Release Of Medical Records: Fill & Download for Free

In my opinion, one of the most complex heroes of American history was John F Kennedy.By all accounts he was pretty much a wild playboy type growing up. He served on a PT boat in the Pacific theater. When the boat was damaged his back was broken. This didn't stop him from swimming out to rescue several members of his crew.He won a guerrilla campaign for a US Senate seat, writing "Profiles in Courage" during his tenure. The book is about politicians who risked their political careers on tough votes.He suffered lifelong from his injuries in WWII, developing Addison's Disease and being treated with ever-rising amounts of painkillers and stimulants. We'll never know what his mindset was during the Cuban Missile Crisis. By all accounts he was the coolest customer in the room at the time. Medical records that have been released show that he was receiving a level of painkillers and amphetamines that would have incapacitated a person with a low tolerance.As for the US involvement in Vietnam he had escalated the number of advisors and the level of military involvement. But documents and accounts from government officials show he was looking for ways to deescalate the conflict. We can only guess at what his ultimate Vietnam policy would have looked like.On civil rights he was reluctant at first to take any stand. But when he came out in support of MLK (himself a complex hero), he gave the movement strong legitimacy.It's pretty well known that he was a serial philanderer in and out of office, but was nevertheless dedicated to his family's well being. He had marital problems but by all accounts he and Jackie had resolved them by 1962.So IMHO President Kennedy is unquestionably a real life hero. His actions in WWII were courageous and personally costly. As President he had clear failures, such as the Bay of Pigs disaster, but also succeeded in his most difficult trial. His economic agenda laid a foundation for the strongest decade of economic growth the US has ever experienced. He had many strengths along with many glaring weaknesses. And his untimely, highly public assassination meant many questions about him could never be answered.

Why are people fine with what Ali said 45 years ago, but despise Floyd Maywether’s arrogance?For three reasons.One: Ali’s bluster was to hype the show, in person he was charming and likable. Ali based his hype on Gorgeous George’s persona in wrestling, whom he watched as a young person. He learned the louder you talk, the bolder you talk, the more interest you stir up in a fight.Ali in person was never accused of domestic violence, or any of the sordid legal troubles Mayweather has been plagued with.Indeed, Floyd Patterson said later in his life:“Ali in person was a real great guy. Nice to talk to, nice period. I asked him about all that hysteria during his fight days, and he laughed and said ‘Floyd, it was all for the gate, buddy!”As to Floyd, he is just as nasty in person as he is on TV. It is not hype with him, Floyd is, by all accounts, a nasty jerk.Between his bouts of domestic violence, his hate filled rants, and his nastiness to fans, Floyd is, genuinely, a lousy human being.Why Floyd Mayweather Jr. is a true villainOne of Floyd’s entourage has been recently accused of assaulting someone for asking Floyd for an autograph. This is not the first time Floyd has blown up at someone for daring to recognize himFloyd Mayweather Crew Member Punches Fan After Photo Request RejectedTwo, Ali was a genuinely good and charitable human being, who fed the poor, championed the weak and oppressed, and literally risked his life to save other people.Muhammad Ali (right) leans out of a window of a high-rise building on Jan. 19, 1981, in Los Angeles and talks with a man, later identified by reports as Joe, who threatens to jump. Credit Boris Yaro/Los Angeles TimesCredit also details of the event to Boris Yaro and the Los Angeles TimesAlso credit the New York Times, which carried details of this story:When Muhammad Ali Met a Man on a LedgeThe story of Muhammad Ali going out on a ledge, literally, to stop a man from jumping to his death is preserved forever by Los Angeles Times photographer Boris Yaro. On Monday, Jan. 19, 1981, Yaro was monitoring a police scanner in LA and heard a report of a suicidal jumper. His editor at the LA Times was not interested, but Yaro drove over to Los Angeles’s Miracle Mile, where the man had been reported on a ledge despite that,There, Yaro found a young black man in jeans and a hoodie, on an office-building fire escape nine floors above the ground.The young man, “Joe,” as he was named in reports, had evidently been up there for hours. The police at the scene said:“he seemed to think he was in Vietnam with the Viet Cong coming at him.”A crowd had grown, of course, on the street below, and was happilly screaming to “Joe” to jump to his death.Police officers, a police psychologist and a chaplain was stationed at a window close by, begging him to come inside:“I’m no good,” he shouted, moving to the edge and hanging out when it appeared someone was going to intervene. “I’m going to jump!”In a twist of fate, Muhammad Ali’s best friend, Howard Bingham, was there that day, and called Ali, who at that time was living in LA not far from the Miracle Mile. Bingham said in recalling the incdent:“About four minutes later, Ali comes roaring up the wrong side of the street in his Rolls with his emergency lights blinking.”Boris Yaro watched in amazement as Ali talked briefly with the police, then saw the former champ run into the building. Yaro’s pictures, including the one above, recorded the rest of the incident for history.Ali, in a dark suit and tie, is seen leaning out of a nearby window, trying to see the young man threatening to jump. Just a few feet away, Joe is perched dangerously on the ledge, holding a pillar as he leans out over empty space.By The Los Angeles Times’s account, Ali leaned out and shouted to Joe:“You’re my brother! I love you, and I couldn’t lie to you.”Dodging back inside, Ali found his way to the fire escape, came out, put an arm around Joe and lead him back inside. The two walked out of the building together, got in Ali’s car and drove, after a stop at a police station, to a nearby V.A. hospital.Ali, deflected credit for saving the young man’s life, saying the first responders were the heroes.But of course nothing is ever quite what it appears, and though the police reported that Joe was “badly disturbed,” a few days later when the Los Angeles Times published a story on Joe, it was found that he had never served in Vietnam.Nonetheless, on Wednesday, Jan. 21, at a news conference for a company he was endorsing, Ali announced that he was going to buy Joe clothes and travel with him to his home state, Michigan.Robert Lipsyte, who spent a large part of his life chronicling Ali’s says any claim that Ali was doing it for acclaim was, even if true, only possible one part of why he would try to talk a man off a ledge. Lipsyte said at the time:“The other part was he was capable of acts of kindness; almost casual acts of kindness,”Lipsyte said at the time. Lisyte believed Ali showed up to the office building not only because he thought he could help Joe, but because he wanted to:“In some sort of ways, he talked a lot of people off the ledge, I think about a guy who made people brave. That’s what he did.”Acts like these were common in Ali’s life. Angelo Dundee once recalled an incident that took place after Ali’s last fight before his almost 4 year exile in 1967.On September 10, 1966, a young Ali defended his title in Frankfurt Germany against Karl Mildenberger as part of his "European tour." He was tired and stressed by a return to the USA to continue his fight against the military draft, but he won the fight nonetheless. In the 12th round, with Mildenberger on the ropes, referee Teddy Waltham stopped the fight. At the airport the next day, Waltham’s fee of 1,000 pounds was stolen. Waltham, who was counting on the money to pay his mortgage and bills, was distraught. When Ali heard, he gave Waltham the money from his own pocket.When asked about the incident, Ali shrugged it off, saying:“man, don't make this a story, he needed the money more than I did."In the 1970’s, Ali, much to Joe Frazier’s annoyance, lived in Philadelphia for three years. Ali was very much a part of his new home, trying to help calm racial strife at South Philly’s Tasker Homes, visiting nursing homes and hospitals, and hiring old fighters to work his camps.Maury Z. Levy in a 1975 Philadelphia magazine article relates a story about Ali:“One day he got into training camp at Deer Lake late because he heard a thing on the news about this little kid who had gotten his legs cut off by a train, He went to the hospital, unannounced, and held the kid in his arms and started dancing around. ‘This,’ he said, ‘is the Ali shuffle. And one day you’re gonna be doing it yourself.”But perhaps nothing sums up Ali's life, and who he was, than what he did in 1990. That year, Ali went to Bagdad as the first Gulf War was looming, to try and free 15 American hostages being held by Saddam Hussein. Ali, already badly ill with Parkinson's, ran out of his medications while in Bagdad, and endured very real suffering, yet refused to leave, and persevered until Saddam allowed him to take all 15 American hostages home to their families.On Dec. 2, 1990, Ali and the hostages flew out of Baghdad, headed for JFK.The men remain overwhelmed to this day.:“You know, I thanked him,” said former hostage Bobby Anderson. “And he said, ‘Go home,’ be with my family . . . what a great guy.”Ali asked the media not to make the story about him, but about the hostages and their reunited families.The New York Times, after Ali rescued the 19 hostages in Iraq in 1990, said "however great he was in the Ring, Ali is greater as a human being. Despite being ill, the Champ has given millions of his own money, raised tens of millions more for charity, to feed people, for medical treatment, and perhaps most importantly for a man who is ill, he donates his time to help others. His recent trip to Iraq to rescue hostages held there, during which he ran out of medications he must take, and which caused him considerable suffering, is an example of one man reaching out to help others with no regard for his own health or safety."After retiring from boxing in 1981, at age 39, Ali focused on religion and charity, until his declining health prevented him from public appearances. Ali donated millions to charity organizations and disadvantaged people of all ethnic, racial and religious backgrounds. He helped raise tens of millions more. Ali helped to feed more than 22 million people afflicted by hunger across the world. He never asked for, or wanted, praise for these efforts.Among his many charitable efforts, Ali worked with the Michael J. Fox Foundation for Parkinson's Disease to raise awareness and encourage donations for research. In 1987, the California Bicentennial Foundation for the U.S. Constitution selected Ali to personify the the U.S. Constitution and Bill of Rights. Ali rode on a float at the following year's Tournament of Roses Parade, launching the U.S. Constitution's 200th birthday celebration.In 2012, Ali was awarded the Philadelphia Liberty Medal in recognition of his lifelong efforts in activism, philanthropy and humanitarianism.Make no mistake, Ali was human enough, and he made plenty of mistakes. He himself regretted the rest of his life not standing by Malcolm X when Malcolm left the Nation of Islam, and he also regretted the way he had treated Joe Frazier.The last thing Ali said about his old rival was:“I'm sorry Joe Frazier is mad at me. I'm sorry I hurt him. Joe Frazier is a good man, and I couldn't have done what I did without him, and he couldn't have done what he did without me. And if God ever calls me to a holy war, I want Joe Frazier fighting beside me.”Ali tried, on many occasions, to mend the rift with Joe. When Joe was dying, Muhammad visited him and for the last time asked his forgiveness. (He told Joe he wasn’t leaving till Joe forgave him! And Joe finally did forgive him, and his son Marvis feels he was at peace with the past when he died)In September of 2015, after Joe Frazier was long gone from this world, the City of Philadelphia, thanks mostly to Larry Holmes and Bernard Hopkins, finally put up a long overdue statue of Joe Frazier in Philadelphia, and Ali’s business manager, Gene Kilroy went to the ceremony. He and Marvis Frazier, Joe’s oldest son, then went to Frazier’s grave and laid a wreath inscribed with a message from Ali.The wreath and message from Ali said:“To Joe Frazier from Muhammad Ali, Rest in peace, Joe, until we meet again. Next time we’re not going to fight, we’re just going to hug each other.”All of that was what made Ali a great and inspirational human being.Floyd never risked his life for anything but money in the ring, and he has not, to the best of my knowledge, contributed anything to charity or even done any charitable works.Third, and finally, the only legal trouble Ali ever had was his heroic stand against the Vietnam War, while Floyd was charged multiple times for beating women.Ali’s opposition to the War in Vietnam, but more importantly, the fact that he stayed in the States, risked 5 years in prison, instead of fleeing the country - which he easily could have done, got him, over time, the admiration of almost all of his countrymen. Any Muslim or African country would have granted him asylum, and probably most European countries as well.But he didn’t run, he stayed and fought it in the courts, and said he would accept the outcome, even if was prison.Floyd, on the other hand, repeatedly ran afoul of the law for beating women, not once, not twice, but repeatedly.Details of Mayweather’s domestic abuse are specifically drawn from a story by Business Insider and credited to Business Insider:Floyd Mayweather has a disturbing history of domestic violenceWhat social impact has Mayweather had? Ali fed the poor, and raised millions for charity, and literally went out on a ledge to save a man, and flew to a war zone to save hostages. Mayweather beat up women.Mayweather has a long history of domestic violence. Since 2002 Mayweather has been accused of violence against women with alarming frequency. He pleaded guilty in two of those incidents, and in another he was convicted only to have the charges dismissed four years later. The most recent incident, in which he hit his ex-girlfriend in front of two of their children at 5 a.m. in 2010, resulted in a 90-day prison sentence.Those three incidents are:1. Over a five-month span in 2001 and 2002 he pleaded guilty to two counts of battery domestic violence, a search of his criminal record on the Clark County website shows. He received 48 hours of community service and two days of house arrest. Three other charges — stalking, obstruction of a police officer, and violation of a protective order — were dismissed.According to the Las Vegas Review-Journal, Melissa Brim, the mother of Mayweather's oldest daughter, was the victim. She later claimed in a lawsuit that Mayweather:“swung open a car door, hitting her jaw, pushed her into the car and punched her several times in the face and body," the Review-Journal reports.That lawsuit was dismissed in 2003, according to the Review-Journal.2. In November 2003 Mayweather was arrested and charged with two counts of battery for allegedly fighting with two women at a Las Vegas nightclub. He was later convicted of misdemeanor battery and ordered to serve 100 hours of community service, the Associated Press reported at the time. According to the AP, one of the accusers, Herneatha McGill, testified that Mayweather:“punched [her] on the cheek, and then punched [Kaara] Blackburn on the back of the head as she tried to help her friend."A search of Mayweather's criminal record shows these charges were "dismissed per negotiation" in 2008.3. In December 2011, Mayweather pleaded guilty to one count of misdemeanor battery domestic violence and no contest to two counts of harassment for hitting the mother of three of his children. He was sentenced to 90 days in jail and released after 60 days.One of Mayweather's sons saw the fight, ran out of the house, and alerted a friend of his mother's, who called the police, according to the police report.Harris told Yahoo's Martin Rogers in 2013:“Did he beat me to a pulp? No, but I had bruises on my body and contusions and [a] concussion because the hits were to the back of my head. I believe it was planned to do that, because the bruises don't show."Outside of these three incidents, Mayweather has been accused of domestic violence numerous other times. Deadspin published an exhaustive report of these accusations in 2014. According to their report, Mayweather has been accused of violence against women seven times in the last 13 years, including a 2005 incident where he was found not guilty of battery after Harris recanted an allegation that he hit and kicked her outside a club.Credit also Deadspin for details of this story:The Trouble With Floyd MayweatherI could also mention that Ali fought every great contender of his time, never cherry picked his opponents, or fought a rank amateur and claimed it was his record breaking victory - but the truth is, Ali was a great man in person, and proved it when it counted the most, by literally going out on a ledge to save a man from jumping, and going to Iraq when he was badly ill, to save hostages. Floyd beat women.And that is why boxing fans love Ali and not Mayweather, for very good reasons.

As a person who has made drugs and is planning on making a career out of it, I hope that a lot of things change by the time I reach the middle of my career. The ideal drug development process would and should look very different from the current system in place.The interesting thing is that most of the interactions that already exists should stay in place. A large problem with the current inefficiency of the drug discovery / development process is that the incentives and goals are misaligned for all of the individual players in the drug making process. It's certainly an acknowledged problem and everyone in the drug industry talks about it. To describe how deep of a hole we're in, I show you Eroom's law (Moore backwards) which suggests that the cost of developing a new drug doubles every nine years.EROOM's Law [1]This is pretty unsustainable and Pharma knows it so there are a lot of experiments and proposals to change the drug development process so that failures occur earlier and successes are identified early and pushed through.Everything I will describe tackles the underlying goal of reducing the attrition rate and costs of the drug development pipeline. To briefly outline MY OWN opinions on what needs to happen to have a cost effective system I'm going to dive into:Adjusting the goals of academic research to focus on clinically relevant areas.Changing how medical research appropriately informs and guides that basic researchBridging the gaps between academic and industrial research by both academic efforts and increased drug companies' fundingDiversifying risk between the various stages of drug development by focusing on individual strengths.Revamping the clinical trial process, drug approval system, and influence of marketing to allow for smaller but faster trials.Integrating the drug distribution system into the healthcare networkCreating and rewiring the feedback loops between all of these systemsThe Role of Basic ScienceLet's start from the beginning. Academics are certainly the seed and start of medical discovery and innovation. They ask the questions we don't know the answers to and also find them and from their understanding of biology, chemistry, and medicine, the drug companies can take things to the next level.Unfortunately, the targets that are hot topics in academic will very often be undruggable targets or at least very hard to hit. Targets like protein-protein interactions, transcription factors, protein aggregates, ubiquitin modifiers, RNA, and epigenetic regulators.[2] A great example of a protein target that receives a lot of attention but is completely undruggable is p53 as described in Can p53 be synthesized into a drug to target cancer? It's a target that is extremely dynamic, has a multitude of interactions, and has plenty of off-target effects. People may get the impression that maybe one day we'll figure a way how to make it a useful drug but in reality, we'll probably never hit it and it's merely an very interesting topic of study in molecular biology (with great scientific importance I would add).The result is ~2% of the human genes are actually druggable which largely separates what academics work on and say we can cure vs. what drug companies can actually cure. [3] I describe this more in my answer to Human Genome Project: Was all the promise publicized by the media during the mapping of the human genome simply hype? and Why has genomics been so unsuccessful in the discovery of new medicines?Every now and then, one of those "undruggable" targets become druggable with the invention of new technologies or chemistries. Things like recombinant technology, antibodies, stapled peptides, and PEGylation have made it possible to attack new targets. Indeed one of the widely assumed "undruggable" targets, K-RAS, was recently targeted by a team from Max Planck using a combination of structure-based drug design.[4] Yet there is still is separation from what academics are working on and what companies can actually do.This was well stated by Stuart Schreiber (who, I note, gave me much of the structure of this portion of the argument): Academic research ... might have a greater impact if it were redirected to developing methods that change our view of what is doable. [5] While there is much talk about target-based drug discovery, the modern era hasn't produced much in terms of drugs and a large part is the failure for basic science researchers to choose good targets. [6]The fixture to this issue would be toHave real MSTPs. A good number of MD/PhDs don't end up going into research or they lose too much momentum because of residency. Having true hybrid scientists will help bridge that gap between what patients need and what is actually possible.Clearer discussions on what is and isn't "druggable". As others have mentioned, scientists should be doing a better job looking at the final product rather than thinking about what applications their recent discovery can be applied to.Improvement on target identification. People need to recognize signal from noise and unfortunately there is a lot of noise.Commitments to developing new chemistries and technologies to target the "undruggable" space.Better academia/pharma interactions.The first two are cultural things that academics need to be less stubborn about. The third is an area ripe for progress. As mentioned by Taffy Williams and Mike Thompson, the advent of personalized medicine drastically improves the ability to relate a disease to it's molecular mechanism of action. Furthermore, HTS technologies are designed to be more amenable to diseased-based drug discovery rather than target or gene-based. To better connect academic research with disease, we need to go further into the chain to medical research.Connecting Physicians and ScientistsDrug discovery really starts with observations in the clinic. Doctors will observe patients and from recognizing patterns, they will have a better idea of what makes up a disease and maybe begin to have an idea of the underlying mechanism. I go into this more in my answer to How do pharmaceutical companies go about finding cures for diseases?The problem with this model is that doctors are notoriously bad at doing science and statistics and either see patterns out of nothing or will run trivial investigator initiated trials that are under-powered, biased, non-randomized, non-placebo controlled, and poorly designed. Again, a large reason why better Medical Scientists are required in medicine.The ideal situation is better data collection using Electronic Medical Records and releasing that data from the EMR companies so that information about patient habits, diagnoses of disease can be used. Unfortunately, this information is very difficult to get unless we have a complete overhaul of the healthcare system which I will go into later. I illustrate the value of having this data with the alternative route.For now, I suggest reading the 5 part series: How to build a good EMR by Jae Won JohThe existing model for data collection is the use of patient communities like Susan Komen and Cystic Fibrosis Foundation, which have been extremely helpful to both doctors and pharmaceutical companies. It helps to link symptoms to the underlying case of disease and pools together the patient populations to understand the epidemiology and guide companies to which drugs will have the broadest effect.As seen in questions below, there are very good reasons for pharmaceutical companies to create a strong patient community to better understand the disease and to help with clinical trial enrollment.How should Pharma work with online patient communities?Which pharma companies are currently working with online patient communities?Should pharmaceutical companies support existing online patient communities or create their own?This has been extremely effective in the Rare disease community in collecting and sharing data to better inform patients, doctors, and drug companies. However, a shared worldwide network that better captures all of the variance of the disease will vastly improve physicians' ability to systematically track trends along with maintain a consistent standard of care. Furthermore, in post-approval studies, this type of network allows us to better identify side effects and drug-tolerant patient populations.The Bridge to PharmaceuticaObviously this isn't merely academia's fault. Pharmaceutical companies need to carry their weight in the drug discovery side. Given the large amount of money that is already dumped into research it is important to prioritize research funding. However, the use of those funds are currently poorly utilized.I go more into the economics in the marketing section but for now, it is important to realize that there are large non-trivial cost barriers from translating an idea from academia to company. As every startup knows, there is something called the "valley of DEATH".[7]Ignoring the y-axis "cumulative profit/loss" and replacing it with "expected value", the graph is essentially the same in the eyes of Venture Capital and investors. During the early stages of drug development, the probability of success is extremely low and expected value of the drug is equally low. Only after a lot of time and money does the "commercialization" or the proof of concept occurs and a drug becomes worth investing in.Unfortunately for the biotech industry, the valley of death usually coincides with a Phase II clinical trial which takes ~$20-100 million dollars to get to which can be demonstrated with the next figure [8].So either VCs need to start doing a series A earlier during the process and regularly fund companies pre-IND, pre-Phase III or another large player needs to step in. In addition, academic groups need to do a better job connecting their publications to the final product to reduce uncertainty and risk.This is probably the most exciting current area of drug development as it requires the least amount of momentum to achieve large meaningful results. Universities, Drug companies, and VCs are largely experimenting with how they are tacking this cap.Academics making their drug fundableI'll start with what Academics. I mentioned earlier that Academics tend to work on problems that don't usually yield to tangible results. However a deeper issue is not realizing the disconnect between a successful publication and the commercialization of that idea.The inability to draw in a licensing deal or VC funding can be summarized by:A poor understanding of the economics of the diseaseLack of meaningful clinically relevant dataAn inability in academia to weed out false positives.A poor understanding of the economics of the diseaseSince most PhDs aren't MBAs, they really have no clue how health insurance works and how much drugs actually cost. Typically the way how research is funded is:Find something coolFind what that cool thing doesSee if that thing it do is usefulJustify doing more research on that cool thing based on what it doesTotally reasonable way of doing research but it's also the reason why the NSF is getting in trouble with Lamar Smith. Essentially most of biological research is driven by finding random applications of the science rather than finding the appropriate application and making involved hypotheses to guide that science.For academics to seriously make an impact, they must first check in with the physicians to see what actually happens in the disease that they are interested in and then adjusting the drug in a manner than is suitable for that disease.For instance, several "cures" of HIV including bone marrow transplants and aggressive antibody treatments are impractical since a handful of "inexpensive" oral drugs will essentially do the same + be safer.Lack of meaningful Clinically relevant dataEveryone has seen the article "X cures cancer". What most people forget to do is to read the small text "this might be useful as a drug in 15-20 years". Typically these high-impact publications go along the lines of demonstrating efficacy in an early model system and then following up those observations with the next logical series of experiments.The common saying in the drug discovery world is that "you get what you screen for". As critics of the pharmaceutical industry will say, we're good at curing mice. While we still face the same drug development issues when we attempt to treat mice, the result remains the same, our drug discovery pipeline isn't optimized for finding drugs that treat human diseases. That is, things like chemical-based screening and target-based screening doesn't necessarily produce clinically relevant results. As mentioned, later, the major sources of failure come from lack of efficacy or toxicity. This basically suggests that you've chosen the wrong target to attack.The alternative is to design the screens to identify clinically relevant compounds from the start. Using disease-specific cell-based assays are one method. Using several filters for activity is another. There are also several efforts to build better mice models which actually have human immune systems and die from human cancers. The world of iPSCs also opens the door to the creation of immortalized cells that come directed from a diseased patient.The ideal scenario is to change drug discovery from a linear process to an integrated research pipeline which eliminates false positives from the start. I'll go more into the research integration later.Proposal for bridging the valley of death [9]An inability in academia to weed out false positives.Certainly a sensitive topic in research is the question Is most medical research wrong? Why or why not?A classic paper Why Most Published Research Findings Are False by John Ioannidis suggests that there is an unfortunate tendency for publications to select for positive data. In my own answer, I claim that this falsehood comes from the misinterpretation of the data and answer by Manish Kothari and Michael W. Long also go along those lines. It surprisingly isn't because of fraud or data manipulation, it's more that people are pressured into seeing what they want to see and making the wrong analysis.This issue also reflects the very difficult task of reproducing research. As a personal example, we have one company that is trying to replicate our data using a similar experimental setup and they were failing to do so. In fact, they had to send "experts" to directly observe my labmate doing his experiment and even made him use their own reagents to confirm. Ultimately we narrowed it down to them using a poor source of a few reagents along with forgetting to mix certain chemicals in a certain order. Unfortunately the guy who figured this all out left so after we taught this information, we had to teach it all over again.A lesser known study done by Bayer and Amgen formed validation teams that essentially spend a year trying to reproduce other people's data. Their conclusion: ~20-25% of the data was reproducible; 2/3 of the data there were inconsistencies. [10]Again, this isn't because of fraud or data manipulation. In many of these cases, the teams had to replace cell lines or change the assay formats to get the hypothesis to work. However, even then, there were inconsistencies. There is a lot of variation in biology and are several factors that may cause a false positive.The moral is: Just because your paper was accepted in Nature, it still doesn't mean that it's scientifically sound enough to spend $1 billion dollars on it. To successfully and scientifically validate your idea to the point where a company is willing to take a risk requires several confirmations of your idea. If the drug works in an assay, use a new assay; if it works in another assay, use a cell-based assay; if it works in a cell-based assay, use another cell-based assay; if it works in that cell-based assay, use a mouse; if it works in a mouse, use a rat; etc. See How do drug researchers address effects that only occur in rats?For intellectual pursuits, these studies may not be particularly rewarding but they are the scientifically correct thing to do and ultimately brings in investors. There is also the whole revamping of the publishing model which I will also go into later.I conclude this chapter with a brief telling of The Sirtuin Saga regarding Resveratrol.[11]Triggered by a study by David Sinclair in 2003 that suggested that the molecule in red wine extended the lifespan of yeast cells and at one point showed the reduction of aging in mice. The resulted in the starting of the biotech company Sirtis which ultimately got acquired by GSK for $720 million. However, later studies suggested that the in vitro assays that suggested this activity had some artifacts due to the presence of the fluorescent molecule used in the experiment. Recent data suggests that the assay only worked in specific conditions but still worked. In the end, the scientists did isolated activity, they just started a ~$1 billion company off the wrong lead compound. [12] [13]This debate itself has lead to multiple Quora questionsDo sirtuins really lengthen lifespan?Does resveratrol keep our cells from aging?Why is red wine good for you?If you ask Alex K. Chen for his opinion, the answer is maybe.Academic pipelinesIn order to get researchers to recognize these pitfalls, Universities have created internal pipelines to help academically minded people solidify business-friendly science that can be outsourced.Most of these groups help Professors and students get through the hurdles mentioned above and uses industrial expertise to indicate what risks remain with the proposed technology. Ultimately these ideas would become mature enough to be licensed or spun out into a company and allow Professors to get back to their professing.A few of these programs already exist and the best examples includeStanford SPARKMIT NEWDIGSNorthwetern CMIDDEmory Institute for Drug DevelopmentU Toronto MaRSUCSF CDDSDrug companies funding academicsAs the academics reduce their risk, companies and VCs need to do a better job taking risks. There are usually two schools of though on how to approach this problem.Drug companies should start pulling out the checkbooks and with an aggressive M&A or partnerships fund early stage researchDiversify the risk to Contract Research Organizations and let them handle early stage Clinical development.Those who believe in virtual and lean startups will tell you to go with option 2 and since they have a MBA, they are probably right. I will tell you to go with option 1 since only Pharmaceutical companies had the long term discipline and vision to prevent further fragmentation of an already shaky potential drug. The current reality is something in the middle since Pharma companies are too unweldy to move quickly through development and small biotechs are too desperate to do good science.The ideal model is a Pharma funded early stage pipeline program that operates independently of the mother program but has the financial and intellectual capital to success.Good examples of these early pipeline programs includeGenentech (gRED) / RocheChorus / LillyCORTEX / PfizerCentocor/ JnJBad examples of early pipeline programs that weren't independent includeGroton / PfizerSandwich / PfizerKalamazoo / PfizerWyeth / PfizerKent / PfizerSirtris / GSKResearch Triangle / GSKHarlow / GSKWhitehouse Station / MerckBasically don't be Pfizer. What essentially happened was that pharmaceutical management interfered with early R&D and started outsourcing certain functions to other countries with "expertise" for the sake of "efficiency". However, what that actually means is waiting for a chemist in China to ship their compound to the assay development team in North Carolina which uses a protein created in Switzerland. It's pretty much guaranteed to not work. What you really want is a small well funded mini biotech that cranks out a bunch of compounds.GSK had shifted to a Therapy Area Units (TAUs) system but they are in trouble since they keep on changing the model every 8 years whenever they get a new CEO. Novartis uses the NBIR model; JnJ never bothered to integrate their units; Roches has pRED and gRED; Merck stuck with MRL but the new R&D chief is proposing an aggressive reshuffling at the time of writing. [14]Pfizer has changed their research model from independent research labs to "Centers of Therapeutic Innovation" which collaborate heavily with several Universities. They are essentially outsourcing all of their R&D to academic labs. Probably a wise move but probably not worth imploding their research units.In summary: Pharmaceutical Managers needs to stop moving units around every ten years especially involving products that take 15 years to work.Part of this is a disciplined approach to outsourcing which gets back to the MBA's approach to doing research. There is a lot of value in contracting out research.It allows companies to focus on what they are good at.Reduces training time of new hiresSpreads out capital costs (especially with contract manufacturing)Where this quickly goes wrong is when expertise gets lost and communications gets severed. I mentioned my own outsourcing story earlier and Derek Lowe has several deep and bitter discussions on the problems of outsourcing. When outsourcing causes you to spend more time troubleshooting your supply chain rather than doing science, you're sacrificing time and money. [15]Making Marketing Departments SHUT UPAccording to Adithya Balasubramanian's answer to What is the detailed cost breakdown of an expensive clinical trial? ~90% of the cost to approve a single drug comes during the Phase III clinical trial. Phase III trials are expensive and unfortunately still fail 40% of the time.The major reasons behind failure: efficacy and toxicity. [16]At some point we had information from Phase II trials that informed us that this drug had a pretty good shot at working. As indicated in the cost breakdown, In addition to the fact that they already cost a lot, Phase III trials are get more expensive because they are getting longer, more complicated, have a lower patient retention rate, lower patient enrollment rate. All in all, we are being too aggressive with the way how we design clinical trials and pushing compounds into phase III.A good example of getting impatient and going blindly into Phase 3 trial was the recent Pfizer, JnJ, and Elan efforts with Alzheimer's and blew over $1 billion on two trials with Bapineuzumab despite very indifferent Phase II data. See Where did most of the money in the failed Bapineuzmab Alzheimer’s antibody phase III trial go? The companies had their eye on the $5 billion / year Alzheimer's market but didn't allow the science to dictate their strategy and placed a bad gamble. [17]My hypothesis is that we rush to Phase III too quickly and design the trials to be too broad. If the Phase II data indicates that the drug works in half of the patients, we should be testing the drug in the responsive half. The marketing team will say, that's too complicated, let's test all of the patients and get twice as much money obtaining a blockbuster.The unfortunate result is to appropriately design a suitable trial, you will need a larger subject population and a longer enrollment period to sufficiently power the trial. This ultimately will cost several times more and has a higher chance of failure than designing a smaller well powered trial. This comes back to efficacy and toxicity. If you have a good idea which patients will likely show the best efficacy and least toxicity, you should design your trial for those patients. As mentioned earlier, this is partially due to choosing an incorrect target. However, enrolling the patients that have the wrong target is also a sure way to get a dud.The clinical trial that goes against this tide was Herceptin which looked to attack a gene that was expressed in only 20% of Breast Cancers. From a disciplined scientific approach, Genentech resisted the pressure of increasing their market size 5x by narrowing into the smaller group of Her2-positive patients. Doing so allowed them to use a significantly smaller population (10-20 times smaller) and get approval more quickly.However, there is a reasonable question whether the marketing people were right. Recent reports do suggest that Herceptin works even for certain Her2 negative patients and a non-trivial proportion of Doctors don't pay attention to Her2 status prior to prescribing the drug. In the end, you want the broadest indication since it gets you the most money in the brief period of time the drug patent exists. Marketing got their Blockbuster anyways.You can't blame Pharma companies for thinking this way. I;m sure that some MBA has shown that taking these type of these aggressive gambles should actually get more money in the short term despite the higher failure rate. As a result, to incentivize a trend towards these smaller but better designed trials we need to have an overhaul of the drug approval process.A new interaction between the FDA, Insurance, and PharmacyWhile a lot of drugs fail simply because we didn't identify failiures early like in the case of Bapi, there are some drugs that failed since too many non-responders were enrolled. In my non-medical opinion, drugs like Vioxx and Avandia should probably be on the market since they do work despite what Steve Nissen says. Their problem is that they are being marketed to the wrong people.Despite the large controversy in data reporting for Rofecoxib (Vioxx), it was an extremely effective drug for some patients. It certainly had risks but both the US and Canada voted in favor of allowing the drug to be returned since they thought that the benefits outweighed the risks. However, the publicity hit already happened and Merck decided to permanently withdraw the drug.Another good drug that had devastating side effects was Thalidomide, the drug that triggered the strengthening of the FDA in the first place. The drug infamously caused numerous birth-defects and was quickly withdrawn from the market. As we can see in Can Thalidomide -- a drug with an exceptionally controversial history -- actually be used to treat multiple diseases as claimed in the article cited below? the once dangerous drug has reemerged as a potential Multiple Myeloma drug.This brings us into need to change the drug approval process. The potential of Pharmacogenomics can significantly change our ability to rationally identify patients who will respond well to drugs. This allows us to better design clinical trials that will enroll patients.The risk of these trials are still high and there are real concerns about generating enough of a profit to bridge the valley of death.The appropriate proposal is the use of adaptive licensing, which takes advantage of accelerated approvals to start charging patients to recuperate the costs of drug development but under extremely restrictive conditions. However, while it may cost more per patient initially, it does lower the barrier to entry and reduces the time spent in the valley of death.Depiction of Adaptive licensing [18]A good example is the recent approval of Lomitapide which ran a tiny 29 patient phase III trial for the ultra-rare genetic disease homozygous familial hypercholesterolaemia and got FDA and EMA approval for only that indication. However, the compound has potential efficacy in hetereozygous patients and with the initial approval in the small patient population, they should have enough cashflow to initiate the larger phase III trials.This is heavily on the FDA to allow these trial designs to occur. Their role is to ensure that efficacy and safety are in place. With that in mind, they need to reassure companies that they won't consider these early stage Phase III trials as "proof of concept" trials and are willing to look at earlier NDA fillings.It should be acknowledged that reducing the patient population does complicate enrollment and as indicated by several answerers in What are some of the biggest challenges with setting up and conducting clinical trials? enrollment is one of the hardest steps with clinical trials. However, by tapping in to the patient communities and the use of smaller trial designs, I am hopeful that this dilemma can be resolved.Closing the Feedback LoopTypically when you see something about drug development you see funnel like this:I've always hated this diagram.It makes the entire drug development process seems extremely linear and essentially the secret to getting a drug is taking more shots. Also it assumes that failure is built into the process.The real drug development diagram looks more like the next two diagrams [19]The key thing that makes these proposed systems work is the ability to use the current data to better design future experiments. Rather than working on several compounds and removing them by a process of elimination, you're working on a single product that gradually gets refined and polished by the time it reaches approval. Failures should lead to new hypotheses and guide the development rather than close the door. For this loop to be complete several things need to change.Doctors and InsuranceThese folks were blamed before but now they are getting blamed again. For adaptive approvals to work, Doctors will have to restrain one of their most powerful tools: off-label use. At the same time, insurance companies need to do a better job enabling off-label use when it is appropriate.As mentioned, Doctors need to do a better job observing and reporting patient outcomes. With the increased role of Phase IV monitoring this becomes even more important. Doctors will also need to adjust to the increased role of companion diagnostics and personalized genomics information. For instance, an abnormally large percentage of doctors prescribe herceptin without checking their patient's HER2 status. While the next wave of doctors are beginning to be trained with this mindset, a full overhaul of medical practice won't occur for at least another 30 years when veterans finally die out (however, we still want our Drs on Quora to live forever). However, even the current medical education that was given to people like Jae Won Joh and James Pan doesn't fully integrate a mindset of using personalized medicine.Insurance companies will also need to shift from a high-deductible mindset to a preventative mindset. Drugs in the US are still extremely expensive to the end-user and insurance companies aren't doing enough to negotiate those prices down and appropriately. They will also need to shift from a disease-based model to a target-based model. We can no longer treat breast cancer as breast cancer but instead, treat HER2-positives vs. EGFR-positive cancers. With these systems in place, drug repurposing would become more easy to recognize and push through.Completing this side of the feedback loop will be a key step. For this to happen, Electronic Medical Records will have to be commonplace and better and systematic data collection needs to be implemented.The interesting arena of clinical trials with personalized medicine are the MD Anderson BATTLE Trial and the British Columbia Cancer Agency's Utilization of Genomic Information to Augment Chemotherapy Decision-making for People With Incurable Malignancies in combination with PREDICT. These efforts use full genome sequencing from single-patients in attempts to do personalized cancer treatments. However, according to Marco Marra (I saw him at a conference), there are all sorts of logistical hurdles including biopsy collection and access to off-label drugs. There is also the whole inability to making meaningful connections between genomic datasets and the root cause of cancer.Revamping Data TransparencyAs it can be seen in questions likeMedical Research: Are a significant fraction of drug studies private and not released out to the public?Food & Drug Administration: What is the best way to track the progress of experimental treatments undergoing clinical trials?Where can I find meta-analysis reports on clinical trials?Is every clinical trial recorded on ClinicalTrials.gov?Is that true the clinical trials or biology research data in university labs are chaos and not recorded properly for a feasible usage of the co-worker and the succeeded researcher?Is most medical research wrong? Why or why not?There are all sorts of problems with collecting and releasing data. Again, it's not as if we're doing all sorts of fraud and making stuff up (at least most of us). I've already talked about this extensively in the section: An inability in academia to weed out false positives. In addition to the steps to validate those results, another major change would be to incentivize the publication of more negative data.To ask private companies to publish negative results, we must first ask this of our own government sponsored researchers. The bias towards positive data and the lack of acknowledging the negative data is a huge problem in academia and often leaves well intentioned hypotheses to linger longer than they should. The reasons are numerous as described in Why don't academics regularly publish their negative results?However, there are new better outlets for publishing these results and with the onset of new low-cost open-access journals like PeerJ and PLoS One, the barriers toward publication are being reduced. Ultimately it will take a massive culture change before that happens.GSK and others have also recognized that lack of data sharing in Clinical trials have also hindered their ability to predict potential failures. Unfortunately, the current situation is a prisoner's dilemma where companies that share the data get hurt by the companies that don't but all of the companies would greatly benefit if everyone shares. However, through outside political pressure from the NIH and FDA along with internal pressure, this should be a dilemma that gets resolved as the inertia changes. [20] You can find out more at All Trials Registered. There is also an extensive discussion by Ben Goldacre that is summarized in What do medics, researchers, drug company employees or drug regulators think about 'Bad Pharma'?There currently is a lot of valuable data out there. Genome sequencing has open the floodgates in genotype information and doctors see interesting observations all the time. However, there isn't an efficient system capturing all of this knowledge and despite all of the hate towards the Patient Protection and Affordable Care Act, if it accomplishes anything, it will be the mandated migration to EMRs.The SummaryCongrats. You are approaching the end of this giant tirade about the stiff and stubborn drug making complex. I hope that people understand that there are a lot of factors at play and the high cost of drugs isn't entirely the drug industry's fault. In addition, there are complicated politics that prevent the major players from interacting. Do to this, we need to do a better job passing a compound from one stage to the next.Academics need to do a better job convincing companies of their science.Doctors need to do a better job relying their problems to the academics.Pharma companies need to do a better job funding the researchers.Pharma needs to do a better job designing their trials.The FDA needs to do a better job allow people to design these trials in that manner.Everyone needs to publish their data.At the end of the day, it comes down to having a system where science is relevant to the medicine and guides the drug development process. The industry needs to shift to a system where hitting singles and getting compounds through is more cost effective and efficient than swinging for homeruns. This is a topic that I talk about quite a bit and I suggest following In the Pipeline: and the Quora blog Making Drugs.[1] Diagnosing the decline in pharmaceutical... [Nat Rev Drug Discov. 2012][2] Outsmarting Cancer: Why It's So Tough[3] Druggability[4] Small molecule inhibition of the KRAS-PDEδ interactio... [Nature. 2013][5] The State of the Art of Chemical Biology[6] A critique of the molecular target-based drug disc... [Metab Eng. 2008][7] Osawa and Miyazaki, 2006[8] Organic synthesis toward small-molecule probes and drugs[9] http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0020124[10] Believe it or not: how much can we rely ... [Nat Rev Drug Discov. 2011][11] The Sirtuin Saga[12] Thinning the Fog around Sirtuins | Guest Blog, Scientific American Blog Network[13] http://www.sciencemag.org/content/334/6060/1194.full[14] Making Changes Inside Merck's R&D[15] An Outsourcing Blast[16] Translational research: 4 ways to fix the clinical trial[17] How A Failed Alzheimer's Drug Illustrates The Drug Industry's Gambling Problem[18 ] Adaptive Licensing: Taking the Next Step in the Evolution of Drug Approval[19] Discovery of small molecule cancer drugs: successe... [Mol Oncol. 2012][20] GSK commits to publishing all clinical trial results (Wired UK)