E-DRUG: Human testing to assess health risks
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Dear E-druggers,
The recent flurry of correspondence concerning human and animal testing to assess health risks brought to mind an article I published several years ago.
It is just as pertinent now as it was then. Our societies need to mount an effort to require the release of all toxicology data so our studies can be better designed thereby reducing the need for animal and human testing.
Tom Layloff
tom@layloff.net
www.layloff.net
[Apologies for the messy lay-out; can E-druggers please submit their postings in PLAIN ASCII text? Thanks, Wilbert Bannenberg, moderator]
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“A Stain on Contemporary Science: Will Others Be Able to Stand on Our Shoulders?” _[1]_ (aoldb://mail/write/template.htm#_ftn1)
By Tom Layloff _[2]_ (aoldb://mail/write/template.htm#_ftn2)
Abstract: Legislation in the developed nations requires the acquisition of vast amounts of toxicology data to ascertain the effects of various chemicals on life and health. In many instances these data are acquired through tests conducted on animals and humans; other data are acquired retrospectively through epidemiological studies. Most of these data are considered proprietary and are not available to the general scientific community for study to develop new intervention and prevention strategies to improve and/or preserve health. Legislation should be enacted to make all of these data available to the scientific community to possibly reduce animal and human testing needs. Access to those data are essential to protect animal rights and human rights but also the rights of humanity to continue our relentless pursuit to protect and enhance our health.
"If I have seen further, it is by standing on the shoulders of giants."
_[3]_ (aoldb://mail/write/template.htm#_ftn3)
If we reflect on the great advances in therapeutic products which enrich our lives we must give credence to those members of humanity who, initially by happenstance and later by design, brought us to our current therapeutic pinnacle or inflection point. Who was the person with a headache who discovered that chewing on willow bark relieved the symptoms? Who was the “traditional healer” who interviewed that person and incorporated willow bark into their therapeutic medicine bag? And who was the person who found that the active therapeutic compound was salicin? That salicin was later found to be a salicylate derivative lead to the therapeutic salicylate trail which eventually led to the synthesis of aspirin. This move from an extractive therapeutic source to chemical manufacture was a remarkable transition which eventually created a multitude of employment opportunities for scientists from many disciplines which continues to this day. This transition was a major industrial revolution innovation which in itself was a part of “… this irresistible revolution that for so many centuries has marched over all obstacles, and that one sees still advancing today …”_[4]_ (aoldb://mail/write/template.htm#_ftn4)
Who was the person who first chewed Rauwolfia serpentina, discovered its therapeutic activity, and reported it to the “traditional healer” to lead us eventually to reserpine? And what of the poor souls who gnawed on Digitalis purpurea_[5]_ (aoldb://mail/write/template.htm#_ftn5) to discover the cardiotonic effect of the glycosides digitoxin and digoxin which ultimately lead to their isolation and characterization? The discovery trail from the new mown hay blood anticoagulant isolate coumadin_[6]_
(aoldb://mail/write/template.htm#_ftn6) is well-documented. An undesirable property, hemorrhaging, discovered in animal farming leading to a desirable animal extermination property, rat-poison, and finally to a desirable human health intervention, blood thinning. And who discovered the therapeutic properties of Cascara Sagrada,_[7]_ (aoldb://mail/write/template.htm#_ftn7) the laxative, and Ipecac,_[8]_ (aoldb://mail/write/template.htm#_ftn8) the emetic which has saved thousands of children from their misdirected culinary experimentation. These will forever remain mysteries in the history of mankind but are some of the “shoulders” upon which we stand to see further. This trail of therapeutics eventually expanded to include animal derived products such as Insulin, Thyroid, Extracts, Pituitary Extracts, etc., while the continuing deluge of plant material extracts and derivatives investigations brought products like paclitaxel to our therapeutic armamentarium. This trail led first through chemical purification of plant and animal extracts to the identification of well-defined chemical entities. Those chemistry successes eventually the search for therapeutics to the chemist’s storerooms where classes of chemical agents not based on a natural source product were discovered, e.g., sulfa drugs, beta-blockers, etc. These successes led to the establishment of our great pharmaceutical industries. In their pursuit of new therapeutic entities they have expanded the chemical storerooms by introducing automation and high throughput syntheses and screening. These high technology introductions have provided an astounding array of potential therapeutic interventions. In addition to these synthetic innovations to identify candidates, there continues a vast parallel effort to scour the lands and oceans of the world to identify additional natural source therapeutics. We became so enamored with our technological successes that we ignored the centuries of hit-or-miss human experimentation which gave rise to the therapeutic repertoires of “traditional healers” as possible sources of new products. However, in our current frenzy to identify new therapeutic leads those “traditional healers” have been resurrected as participants in the process to fill the screening laboratory pipelines. All of this effort has brought forth an astounding array of potential therapeutic interventions. These potential interventions then undergo an equally astounding product development attrition rate: only five in 5,000 or 0.1% of the potential therapeutic entities identified advance through preclinical testing to FDA filings as Investigational New Drugs (IND). _[9]_ (aoldb://mail/write/template.htm#_ftn9) This pre-clinical development stage is conducted
over a ca. 3.5-year period and involves laboratory and animal studies conducted to assess safety and biological activity. As noted 99.9% of the preclinical candidates are found failing some aspect of the assessments and are dropped from further development. From these preclinical tests five substances advance for submission to the FDA for testing as Investigational New Drugs (IND)._[10]_ (aoldb://mail/write/template.htm#_ftn10) Phase 1 IND testing is conducted over a one-year period on approximately 20 to 80 healthy volunteers to further explore the product safety and to fine tune the dosage levels. The Phase 2 IND testing level is conducted over ca. two-year period with 100-300 patient volunteers to evaluate effectiveness and look for side effects. Following this testing the products enter Phase 3 IND testing over a ca. three-year period with 1000 to 3000 patient volunteers. Phase 3 helps to verify effectiveness, and to further monitor adverse reactions from long-term use. If all of this testing is satisfactory an NDA is filed with the FDA for approval.
Of five NDAs submitted only one is ultimately approved for marketing and Phase 4 follow-up studies. The overall attrition is from 5,000 preclinical candidates to one approved product; only 0.02% of the starting pipeline makes it through to an approved product.
In 2001, pharmaceutical and biotechnology companies added 32 new treatments to the nation’s medicine chest – 24 drugs and 8 biologics, and invested an estimated $30.3 Billion in R&D._[11]_ (aoldb://mail/write/template.htm#_ftn11)
The average cost of bringing a prescription drug to market in 2000 was estimated to be ca. $800 million according to a study by The Tufts Center for the Study of Drug Development._[12]_ (aoldb://mail/write/template.htm#_ftn12)
This amount per drug in 2000 for the 32 entities approved in 2001 is consistent with the 2001 estimated $30.3 Billion R&D investment. This level of drug development investment is on the order of the recently approved $27 Billion annual budget of the entire US National Institutes of Health (NIH)._[13]_ (aoldb://mail/write/template.htm#_ftn13)
In addition to this vast therapeutic development investment targeted for FDA approval for product marketing there are a number of other government programs which require the submission of biological safety test data for product approval, e.g., FDA for food additive approval; EPA for products and degradants; NIOSH for MSDS chemical exposures, etc. The bottom line is that we as a scientific industrial society generate an extraordinary amount of safety and toxicology data for the development of therapeutic agents and to protect our health from various and sundry chemical entities, both natural and synthetic.
What becomes of the data obtained through this vast societal undertaking? For each approved new drug there is through the IND process between 3,220 to 9,640 person years of controlled exposure to a chemical entity. For the four substances which entered the IND testing but were not approved there would be an additional 12,880 to 38,560 person years of controlled exposure. This amount of controlled exposure is expended annually for drug development only and does not include studies for other safety and toxicology assessments. Of course there also is extensive laboratory and animal testing performed on the ca. 4,995 chemical entities which did not pass muster to be advanced into the pre-clinical development. As noted previously there is in addition to this drug development enterprise extensive animal and human testing conducted for other agencies.
What becomes of all this magnificent mountain of data? Is it warehoused in locations reminiscent of the last scene of the movie “Raiders of the Lost Ark?” Is it buried and lost to the enrichment of our science and knowledge? It is archived in knowledge dead-ends and is lost to exploitation by the new information technologies such as web-browsing with learning machines and Artificial Intelligence. There have been over the years developed retrospective Structure Activity Relationships (SAR) to help guide the development of new therapeutics. The quality of these SAR investigations can be no better than the quality of the data which is being mined. Further the SAR development model is a limited concept which cannot include the full richness of all of the safety, efficacy and toxicology data which is accumulated through these various programs.
What should be done?
1. US Federal legislation should be passed which requires the public release of all toxicological and safety data submitted to the government three years after the date of receipt of the submission.
2. A contract should be issued to a large competent scientific abstracting and database generating organization_[14]_ (aoldb://mail/write/template.htm#_ftn14) to first develop standard descriptors and data formats for toxicology and safety data and second to begin establishing the database starting with the most recent public released data, i.e., after the three year submission period, and then move retrospectively through the mountains of data to place them in the standard descriptor and data formats.
3. The ordered data then should be made publicly available so academicians, industries, interested individuals, etc. could contemplate, machine search and glean new correlations and knowledge with artificial intelligence learning machines.
Of course there will be flaws in some of the data; also some errors, omissions and probably some instances of fraud. However these instances will be a minority and if we focus on these “pimples” we will miss the magnificence of this great resource. Also of course opening these databases to public scrutiny will bring forth an array of headline-seeking muckrakers and scientist bottom-feeders to attack various aspects of this scientific enterprise. However, that risk would be more than offset by the opportunities presented to bright and aggressive scientists to have available those data to make striking advancements in the design of new therapeutic interventions as well as new insights into possible hazards to substance exposure. There are property rights issues concerning the release of these proprietary submissions. However, there are also human rights involved in that it is highly likely that the data bases will reduce the amount of human testing required for the IND phase drug investigations and other chemical testing. There also are animal rights involved in that similar reductions in the preclinical search for new target products would occur because the improved drug targets would have less attrition. There also would be a significant reduction in animal testing to support safety evaluations for Material Safety Data Sheets (MSDS), etc.
Lastly of course there are humanity’s rights. We stand on the shoulders of giants who have come before us. The question is can we bring together the shoulders of the pharmaceutical industrial revolution and the related chemical processing revolution for the information age to stand on so we can see further. It is time to bring forth the shoulders for the next generation of scientists. That is our ongoing debt to the “irresistible revolution” that has brought us here.