will become increasingly attractive litigation targets. Mo’ money, mo’ problems, as the saying goes.

In the coming months, genomic sequencing is likely to follow a familiar storyline, with a flurry of new technologies and business models giving way to consolidation within the marketplace. Only a fraction of the current platforms and companies will make it and, as Helicos has already demonstrated, those that fail to succeed as sequencers will have plenty of incentive to sue their more successful competitors in an attempt to recoup substantial investments.

While the outlook for next-gen sequencing companies is certainly positive, at least in the short-term the prospects for life science litigators appear to be every bit as rosy as the companies they represent.

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¹ It appears that the public markets may be opening for biotech more broadly. According to The Wall Street Journal, there were “18 offerings in October, the most in three years.”

² Not to be overlooked, as Luke Jostins reports from last week’s ASHG meeting, is the role of exome sequencing using next-gen platforms and which is currently estimated at “roughly 1/7th the price of whole genomes.”

[Editor’s Note:

On Tuesday, Carmichael and five commentators examined what can be learned from a DTC genetic test. Yesterday, the topic was whether DTC genetic tests are trustworthy, and whether the results can be cause for concern. Today’s topic is the regulation of DTC genetic tests. In addition to several short commentaries, including a much shorter version of the piece below, Carmichael has also posted a lengthy interview with two top FDA officials on the subject of DTC genetic testing regulation.

The column below is an expanded version of what appears over at Newsweek. To see all of the commentaries in Carmichael’s series, click here.]

The recent media attention focused on direct-to-consumer (DTC) genetic tests has left companies, investors, consumers and even regulators scrambling to figure out what comes next.

As the situation stands today, companies and their investors live in a climate of unprecedented regulatory uncertainty, causing delays in the introduction of new products and rendering an already inhospitable economic climate – for both fundraising and sales – even more challenging. Commentators and regulators caution consumers that some DTC genetic tests may be unreliable or, worse, harmful, but have yet to provide clear tools and guidelines for evaluating competing tests. And regulators, including the FDA, must balance their mandate to protect the health and safety of the public with that same public’s desire for autonomy, while also recognizing that innovation is a prerequisite for a healthcare system that must continue to improve outcomes while reducing costs.

Clearly, something must change. But what will that change be? And how will the field of DTC genetic testing evolve? Will DTC be able to continue its current business while regulators and companies engage in protracted negotiations? Will oversight weed out the “snake oil salesmen” and permit legitimate companies to flourish? Will it drive all genetic testing (temporarily) out of the hands of consumers?

Or will the field change in a dramatic and completely unexpected way?

These questions, and others, caused Newsweek science editor Mary Carmichael to realize her oft-debated question – To Test or Not To Test? – might demand an answer sooner rather than later:

. . . I started to worry . . . . How much time did I even have left to decide whether I was going to take a test myself? Even before [last month’s Congressional] hearing, the FDA had announced its plans to regulate all DTC genetic tests, possibly so heavily as to keep them off the market; the hearing was just the sort of thing that could push it to move faster. What if, by the time I finally decided if I wanted one of these tests, I couldn’t buy one anymore?

Setting aside the question of whether Carmichael, or anybody else, should buy a genetic test, this column examines the history of DTC genetic testing regulation in the United States¹ and, in the final section, whether the DTC option is likely to persist in the future.

Because this post is longer than usual, here is a quick, clickable roadmap to its various sections. If you’re already familiar with the history of DTC genetic testing you may wish to jump ahead to the final section or two.

1. 2006: DTC and the First GAO Report.

2. 2007: The Beginning of Modern DTC

3. 2008: SACGHS and a Scare From the States

4. 2009: All Quiet on the DTC Front

5. 2010: DTC Goes to Washington

6. Today: Uncertainty Reigns

7. Tomorrow: Unintended Effects (and More Uncertainty)

8. Beyond: A Delicate Balancing Act

2006: DTC and the First GAO Report. Four years ago last month, the Federal Trade Commission (FTC), Food and Drug Administration (FDA) and Centers for Disease Control and Prevention (CDC) published a consumer fact sheet entitled “At-Home Genetic Tests: A Healthy Dose of Skepticism May Be the Best Prescription.” The guidance warned consumers to be wary of claims made by DTC genetic testing companies and to involve “a doctor or trained counselor who understands the value of genetic testing for a particular situation” when ordering or interpreting any genetic test.

The joint agency guidance document was published in concert with a report from the Government Accountability Office (GAO) entitled “Nutrigenetic Testing: Tests Purchased from Four Web Sites Mislead Consumers” (pdf). The GAO report reviewed a “nonrepresentative selection” of genetic tests available to consumers at that time and concluded that those tests “mislead the consumer by making health-related predictions that are medically unproven and so ambiguous that they do not provide meaningful information to consumers.” The report was praised for “drawing attention to potentially important consumer protection issues,” even as it was criticized for “serious methodological flaws that undermine[d]” those very criticisms (pdf).

Whatever its methodological flaws, the GAO’s description of the system of regulation for DTC genetic testing, which it characterized as one of “minimal oversight [that] makes it difficult for consumers to determine whether a genetic test provides meaningful, scientifically based information,” was entirely accurate.

2007: The Beginning of Modern DTC. With the launch of DTC products from a publicly traded biopharmaceutical company (deCODE Genetics) and a Google-backed startup (23andMe) on back-to-back days in November 2007, the modern era of DTC genetic testing was born. With 23andMe, deCODE and, soon, Navigenics, consumers could now pay around $1,000 to review hundreds of thousands of SNPs. Following Knome’s launch, also late in 2007, they could pay much, much more ($350,000) for access to their entire genome.

Despite this dramatic shift in the DTC product landscape, the legal landscape remained essentially unchanged from 2006. Regulatory oversight was still incomplete, confusing and rarely invoked.

At the federal level, while most DTC genetic tests were likely covered from the outset by the Clinical Laboratory Improvement Amendments of 1988 (CLIA), it was typically difficult to determine whether DTC genetic testing companies were operating using CLIA-certified labs. (23andMe, for example, did not begin using a CLIA-certified laboratory until 2008, making the change in response to “evolving” regulatory requirements.) CLIA, which is implemented by the Centers for Medicare & Medicaid Services (CMS), requires laboratories to demonstrate the analytical validity of their tests, and covers most genetic tests regardless of whether they are provided directly to consumers or not.

In addition to CLIA, a limited number of genetic tests were also regulated by the FDA. Although the proposition was not immediately tested, it was widely assumed that DTC genetic tests constituted a new form of laboratory developed test (LDT), a large and well-established category of tests over which the FDA exercised “enforcement discretion.” While the FDA had historically declined to regulate LDTs, in 2006 and 2007 the FDA expressed its desire to regulate certain types of high-complexity LDTs (so-called IVDMIAs). As is still true today, it was unclear where, if anywhere, the newly introduced DTC genetic tests fell within the LDT conversation and FDA’s larger regulatory universe.

In addition to uncertainty at the federal level, some states possessed (and still do possess) statutes that appear to prohibit – or at least restrict – DTC genetic testing (pdf). However, it was unclear whether such statutes, which clearly predate the arrival of DTC genetic testing in its current form, were intended to prevent DTC genetic testing or whether they would be enforced by state regulators in any event. State-level regulatory restrictions contributed to at least one company withholding its service from citizens in at least 10 states at the time of its launch.

Despite all of this legal uncertainty, no federal or state regulatory agency took any formal action immediately following the introduction of DTC genetic testing to the consumer marketplace.

2008: SACGHS and A Scare from the States. During its first full year, the DTC genetic testing marketplace continued to grow as new companies arrived on the scene and existing companies refined and expanded their offerings.

Meanwhile, an influential government policy committee (SACGHS) had undertaken a review of the “U.S. System of Oversight of Genetic Testing.” When it was published in April of 2008, the 276-page report surprised almost no one when it identified major gaps in the regulation of genetic testing, including insufficient oversight of laboratory quality, clinical validity and a lack of knowledge with respect to the nature and uses of genetic tests available for purchase, whether directly by consumers or otherwise. Among the report’s several recommendations were increased FDA regulatory oversight and the creation of a mandatory, public registry for all laboratory tests.

Shortly after the publication of the SACGHS report, public health officials in New York and California sent “cease and desist” letters to a number of genetic testing companies. The states warned the companies – including 23andMe, deCODE and Navigenics, the three most prominent DTC providers at that time – that they were operating without necessary state licenses.

The SACGHS report and state regulatory letters produced widespread debate about the appropriate regulatory framework for DTC genetic testing. Companies were concerned that other states might follow the example set by New York and California and seek to regulate DTC genetic tests directly, potentially exposing DTC companies to a nightmare scenario of inconsistent, state-by-state regulation. Proponents of regulation, meanwhile, argued that the nascent field needed some regulation “lest abuses discredit the whole industry before it has a chance to thrive.”

In the following weeks, months and even years, some DTC companies received state licenses, although this came at the expense of offering tests directly to consumers in some cases. Other companies ceased selling to customers in specific jurisdictions, and still others simply went out of business. At the federal level, the SACGHS recommendations continued to generate far more discussion than action, and the regulatory landscape remained materially unchanged. Meanwhile, major DTC companies continued to press ahead, and 2008 closed with 23andMe’s DTC genetic test being named Time’s invention of the year.

2009: All Quiet on the DTC Front. In comparison to the years on either side, 2009 was a relatively quiet year for DTC genetic testing, at least from a regulatory perspective.

On the commercial side, however, 2009 saw a number of changes ripple through the DTC genetic testing marketplace. As the price of DTC genetic tests continued to fall, a new competitor, Pathway Genomics, arrived on the scene and 23andMe significantly revamped its product offerings and pricing shortly thereafter. Meanwhile, the financial crisis played a major role in causing DTC pioneer deCODE Genetics to file for bankruptcy protection, although the company quickly emerged under private control and its deCODEme test remains on the market today.

To be sure, regulators continued to ponder how to respond to the rapidly evolving genetic testing marketplace, which included but was not limited to DTC products. For example, the FDA continued to express an interest in regulating some LDTs and the California legislature considered a bill – championed by 23andMe – that would create a special regulatory framework for so-called “post-CLIA bioinformatics services,” although nothing would come of either initiative, at least in 2009. Perhaps most significantly, but unbeknownst to either the public or the major DTC genetic testing companies, Congress had instructed the GAO to begin a second investigation into the DTC genetic testing industry, the results of which would not be made public until the following year.

With regulators seemingly on the sidelines, academics and other commentators, including the Genomics Law Report, continued to stress the need for meaningful self-regulation in order to:

(1) discourag[e] consumers from purchasing products not adequately supported by scientific evidence, (2) provid[e] regulators such as the Federal Trade Commission (FTC) with a standard against which to evaluate (and sanction) false or misleading DTC tests or services, and (3) ensur[e] that inevitable governmental regulation is not overly restrictive.

Prominent scientists, including soon-to-be NIH chief Francis Collins and genomics pioneer Craig Venter, also emphasized the need for greater transparency and consistency in the way DTC companies presented genetic risk of disease to consumers. While there was widespread consensus, including on the part of DTC providers, that self-regulation and even some form of government regulation would be beneficial for the industry as a whole, by the end of 2009 no notable changes – government mandated, voluntary or otherwise – had materialized.

2010: DTC Goes to Washington. Although we are not yet two thirds of the way through the year, 2010 has already seen an explosion of activity in the oversight of DTC genetic testing.

The first major development came in March, when the NIH announced the creation of a voluntary genetic testing registry. In its 2008 report (pdf), SACGHS had recommended the creation of a “mandatory, publicly available, Web-based registry for laboratory tests” in order to “enhance the transparency of genetic testing and assist efforts in reviewing the clinical validity of laboratory tests.” The NIH adopted this recommendation with one crucial exception: the registry, at least as proposed, will be voluntary.  However, it remains to be seen, particularly in light of everything that has happened since the announcement in March, what form the NIH’s registry will ultimately take when it debuts later this year or in early 2011.

For DTC genetic testing, the excitement really began on May 11th, when Pathway Genomics announced it was partnering with Walgreens to offer its genetic testing service on the shelves of most of the drugstore giant’s 7,500 stores. The FDA responded almost immediately with an “Untitled Agency” letter to Pathway Genomics in which the agency informed Pathway that it could find no record of the necessary FDA clearance or approval for Pathway’s test. The Pathway letter – which represented the FDA’s first public foray into the oversight of DTC genetic testing – was followed by similar letters to five prominent DTC genetic testing companies in early June and letters to 14 more genetic testing companies in late July. These letters were, of course, something of a surprise to the companies. The FDA could not find evidence that it had approved the companies’ tests because, in at least some and possibly all cases, the agency had not told the companies that such approval was necessary.

In addition to taking aim at DTC genetic testing companies, the FDA also announced that it was shelving its plan to regulate a subset of LDTs (i.e., IVDMIAs) in favor of a new plan to regulate all LDTs. Late last month the FDA held a two-day “Public Meeting on Oversight of Laboratory Developed Tests” to discuss that plan. (It is important to point out that, despite devoting an entire portion of the public meeting to DTC genetic tests, on multiple occasions the FDA has indicated that it considers at least some DTC genetic tests not to constitute LDTs since the products are “not developed by and used in a single laboratory.”)

Not to be outdone, Congress quickly announced its own investigation into DTC genetic testing (one it had quietly initiated the year before) and followed that up with a public hearing on “Direct-To-Consumer Genetic Testing and the Consequences to Public Health.” The centerpiece of July’s Congressional hearing was yet another GAO report (pdf) whose conclusion was announced in the title: “Direct-To-Consumer Genetic Tests: Misleading Test Results Are Further Complicated by Deceptive Marketing and Other Questionable Practices.” The GAO also presented a striking and widely circulated YouTube video as partial support for its conclusion. (For a more detailed review of the Congressional hearing and the GAO report please see this recap.)

At the Congressional hearing, Jeffrey Shuren, the Director of the FDA’s Center for Devices and Radiological Health (CDRH), assessed the FDA’s recent activity by agreeing with Congressman Michael Burgess (R-TX) that the FDA “should have acted sooner” to regulate DTC genetic tests. Shuren was likely referring to a perceived failure on the part of the FDA to adequately safeguard the public.  Given the absence of any publicly documented harm resulting from consumer access to genetic tests , however, there are certainly those who would disagree, arguing that the FDA should still refrain from regulating DTC genetic tests.

Listening to Shuren’s remarks at the hearing, one could easily wonder whether his lament was actually directed at the agency having been caught off-guard, at least to a degree, by the debut of the GAO’s striking report, which was unveiled to the public – and the DTC companies themselves – at the hearing.  According to the report (pg. 19) the GAO officially briefed the FDA, NIH and FTC on the contents of the report in late May and early June. However, when I raised this point yesterday during an FDLI webinar on FDA’s (Emerging) Oversight of LDTs, fellow panelist Dr. Elisabeth Mansfield, Director for Personalized Medicine at CDRH, clarified that the GAO’s “briefing” consisted of a teleconference where the FDA learned only the bare fact that the GAO had conducted an inspection and had “found problems.”

Perhaps it is just a perfect storm of coincidences. But in any event, the FDA actions and the GAO report – along with other recent high-profile developments including the Pathway / Walgreens pairing and 23andMe’s “sample swap” – have created unprecedented uncertainty.

Today: Uncertainty Reigns. The GAO report, the FDA’s letters and all of the other events of the past few months have indisputably ratcheted up the level of uncertainty throughout the genetic testing industry.

However, as a purely legal matter, it does not appear that the formal regulatory framework governing DTC genetic testing has changed much if at all in recent months, or even since 2006, particularly at the federal level. Congress has passed no new legislation, and neither the FDA nor any other federal agency has promulgated new regulations or formal agency guidance.   This, of course, is not at all surprising: the rate of development in any new area of science and commerce inevitably surpasses the ability of lawmakers and regulators to keep pace. DTC genetic testing has hardly proved an exception to that rule.

Setting aside the myriad hearings, public and private meetings and statements made to the press by regulators – which, while significant, do not rise to the level of rulemaking – the only formal, public action one can point to is the FDA’s ongoing letter-writing campaign. However, as the FDA has clarified in the past, these “Untitled Letters” remain several steps removed from an FDA enforcement action:

While Warning Letters set out specific violations of law that a company must address immediately or else the agency will take an enforcement action, an Untitled Letter identifies agency concerns and gives a company the opportunity to meet with the agency and to have time to take appropriate steps to address these concerns….Based on how the companies respond to the Untitled Letters, FDA may follow up by sending Warning Letters.

Of course, an absence of documented regulatory change does not imply that the commercial DTC genetic testing landscape has remained anything close to stable.

Responses from DTC companies and investors to today’s uncertainty have varied. Some companies (including Pathway Genomics and Counsyl) have ceased offering their tests directly to consumers, at least for the moment. Others, including two original DTC genetic testing companies (23andMe and deCODE), have expressed a desire to work with regulators while continuing to make their products available to consumers. Many of the major DTC companies, whether or not they are currently offering products directly to consumers, have also criticized both the GAO and the FDA for their approach to DTC genetic testing (see these blog posts at Navigenics, 23andMe and Pathway Genomics) while simultaneously expressing their desire to work with regulators to bring greater oversight to the industry.

Meanwhile, new companies and investors must reevaluate business plans to take into account anticipated regulatory changes.  And customers, including Mary Carmichael, must weigh the possibility that today’s DTC options may disappear from tomorrow’s digital storefronts.

Since 2006, the regulation of DTC genetic testing has been consistently characterized as confusing, incomplete and inconsistently applied. That characterization remains as true today as it was four years ago. So perhaps the only meaningful difference from four years ago is one of degree: more so than at any time over the past four years, there now appears to be a consensus that something must – and will – be done to overhaul the regulation of DTC genetic tests.

Tomorrow: Unintended Effects (and More Uncertainty). But not so fast. Despite the apparent agreement among regulators, industry and most commentators that DTC genetic testing is in need of additional oversight, there is still no guarantee that change is coming soon, or even at all.

Indeed, it is not difficult to look at the events of the past few months and conclude that DTC has been down this road before:

• A GAO report decrying the evils of DTC genetic testing and subsequent Congressional hearing? 2010 and 2006.
• Threatening regulatory letters to DTC companies? 2010 and 2008.
• A controversial FDA regulatory proposal that might – or might not – encompass DTC genetic tests? 2010 and 2006.

Industry watchers who have been around since the beginning would be excused for expressing at least some skepticism that this is the time, finally, when the DTC genetic testing landscape will be fundamentally remade.

Continuing Uncertainty. There is also the possibility that a new regulatory regime for genetic tests will emerge, but that it will push DTC genetic testing to the side and in so doing cause the industry to remain mired in uncertainty.

As the FDA pushes forward with the development of agency guidance for the regulation of LDTs, there are concerns that the agency may carve out many or most DTC genetic tests from this regulatory framework. In June, the FDA expressed its belief that several prominent DTC companies (23andMe, Knome and deCode) are offering tests that do not constitute LDTs because they are “not developed by and used in a single laboratory.”

Recent signals – including the designation of a separate panel for LDTs during the FDA’s two-day public meeting and Jeffrey Shuren’s presentation of DTC genetic tests within the confines of the larger LDT regulatory conversation (pdf) at the recent Congressional hearing – suggest that the FDA may yet find a way to incorporate the regulation of DTC genetic tests into its more ambitious plan to develop a risk-based approach for all LDTs. But for the moment, the FDA appears to be intent on continuing with test-by-test review and regulation.

Unintended Effects. Among its several shortcomings, the current test-by-test approach to DTC genetic testing regulation creates the possibility that a regulatory agency such as the FDA could seek to reshape the industry using indirect methods.

When the FDA sent out its first batch of letters post-Pathway, the one unexpected recipient was array manufacturer Illumina, which, unlike the other companies receiving letters, does not appear to have ever offered its services directly to consumers without the involvement of a physician intermediary. Nor did the FDA allege that it had. Instead, the FDA’s letter to Illumina (pdf) focused on the company’s “Infinium HumanHap550 array used by deCODE Genetics and 23andMe to provide genetic information to their customers.” The FDA charged Illumina with making available an array approved for “Research Use Only” to 23andMe and deCode for use in their own DTC genetic tests.

Why does this matter? As I wrote at the time, not every company has the same set of incentives to resist the FDA’s regulatory proposals. Whereas a company such as 23andMe, which has built its business around DTC genetic testing, has a clear interest in challenging any FDA action that results in its service becoming unavailable to consumers, array manufacturers like Illumina are not similarly situated. As Illumina’s CEO, Jay Flatley, recently noted, the revenue the company “generates from sales of arrays to the DTC market is ‘immaterial.’” By targeting array suppliers such as Illumina, for whom DTC represents only a fraction of their business, the FDA may have identified a way to exert indirect but potentially much more effective regulatory pressure over the industry.

In response, Daniel MacArthur asked yesterday whether the FDA was planning to strangle the supply lines of DTC genetic testing companies by targeting array manufacturers like Illumina. As a regulatory agency charged with implementing legislation passed by Congress, the FDA is extremely unlikely to have an official “agenda” when it comes to DTC genetic testing. That does not mean, however, that the FDA could not determine that genetic testing simply cannot be paired with DTC and still satisfy its interpretation of the law.

If 23andMe or deCode (which is partially owned by Illumina) were to lose access to Illumina’s arrays, would those companies be able to contract with another manufacturer, either based in the U.S. or abroad? Would Illumina take the necessary steps to work with 23andMe and the FDA to clear its array for use in 23andMe’s product? Would this development force such a fundamental shift in the business models of these DTC companies that they would be driven out of business, or perhaps driven overseas?

Even as a hypothetical, the Illumina example illustrates the importance of considering the knock-on effects of regulation. Although the FDA may take the position that its goal is to enforce agency regulations regardless of the effects they produce on a specific business, or even an entire industry, the reality is that there are a number of viable regulatory strategies on the table, and not all of them are equal in their effects.

One of the unfortunate consequences of the test-by-test regulation currently employed by the FDA is that these effects are unlikely to be fully anticipated or explored in advance by regulators. By the same token, one obvious advantage of publicly pursuing a formal system of regulation for DTC genetic testing – e.g., through the development of agency guidance or notice and comment rulemaking – is that such regulatory effects can be explored in advance (in some instances this may even be required of the FDA), rendering them at least intended, even if they remain unwelcome to some.

Other Regulatory Routes. Finally, remember that the FDA may not be left entirely to its own devices in determining how to regulate either LDTs or DTC genetic tests. Several pieces of draft legislation, if enacted, could provide specific Congressional direction as to how the FDA or other regulatory agencies should respond to the challenges raised by these tests.

Current proposals include the Genomics and Personalized Medicine Act – originally introduced by then-Senator Obama and now in its fifth year on Capitol Hill – and the inelegantly named Better Evaluation and Treatment Through Essential Regulatory Reform for Patient Care Act.

The prudent approach – particularly for companies, investors and consumers with an interest in DTC genetic testing regulation – is to assume that some type of regulatory reform is coming to the industry. Unfortunately, important details like “what regulation” and “when will it arrive” continue to remain elusive.

Beyond: A Delicate Balancing Act. Assuming that lawmakers and regulators do decide to develop a formal DTC regulatory regime, the details will be a long time in coming. Stakeholder input will be crucial, and the rapidly changing scientific and commercial landscape will continue to pose a challenge for slower-moving lawmakers and regulators.

Despite all of this uncertainty, it is yet possible to identify (i) several key areas of relative consensus for any prospective DTC regulatory framework and (ii) some of the most pressing areas of dispute that must be resolved in order to proceed.

The First Step: Defining DTC. Before we get to areas of consensus and dispute, however, a brief word about definitions. Any formal regulatory framework will need to set out a clear definition of what, exactly, constitutes a “direct-to-consumer genetic test.” As the personal genomics industry has grown increasingly diverse, the application of the label “DTC” to all consumer-oriented genetic products has become increasingly untenable.

There are, at the moment, at least three different types of DTC genetic tests:

• tests marketed to consumers but ordered and interpreted by a healthcare provider;
• tests marketed to and ordered by consumers but received and interpreted by or only in the presence of a healthcare provider; and
• tests marketed to, ordered by and received by consumers without any requirement that a healthcare provider be involved (although this option is frequently made available to consumers).

While the focus has frequently been on the third and most consumer-oriented type of genetic test, not all so-called DTC genetic testing companies fall into this category. This is significant since the risks – whether hypothetical or actual – of “DTC genetic testing,” as well as the appropriate regulatory response, clearly depend in large part on what exactly is meant by that term.

Finding Common Ground. Although few in number, it appears that consensus is emerging in certain areas pertaining to DTC genetic testing.

Access to Raw Data. Even those who strongly support the robust regulation of DTC genetic testing, agree that individuals should have the right to directly access their raw genetic data (pdf). In public and private comments, the FDA has appeared to embrace this position as well, indicating it is medical claims or interpretations – and not genetic information per se – that concerns the agency.

We need to be careful, however, to define exactly what this outbreak of agreement covers. Although important for what it says about an individual’s right to access their own genome, it likely refers only to the most basic level of access – a large file of As, Cs, Ts and Gs – and to nothing more. This is only a first step. Meaningful “access” for the vast majority of individuals begins only with the ability to access interpreted data.

Registration and Truth in Advertising. As the recent GAO report laid plain, there is a clear need for more robust regulation of the advertising and marketing practices of existing genetic testing companies, including DTC companies, to ensure consumers are not being intentionally or even accidentally misled.

Addressing this issue requires a thorough understanding of the tests currently offered to consumers, including how they are marketed or advertised, how they are intended to be used, and how they are actually used. The FDA has acknowledged several times in public discussions, including yesterday, that the agency lacks this information and that it would be useful in developing appropriate regulations.

While there remains some disagreement over the proper agency or agencies to collect this information and to take appropriate enforcement actions where necessary (the FDA and the FTC have both demonstrated some interest, and the NIH is currently developing a genetic testing registry), there is widespread agreement that these steps should be taken, and soon.

Industry-Wide Standards. Finally, almost since the inception of DTC genetic testing in 2007, there has been a widespread recognition that the industry would benefit from a more standardized approach to interpreting and reporting genetic data.

Early efforts led by the Personalized Medicine Coalition to produce industry-developed standards have stalled, but the inconsistency demonstrated by Collins, Venter et al. and most recently the GAO report have resulted in renewed interest from industry and regulators in addressing this issue.

Here, again, it is important to acknowledge the limited scope of this consensus. There is real agreement that standards are needed. The development and application of those standards, however, raises a host of questions, some of which are discussed below, to which there are hardly consensus answers.

Resolving Disputes. Beyond the few but important areas of consensus described above, it is certain that any emerging regulatory framework will have to tackle numerous difficult questions about which there is a decided lack of agreement. While it is impossible to list all of the areas of disagreement, some of the most pressing issues are:

• whether genetic tests should ever be offered directly to consumers without the involvement of a trained intermediary such as a physician or genetic counselor (i.e., should the third type of DTC genetic testing described above disappear);
• whether to create separate standards for non-clinical genetic tests, including genetic ancestry testing, and how to appropriately define the line between clinical and non-clinical tests;
• how to regulate genetic tests or products that include a large number of interpretations and claims in light of the need to constantly update those claims to best reflect current scientific understanding;
• whether clinical utility, or lack thereof, should be included in determining whether a particular genetic test or association is made available, whether DTC or otherwise;
• how to regulate interpretative tools that do not involve any new testing, but simply offer additional interpretations of raw genetic data already in a consumer’s possession;
• how to address the role of preliminary scientific findings and research in the development of interpretive tools, including genetic tests; and
• whether to focus regulatory efforts on pre-test measures that restrict the availability of potentially harmful genetic tests or post-test initiatives designed to evaluate how consumers perceive, use and react to genetic tests.

The answers to these questions and others, as well as the role industry, consumers and healthcare providers are permitted to play in the conversation, will determine the substance of any forthcoming DTC regulatory framework.

Answering Mary’s Question: To Test or Not To Test? While tomorrow always carries the possibility of a new and clearer day for the regulation of DTC genetic testing, the reality is that, for the moment, all we can say for sure is that the conversation is continuing. What was true in 2006 is still true today: genetic tests are available for purchase directly by consumers, and the regulatory requirements imposed on the companies that offer those tests are unclear and seemingly poised to shift at a moment’s notice.

As I have written several times before, I am optimistic about the long-term prospects for personal genomics in the United States, including DTC genetic testing. As the underlying technology and science continue to improve, the price and value of individual-level genomic data will continue to move in opposite directions, generating increased demand. In time, as increasing demand leads to increasing accessibility and, ultimately, to increasing familiarity – on the part of both consumers and regulators – the development of a tailored system of oversight that permits direct access while adequately protecting consumer safety and ensuring the accuracy and validity of DTC products can be developed.

But none of this will happen overnight. For all of our own interest, DTC genetic testing remains decidedly a niche phenomenon, and the industry poses novel and difficult challenges to regulators. It will take time for these to be ironed out and, in the short-term, it is possible that DTC genetic testing will be presented with a substantially more restrictive regulatory framework than at present.

Ultimately, while I cannot advise Mary Carmichael as to whether she should or should not go through with a DTC genetic test – that’s a personal decision – I can say that if she decides to proceed there is no time like today, for there is no guarantee that the option will still be on the table tomorrow.

_______________

¹The regulation of DTC genetic testing is far from uniform at the international level. Some countries, including Germany, appear to have effectively legislated DTC genetic testing out of existence, at least for the time being. Elsewhere, most notably the U.K., the conversation remains at the level of voluntary guidelines instead of formal – or even informal – regulation. Recent examples include the 2009 House of Lords report on genomic medicine and yesterday’s publication by the Human Genetics Commission of “A Common Framework of Principles for direct-to-consumer genetic testing services” (pdf).

In letters dated July 19th, the first day of the FDA’s public LDT meeting, the Agency continued its crackdown on direct-to-consumer (DTC) genetic test providers, mailing letters to 14 providers of genetic tests. A list of all 14 companies and tests appears below.

The Letters. The letters are similar to the five untitled “letters to industry” the FDA sent out in early June to 23andMe, Navigenics, deCODE Genetics, Knome and Illumina. While briefer than the earlier letters, the new batch of letters reach the same conclusion: each of the companies is marketing a genetic test that, according to the FDA, meets the definition of a “device” under Section 201(h) of the Federal Food Drug and Cosmetic Act (FFDCA). Therefore, each test must receive FDA clearance (510(k)) or approval (PMA). Not surprisingly, the FDA “conducted a review of [its] files” but was “unable to identify any [such FDA] clearance or approval” for any of the tests. The companies are asked to respond to the FDA within 15 days.

By comparison, the June 10th DTC letters were lengthier and also contained (1) information regarding the specific devices/products identified as problematic by the FDA, (2) a recitation of the FDA’s authority for premarket regulation of medical devices under the FFDCA and (3) a description, in most cases, of a prior meeting between the company and the FDA. The June 10th letters also urged the companies to “take prompt action to respond” to the letter, instead of setting out a definite timeframe.

The other notable difference between the two sets of FDA letters is who signed them. The June 10th letters were signed by Dr. Alberto Gutierrez, Director of the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD). The July 19th letters, on the other hand, were signed by OIVD Deputy Director James Woods. It appears that over the last month OIVD and Dr. Gutierrez have gained sufficient comfort with their letter-writing campaign to push the task down the chain of command.

The Tests. Here is the list of all 14 companies who received FDA letters dated July 19th:

• Graceful Earth Inc. Concerning the Graceful Earth Alzheimer’s Test
• SeqWright DNA Technology Services, Inc. Concerning the SeqWright Genomic Profiling Service (GPS)
• Interleukin Genetics, Inc. Concerning the Inerent [sic] Health
• DNATraits Concerning the Ashkenazi Jews Genetic Disease Panel
• CyGene Direct™ Concerning the Metabolic Health Assessment DNA Analysis Test
• Consumer Genetics, LLC Concerning the AsthmaGEN DNA Test
• Matrix Genomics, Inc. Concerning the Matrix Genomics Breast Cancer Panel
• The Genetic Testing Laboratories, Inc. Concerning The Genetic Testing Laboratories DNA Predisposition Test
• Sequenom, Inc. Concerning the SEQureDx™
• EnteroLab Reference Laboratory Concerning the Gene Test for Gluten Sensitivity/Celiac Sprue
• BioMarker Pharmaceuticals, Inc. Concerning the Gene Essence™
• DNA Dimensions Concerning the Predisposition DNA Test
• HealthCheckUSA Concerning the HealthCheckUSA Celiac Disease DNA Test
• easyDNA Concerning the Genetic Predisposition Health Test

Most but not all of these tests appear to be offered for sale directly to consumers. All appear to be marketed DTC. For some tests it can be difficult to tell. For instance, while Matrix Genomics’ breast cancer test can be purchased directly online, I was unable to find a way to order DNA Dimensions’ “Concerning the Predisposition” test through the company’s website, although the company does have a Facebook page. Other products, such as Sequenom’s SEQureDx™ test which, according to the FDA (pdf), measures “circulating cell-free fetal (ccff) nucleic acids (RNA or DNA) in a pregnant woman’s blood sample for fetal gene and chromosome abnormalities, do not appear to be available for purchase without a physician’s involvement.

The range of tests and test providers makes it impossible to determine why or how the FDA selected these particular tests for the current round of letters. Matrix Genomics, for instance, also offers Alzheimer’s, Heart Attack, Warfarin, Plavix and Parkinson’s tests. The FDA’s letter, however, only mentioned its breast cancer panel. And even with these 14 additional letters, as I wrote last time, there are still dozens – and possibly more – of genetic tests marketed and sold directly to consumers that have not been identified by the FDA. The Genetic and Public Policy Center’s (GPPC) recently updated chart of DTC genetic testing companies (pdf) lists 30 companies, and similar lists from AccessDNA and DNA Test Index include dozens more.

What’s more, as with the case of Sequenom, it’s not clear that the test is being offered directly to consumers. If that’s the case, and the FDA has moved on from sending letters to DTC genetic testing providers to sending letters to providers of more traditional LDTs, then the FDA has thousands of potential letter recipients to choose from at GeneTests.org. [Update: Kirell Lakhman of GenomeWeb's The Sample writes that Sequenom was the only non-DTC genetic test maker of the 14 and, what's more, "Sequenom hasn't even begun selling the assay. In fact, the company is still collecting clinical samples for studies..."]

More than a month after the first five DTC letters went out, and in the immediate aftermath of the FDA’s public meeting, companies, consumers, healthcare providers, investors and the general public remain largely in the dark about the factors the FDA is using to determine which tests and test providers to target. Is it a test’s intended use? The fact that it is marketed DTC? The fact that it is sold DTC? The complexity of a particular test? The perceived or actual lack of analytical validity, clinical validity and/or clinical utility? Any or all of those factors, as well as numerous others, might be influencing the FDA’s activity in this area. Until the FDA offers up a general policy for public review – and hopefully for comment as well – there is no way for anyone outside of the Agency to know where the FDA might be headed next. For the moment, at least, it appears that company-by-company, test-by-test letter mailing continues to be the Agency’s preferred approach.

The Timing. During the FDA’s two-day public meeting earlier this week, the Agency repeatedly emphasized that its policy with respect to the regulation of LDTs – including DTC genetic tests – had not been finalized. That was, after all, one of the primary purposes of the meeting: to “serve as a forum to discuss issues and stakeholder concerns surrounding LDT oversight.” The meeting even included an entire session devoted to DTC testing, in which participants were invited to discuss the risks and benefits of DTC genetic tests.

On the topic of the FDA’s willingness to listen to the LDT community, here is what I wrote after the first day of the meeting.

Openness. One reason that a fully articulated regulatory policy is unlikely to emerge from the FDA in short order is that the Agency appears strongly committed to gathering stakeholder input and developing regulations that respond to that input. This is a standard talking point for any regulatory agency, and with numerous conflicting opinions over whether and how the FDA should regulate LDTs, it is obvious that the Agency will not satisfy every stakeholder. Still, I was struck by the Agency’s commitment—in both private and public conversations—to understanding the issues and keeping an open mind about how to proceed. There seemed no reason to doubt Dr. Mansfield when she said that when it comes to LDT regulation, “nothing is set in stone; we have not made any decisions.” This only serves to underscore the importance of participation in the regulatory process which, if attendance at this meeting is any indication, is a strategy that the LDT community has embraced. (emphasis added)

The July 19th letters certainly seem to give the lie to the Agency’s position, including Dr. Mansfield’s comments, that nothing is set in stone when it comes to LDT regulation.

The FDA’s policy with respect to DTC genetic tests, while far from clear, certainly seems to be moving ahead unchanged, public meeting or no. The timing of the letters, which were mailed the same day as the meeting began, suggest that the FDA had no intention of revisiting its decision to step up oversight of DTC genetic tests, no matter what might have been said on Monday and Tuesday.

So what are we to make of the timing of the timing of the FDA letters?

On the one hand, as was pointed out by the Agency after the previous round of letters, these are untitled “letters to industry” and are less severe than a formal FDA “warning letter.” The letters identify Agency concerns and give the named companies time to respond. (Depending on the response, or lack thereof, the FDA may follow up with warning letters down the road.) The letters also subject other lesser-known DTC companies to FDA scrutiny similar to that received by the companies named in the June 10th letters, although, as mentioned above, that level of scrutiny is hardly industry-wide at this point. It is possible that the FDA is slowly but surely identifying DTC (and select other) genetic tests that it believes are particularly problematic, and mailing out standardized letters as it does so. It is possible that the timing is largely coincidental.

On the other hand, coincidence or not, it is difficult to believe that the timing of the FDA’s latest letters won’t provide significant fuel for those who believe that the Agency has already made up its mind about how it intends to regulate LDTs – including DTC genetic tests – and that the two-day public meeting was simply window dressing to help bolster the Agency’s defense against any future challenges to its soon-to-be-enacted regulatory policy.

While I continue to think that the FDA is indeed listening to the LDT community as it develops its regulatory strategy – if for no other reason than that the topic is so complex that the FDA is unlikey to sort out all of the details quickly, or on its own – this latest development gives me pause. One of the many themes that emerged over the two-day public meeting was that the FDA will need assistance and buy-in from regulated parties in order to effectively implement its new system of LDT oversight, whatever it may be. Allowing those stakeholders to have a say in the development of the FDA’s regulatory policy is an excellent way to secure that assistance and buy-in; but that strategy only works if the FDA can convince the LDT community that it is actually listening. Coincidental or not, the timing of this round of FDA letters is unlikely to help the Agency in that regard.

What’s Next. Three of the five companies named in the June 10th letters will be on Capitol Hill first thing tomorrow morning for a House of Representatives hearing on “Direct-to-Consumer Genetic Testing and the Consequences to the Public Health.” The House Committee on Energy and Commerce posted a briefing memo (pdf) for the hearing earlier today. The memo provides additional background information (including information about the GAO investigation, which apparently was initiated all the way back in March 2009) and includes a witness list.

In addition to representatives from Pathway Genomics, 23andMe and Navigenics, the GAO and FDA will be represented. Dr. James Evans of UNC-Chapel Hill, and a member of the SACGHS, will also testify. For those interested in following the hearings from afar, Andro Hsu has posted a link to a live webcast that will, hopefully, be active once the hearings begin.

None of the 14 companies recently named by the FDA have been invited to appear before the House, but that’s no guarantee that Congress won’t invite some or all of them to take their own trip to Washington at some future date.

Below, we will discuss the immediate and long-term implications of the FDA’s most recent regulatory actions for the five companies receiving letters, as well as for the DTC genetic testing industry. First, however, a review of the letters themselves is required. Each of the five two-page letters is signed by Alberto Gutierrez, Director of the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), and follows a similar format throughout. To gauge the impact of these letters we will take them paragraph by paragraph.

1. The Devices in Question. Each letter begins with a description of the product the FDA has determined qualifies as a device under Section 201(h) of the Federal Food, Drug and Cosmetic Act (FDCA). Section 201(h)(2) of the FDCA defines “device” as:

an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is…intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals

The agency’s letter focuses in on the second half of the 201(h)(2) definition, and adds in language from 201(h)(3) which allows the FDA to categorize products as a device if they are “intended to affect the structure or any function of the body of man.” The “devices” identified by the FDA are: 23andMe Personal Genome Service™, Navigenics Health Compass, deCODEme Complete Scan, KnomeComplete™ and the Illumina® Infinium HumanHapp 550 array. It’s difficult to see how any of these products would fall under 201(h)(3) but not 201(h)(2) but, regardless, the FDA is making a clear statement: based on the plain language of the FDCA, it considers these products to be medical devices.

2. Has Your Doctor Seen This? The second paragraph, which appears to be identical in every letter, is a generic overview of the Medical Device Amendments (MDA) to the FDCA. The MDA grants the FDA the authority to require premarket regulation of medical devices. The letter stresses the importance of demonstrating both analytical and clinical validity to ensure that “individuals are not misled by incorrect test results or unsupported clinical interpretations” and that the products are “used to support good healthcare decisions.”

We wrote earlier this week about the difference between analytical and clinical validity, and the role that CLIA (which is administered by CMS, not the FDA) is meant to play in ensuring the former. The letters clearly indicate that the FDA has its eye on both measurements of genetic test quality, as it should. More significantly, the letters appear to indicate that the agency considers the products in question to provide “clinical interpretations” and/or to be used in “healthcare decisions.” In the long-running debate over whether DTC genetic testing qualifies as clinical medicine, it appears that the FDA may have come down on the clinical side of the fence, at least for these particular products.

In fact, Director Gutierrez clarified this point in an interview this afternoon with Newsweek. Director Gutierrez seemed particularly concerned with products that report on genetic variants related to drug metabolization:

If you’re making a claim about [a genetic variant that affects the metabolism of the anticoagulant drug] warfarin, and somebody decides based on the result they get that they want to change their dosing, that is a fairly risky decision. That could affect their health. If they’re not feeling well on their current dose and the drug is expensive, we don’t know what they would do.

These concerns are reiterated, albeit in less detail, in several of the actual letters (see next paragraph).

3. Where’s the Approval? The third paragraph in four of the five letters informs the company that the FDA has not received any information pertaining to the analytical or clinical validity of the products for use in the FDA’s “clearance or approval” of the products. The letters go on to describe the type of genetic information provided by the companies that is of particular concern in this regard, for example the warfarin and clopidogrel response information reported by 23andMe and Navigenics and the breast cancer risk and detection information provided by deCODE. The FDA, echoing Gutierrez’s comments above, warns that “consumers may make medical decisions in reliance on this information.”

The use of the word “consumer” is an interesting choice, particularly in light of the focus that the FDA is clearly placing on the potential clinical use of the products. It is particularly confusing in certain letters, 23andMe’s for instance, where the recipient of the genetic information is referred to in the same paragraph as both a “patient” and as a “consumer.” Clearly, one task for the future regulation and description of genetic testing products will be to clean up the terminology.

It’s also important to point out that Illumina receives special treatment in this paragraph. Of all the companies receiving letters, Illumina is the only one not to offer at least one product directly to consumers (the company does offer a commercial whole-genome sequencing service, although that product requires the participation of a healthcare professional). Illumina’s letter notes that the company has “received FDA clearance or approval for several of its devices,” but not for the HumanHap550 array. “Yet Illumina is knowingly providing the HumanHap550 array to 23andMe and deCODE Genetics for clinical diagnostic use without FDA clearance or approval” despite its being labeled “For Research Use Only.” As Gutierrez notes, “…Illumina has to follow the law, and they are aware that the chips are not being used for research only.”

Again, it appears that the FDA’s determination that the products are being used for clinical diagnostic purposes and delivered directly to consumers appear to be important factors, with the FDA drawing no enforcement distinction between enabling DTC genetic testing and providing the DTC genetic tests themselves.

4. We Know What You Said Last Summer. All but one of the letters then go on to describe a meeting last summer between the company in question and the FDA (July 29th for 23andMe, July 31st for Illumina, August 6th for Knome and August 13th for deCODE.) Surprisingly, there is no mention of a Navigenics / FDA meeting although, in part due to this paragraph’s conspicuous absence from the Navigenics letter, I wonder if this may have been an inadvertent omission.

During these summer meetings the companies presented information about their products to the FDA. On the basis of that information, as well as other available information (e.g., the FDA notes that 23andMe has “recently begun distributing the collection kit for your device through a third party distributor, Amazon.com”), the FDA has concluded that the products in question are diagnostic devices subject to FDCA regulation.

In its letters to 23andMe, Knome and deCODE, the agency goes on to explain that, since the products are “not developed by and used in a single laboratory,” it does not consider them to qualify as laboratory developed tests (LDTs). This is an important point because the FDA has long exercised “enforcement discretion” over LDTs, choosing generally not to regulate this category of test, one which includes a majority of currently available genetic tests. Since so many genetic test providers – not just those of the DTC variety – have relied on the LDT determination as a basis for skirting FDA regulation, this section in particular is likely to raise the blood pressure for companies that purport to offer one or more LDTs but do not conduct all of their development, testing and interpretation in house.

5. Where is Your Letter? Next is a paragraph, nearly identical across all five letters, that reminds the companies they have not received what FDA believes to be the necessary regulatory approvals. Or, as the agency puts it, “we are not aware that you have an approved application for premarket approval (PMA) in effect pursuant to” the FDCA, nor have you “notified the agency of your intent to introduce the device into commercial distribution as required by section 510(k)” of the FDCA.

Briefly, the FDA regulates medical devices in three classes.

Class I devices are simple devices that pose a minimal risk, and are generally exempt from FDA premarket approval or clearance. However, registration of the device is required (as is true of all FDA regulated devices).

Class II devices represent an intermediate level of risk, and require regulatory clearance (as opposed to an “approval”) before they can be sold in commerce. The FDA must determine that the “device to be marketed is as safe and effective, that is, substantially equivalent (SE), to a legally marketed device not subject to premarket approval.” The clearance track for Class II devices is set forth in section 510(k) of the FDCA.

Class III devices are the riskiest device class, and the products that receive the most stringent FDA scrutiny. FDA approval is required before the device can be sold in commerce, and is granted only when the FDA determines that there is “sufficient valid scientific evidence…that the device is safe and effective for its intended use.” The regulatory submission is substantially more detailed than under 510(k), and the FDA is not obligated to respond as quickly.

The FDA letters provide no real insight into whether the agency considers the products it has identified to represent Class I, Class II or Class III devices, a classification that will determine the size of the regulatory burden imposed by the FDA.

6. We Will Be Waiting. Finally, the FDA advises each company to “take prompt action to respond to this letter” and offers to meet with the company to “discuss whether there are tests you are promoting that do not require review by FDA…”

“Prompt” is not defined, and most or all of these companies have had open channels of communication with the FDA for some time now, so it is unclear what type of timetable this imposes. It is clear, however, that this is an invitation to further agency dialogue, and that these companies decline only at their peril.

The second part of the paragraph – the agency’s offer to “discuss whether there are tests you are promoting that do not require review by FDA” – strikes us as a possible opening, at least for some of the identified companies and tests. Last fall, 23andMe, following in the footsteps of its competitor (and recent FDA regulatory target) Pathway Genomics, announced that it was breaking up its genetic testing service so that it could offer separate products for customers seeking to explore their genetic ancestry but who were not interested in the more medical applications of personal genetics, or vice versa. (23andMe also offers a combined product that includes all of those features). As I wrote at the time, that is just the sort of distinction that might be significant to the FDA as the companies and the agency discuss which specific products require premarket clearance and approval (more on this below).

What Does It Mean For the Five Named Companies? The immediate implications of the FDA’s letters may be less significant than some might initially suspect. After years of speculation about whether and how the FDA would regulate DTC genetic testing products, the agency has now publicly delivered at least a partial answer: it considers these specific products to be medical devices requiring either premarket clearance or approval, and it does not consider them to be LDTs subject to regulatory enforcement discretion.

For the companies named in the letters, at least, this provides a concrete agency determination to which they can react. It’s unlikely that the response from any of the companies will be to pull their products completely off of the market and, as The New York Times reports, Director Gutierrez has indicated that “it would be unfair to remove the tests from the market because the agency had not, until now, clearly told the companies that the devices needed approval.”

[Added in Edit, 6/11: Turna Ray of Pharmacogenomics Reporter has published her own recap, which contains additional comments from Erica Jefferson, an FDA press officer. Jefferson's comments make a point of distinguishing the five untitled "letters to industry" from "warning letters." Jefferson explained the difference between the two types of letters:

While Warning Letters set out specific violations of law that a company must address immediately or else the agency will take an enforcement action, an Untitled Letter identifies agency concerns and gives a company the opportunity to meet with the agency and to have time to take appropriate steps to address these concerns...Based on how the companies respond to the Untitled Letters, FDA may follow up by sending Warning Letters.

Jefferson also added that the letters were sent based in part on recent discussions between the FDA and several of the companies that took place in the aftermath of the FDA's decision to send Pathway Genomics a similar letter last month. According to Jefferson, those meetings "helped inform the agency's decision to send the Untitled Letters." End Edit, 6/11]

So, at least for the moment, we may see little or no immediate change while these companies weigh their options internally and through discussions with the FDA. What exactly are those options? They obviously vary based on the specific company and product, but here are a few of the most likely possibilities:

Wave Goodbye. For products that have failed to meet expectations, or are no longer an integral part of the company’s future plans, one possibility is to simply pull the product from the market. The most likely candidate for this response would appear to be the deCODEme test, which is considerably more expensive and less popular than a number of its competitors. deCODE Genetics recently emerged from a well-publicized bankruptcy, and there have been hints that deCODEme might not be part of the reorganized company’s long-term plans. (However, in comments today to The New York Times, neither deCODE or its head of research, Kari Stefansson, indicated that they would do anything other than cooperate with the FDA). If deCODE or any other company does decide to pull its test from the market, existing customers will likely be anxious to know what will happen with their genetic data.

Say Hello (to the FDA). For other companies (e.g., Illumina, a company with considerable experience navigating the FDA approval process), the path of least resistance may be to simply agree with the FDA and seek the appropriate clearance or approval. The viability of this option will depend on how the FDA intends to categorize the specific product (e.g., Class I, II or III) and whether the company believes (a) it can bear the burden imposed by such a regulatory submission and (b) that its product will be approved without changes to its substance or commercial availability that would materially undermine the product’s commercial viability.

Change Pathways. Perhaps the most palatable option for many of these companies is to consider altering the product in a manner that would convince the FDA it no longer qualifies as a device requiring premarket approval or clearance, for instance by removing the ability of consumers to purchase the product without the participation of a healthcare provider.

In his interview with Newsweek, Director Gutierrez discloses that Pathway Genomics was not sent a letter yesterday because the company responded to the agency’s previous letter and has indicated that “they are planning to move away from direct-to-consumer testing…” While that disclosure is news to me, and not one I believe the company has made publicly (the website still appears to allow consumers to purchase directly), it is not a surprising one. As Gutierrez notes, another genetic testing company, Counsyl, made a similar decision in the aftermath of the Pathway / Walgreens commotion.

Of the five companies that received FDA letters this week, Navigenics and Knome would appear to be the most likely candidates to pursue this option. Navigenics has increasingly shifted its product focus over the past year in the direction of more traditional medical channels (as evidenced by its receipt earlier this year of a clinical laboratory permit from the State of New York, apparently the first awarded to a personal genomics provider), and this development could be the final nudge it needs to pull the plug on its DTC option. Similarly, Knome, which once offered whole-genome sequencing directly to the super-rich for $350,000, has increasingly positioned itself as a provider of genomic software and interpretation, with a focus on research and clinical applications. As with Navigenics, if Knome can forestall FDA regulation by eliminating all DTC versions of its products, it may have a strong incentive to do so.

A related approach, discussed above, would be for companies to seek different regulatory treatment for products that have clearly different uses. 23andMe, for instance, might seek a different classification for its ancestry testing product as compared to its products that provide genetic testing of a more arguably medical variety, such as disease prediction or drug response.

Prepare for War.  Finally, there’s always the possibility that one or more of the companies will challenge the FDA’s determination that they are either (a) offering a medical device or (b) not offering an LDT. There’s no question that going toe-to-toe with the FDA represents the path of greatest resistance, but if any of these companies feel sufficiently backed into a corner by the FDA’s approach this could surface as a viable option.

While no company has yet indicated its intent to challenge the FDA’s interpretation, 23andMe has thus far been the most outspoken in its criticism of the agency’s recent actions. As reported by The New York Times, one 23andMe director suggested that denying consumers direct access to their genetic information would be “appallingly paternalistic” (a characterization Director Gutierrez found inapplicable to the FDA’s regulatory decision), and the company has indicated that it “disagree[s] with the FDA’s conclusion” but is “open to discussion on ways to regulate the personal genetics industry.” Only time will tell whether 23andMe, or some other party, attempts to challenge the FDA’s regulatory approach to DTC genetic testing.

What Does it Mean for the Rest of the DTC Genetic Testing Industry? For the rest of the industry, the regulatory outlook is little clearer today than it was yesterday. The FDA has offered specific regulatory determinations for a limited set of DTC genetic testing products, but it has not offered broader industry guidance.

From the letters, and from Director Gutierrez’s statements, it is clear enough that the agency considered several important factors in identifying these five specific companies and products as regulatory targets. These include the DTC availability of the product (or, in the case of Illumina, contribution to DTC availability), the perceived medical use of the product and, in all likelihood, the complexity of the testing and interpretation involved in the product.

But how the FDA weighed those factors against others – including the utility of the tests, the reality of its limited regulatory resources, and the presence of numerous other genetic tests offered to consumers and to patients – remains unclear. Keep in mind that the FDA sent letters to five companies that, while they represent some of the best known genetic testing providers, do not comprise the entire DTC genetic testing industry (see, for example, this list at DNA Test Index or this list at AccessDNA). For other DTC companies, as well as companies and investors seeking to break into the DTC marketplace, there continues to be a lack of clarity into the FDA’s DTC genetic testing regulatory strategy.

For that reason and others, my own opinion continues to be that transparency – and not regulation – is what would be most beneficial to the DTC genetic testing industry and its customers at this time. Until companies, consumers and regulators better understand the tests that are available and, importantly, how those tests are being used, it will be difficult to develop a regulatory policy that protects the health and safety of individuals without stifling commercial innovation and individual exploration. In the meantime, expect the FDA’s latest actions – as well as, possibly, the ongoing Congressional investigation – to significantly shake up the personal genomics landscape in the coming weeks and months.

Long’s column is a seriously one-sided and misinformed portrayal of not only personal genomics in the direct-to-consumer (DTC) context but also of the utility of genetic information in any context — clinical, commercial or otherwise. At Genetic Future, Daniel MacArthur’s response (“Willful ignorance is not an effective argument against personal genomics”) is every bit as accurate as it is scathing, and appropriately characterizes Long’s writing as “a true masterpiece of unsupported criticism, and an ode to willful ignorance.”

Willful ignorance. On the one hand, Long’s column is unremarkable. Long marries incorrect facts and a clearly uninformed perspective to reach the conclusion that personal genomics is a monolithic marketplace offering “an expensive, largely pointless service endorsed by a celebrity for misleading reasons: it is the genetic equivalent of space tourism.”

It’s hard to be too surprised when a writer with no apparent background or understanding of the personal genomics industry, or the science that supports it, sees a celebrity genomics story and produces a bad piece of journalism. After all, as I wrote last week in “Why the State of Personal Genomics is Not as Dire as You Think,” that’s one of the impacts we should expect as increasing numbers of celebrities embrace personal genomics, the industry as a whole reaches the mainstream and entirely new groups of individuals come face to face with the complicated ethical, legal, social and scientific issues that surround personal genomics.

What surprises me about Long’s editorial (to say nothing about the distinguished publication that published it), and what I think merits further examination, is the complete lack of understanding with which she approaches what is clearly a new area for her – what MacArthur terms “willful ignorance” – and the degree to which she would inflict this mindset upon her readers, many of whom may be similarly uninformed on the subject of personal genomics.

Ignorance may be bliss, but only for some. The crux of Long’s objection to personal genomics is that it provides at best a way for consumers to waste hard-earned money and at worst the opportunity to be hit with a “Damoclean diagnosis,” the impact of which “is almost impossible to imagine.”

Since I do not know Long, I suppose it is possible that she has fashioned a considered opinion that uncovering her genetic status is a very, very bad idea for her. And if her description of the effects of encountering personal genomics information was an accurate one, I might even be inclined to agree with her “ignorance is bliss” approach. As Long tells it, an individual diagnosed with a genetic predisposition to a serious medical condition (a category which appears to include everything from genealogy and paternity testing to actual diseases, including Alzheimer’s, Parkinson’s, multiple sclerosis and schizophrenia, with varying degrees of identified genetic contributors) has a pair of options: (1) worry more or (2) haul off and “have more fun in the short term… buy that speedboat or get wasted more often” until the novelty wears off (at which point one presumably reverts to worrying more). Curiously, she does not suggest a wild weekend with Robert Pattinson.

Thankfully, Long’s fatalistic attitude toward knowing her genetic status is not shared by all. As a journalist, Long would have been well served to speak with Jim Lupski, John Flatley, Sharon Terry, Jamie Heywood, Hugh Rienhoff or any of the many individuals – scientists and non-scientists – who have taken their own genetic diagnosis, or that of a family member, as a call to arms and strive to use personal genomics to improve the understanding and treatment across a wide range of diseases. Without individuals such as these, as well as the governments, investors and businesses willing to support scientific and technological risk-taking, there would be no scientific advancement other than accidentally.

While I respect Long’s right not to know her genetic status, her complaints in this regard seem almost trivial. After all, nobody is forcing Long to spit into a tube to be sent off to 23andMe or join Glenn Close in the whole-genome sequence club by sending $48,000 off to Illumina.

The most unfortunate part of Long’s editorial is her decision that her own ignorance is not enough. She has decided she needs to inflict it on her readers too. It is one thing to choose ignorance for oneself; it is quite another to evangelize in favor of it and impose it on unsuspecting readers. Many in Long’s audience will not be familiar enough with the issues surrounding personal genomics to critically evaluate her writing.

It is unfortunate that damage of the sort created by careless columnists is easy to inflict and difficult to overcome. We can only hope that policymakers and the public alike will hold themselves to a higher standard than Long in evaluating the promise of personal genomics.

In brief, the SOLiD 4 generates 100 gigabases of data per run at a cost of $6,000 per genome, a cost that appears to account solely for the consumables and does not include the cost of the machine or of interpreting all of that sequence data. According to GenomeWeb, Life is also promising an upgrade to its system – SOLiD 4hq – in the second half of 2010 which it expects to triple the data output at half of the cost: 300 megabases per run, $3,000 per sequence.

As for the impact of Life’s SOLiD 4 announcement, Matthew Herper hits the nail on the head:

But although the news is good for Life and will keep it in the game as the price of decoding the genetic code continues to drop, the specs of this new machine don’t seem good enough to upset Illumina’s place as the first choice of geneticists. “It’s a solid improvement, but I don’t think this changes the game,” says Isaac Ro, an analyst at Leerink Swan who follows both companies.

Ro estimates that Illumina currently has 60% of the market in gene sequencers, with the rest split by Life and Roche and perhaps 1% going to Helicos BioSciences. At genome centers, it’s more like 70% Illumina…

New challengers like Pacific Biosciences, which is close to marketing a faster sequencer that can read longer stretches of DNA, and Complete Genomics, which sells sequencing as a service, might be able to compete with Illumina by offering very different products — even if they don’t do the job as cheaply on a per genome basis. But for the time being, Illumina may remain dominant partly because it is so dominant.

Clearly, though, neither Life nor Illumina’s other competitors have any intention of ceding the sequencing market just yet. And with genome sequencing combatants Life, Illumina and Complete Genomics all making headlines in the past few weeks, one has to wonder what the sequencing companies that haven’t made a big splash yet in 2010, including Roche and third-generation sequencing companies such as Pacific Biosciences and Oxford Nanopore, have up their sleeves. The 11^th annual Advances in Genome Biology and Technology (AGBT) meeting looms in just under a month, but given the breakneck pace of recent developments, it wouldn’t be surprising to hear more news before then.

What to do with all those new tools? While we wait for the next big sequencing development, one aspect of Life’s announcement that should not be overlooked is the provision by the Life Technologies Foundation, the company’s philanthropic arm, of $5 million in grants over the next two years “to accelerate the education of physicians in the field of molecular medicine.”

Of the initial grants, which total $600,000, the most intriguing is the one made to the Scripps Translational Science Institute to create a new accreditation board, the Association of Genomic Medicine, which “will be tasked with… establishing an educational curriculum that would lead to the accreditation of physicians in genomic medicine.”

The Genomics Law Report’s recently concluded series – What ELSI is New? – tackled the most pressing ethical, legal and social issues facing genomics and personalized medicine. One of these, as discussed in commentaries by Hank Greely and Misha Angrist, among others, was the general inability of practicing physicians to integrate rapid advances in genomic medicine into patient care.

There is tremendous innovation in the whole-genome sequencing market which produces, in turn, increasingly inexpensive genomic data. But data, no matter how inexpensive, is still just data. As I have written before, for healthcare providers and their patients, the success of personal genomics ultimately depends on the ability to leverage that data in a way that benefits individuals, including by improving patient outcomes and reducing healthcare costs. Credit should go to Life Technologies for recognizing that a sequencing platform represents only one tool in the personal genomics toolkit.