Biotechs Seek Opportunities with Social Media, FDA Still Murky…

On 6/16/11, I attended the BioConference Live interactive online-only life science conference and attended the Panel Discussion titled, “Social Media in Regulated Industries: What are the Opportunities and where is the line?”  I thought I would share some the interesting points brought up during the discussion.  Panelists included Moderator Tina Baumgartner from Accella Group, Pamela Lund from PL Interactive, and Lianne McLean and Mya Thomae from Myraqa.

Baumgartner said that some of the opportunities in social media are the ability to “listen to customers, recruiting employees, attracting funding, and increasing visibility.”  She discussed three of the common misconceptions of social media, which include that it is primarily a tool for marketing and PR, it is too complicated and time consuming, and it has the same regulatory compliance risk as traditional PR and advertising.  None of which are true, according to Baumgartner.

McLean discussed a number of challenges to marketing in a regulated environment such as companies are only allowed to promote their product for the legally approved label and they must report adverse reactions.  She also pointed out that “the FDA’s regulatory stance has been unclear.”  Apparently, the FDA has been promising a guidance document since 1996.  In the meanwhile, the FDA has been issuing warning letters to companies that they think have crossed the line.   In July 2010, the FDA sent Novartis a letter issuing four violations for its “Facebook Share” widget saying among other things that it did not present a balanced viewpoint of its leukemia drug, Tasigna.

One of the attendees asked the panel, “will there be regulatory documents coming soon from the FDA?”  The answer was “not really.”  Another attendee asked, “what is the time horizon of widespread adoption of social media?”  Panelist McLean said “in the next couple of years or so.”  She also said that “pharma companies would adopt more quickly than diagnostic companies.”

Next Gen. Sequencing for Dx – Exome v. Whole Genome?

While I was at CHI’s Molecular Medicine Tri-Con in San Francisco last week (Feb 23rd), I had a chance to sit in at a discussion table at the end of the day.  The topic at Table 6 was about diagnostic applications that used next generation sequencing (NGS).  About 16 people discussed the pros and cons of targeted resequencing versus whole genome sequencing. Karl Voelkerding M.D.,(Assoc. Professor, Pathology, Univ. of Utah; Medical Director, Advanced Technology and Bioinformatics, ARUP Laboratories), moderated the discussion. Karl said that NGS is being applied to multi-gene panels, exomes and whole genomes in clinical research and diagnostics. Each approach has different costs and complexity of data analysis and interpretation.

NGS for Multi-gene Panels v. Whole Genome
Karl started off by talking about multi-gene panels and NGS. Karl briefly talked about using multi-gene panels and Marfan Syndrome.  He said that the challenge involves sample preparation and noted that Fluidigm has a workable solution for this.

He asked the group “What’s being seen in Europe?” A person from Europe said that he has seen targeted NGS vs. whole genome NGS used by a fee-for-service company in Europe.  A person from Genomic Health said that, “if cost is not an issue, it’s OK to use whole genome.  But otherwise it’s better to use targeted resequencing.”  Karl said that at his lab, it takes over a year to do a CE- based multi-gene sequence [ vs. NGS].

Others at the table asked about costs.  The person from RainDance said that they have an in-solution capture method that could reduce costs.  Karl said that even there, there are non-trivial labor costs.  He said that “Some commercial companies do use robatic liquid handlers to reduce cost.”

Scenarios, Approaches, Costs
He said that this area is a moving target.  Amplified appproaches in multi-gene panels increase specificity for up to ten genes.  Otherwise if over ten genes, it takes many months of CE sequencing work. Researchers need to develop a special workflow for this type of CE- sequencing.  Karl said “An elusive goal is to make sequencing work like PCR.”  They are not there yet.

One person asked about simplifying the data content in a database by choosing some data as benign.  Karl said that academics are randomly updating their data by using a grad student or even an undergrad student.  But this approach gives inconsistant data quality.  He said that some commercial-based databases use more regularly scheduled updating.

He said that you need to ask the question “Are the genes associated with pathology?  Some genes are benign, some others are linked to disease.  We need to know, over time, what data items get classified as a changed data set.”
Some companies do targeted resequencing as a business and make IP from the database content. The database tells what is benign or what is something else.

A consultant asked “It would be interesting to see what in the database is predictive.”  Karl said “Extract the DNA, do PCR, do CE-seq, and analyze.”
The consultant also asked “What if you do NGS, then find genes, then pass data on to CE-seq to verify for Dx accuracy?” Karl said “Some research corelabs do exome sequencing for genome sequencing.  NHGRI is good with that approach.  He does 30x coverage at his lab.

Another person asked “What is the control level for false positives?
Karl said that, downstream, it depends on technologies used such as mass spec, v. NGS v. CE sequencing v. PCR.  Karl mentioned that the American College of Cardiology considered testing for hypertrophic cardiomyopathy (HCM)  and asked “Should we do multi-gene testing”  They test by using using echocardiograms.  Karl give the statitics for WW incidence.

So with the exome v. whole genome question. Karl asked, “When can you use gDNA for Illumina. The workflow is to do DNA sonograph, do Agilent Bioanalyzer 2100 to get total DNA, do qPCR to get fragment library which can go to the SOLiD or to the Illumina cluster [for HiSeq2000].

The sequencing workflow is:

• Day 1 do gDNA
• Day 2 do qPCR,  then transfer to Cbot
• Day 3 run the HiSeq2000 at 2×100 for 8 days
• Then run SeqTest, run QSeqTest, then output in Qfile format

Karl said it takes 105 days from start to end.

He said that, if you do exome sequencing, you need to do a purification step at the beginning, which adds 3-4 days to the workflow, but the exome sequencing is at a lower cost. Karl said the his lab is hooked up to the Univ. of Utah’s cluster computer and can do a data alignment in 1-day.  The cluster computer at the Univ. of Utah is also HIPPA compliant for privacy.

So cost drives exome sequencing. Karl said that “When doing exome sequencing you are doing a lot less sequencing, but you do more sample preparation.  You sequence on 2 lanes v. on 8 lanes [on Illumina].

Some List Prices
Karl gave some cost numbers.

• For whole genome sequencing it costs $10K  with all reagents, including for library preparation.
• For exome sequencing, it costs $1,200-$1,300 at 200X to 900X coverage.

So an answer for supporting multi-gene sequencing is to use exome sequencing of all genes in a panel.  e.g. Broad can sequence 2000 exomes per week. They streamlined a special workflow for this. Anyway, at the end of the day, you need to do down stream validation.

Consent Approaches that Should be Considered
A woman asked, “But in the clinical environment, what if you find other genetic information?, Some other genetic information?, Do you not tell the clinician?”
Karl said that “the key is informed consent.”  He said “ARUP is developing a tiered consent process — its mostly used for pediatrics now. So if they set out looking for one genetic area, but what if they find something else?  They age-level at age-14 for consent.”

Karl gave an example about the rare disease area at the NIH..  The NIH does exome sequencing.  Their success rate is 20% to identify a suspicious gene.  “So why just 20% with de novo mutations?”  He said that they are using exome sequencing and they just use a small population.  He mentioned a paper in Nature Genetics involving a group in the Netherlands  that saw a lot of power in NGS of a child that is an alternative to use laborious CE sequencing.

Karl said that the items not covered in the consented area are marked off.  He said that this is usually done in laboratory medicine.  When it comes to a recessive gene, the answer is often guided by family history.  Therefore “consent with tiering” is the way to be able to manage what diagnostic information is delivered to clinicians.  Karl wrapped up the discussion by saying that “NGS is pushing the envelope!”

Recent AMP Meeting Brings Signs of Life to McEnery Convention Center

The Association for Molecular Pathology’s annual meeting was held at the McEnery Convention Center in San Jose on November 18 and 19, 2010. This impressive meeting included about 319 vendor exhibits, many poster exhibits, and numerous plenary talks about molecular pathology and diagnostics.

The first session that I attended was the “Single Cell Analysis Of Circulating Tumor Cells In Cancer.”  Stefanie Jeffrey, MD, at Stanford University School of Medicine discussed single cell analysis of circulating tumor cells in cancer.  She talked about the 20 most commonly expressed genes, CTC’s grown in vivo, and FAST (fiber array scanning technology).

I listened to Madhuri Ramanathan from the University of Medicine and Dentistry in New Jersey who gave a talk about autism.  She discussed the percentage of pro-inflammatory genotypes. In another session Betty Wong, MS, at Sunnybrook Health Sciences Centre in Canada discussed the search for functional polymorphisms in the vitamin D binding protein gene, Gc.  She said that Gc was discovered in 1959 and named Group-specific component or Gc.  She said the objective was to search for functional DBP gene polymorphisms.  The study population was 66 percent Hispanics, 23 percent African-Americans, and 11 percent Europeans or other descent.  The methodology was denaturing HPLC and sequencing, etc.  The results were 24 different DBP gene variations in their 2-tail sample.  DBP is a highly polymorphic multifunctional protein.  Very little is known about the molecular variations responsible.

The size of the vendor exhibition suggested to me that business might be picking up in the molecular diagnostic product space.  Companies such as Roche Diagnostics, Illumina, Abbott Molecular, Illumina, Agilent, Qiagen, Siemens and others were there. Maybe 2011 will become a growth year for these vendors.