Henry Miller was there at the beginning. Here is his recounting – when in 1982 a new product of bioengineering could be approved in 5 months. Now the average is 15 years for a new drug. Is this progress?
“Photo courtesy of Eli Lilly and Company”
Today marks the 30th anniversary of an event that kicked off an important new era in drug therapies – the approval by the FDA of human insulin synthesized in genetically engineered bacteria. The saga is remarkable in several ways, not least of which is that although both the drugmakers and regulators were exploring unknown territory, the development of the drug and its regulatory review progressed smoothly and rapidly.
Insulin in crude form was first produced in 1922 by Canadian researchers Frederick Banting and Charles Best, lifting the death sentence that had previously been imposed on diabetics. By the end of that year drug company Eli Lilly and Company had devised a method for much higher purification. Over the next half century or so, the purified insulins obtained from pig or cow pancreases were constantly improved in purity and formulated in ways that refined their performance.
During the early 1970′s, as the supply of animal pancreases declined and the prevalence of insulin-requiring diabetes grew, there were widespread fears of possible future shortages of insulin. But around the same time, a new and powerful tool – recombinant DNA technology, “genetic engineering,” or “gene-splicing” – became available and offered the promise of unlimited amounts of insulin.
The seminal experiment was reported in a 1973 research article by academic scientists Stanley Cohen, Herbert Boyer and their collaborators. First, they isolated a ringlet of DNA called a “plasmid” from a bacterium, used certain natural enzymes to splice a gene from another bacterium into that plasmid, and then introduced the resulting “recombinant,” or chimeric, DNA into E. coli bacteria.
When these now “recombinant” bacteria reproduced, the plasmids containing the foreign DNA were likewise propagated and produced amplified amounts of the functional recombinant DNA. And because DNA holds the genetic code that directs the synthesis of proteins, this new methodology promised the ability to direct genetically modified bacteria (or other cells) to synthesize desired proteins in large amounts.
The “new biotechnology” was born.
Lilly saw immediately the promise of this technology for the production of unlimited quantities of human insulin in bacteria. After obtaining from Genentech, Inc. the recombinant E. coli bacteria that contained the genetic blueprint for and that synthesized human insulin, they developed processes for the large-scale cultivation of the organism (in huge fermenters similar to those that make wine or beer) and for the purification and formulation of the insulin.
Insulins had long been Lilly’s flagship product, and the company’s expertise was evident in the purification, laboratory testing and clinical trials of human insulin. The company’s scientists painstakingly verified that their product was identical to pancreatic human insulin (which differs slightly in chemical composition from beef or pork insulin) and that it was exquisitely pure.
Lilly began clinical trials of its human insulin in July 1980. The product performed superbly. There were no systematic problems with treating “naive” patients (who had never before received injections of insulin) or those switched from animal to human insulin. A small number of patients who had had adverse reactions of some kind to the animal insulins tolerated the human insulin well.
The dossier which provided evidence of safety and efficacy was submitted in May 1982 to the FDA, where I was the medical reviewer and head of the evaluation team. Over many years the FDA had had prodigious experience with insulins and with drugs derived from various microorganisms, so it was decided that no fundamentally new regulatory paradigms were necessary to evaluate the recombinant human insulin.
In other words, recombinant DNA techniques were viewed as an extension, or refinement, of long-used and familiar methods for making drugs. That proved to be an historic, precedent-setting decision.
Based on a thorough review of data submitted by Lilly that was obtained from pre-clinical testing in animals and clinical trials in thousands of diabetics, FDA granted marketing approval for human insulin in October 1982. The review and approval took only five months at a time when the agency’s average for new drugs was 30.5 months. In retrospect, that timing was particularly remarkable for a drug that was produced with a revolutionary new technology, and that after approval would be available in pharmacies nationwide to millions of American diabetics.
An article on the front page of the New York Times (Oct 30, 1982) contained my prediction that the speedy approval was a major step forward in the “scientific and commercial viability” of’ recombinant DNA technology. “We have now come of age,” I was quoted as saying, and potential investors and entrepreneurs agreed: Seeing that biopharmaceuticals would compete with other medicines on a level playing field, the “biotechnology industry” was on the fast track.
During the past three decades, untold numbers of drugs and diagnostic tests based on recombinant DNA technology have been tested and hundreds have been approved for marketing. Sales are over $100 billion annually, and dedicated biotechnology companies employ more than 100,000 people. The big pharma companies also make and market biopharmaceuticals.
Some of the most important members in this class of drugs include tissue plasminogen activator, or tPA, to minimize the damage from heart attacks; erythropoietin (EPO), to stimulate red blood cell production in various anemias; granulocyte-colony stimulating factor (G-CSF), to boost bone marrow production of certain blood cells; interferons, used to treat certain cancers and serious viral infections; various vaccines; and enzymes used to treat life-threatening genetic diseases. A related manifestation of biotechnology called “monoclonal antibody technology” has produced other medical miracles.
Not surprisingly, advances in recombinant DNA technology continue. Besides obtaining therapeutic amounts of “natural” substances such as human insulin, it is now possible to create “designer” molecules with unique capabilities. In June 2011, for example, Lilly announced a multimillion-dollar investment in “multi-specific” therapeutics — molecules that combine two mechanisms of action into one, with the hope that this will provide increased efficacy and reduced side effects.
Regrettably, the early salubrious regulatory climate has changed. Even with a toolbox of improved technologies and greater knowledge of pharmacogenetics, bringing a new drug to market on average now takes 10-15 years and costs over $1.4 billion. Regulators have adopted a highly risk-averse and even adversarial mindset, few new drugs are approved without convening extramural advisory committees, and decisions are sometimes hijacked by political forces outside the FDA. Approval of a drug or other FDA-regulated product made with a brand new technology now would probably be further delayed by navel-gazing at a series of government-sponsored, “consensus-building” conferences.
The result is that fewer drugs enter the development pipeline and become available for patients who would benefit from them. Over the years government regulation hasn’t aged as gracefully as recombinant DNA technology itself.
Henry Miller, a physician, is the Robert Wesson Fellow in Scientific Philosophy and Public Policy at Stanford University‘s Hoover Institution. He was the founding director of the FDA’s Office of Biotechnology. His most recent book is “The Frankenfood Myth.”
(via Mr. Reader)
Cheers, Steve & Dorothy
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