NEW VC Fund! Angelini Ventures just launched their $300 million dollar investment fund to support early-stage biotech and digital health startups in the US, Europe, and Israel. CEO & Managing Director Paolo Di Giorgio and Managing Director Elia Stupka explain the fund’s thesis which is different than the usual corporate investment funds because of its “very long-term” strategy and interest in supporting disruptive health innovation that doesn’t necessarily need to relate to the core businesses of its multi-national parent, Angelini Industries. Find out more – including details about where this fund has already placed some investment dollars – from this quick chat in Milan.

By KIM BELLARD

I learned a new word this week: bioresorbable.  It means pretty much what you might infer — materials that can be broken down and absorbed into the body, i.e., biodegradable.  It is not, as it turns out, a new concept for health care – physicians have been using bioresorbable stitches and even stents for several years.  But there are some new developments that further illustrate the potential of bioresorbable materials. 

It’s enough to make Green New Deal supporters smile.

Bioresorbable stents and stitches are all well and good – who wants to be stuck with them or, worse yet, to need them removed? – but they are essentially passive tools.  Not so with pacemakers, which have to monitor and respond.  Medicine has made great progress in making pacemakers ever smaller and longer lasting, but now we have a bioresorabable pacemaker. 

Researchers from Northwestern University and The George Washington University just published their success with “fully implantable and bioresorbable cardiac pacemakers without leads or batteries.”  What their title might lack in pithy is more than offset by the scope of what they’ve done.  Fully implantable!  No leads!  No batteries!  And bioresorbable! 

Most pacemakers are, of course, designed to be permanent, but there are situations where they are implanted on a temporary basis, such as after a heart attack or drug overdose.  Dr. Rishi Arora, co-leader of the study, noted: “The current standard of care involves inserting a wire, which stays in place for three to seven days. These have potential to become infected or dislodged.” 

Dr. Arora went on to explain:

Instead of using wires that can get infected and dislodged, we can implant this leadless biocompatible pacemaker. The circuitry is implanted directly on the surface of the heart, and we can activate it remotely. Over a period of weeks, this new type of pacemaker ‘dissolves’ or degrades on its own, thereby avoiding the need for physical removal of the pacemaker electrodes. This is potentially a major victory for post-operative patients.

The device is only 15 millimeters long, 250 microns thick and weighs less than a gram, yet still manages to deliver electric pulses to the heart as needed.  It is powered and controlled using near field communications (NFC); “You know when you try to charge a phone wirelessly? It’s exactly the same principle,” GW’s Igor Efimov, a co-leader of the study, told StatNews. 

It dissolves over a period of days or weeks, based on the specific composition and thickness of the materials.

Watch it dissolve:

The researchers are pretty pumped.  Dr. Efimov says:

The transient electronics platform opens an entirely new chapter in medicine and biomedical research.  The bioresorbable materials at the foundation of this technology make it possible to create whole host of diagnostic and therapeutic transient devices for monitoring progression of diseases and therapies, delivering electrical, pharmacological, cell therapies, gene reprogramming and more.

They’re not the only ones.  Moussa Mansour, director of the Atrial Fibrillation Program at Massachusetts General Hospital, who was not involved in the study, told StatNews: “It seems to be a very revolutionary idea. I believe it’s going to be well-received in the field. It targets an unmet need, and I believe it’s going to benefit patients… not only because it targets a temporary patient application, but because of its potential to be expanded to other applications in medicine.”

Northwestern’s John A. Rogers, who led the device development, predicts: “Transient technologies, in general, could someday provide therapy or treatment for a wide variety of medical conditions — serving, in a sense, as an engineering form of medicine.”

Let that sink in: “An engineering form of medicine.”

Then there is a fracture electrostimulation device (FED).  Researchers at the University of Wisconsin have developed an implantable, self-powered, bioresorbable device that stimulates bone growth and healing, then dissolves when its job is done.  The device gets its power by converting mechanical energy generated by tiny movements into electric power, which then stimulates the bone.  In some situations, they admit, “We may need the device to respond to other types of internal mechanical sources, like blood pressure changes.”

As with the pacemaker, the device can be “fine tuned” to last from weeks to months by “tweaking” the make-up of the materials. 

Right now, the device has only been tested on rats, but lead researcher Xudong Wang is eager for the next steps: “It will be very interesting and impactful to address the development from animal to human.” 

If you think those are cool, then hold still for bioresorbable 3D printed tissue scaffolds.  Tissue scaffolds, if you didn’t know (I didn’t) are used in tissue engineering to provide structures for tissue growth/repair/regeneration, such as after breast cancer treatment.  The study concludes:

We have demonstrated that it’s possible to produce highly porous scaffolds with shape memory, and our processes and materials will enable production of self-fitting scaffolds that take on soft tissue void geometry in a minimally invasive surgery without deforming or applying pressure to the surrounding tissues. Over time, the scaffold erodes with minimal swelling, allowing slow continuous tissue infiltration without mechanical degradation.

These new scaffolds offer several advantages over current approaches, including better elasticity, more ability to retain “shape memory” after compression, compatibility with tissues, and, of course, being bioresorbable.  The researchers describe them as “4D” materials because how the materials change over time is a factor.

The researchers believe: “By focusing on the design of a material with a unique combination of features, we have been able to achieve a minimally invasive 4D structure that could reduce surgical impact while enhancing rates of healing and patient recovery.”

Again, they’re not yet testing on humans, but a separate study – the INSPIRE study – has tested a Neuro-Spinal Scaffold that is made of a bioresorbable polymer on patients with a severe spinal cord injury, demonstrating “that the potential benefits of the NSS outweigh the risks in this patient population and support further clinical investigation in a randomised controlled trial.”

I love the idea of using bioresorbable materials in health care.  I love the idea of an engineering form of medicine, just as I love the idea of a biochemical form of medicine.  Much of the history of medicine has involved inserting foreign substances/materials into us, with varying degrees of violence and success.   Bioresorbable approaches should give us better options. 

Kim is a former emarketing exec at a major Blues plan, editor of the late & lamented Tincture.io, and now regular THCB contributor.

By MIKE MAGEE

What will be the lasting impact of the Covid 19 pandemic?

We still don’t know the answer to that question in full. But one thing that can be said with some certainty is that it has strengthened the hand of Big Tech and all things virtual. Consider the fact that within the Biden White House administration, 13 senior aides have Big Tech resumes with time spent in firms like Google, Facebook, Twitter, Apple, Amazon, Microsoft and more.

This pandemic-induced scrape with mortality has instigated widely varied responses ranging from existential re-awakenings to explosive entrepreneurship.

In health care for example, health tech start-up’s are altering research, education, care delivery and coordination, data mining, patient privacy and financing.

As we know well from health care, intermingling profit, policy and politics can eventually lead to conflict and recrimination. The current controversy over NIH indirect funding of Shi Zengli’s Wuhan “gain-of-function” viral research through Peter Daszak’s New York based EcoHealth Alliance is a case in point.

But we’ve been there before. In the 1990s, James M. Wilson received a PhD and an MD degree from the University of Michigan, then completed an internal medicine residency at Massachusetts General Hospital and a postdoctoral fellowship at MIT. By 1997, he was one of the leading stars in the new gene-therapy movement, directing his own research institute at the University of Pennsylvania.

The institute focused on adjusting the genes of children born with a hereditary disease called ornithine transcarbamylase deficiency (OTD), which prevents the normal removal of ammonia in the body. Wilson’s experimental technique involved genetic engineering, splicing therapeutic genes into supposedly harmless viruses that, once injected into the body, could carry their payload to defective cells and repair the genetic errors.

Dr. Wilson was attempting to determine the maximum dose of genetically modified material that could be safely injected into affected youngsters. He had enlisted 18 participants, including a teenager named Jesse Gelsinger who had a version of the genetic disease in which some of his liver cells carried the genetic abnormality but other cells were entirely normal. Those who have the full-blown disorder die in early childhood. But with his mosaic, Jesse most of the time felt well, as long as he continued to take 32 pills a day.

Jesse and his parents heard about the experiments in nearby Philadelphia and were anxious to help those less fortunate who had the full-blown disease. When he arrived at the clinic on September 13, 1999, to begin the study, his blood ammonia levels were above normal, which in and of itself should have blocked his participation. Nonetheless, Wilson’s team infused Jessie’s bloodstream with 38 trillion colonies of a virus carrying genes engineered to reprogram his cells. Eight hours later, Jesse’s fever hit 104.5 degrees. Two days later he was brain-dead.

The patent for the technique of genetic modification being studied was owned by a company called Genovo, cofounded by the above mentioned James M. Wilson, the institute director. Wilson owned a 30 percent stake valued at over $30 million, and the University of Pennsylvania, which under the rules of the National Institutes of Health, was responsible for ethical oversight of the research protocol design and execution, was a hidden investor. The informed consent Jesse had signed made no mention of Wilson’s financial conflict of interest, or the university’s, or the fact that some of the prior 17 participants had suffered significant liver inflammation, or that three laboratory monkeys had died from massive inflammatory immune responses to injections of the very same agent.

But the perverse financial incentives and conflicts of interest that led to such risk-taking went further up the academic food chain. Dr. Bill Kelley, an accomplished and aggressive medical researcher from the University of Michigan, had assumed the top post at the University of Pennsylvania in the early 1990s. Kelley’s goal was to achieve dominance in a crowded and competitive local medical market that included six medical schools. The age of genomics was just gaining steam, and Kelley wanted Penn to lead the way and share the rewards. His rapid expansion and heavy investment in technology and personnel had resulted in a reported $198 million loss by the University of Pennsylvania’s health system in fiscal year 1999. No doubt Kelley harbored hopes that Penn’s investment in Dr. Wilson’s gene company, bolstered by NIH grants and private investors, might help balance the books. Jesse Gelsinger’s death ended not only that research but Bill Kelley’s tenure as well.

The point being that regulatory boundaries, full transparency, and self-imposed brakes on profit-infused optimism protect researchers, the public, and society overall. As Big Tech’s romance with Big Health flowers and blooms, our leaders need to step back and consider where we are going, and not just how fast we can get there.

Coming Next: Health Tech: Part II – Powering Up The Vision.

Mike Magee, MD is a Medical Historian and Health Economist and author of “Code Blue: Inside the Medical Industrial Complex.“

The THCB Book Club is a discussion with leading health care authors, which will be released on the third Wednesday of every month.

This month we hosted Jane Metcalfe (Founder of NEO.LIFE) to talk about her 2020 book NEO.LIFE. You can get a copy of it here!

NEO.LIFE is a very unusual book. It’s over 25 very short chapters (ranging from 1 page to 78) which include interviews, concepts, art, science, science fiction, and one short story. All from different authors or groups of authors that are all edited into place by Jane Metcalfe and Brian Bergstein.

The topic is the future of humans! And the loose focus is on biotech, human engineering, and well watch along and get a copy!

You can see the video below (and the podcast version will be in our iTunes & Spotify channels very soon).

In October the THCB BookClub will feature Mike Magee’s book, Code Blue.

Can artificial intelligence help prevent cardiovascular diseases? Biotech startup, Prevencio, has developed a proprietary panel of biomarkers that uses blood proteins and sophisticated AI algorithms to detect cardiovascular conditions like coronary and peripheral artery disease, aerotic stenosis, risk for stroke and more. Dean Loizou, Prevencio’s VP of Business Development, breaks down the process step-by-step and explains exactly how Prevencio reports its clinically viable scores to doctors. How does the AI fit into all this? We get to that too, plus the details around this startup’s plans for raising a B-round on the heels of this work with Bayer.

Filmed at Bayer G4A Signing Day in Berlin, Germany, October 2019.

NEHI recently convened a meeting on health care innovation policy at which the Harvard economist David Cutler noted that debate over innovation has shifted greatly in the last decade. Not that long-running debates about the FDA, regulatory approvals, and drug and medical device development have gone away: far from it.

But these concerns are now matched or overshadowed by demands for proven value, proven outcomes and, increasingly, the Triple Aim, health care’s analog to the “faster, better, cheaper” goal associated with Moore’s Law.

To paraphrase Cutler, the market is demanding that cost come out of the system, that patient outcomes be held harmless if not improved, and it is demanding innovation that will do all this at once.   Innovation in U.S. health care is no longer just about meeting unmet medical need. It is about improving productivity and efficiency as well.

In this new environment it‘s the science-driven innovators (the pharma, biotech, and medtech people) who seem like the old school players, despite their immersion in truly revolutionary fields such as genomic medicine. It’s the tech-driven innovators (the healthcare IT, predictive analytics, process redesign, practice transformation and mobile health people) who are the cool kids grabbing the attention and a good deal of the new money.

To make matters worse for pharma, biotech and medtech, long-held assumptions about our national commitment to science-driven innovation seem to be dissolving. There’s little hope for reversing significant cuts to the National Institutes of Health. User fee revenues painstakingly negotiated with the FDA just last year have only barely escaped sequestration this year. Bold initiatives like the Human Genome Project seem a distant memory; indeed, President Obama’s recently announced brain mapping project seems to barely register with the public and Congress.

At this point many pharma, biotech and medical device companies have little choice but to enlist in the faster-better-cheaper cause. We can see this in the increasing interest among these companies in fields such as outcomes research and patient engagement technologies.

It’s a case of “if you can’t beat’em, join ‘em” for science-driven innovators, now driven into the arms of tech-driven innovators.

This is a critically important development — and not just for the most obvious reason.

The obvious reason is that tighter collaboration between science-driven and tech-driven innovators may make at least some science-driven innovations cheaper and easier to afford. Consider the Big Data phenomenon: one of the attractions of Big Data is that findings from massive patient databases will provide safety and efficacy signals that can be fed back into clinical research, and allow a redesign of clinical trials that will make them faster, better and cheaper.

The less obvious reason is that if tech-driven innovations succeed in wringing enough cost savings out of health care delivery, then health care payers will be much better positioned to absorb the costs of new science-driven innovations. Payers can offset the cost of these innovations through savings achieved elsewhere.

It’s simply a reality that many new science-driven innovations are likely to remain expensive for some time to come. Manufacturers and purchasers may haggle over price – and they will – but it seems unlikely that cheap, new therapies will enter the market en masse. Even if the techniques for comparative effectiveness research and value-based purchasing improve rapidly – a big if – health care payers and health care providers will still feel compelled to purchase at least some high-cost innovations (such as new cancer therapies) because the public will demand it. For all the cost consciousness that payment reforms like Accountable Care and bundled payments are bringing to the health care system, it’s hard to imagine that providers will compete on the basis of their prowess in shutting off patient access to every new thing available.

In order for us to afford the extra-ordinary things that science can do for medicine in the next many years, we are going to have to make the cost of more ordinary things very, very cheap.  Anyone rooting for new cures, be they patient advocates or pharma companies, should be rooting extra hard for costs to come out of the health care system as a whole. In today’s hyper-polarized health policy environment this is about as close as we are going to come to a new social contract on meeting unmet medical need.

That being the case, we should be looking for ways to make the marriage of science-driven and tech-driven innovators as productive as possible, as fast as possible.  A few thoughts inspired by the same meeting noted above:

Big Data: The rush is on to exploit Big Data, but many stakeholders feel the rush is going off in several directions at once. Efforts to standardize methodologies of analysis, and even to establish some clear priorities for analysis, need to be intensified, if not created from scratch. The public    (and public policymakers) need a much greater understanding of the counter-intuitive notion that Big Data might produce health care that is actually tailored to a patient’s individual characteristics and needs. Privacy concerns need to be addressed in an atmosphere that is now colored by the NSA surveillance controversy.

Clinical Research: Health care is in dire need of safe, effective alternatives to randomized clinical trials (RCTs) that represent a “gold standard” but are so expensive and so dependent on a homogenous group of patients that  (a) they aren’t well matched to the practice of real world medicine among real world patients, and (b) just don’t get funded in the first place. Initiatives such as PCORI’s aim to fill this gap but, here again, the public expects clinical research to yield answers that are either “right” or “wrong” and innovative research is going to give them answers that are neither. This is really a challenge for patient engagement throughout the system and ought to be attacked that way by patient advocates, payers, and providers, as well as pharma, biotech and medical device firms.

Collaboration: If the marriage of science-driven innovators and tech-driven innovators is about anything, it is about feedback loops. Many of the most intriguing new apps and gadgets are patient monitoring or self-care innovations: they are quite literally about feedback loops. But feedback is essential to a wide range of innovations. Drug and device developers cannot design better trials, target patients more accurately, or improve safety and effectiveness unless they get feedback from actual utilization of their products. Healthcare IT and mobile health innovators need early feedback from adopters and payers as they design  products so the  products  won’t be DOA in the marketplace. Creating good feedback loops presumes collaboration among manufacturers, patients, payers, and providers. Many regulators seem open to new forms of collaboration but many of our laws and regulations are still designed to strictly control the relationships among manufacturers, payers and providers in order to protect competition and consumer rights. We need a new look at how to balance the need for competition and consumer protection with the need to innovate in the interest of wringing costs out of the overall health care system and improving patient outcomes.

Value: The health care system is still struggling with critical issues regarding the value of innovations —- how to recognize it and how to allocate its costs and its benefits. The health care system needs to stop paying or reduce payments for innovations of little value. But it also needs to develop new ways to adopt innovations that create significant value for patients and society but fail to match the short time horizons for return on investment that characterize our health care system as well as our entire economy. For example: think about how much cost could be wrung out of the system, not to mention how much human suffering could be alleviated, if the health care system as a whole embraced innovations to treat depression, anxiety, addiction, and serious mental illness —– conditions that the system continues to carve out or otherwise gloss over. Meanwhile the threat posed by ‘super bugs’ and the failure of antibiotics ought to compel action to reward needed innovation. The political system may not be ready to start a bold dialogue on how to reward long-term value, but that shouldn’t stop the stakeholders (patients, providers, payers, life science companies) from acting themselves.

These goals will not be easy to address, but they are pragmatic goals when compared to the goal of ending gridlock in US health policy. Gridlock, technological change and economic necessity have brought us to this point where science-driven innovators must enter into this marriage of convenience with tech-driven innovators. We should all try to make it a happy and productive relationship.

Tom Hubbard is Vice President of Policy Research for NEHI, a national health policy institute.

Have you ever wondered about what goes on behind the scenes—how new drugs are magically produced and brought forth? We’ll continue to take the mystery out of clinical research and drug development and to provide background information so that both patients and physicians can make more informed decisions about whether they wish to participate in clinical trials or not.

Why care?

To develop a medicine, from the time of discovery of the chemical until it reaches your drug store, takes an average of 12-15 years and the participation of thousands of volunteers in the process of clinical trials (Fig 1).

Very few people participate in clinical trials—it is even less than 5% for patients with cancer—due to lack of awareness or knowledge about the process. We’ll go into detail about how drugs are developed in later posts.

An inadequate number of volunteers is one of the major bottlenecks in drug development, delaying the product’s release and usefulness to the public. Of course, many people may suffer or even die during this wait, if they have an illness that is not yet otherwise treatable. So if you want new medicines, learn about—and decide if you wish to participate in—the process. I have, as a volunteer subject, researcher, and advocate.

Why are clinical trials done?

People naturally want to find things that will help them feel better. So people concocted brews, sometimes known as “patent meds.” But then some asked if the medicine actually worked, or what else the medicine did, besides its intended use. Questions later became more sophisticated, asking if the drug might be dangerous, either to people with specific conditions or people taking other meds. Or how does the drug work? If it works by a specific mechanism, does that suggest it might be useful for another condition? Are there other unintended consequences? So these, and many more questions, are why clinical trials are undertaken.

How clinical trials came to be

In order to understand why trials are done in certain ways, it’s helpful—and interesting—to understand how they evolved.

Experiments were described as far back as biblical times, with Daniel following a diet of pulses and water in lieu of meat and wine. Others followed, with observations between groups receiving treatments. But the first known, prospective controlled clinical trial occurred in 1747 when James Lind gave sailors different dietary supplements, in an effort to prevent scurvy, an illness due to Vitamin C deficiency. While he demonstrated efficacy, Lind didn’t obtain consent from his participants, resulting in his study having the dubious honor of also being the first to be criticized on ethical grounds.

Epidemics of smallpox, a devastating viral infection now eliminated, were common in the 1700s and 1800s. In 1796, Edward Jenner demonstrated that a vaccine made from cowpox, a related but milder illness, could be used to prevent smallpox. In the U.S., attempts were made to develop a vaccine from cowpox scabs imported from England. Because the cowpox virus could not live very long in dried scabs, the virus was propagated by arm-to-arm transmission in successive person-to-person inoculations: an infected vaccination lesion on one person was scraped and used as the source of material with which to inoculate the next person.

Congress mandated that an adequate supply of uncontaminated cowpox be maintained and that the vaccine be available to any citizen. Under this 1813 Vaccine Act, Dr. James Smith, a Baltimore physician propagated cowpox for 20 years via arm-to-arm transmission every 8 days. Unfortunately, in 1821 Dr. Smith mistakenly sent smallpox crusts instead of cowpox vaccine to North Carolina, precipitating a smallpox epidemic, as well as the subsequent repeal of the Vaccine Act of 1813.

Besides this egregious error in vaccinating people with live smallpox virus, rather than attenuated (weakened) cowpox, the arm-to-arm inoculation also often transmitted other infectious diseases along with the cowpox vaccine, dampening the enthusiasm for vaccination efforts. (This nicely illustrates the Law of Unintended Consequences; such person-to-person propagation is no longer done, fortunately).

Many laws were subsequently passed reactively, in response to tragedies, rather than proactively, preventing problems from occurring.

For example, after American troops fighting in Mexico received ineffective, counterfeit medications for malaria, the Import Drugs Act of 1848, was passed, establishing customs laboratories, to verify the drug’s authenticity. Ironically, counterfeit anti-malarials are again a huge problem in Southeast Asia and Africa—but that is for a later story.

In 1880, the first major attempt at passage of a national food and drug law was attempted—and failed, as there was no immediate crisis in the public’s eye.

After the gory, nauseating descriptions in Upton Sinclair’s expose of Chicago’s meat-processing plants, The Jungle, Congress passed legislation in 1906 forbidding commerce in impure and mislabeled food and drugs—though not requiring efficacy. But there weren’t really teeth in the legislation, as the burden of proof was on FDA to show that a drug’s labeling was false and fraudulent before it could be taken off the market.” Similarly, there was no requirement to disclose ingredients of drugs, as they were considered trade secrets, lending the name “patent medicine.” Sound familiar?

There was minimal progress towards consumer protection when, in 1911, the Supreme Court, in U.S. v. Johnson, ruled that the 1906 FDA Act did prohibit false or misleading statements about the ingredients or identity of a drug—but still did not prohibit lying about efficacy.

It wasn’t until 1938, after 107 deaths from “Elixir Sulfanilamide” had occurred, that the FDA was able to require “a manufacturer to prove the safety of a drug before it could be marketed.” This established the need for clinical trials.

Unintended Consequences

Clinical trials seek to learn whether a drug (or device) works as expected—it’s unknown, until tested in people. That’s why early phase trials use only a few people, and more are added as experience is gained. Sometimes unexpected discoveries are made along the way. For example, Rogaine was discovered by an astute clinician researcher during a clinical trial studying high blood pressure. The drug, minoxidil, originally under study as an anti-hypertensive medication, was serendipitously found to have the unexpected side effect of stimulating hair growth, prompting a whole new line of products for baldness.

Similarly, Viagra was discovered by accident. Sildenafil, the generic form, was being studied as a treatment for angina, as it dilates blood vessels by blocking an enzyme, phosphodiesterase (PDE). While not very effective for angina, it was found to prolong erections, stimulating the whole “life-style drug” industry. Fortunately, PDE inhibitors are now being found useful for a host of important medical conditions, ranging from pulmonary hypertension to asthma and muscular dystrophy.

Of course, not all inadvertent discoveries have such rosy outcomes.

For example, Diethylstilbesterol (DES), a synthetic estrogen, was commonly prescribed in the US 1938-1971, to help prevent miscarriages. It was only after many years that DES was found to cause a rare type of vaginal cancer in daughters of exposed women. Later, other types of cancers showed up as well, in small numbers.

The tragic effects of thalidomide on developing embryos is perhaps the most notorious and horrible unexpected outcome in the history of drug development. Thalidomide was first released in 1957, with over-the-counter availability in Germany, to treat morning sickness. It was several years before the link was clearly made between thalidomide’s use in early pregnancy and the rash of children born with small seal-like flippers instead of limbs (phocomelia). Thalidomide was then removed from the market. There was a controversial resurgence of interest in the drug and approval by the FDA for thalidomide’s use in multiple myeloma in 1998; it’s use is now being explored for other serious illnesses.

Good from Evil-Ethical Standards

In 1928, through a chance discovery, Alexander Fleming discovered Penicillin in a “mold juice” that inhibited the growth of bacteria on Petri dishes. The potential value of Penicillin was underappreciated until 1939, when its purification and development began in earnest, as part of a war-time effort. War (and friendlier competition between nations) is, all too often, the impetus for research, and has lead to many useful inventions. Such advances naturally occurred in vascular surgery, regional anesthesia, and orthopedics, as well as less obviously related therapies as immunizations and treatments for malaria and other infections.

For example, animal studies in 1940 showed that mice could be effectively treated for Streptococcus with penicillin. The first patient received penicillin in 1941, under what would now be called “compassionate use.” Unfortunately, although he initially responded to treatment, there was not enough drug available, and he later died of his Streptococcus infection.

This “proof of concept” was enough, however, to spur development and extensive cooperation between the Britain and the U.S., driven by the desire to have the drug available to treat military injuries in World War II. Spurred by the Office of Scientific Research and Development (OSRD), pharmaceutical companies joined this patriotic, war-time effort; Merck was the first to develop the antibiotic for clinical use, followed soon by Squibb, Pfizer, and Lilly. In 1943, the War Production Board (WPB) assumed responsibility for increasing production to meet the military’s needs. The National Research Council’s chairman, Dr. Chester Keefer, had the thankless position of rationing the limited stocks of penicillin available to those outside of the military. Although not via a formal clinical trial, Dr. Keefer, too, gathered data as to the civilians’ response. The same process is followed today when a patient receives an experimental drug outside of a trial protocol.

As of March 15, 1945, rationing of penicillin stopped, as there were adequate supplies for both military and public needs. Unfortunately, the “miracle drug” was squandered and now it, along with many other antibiotics, is of limited use—the bacteria having evolved to become resistant much more successfully than pharmaceutical development has kept pace. Many of us are concerned we are entering the post-antibiotic era—the Infectious Diseases Society of America has been trying to call attention to this critical problem since their “Bad Bugs, No Drugs” campaign began in 2004. In a déjà vu moment, Australian news just reported that international shortages are once again necessitating rationing of Penicillin there.

Regulated, standardized clinical trials formally began in response to the horrors of World War II abuses, and ethical requirements for human research was established by world consensus.

Most drug trials are closely regulated and safe to participate in. Those that aren’t make the headlines, as they sell copy. Rebecca Skloot’s fine, captivating tale, The Immortal Life of Henrietta Lacks, is a superb example both of medical research gone awry and our fascination with the dark side of stories. But without clinical trials, none of us would have any prescription medicines available.

As we’ve seen, the history of drug development has been checkered at times. Clinical research is neither perfect nor without some degree of risk, but these can be minimized, and more safeguards are in place than ever in the past. There have been huge strides in the development of drugs, medical devices, vaccines and novel therapies in recent decades. Each has gone through a similar process of extensive testing before approval for use by the general public. But because these early phases of testing involve, at most, a few thousand volunteers, unexpected outcomes after market approval are inevitable and unavoidable, as the new drug is taken by millions.

Judy Stone, MD is an infectious disease specialist, experienced in conducting clinical research. She is the author of Conducting Clinical Research, the essential guide to the topic, and regular posts can be found on her Scientific American Network Blog, Molecules to Medicine, where this post originally appeared.