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Pharmaceutical & Biopharmaceutical Best Practices, Lessons Learned & ongoing challenges: a work in progress
Evolving Terminologies for Emerging Technologies
Comments? Questions? Revisions?  Mary Chitty 
mchitty@healthtech.com
Last revised March 23, 2012
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21st century Drug Discovery, Drug Development & Drug Safety Map  We're trying to update our popular 2002 Drug discovery and development map   

Best practices, lessons learned & ongoing challenges for pharmaceuticals: work in progress

Bridging the silos between biologists, biophysicists, chemists, IT, toxicologists, patent attorneys, CFOs, CEOs and clinicians [and patients] present some of the biggest challenges of all. My own undergraduate anthropology major is more relevant to me now than it was when I graduated.  

I'm realizing that the variety of skills and domain expertise needed for breakthroughs in the life sciences is more than anyone discipline and/'or lifetime(s) can muster.  While new technologies might be helpful, cultural shifts, incentives for collaborating, and pre-competitive cooperation will also be important.  Incremental changes can be helpful more frequent than  true paradigm shifts. Industrialization, scalability and automating and ramping up processes to move from the R&D lab into the clinic are under-appreciated challenges, as are marketing dilemmas that come about with disruptive technologies.

Best practices so far
Biology and Chemistry:
Nature is very clever. Leveraging biomimetics [high-tech pharmacognosy] can help the odds.  

Business & finance: If you're after quick results and fast profits may not be  the industry for you.  Helping people and public health also have their own rewards.. 

Clinical trials and biomarkers and diagnostics: Selecting patients who will respond to compounds, without toxic effects [pharmacogenomics/ personalized medicine] will enable better, faster, cheaper, more definitive clinical trials, and help to meet unmet clinical needs.

Drug safety:
If compounds are going to fail, killing them quickly saves time and money. Repurposing and repositioning existing drugs can leverage existing tox profiles.  Who would have thought thalidomide would be back on the market?  

Lessons learned and ongoing challenges
Research: Progress from basic to applied research and commercial R&D is distinctly non-linear.  Human lifetimes aren't long enough to learn everything needed to get drugs to market safety -- and keep them there. 

Business Funding & Finance Spending more and more on R&D and getting fewer and fewer new drugs is not a sustainable business model.  Counting on blockbusters is like including winning the lottery in your business plans.  Increasingly collaboration and alliances have important roles to play. 

Biology Genes and proteins, genomics and proteomics are just molecular biological starting points. If DNA is 2-dimensional, and protein structures are 3D, then post-translational modifications and alternative splicing are 4D temporal-spatial relationships constituting profoundly dynamic systems. DNA makes RNA makes protein[s] is still true -- but with infinitely more variations than originally envisioned.

Biomarkers & molecular diagnostics Diagnostics almost always precede therapeutics, and “companion diagnostics” or theranostics are increasingly important and closely aligned.  

Bioprocessing & manufacturing Just getting enough of compounds can be the first challenge.  Biotech started as a means for bioproduction, but now biotechnologies, genomic, proteomic and metabolomic tools and insights permeate every/many? stage of pharmaceutical R&D. Scaling up is a profoundly underestimated challenge.  

Chemistry There isn’t enough matter in the universe to make all possible combinatorial compounds.  

Drug discovery Killing compounds early can be like “drowning puppies in front of small children”.  How many companies reward this vital task?  

Drug development Proofs of concept enable better experiments and fewer [expensive] unpleasant surprises.  ADME -- We know a lot about absorption and distribution, not so much about metabolism and excretion. 

Drug safety & pharmacovigilance From preclinical through Phase IV and post marketing surveillance, drug safety just never ends. Idiosyncratic toxicities don’t emerge now until drugs reach larger populations.  

Drug targets Greatly increased numbers of targets mean more need than ever to validate hits and optimize leads.  Papers per compound have dropped from > 100 to < 10 according to Lehman Brothers 2001 report The Fruits of Genomics.   

Informatics isn’t as much about old knowledge becoming obsolete, but becoming more and more granular, with elements of chaos theory thrown in.  .  

"A month in the lab can save you an hour in the library." says Phoebe Roberts, formerly at Biogen Idec, now at Pfizer  

"The biomedical literature is even noisier than microarray data." says John Quackenbush, of the Dana Farber Cancer Center

Regulatory Affairs GxP -- from GLP Good Laboratory Practice to GCP Good Clinical Practice and GMP Good Manufacturing Practice to INDs Investigational New Drugs and NDAs New Drug Approvals -- and truly NCEs New Chemical Entities and NBEs New Biological Entities -- is a long, expensive, and often unpredictable journey. Regulatory authorities are struggling with trying to figure out how to regulate new and uncertain technologies.

Technologies More technologies are pre-competitive than people like to admit.  New technologies such as microarrays, next generation sequencing and RNAinterference coexist with improvements in century old mass spectrometry and Nuclear Magnetic Resonance.  DNA, genes, RNA and proteins are intimately related, but the technologies for learning about nucleic acids and proteins can constitute almost unbridgable chasms. 

Making new technology work may be easier than using it to discover truth. Roger Brent, "Functional genomics: learning to think about gene expression data" Current Biology 9: R338- R341, 1999

Molecular Medicine Medicine is being reorganized at the molecular and biochemical levels. Traditional pharmaceutical franchises are supplemented by molecular networks, pathways  and insights.

I've taken heart from Steven Weinberg's Four Golden Lessons, Nature 426: 389, 27 Nov 2003 "How could I do anything without knowing everything that had already been done? ... [graduate school] was sink or swim.... I did learn one big thing: that no one knows everything, and you don't have to. Another lesson to be learned ... is that while you are swimming and not sinking you should aim for rough waters.   My advice is to go for the messes -- that's where the action is...  My third piece of advice is probably the hardest to take. IT is to forgive yourself for wasting time... If you want to be creative, then you will have to get used to spending most of your time not being creative, to being becalmed on the ocean of scientific knowledge.  Finally, learn something about the history of science, or at a minimum the history of your own branch of science. The least important reason for this is that the history may actually be of some use to your ... More importantly, the history of science can make your work seem more worthwhile to you. 

Robert Weinberg's Racing to the Beginning of the Road : The Search for the Origin of Cancer  is a very readable account of top rate biomedical research, a good reminder that these "races" are marathons and not 100 yard dashes. The title is one of my favorite metaphors for the complexity of biology. His explanation of how nonlinear progress from lab to clinic can be is highly recommended. 

Learning to live with uncertainty and trade-offs is essential and unavoidable.  Uncertainty became a PubMed MeSH heading in 2003.  We are moving from a very limited Mendelian knowledge of genetics and medicine, almost entirely based upon monogenic diseases with high penetrance to post-genomic awareness of how little we know about polygenic diseases with varying penetrance.  

Whether you need to get up to speed in new areas, or be sure you've kept up with the latest developments in life sciences and pharmaceutical business, informatics, or technologies Cambridge Healthtech products and services may be just what you need.  Not sure where to start?  Try browsing this drug discovery map, consult our Cambridge Healthtech A to Z index & Site map and/or peruse the Biopharmaceutical glossaries & taxonomies.  

What’s on your 21st century drug discovery, drug development & drug safety map?
  
Mary Chitty, Cambridge Healthtech, Library Director & Taxonomist, mchitty@healthtech.com

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