Malignant: How Bad Policy and Bad Evidence Harm People with Cancer

by Vinayak K. Prasad

Each week, people read about new and exciting cancer drugs. Some of these drugs are truly transformative, offering major improvements in how long patients live or how they feel--but what is often missing from the popular narrative is that, far too often, these new drugs have marginal or minimal benefits. Some are even harmful. In Malignant, hematologist-oncologist Dr. Vinayak K. Prasad writes about the many sobering examples of how patients are too often failed by cancer policy and by how oncology is practiced. Throughout this work, Prasad illuminates deceptive practices which

- promote novel cancer therapies long before credible data are available to support such treatment; and- exaggerate the potential benefits of new therapies, many of which cost thousands and in some cases hundreds of thousands of dollars.

Prasad then critiques the financial conflicts of interest that pervade the oncology field, the pharmaceutical industry, and the US Food and Drug administration.

This is a book about how the actions of human beings--our policies, our standards of evidence, and our drug regulation--incentivize the pursuit of marginal or unproven therapies at lofty and unsustainable prices. Prasad takes us through how cancer trials are conducted, how drugs come to market, and how pricing decisions are made, asking how we can ensure that more cancer drugs deliver both greater benefit and a lower price. Ultimately, Prasad says,

- more cancer clinical trials should measure outcomes that actually matter to people with cancer;- patients on those trials should look more like actual global citizens;- we need drug regulators to raise, not perpetually lower, the bar for approval; and- we need unbiased patient advocates and experts.

This well-written, opinionated, and engaging book explains what we can do differently to make serious and sustained progress against cancer--and how we can avoid repeating the policy and practice mistakes of the past.

Genres: Medicine, Science, Health, Nonfiction, Medical, Health Care, Biology

304 pages, Hardcover

Published April 21, 2020

Reviews

[Stefan Mitev · Rating 5 out of 5]

Най-значимата и провокираща книга, която съм чел през 2020 г.

"Злокачествено: как лошото законодателство и лошите данни вредят на хората с рак" е безмилостен анализ на онкологичното лечение в САЩ. Положението дори там не е розово. А тук със сигурност е по-зле. Засегнати са ключови въпроси в медицинската практика, които не се изучават в българските медицински университети.

Нека разгледаме някои от тях.

1. Много проучвания използват сурогатни маркери, а не показатели, които наистина ни вълнуват. Сурогатните маркери са значително по-бързи, лесни и удобни за отчитане и проследяване, но са нож с две остриета. Добър пример е стойността на холестерола в лабораторните ни резултати. Нас всъщност не ни вълнува какво пише на листчето, но със сигурност искаме да предотвратим бъдещ инфаркт или инсулт. Серумният холестерол е сурогатен маркер на важните нежелани събития, от които всъщност се интересуваме (сърдечносъдови инциденти). Тъй като авторът на книгата е онколог и хематолог, той разглежда често използвани сурогатни маркери като Progression Free Interval (PFI) и Response Rate (RR). Не е нужно да влизаме в подробни обяснения какво всъщност означават те, но запомнете, че те са субоптимален заместител на истински важния показател Overall Survival (OS) - преживяемост. Намаляването на размерите на тумора с произволно избран процент (например 30%) звучи супер и се вижда на образните изследвания, но не гарантира нито по-дълга преживяемост, нито по-добро качество на живот. Изглежда нелогично, но е факт. Трябва да измерваме истински важните показатели.

Някои онкологични медикаменти се одобряват и стигат до масовия пазар само с резултати, базирани на сурогатни маркери. Често след това положителният ефект, получен при проведените проучвания, изчезва в общата популация и остават само страничните ефекти. Сурогатните маркери не са перфектен заместител на истински важните крайни резултати. Но се използват все по-често.

2. Регулаторните органи, поне в САЩ, изискват само едно положително (статистически значимо) проучване за одобряването на даден медикамент. Рискова практика. Такъв положителен резултат може да се получи само въз основа на случайността в около 5% от случаите (до 7%, ако се включи ефекта на често присъстващи систематични грешки). Според анализ на автора фармацевтичните фирми имат интерес да провеждат огромен брой проучвания, като малкото положителни от тях (дори само в резултат на шанса) ще им донесат огромна печалба. Това важи дори след отчитане на финансовите загуби от многобройните отрицателни проучвания, при които тестваните медикаменти не стигат до масовия пазар. Авторът дори твърди, че при сегашната ситуация фирмите имат изгода да изследват в проучвания напълно инертни (без никакъв ефект) молекули и да разчитат на 5% фалшиво положителни резултати (за получаване на p <0.05). Пак ще излязат на печалба. Системата е счупена. Трябват промени в здравното законодателство.

3. Почти всички играчи в сложната система на здравеопазване са обвързани с финансов конфликт на интереси - служители в регулаторните агенции, лекари, пациентски организации, лобисти и кой ли още не. В някакъв минал, настоящ или бъдещ етап повечето от тях получават стимули от фармацевтичните компании, което разбираемо променя поведението им по отношение на съответните медикаменти. Прозрачността в отношенията често липсва. Отново, всеки долар, който фармацевтичните фирми "инвестират" като спонсориране на ключови играчи им се отплаща в пъти повече като крайна печалба. Няма случайни неща.

4. Отчитането и представянето на данните от клиничните проучвания е ключово за отношението на лекарите към разглеждания медикамент, съответно за използването му при пациенти. Чрез малко познати (за българските лекари) трикове резултатите може да изглеждат много по-добри, отколкото всъщност са. Освен споменатите сурогатни маркери, други подобни стратегии са - множествени измервания (multiplicity), при които в резултат само на шанса ще се получи фалшиво положителен резултат (ако няма статистическа корекция, напр. на Бонферони), използване на crossover дизайн, използване на non-inferiority дизайн, post hoc анализ на данни, сравняване спрямо плацебо, а не срещу най-добро налично конкурентно лекарство, използване на странни и неадекватни дози или режими на конкурентното лекарство, включване на твърде малък брой участници, непубликуване на отрицателните проучвания (publication bias, file drawer effect), избягване или скриване на intention to treat анализ, нерепрезентативни за общата популация участници (в проучването се включват по-млади и по-здрави пациенти, които не отразяват общата картина в реалността) и много други. Почти винаги резултатите, получени в практиката, са по-лоши от тези в проучванията. Част от обяснението са горните статистически и методологически прийоми. Те са твърде непознати на българската медицинска общност.

5. Надеждата е в младите лекари. Те трябва активно да вземат участие в дискусиите, свързани с медицина и здравно законодателство при всяка удобна възможност. Това включва не само разговори между самите лекари, но и заемане на твърди позиции в социалните и традиционни медии. По неудобните теми трябва да се говори. Иначе нищо няма да се промени, което е изгодно за мнозина в сегашната ситуация.

Нещата, които знаете (или си мислите, че знаете) за организацията и провеждането на лечение са само върха на айсберга. Подводните камъни са разнообразни и многобройни. Системата работи по инерция и трудно ще се промени без външен натиск. Трябва да бъдете активни в отношението си към медицината, базирана на доказателства, защото рано или късно и вие ще бъдете в ролята на пациент. Тогава ще искате ли субоптимално лечение?

Прочетете книгата на Винаяк Прасад. Това ще бъде най-добрата ви инвестиция на време и пари през тази година. Силно препоръчвам!

[Ardon · Rating 5 out of 5]

I’ll freely admit that I do sometimes get hyped up by new cancer therapies which have strong biological grounding. However, the cold hard truth of the matter is that this is never enough - silver bullets in cancer are truly rare. What we need are well designed, randomised controlled trials to test the effectiveness of new drugs, by measuring outcomes which matter to patients (survival, improvements in quality of life, etc). Unfortunately, the reality of cancer drug research is very disappointing.

Prasad delves into many different aspects of drug testing in oncology, dealing with trial design first. The first priority of a pharmaceutical company pushing a new drug is to get it approved, and as a result, they design their trials in ways that maximise the probability of this happening. For one thing, they seem to fill trials up with younger, healthier people, which is odd, given that most cancer patients are older and have other health conditions too. Therefore, they are not really testing the drug among its target group. To speed up approval processes, drug companies also use surrogate outcomes like progression or disease free survival. This is pretty problematic if the measures don’t correlate well with actual outcomes, like overall survival. Sadly, this is often the case with these sorts of trials. The FDA actually approves 2/3rds of all cancer drugs based on these surrogate outcomes, without ever investigating the validity of these metrics; it really is quite disturbing.

Admittedly, it does appear that the FDA is not being as meticulous as it should be when it comes to the approval process for cancer drugs. With accelerated approval, drug makers are obligated to do post marketing studies to confirm the effectiveness of the drug, but only about 50% do, and the FDA stands idly by. Part of this may be because of the “revolving door” problem, which is almost as pervasive with the FDA and pharmaceutical companies as it is with the SEC and big banks.

There is also a rather perverse incentive for drug companies to test marginally effective, or even ineffective drugs. As Prasad lays out in a particularly elegant thought experiment, if a pharmaceutical company were to test enough of a number of drugs known not to work in a huge number of trials, some should appear to give sufficiently positive results (by sheer probability) to go on the market, because of the relatively lax standards imposed. The expected earnings from, say, 5 successful drugs would far outstrip the cost of conducting 100 or more trials, suggesting that the optimal financial strategy is to test a huge number of (possibly ineffective) drugs. Prasad frames this problem well throughout the book with a number of additional examples, explaining how drug companies desperately seek out statistically significant result, which do translate into financially beneficial outcomes, but not clinically meaningful ones.

The epilogue was really enjoyable; I enjoyed the exploration of the 6 hallmarks of successful cancer policy - nice bit of allusion to the famed Weinberg and Hanahan Cell paper, and just as astute. Perhaps the current situation we are in is not as intractable as it seems.

On the whole, this is probably one of my favourite books on cancer, mainly because there are no punches pulled. Prasad forces the reader to confront the harsh realities of the industry, but remains evaluative and fair throughout.

Funnily enough, I ended up reading this while on a research internship, looking for possible drug targets within my pancreatic cancer cell lines. It certainly made me approach a lot of the pharma bits of the project with a healthy dollop of skepticism.

As William Deming once remarked - “In God we trust, all others must have data.”

Perhaps a more modern take on this suited to cancer pharmacology would be “In God we trust, all others must have replicable data from randomised controlled trials.”

[Daniel Hageman · Rating 5 out of 5]

It’s about time I read something that more directly critiques the field in which I’ve found a career for the past 6 years, and Dr. Prasad pulls no punches to say the least. The majority of the critiques leveled in each chapter are ones for which I’ve become familiar with over the years, but there were a few that I had not properly thought through before, as well as a few that I think are less problematic than the author seems to imply.

The author’s POV as a physician is overall refreshing, in contrast to so many healthcare providers who tend to speak out of both sides of their mouths (explicit in their actions, as well) when interacting and collaborating with pharmaceutical companies. It may be tempting to stand at a distance from ‘Big Pharma’ with banal critiques of drug prices and CEO salaries at the ready, but a book like this paves the way for the more nuanced conversation that is needed to fully understand just how many factors are in play, and how we can start making progress against some of these major barriers.

All in all, I find it largely motivating to be on the ‘inside’ of a system where there is so much opportunity for positive improvement/impact. Having one’s position counterfactually replaced by another employee who is less likely to care about and improve the the system is no way to improve the world, so this book did anything but want my to transition away from this industry.

Anyone working on the medical side of the pharmaceutical industry, or especially those who find themselves in the commercial sector, would do well to take an honest look at the many issues that plague progress in cancer research. And those outside of industry who want to understand the many variables involved, beyond just ‘Big Pharma Charges too much for drugs and pays their CEO millions!’, this is also the book for you.

[JP · Rating 5 out of 5]

This is a really interesting book and I'd recommend it to anybody who is in the practice of oncology. This book contains elements of pharmacovigilance, ethics, epidemiology, and investigative journalism. Some topics are touched upon in medical school, but for me these are unfortunately swept under the bed and forgotten due to constant deluge of information that we must keep up with; this is a good refresher. It is a reminder that we should be critical of all new data that comes out and that there is a pervasive force out there that influences our behavior in the clinics. Do not settle for mediocre outcomes and always champion the cause of cancer patients.

[Will · Rating 5 out of 5]

Summary: I think this book lays out a refreshingly honest overview of cancer research and proposes sensible ways to fix what’s gone wrong. He doesn’t pull any punches with his critiques, but is also generally fair-minded about giving the other side their due. Recommended to those in healthcare, to anybody interested in decision-making under uncertainty, health policy, and the pharmaceutical industry. From a technological stagnation perspective there’s some interesting grist as well. 5/5!


"Malignant" is a somewhat atypical book in the cancer space, as Prasad admits in his introduction. It reads a lot more like a combo of investigative journalism and outraged policy wonk (perhaps The Weeds podcast would like him on?) than my preconception of the 'typical' cancer book, which, according to Amazon, is cancer cookbooks, 'holistic' ways to cure cancer, and a sprinkling of cancer biology.

Malignant’s simplified thesis is that over the last 25 years or so, increasingly lax regulatory standards + pervasive financial conflicts of interest +other factors have led to a proliferation of marginally useful cancer drugs, in addition to some truly useful game-changers, all at impressively high prices.

To be honest, when I first heard about the book, I wasn’t too excited. Cancer has never been my wheelhouse, and I wasn’t too excited about a book that I initially thought would be warmed-over criticism of cancer drug prices or something like that.

But, I gotta say, my instincts were wrong: like in the author's other book, "Ending Medical Reversal", the apparent focus of the book—cancer drugs—is really a lens on a ton of other questions.

You might not think that “progression-free survival” should matter to anybody but an oncologist, but the utility or lack thereof of a metric is increasingly important in a metric-focused world. Like Prasad suggests when he quotes Plato, “They see only their own shadows, or the shadows of one another”, there are lots of difficult problems in clinical medicine that should make us think deeply about medical epistemology. Good thing, according to his CV, he was an undergrad philosophy major.

Cancer research, in addition to being philosophically interesting, is also morally compelling: it features the best and worst of modern medicine, the miracle cures like Imatinib and occasionally immunotherapy, and the arguably useless drugs that squeak by with a barely significant increase in surrogate endpoints.

So in addition to recommending “Malignant” to those in healthcare, I recommend it to anybody interested in decision-making under uncertainty, health policy, and the pharmaceutical industry. From a technological stagnation perspective there’s some interesting grist as well. 5/5!


On to the book’s thesis. Prasad makes so many separate points that summarizing in order would be unmanageable, so I tried to categorize them: Lax approval standards + financial conflicts of interests +byzantine cost shifting in American healthcare +irresponsible hype from many sources.
All those put together lead to very expensive, very mediocre drugs, with no real competition, and no market or regulatory forces driving costs down.


In this story, the “original sin” in cancer research is lax approval standards at the FDA. These come in many forms, of which the most important are FDA approvals based on surrogate endpoints that are NOT followed up with hard survival data and RCT’s conducted in ways that don’t mirror clinical practice.

To disagree with Prasad on RCT inclusion criteria a bit, let’s look at it from pharma’s perspective. Clinical trials are enormously expensive and fraught with uncertainty. Too many adverse events (which may be more common with sicker patients, and impossible to predict) can sink a drug. Avoiding polypharmacy with patients with comorbidities is probably challenging. Perhaps looser inclusion criteria would decrease patient compliance rates in trials. Lots of reasons for strict inclusion criteria that are not easily wished away.


On the other hand, we might propose that if a drug is not effective enough to demonstrate a clinical benefit in an imperfect scenario (which is more like the real-world than a strict-inclusion trial) we’re not interested in the drug. That’s a fair argument, and Prasad gestures in that direction by arguing for “trials…powered to detect clinically meaningful benefits. These won’t be trials looking for survival benefits measured in days….guidance from American and European professional societies can be used.”

I think he would agree that there’s some hard trade-offs here, and that a high-impact area would be figuring out ways to make clinical trials cheaper and easier to run: if nothing else, Covid-19 has demonstrated that we need to streamline RCT’s quite a bit.


The second main theme is financial conflicts of interest. It's not that the average physician is all that influenced by a free steak dinner once a year or a handful of free branded pens—though those likely influence behavior at the margin—but that the top physicians in a field, the ‘thought leaders’ receive quite a bit of $ from pharma: “125 guideline writers…84% had taken personal payments from pharma...average was just over $10,000 ($10,011), with a huge range ($0 to $106,859)”. Prasad documents a few studies showing similar findings in that vein and has some neat studies looking at physicians’ Twitter activities and how positively they talk about new drugs. In addition, the practice of paying oncologists a fixed % of the drugs they administer, Prasad notes, perversely incentivizes more costly drug administration.

Prasad also criticizes the practice of patient advocacy groups taking money from pharmaceutical companies and notes that they rarely, if ever, push back against marginal drugs and criticize cost-effectiveness programs.

The revolving door between FDA regulatory officials and pharma executives is also, Prasad argues, a problem. This creates an implicit incentive to be somewhat lenient on pharma from the FDA perspective, so as not to foreclose the possibility of retiring from the FDA and moving into industry.

Prasad rightly criticizes the overwhelming hype in cancer research: “Every new drug seems to be a miracle, breakthrough, game changer, or cure, irrespective of how well it works or for how many people”, and wants to save the headlines for drugs that are truly transformative. A high bar, but the constant overuse of hyperbole likely erodes public trust in scientists, and trust is slow to gain and easy to lose. Much of this fault can be placed on journalists and university press release offices, but he also provides examples of regulatory officials (like former FDA head Scott Gottlieb) making much ado over only incremental improvements.

The book is not all doom and gloom, though it contains enough examples of misconduct that it certainly gave me some transient hypertension. Prasad has several proposals to make things better, which he advocates, as a smart technocrat should, rolling out in incremental testable fashion. Try the reforms out, measure outcomes, and move forward from there. Eminently sensible!
Some of the changes he proposes: studies that use survival as their primary endponts, enroll wider groups of patients, use standard-of-care control arms, and use ASCO guidelines for meaningful improvements.

His more radical proposal is to sever the [clinical trial] portion of pharma companies, fuse it to the FDA, and have a pre-specified agreement by the FDA that basically says “if you meet those endpoints, it’s approved”. These changes would raise the bar for cancer drugs, which would incentivize fewer but more groundbreaking drugs, at the expense of questionable useful but abundant cancer drugs. I think the generally mediocre response of governmental agencies to Covid-19 should make us wary of such a move, relying as it does on government competence, but I think it’s an interesting proposal.



For those outside of the cancer and clinical trial space, the book is also an excellent introduction to medical legalese like “disease-free survival” and “partial response”, and there’s a section at the end with some practical tips on how to choose an oncologist for you or your loved ones.

A random note: Prasad is diligent about crediting collaborators and random people he quotes, which is nice to see. Every other paragraph is “and this random med student who came up with an idea did a study with me.”

And to counter a possible critique of Prasad: Prasad is not some EBM “ONLY RCT!” fetishist—He recognizes where to be more or less flexible about evidence. For instance, he agrees that third-line therapies, which are by their nature less studied than first-line, can be studied in more flexible ways, like with surrogate endpoints, and that individuals with very high genetic risk for cancer (BRCA1 carriers, for instance) should be treated prophylactically without RCT’s because their risk for cancer is so high (IIRC 30%+ lifetime risk?).

In the case of end of life care, he makes the common-sense observation that if patients have limited life expectancies, initiation or continuation of drugs with benefits that take years to accrue, like statins, is probably a bad idea.

[Sebastian · Rating 4 out of 5]

A quite solid and worthy successor to one of my favorite books, Ending Medical Reversal, this time with a focus on oncology, detailing the ways that policy results in drugs that cost too much and do too little. Vinay Prasad is a treasure.

We start with the sobering statistic that for solid tumor drugs approved between 2002 and 2014, "the median improvement in survival was just 2.1 months" [12]. For the privilege of using these dubiously-useful therapies, we are paying out the nose in a way that is hard to argue reflects society's preferences: e.g. $800k a QALY for necitumumab (an EGFR monoclonal antibody), or $900k a QALY for regorafenib (a small molecule RTK inhibitor) [17].

Separate from the question of cost, why are so many lousy drugs getting through trials in the first place? A couple reasons to highlight:
- Trials run on surrogate endpoints, e.g. approving drugs in the metastatic setting on arbitrary things like progression free survival, that do not always correspond to an overall survival benefit. RECIST criteria are weird and arbitrary and I'd like to hear someone defend them intelligently [27]
- The FDA doesn't enforce postmarking requirements after accelerated approval. I don't get this at all. As of 2017, only 54% of 614 postmarketing studies that were promised had been completed [40]. How do you just sweep this under the rug?
(Also there is the story of atezolizumab, an immune checkpoint inhibitor used for bladder cancer that actually FAILED a postmarketing study but still has marketing approval. What? [157])
- Censoring that biases results is sometimes not assessed properly [43].
- Trial multiplicity, if you spin the wheel enough, eventually you get p < 0.05. An expensive way to p-hack [134].
- Inappropriate use of noninferiority studies. These are only warranted when you are offering a new drug that is cheaper or less toxic than the incumbent but often new approvals are neither [161].
- Controlling not against the standard of care but an older, less-effective drug that has already been bested in a well-designed trial [174].

Largely it feels as if FDA is accepting subpar evidence to approve drugs. I can speculate about why that is: the administrative revolving door? Is it a narrow vision of responsibilities that allows them to abdicate in the face of the billions in inappropriate drug spending an approval unleashes? But I am not sure, and open to things that I could be missing as always.

In terms of cost, Medicare is the big payer here since most people with cancer are elderly. And CMS cannot negotiate price if FDA approves a drug. Done and dusted [216]. That has also never made sense to me and I have always felt NICE in the UK was a better way to do this (though stay tuned, I have an even better idea). Then, if particular specialty societies recommend off-label use, CMS has to pay for that too. These groups can of course be influenced by pots of money paid directly or indirect funding of research. [My own addition: PBMs on commercial plans generally end up with a percentage of costs and have little incentive to make drugs cheaper.]

I think the fixes Prasad suggests are too mild so I'll just dive into my plan:

In Seeing Like A State James Scott talks about government trying to reduce variables and make society legible. Biology is messy. We are short sighted to try and make it legible with simple labels like "approved" and "not approved". It's pure high modernism.

Instead of approving drugs for marketing and then giving pharmaceutical companies a license to plunder CMS, what if we refocused FDA as a clearinghouse for trial results? What if instead of trying to assign a label one way or another, FDA focused on presenting the evidence as it is: messy and gray?

From there, independent payers could evaluate it and determine how much they want to pay. Do good studies? OK, you can command a premium. Do bad studies or show poor outcomes? Payers smell the BS and reimburse less or limit use to specific cases where prior auth is required. But the beautiful thing about this idea is that you incentivize good research. I'll tell you a secret if you listen carefully: incentives matter. To that end, we would also have to fix the MLR limit issue with health plans that incentivizes ballooning spending every year.

Obviously if you can move towards consumer directed healthcare the incentives flow even better, although you face a real information problem in building a market there. Most patients are going to have no idea about what drugs are good and are worth paying a premium for. Maybe risk delegation to oncologists is a good way to handle this. Give them a lump sum payment and reward with shared savings if patient is managed under the cost trend. This would have to be fleshed out much more, I am just spitballing at this point.

To get into medical school you spend 4 years on physics and organic chemistry and other things, then in medical school you spend about 2 years memorizing tables of things like the names of holes in your skull or bones in your wrist, 1.5 years in the clinic, and then about 6 months messing around. Then if you want to become an oncologist you spend 3 years in internal medicine residency before starting a heme/onc fellowship. What if we did away with this and had oncologists focus on oncology much earlier? What if we taught what was necessary for that? What if we had oncologists-in-training devote hours to building their working knowledge of the base of evidence from trials? And we gave them the tools they needed in statistics and data science to evaluate these? And copious practice (earlier in careers) in the tough decisions that oncologists and patients need to make about what course of treatment to pursue and when? And then we incentivized them to practice value-based medicine based on their unique ability to evaluate the costs and benefits of drugs in conjunction with patient preferences?

Bad systems with heroic people in them frustrate me.

[Evan Hall · Rating 5 out of 5]

Prasad clearly lays out opportunities to improve cancer research and patient care. Well-written and a nice written accompaniment to his successful, engaging podcast (“Plenary Session”)

[Alison Palumbo · Rating 5 out of 5]

Finally finished this. Had to put it down for a few months because I got bogged down with book clubs and because honestly I was getting too burnt out my own cancer research and teaching cancer research to go home and read a book about...cancer research. I’m glad I finally got to a good place so that I could finish this.

It’s awkward reviewing a book written by someone you know on the off chance that they read it, but here goes. Will try to remain objective.

- If you’re someone who has listened to much of the Plenary Session podcast, the book may not be as helpful because a lot of what’s covered in the book is covered in the podcast. As someone who has listened to many episodes of the podcast, what I do appreciate about having the book is having all the references. I don’t have to try to remember which podcast talked about a particular topic and then hope I can find the corresponding paper, it’s all right here in the book. Going forward I may use it as my external brain and refer back to it for important policy/research questions.
- I appreciated the sections on trial appraisal the most. I care less about cost, or rather it all just makes me too angry to want to read about the exorbitant cost of cancer care and rampant COI for very long. Again a lot of the appraisal pieces are in the podcast, but it did help me to solidify my understanding of when crossover is and isn’t appropriate, etc.
- It was a bit hard to nail down the audience. I feel like the book tried to reach EVERYONE with the merest interest in cancer care. The book is helpful for clinicians, but I think the epidemiology nerd in me wants a deep dive into biostats principles and their application to cancer trials.
- All in all, I liked the book as I am a big fan of Dr. Prasad’s work. I think it’s best for learners and for clinicians who are new to these principles. I will likely buy a few copies to give to my residents and students who are particularly interested in cancer research.

[Kunal Kamboj · Rating 5 out of 5]

Eye opening read regarding the games played in healthcare.

[Talent · Rating 5 out of 5]

In short, this is a great paradigm-shifting book for me from someone who was sold on the hype of "precision medicine" in a professional capacity. Vinay Prasad focuses on the policy aspect of cancer care, which requires delving into the nitty gritty of certain cancer studies and the intricacies of study design. These are all great and fascinating, particularly for trainees or other healthcare professionals who are not well versed in the treatment oncology literature. The writing is mostly clear and witty, but Prasad does get a bit repetitive at places (which seems to stem from his desire to *definitively* communicate his ideas across).

Prasad himself summarizes the issues of the book as follows: "conflicts of interest, endpoints that do not measure what matters, difficulty applying trial results to average people with cancer, lofty and unsustainable prices, suboptimal research funding, and duplicative, redundant, uninformative, and even unethical trials."

The current way oncology treatment is structured indeed does not inspire confidence. As a previous disciple of the "precision medicine" school, I had mistakenly thought that at least we have some gains in new wonder drugs and improved treatments to show for it (or the potential for such). However, Prasad convincingly describes how actual wonder drugs are few and far between, and there really is no incentive to develop these wonder drugs since the toxic crud brought to market are profitable enough under the current regime.

It is also sad to read about how conflicted so many doctors and clinical trialists are, even among those in prestigious academic institutions--not to mention the regulatory capture of the FDA by industry. All of these things are happening under the aegis of a conflicted Congress that receives cash (free speech) from lobbyists. Yet another disaster attributable to the contemptible Citizens United decision?

He also blows away my previous confidence in the FDA as an impartial player. After recently FDA debacles with aducamumab and reviewing some of these trials on my own (and learning the key difference between PFS and OFS), I have come to realize how useless some of the approved drugs are and how much hype there is in the market (and the literature).

Lastly, Prasad's suggestions for reform are reasonable. They ideally would promote research into truly efficacious drugs, preclinical research, impartial trials, and expanded statutory powers for the FDA in the right places, with the best part being that these proposals themselves to be trialed. Excellent! Now if only it would happen….

[Thomas · Rating 5 out of 5]

Down to earth investigation into the unbeknownst world of cancer drug creation, testing and marketing. Back in 1970, there was cancer research funding of $1.6 billion initiated by Nixon with the purpose of finding a cure by the end of that decade. Here we are 50 years later and not much has changed after spending $100's of billions on cancer research.

The entire system (process) is deeply flawed. Many new cancer drugs end up on the market, at ever higher costs to the public, and some after 3 to 6 years of further trials, it is discovered they add very little to life expectancy of most cancer patients. Meanwhile pharma has raked in $100's of million in revenues for cancer drugs that are virtually useless.

The author presents an in depth look at the process of how new cancer drugs evolve. He does get a bit technical at times, but mostly the information is comprehensible. The author gives some ideas on how to change the way new drugs are put into trials and approved for use. Thus efficacy and costs could be lowered.

The real test of these drugs is if they actually add months or perhaps years to the life of people diagnosed with cancer. Unfortunately, most of the newer drugs that have been approved in the last 2 decades offer little in the way of extending life. The way this process is currently undertaken, don't hold your breath for any new breakthroughs in the next 50 years. Many so-called miracle cancer drugs and protocols are missing one vital ingredient...the miracle part.

[Alec · Rating 4 out of 5]

Malignant is an accessible and interesting read for anyone looking to understand how much of a jumbled mess cancer research and drug policies are. Some of the information, especially all the studies Prasad sites, can bog down the reading experience, but the book is formatted so that a reader can skip over sections easily if they are already knowledgeable about a certain section or just want to understand the idea without getting into the nitty gritty. I wish I had this book earlier in 2020 after I read Siddhartha Mukherjee's The Emperor of All Maladies: A Biography of Cancer. Reading Mukherjee's deep dive into the history and biology of cancer alongside the Prasad's examination of policy regarding cancer research would be especially interesting.

[Richard Simcock · Rating 5 out of 5]

We are in an age where it is perfectly normal to accept cancer drugs that cost 10s of thousands for minimal gains and for drug companies to continue make 'me too' drugs at the same price. A broken market.

Dr Prasad is someone who is happy to say that the Emperor has no clothes and explain exactly why.

The book is an excellent distallation of the views that he shares on his podcast 'Plenary Session' or in his published academic works or tweets. It continues in a tradition set by his previous book and by others such as Ben Goldacre's 'Bad Pharma'.

I would recommend this as required reading for cancer triallists and trainees. Colleagues working int he pharma industry and policy makers will all find insights of value here. There is a strong USA focus (particularly in the optimistic 'solutions' section in Part IV) but the lessons here are global.

Contains a large glossary for the non specialist reader and a large list of references for those who want to dive deeper.

[Dr. Ashori · Rating 5 out of 5]

Though this book is about oncology, the topics and concepts apply to other specialties as well. Another book by the same author helps shed light on why medical reversals happen and how to safeguard against unhelpful biases in clinical medicine - this is relevant to both patients and doctors.
1. Surrogate endpoints is a must to understand (as opposed to relevant clinical outcomes)
2. Fast approvals are often more problematic than helpful
3. Drug prices aren't just a cost problem but also dictate policy
4. Trial designs favor positive results and not real results
5. Patients must understand what cancer screening really shows

There are other physicians who speak up on such topics to drive better health outcomes for patients but unfortunatly most are viewed as renegades and troublemakers.

[Anke · Rating 5 out of 5]

I’ve read this book from the perspective of an epidemiologist working in oncology research. I will be recommending this book to all my colleagues from clinical and non-clinical backgrounds, because it addresses issues that everyone working in oncology research or consuming oncology research should be aware of in order to adequately interpret research findings. It is full of eye openers and does not only explain (and more importantly, show by example or even substantiate with own published research) problematic practices but also provides real and overdue solutions to them. Although I do have some minor issues with some methodological aspects described in the book, it does not undermine any of the messages.

[Erik Olsson · Rating 5 out of 5]

A very important book that highlights what is rotten in cancer medicine and how big pharma is given too much influence in designing sometimes unethically bad clinical trials that only serve to increase their bottom line and not help cancer patients. Dr Prasad is one of few doctors that is vocal about problems that have to be fixed in order to create incentives for scientists and big pharma to develop drugs that cancer patients benefit from. As an oncology resident I found this book and Dr Prasad's podcast "Plenary session" eye openers. I recommend the book to medical professionals as well as laymen.

[Diane Henry · Rating 2 out of 5]

A book trying to reach multiple different audiences and so has content that is overly simplified at times and overly technical at others with seemingly little rhyme or reason.

There’s good stuff in here, but it’s erratic. Also, the book is written like spoken text and it’s a little hard to follow at times.

Overall, I wish the book had spent more time explaining concepts in depth, rather this superficial gloss over the many problematic aspects of cancer drug costs and crappy cancer drug studies.

[Tracy Solak · Rating 4 out of 5]

As a cancer patient and research advocate, I enjoyed this book. I've heard Dr. Prasad speak, and this expanded on a lot of the information he has provided in those talks. However, I must say that I cannot agree that every single trial should have an endpoint of overall survival. Yes, OS should be the goal. However, if a drug provides comparable OS with less toxicity, that is a "better" drug--despite the fact that it does not improve OS.

[Daniel Portik · Rating 5 out of 5]

Great book about policy that makes you think in larger perspectives. Can be read by both medical professionals and by people not in the field of medicine.
For comparison: not as heavy on info and history like The Emperor of All Maladies, but also not completely easy on the medical information as a 'medical' novel for example When Breath Becomes Air (if this helps anyone).

[Pamela · Rating 5 out of 5]

If you have cancer or are helping care for someone you love in that situation, I think you will find this book helpful in navigating the decisions that you will face. This is especially true if you desire to make informed decisions and research the things offered before agreeing to say yes to them.

[Sharath Reddy · Rating 4 out of 5]

Good overview of the issues with cancer drug approvals and use. Dr Prasad does a great job explaining things clearly. It’s accessible to anyone with some high school biology. Beyond assessing cancer drug approvals, a great book to quickly come up to speed on the layout of oncology therapies as they are used today.

[Zaid · Rating 5 out of 5]

This is an excellent book and is an excellent read for anyone dealing with cancer patients, including patients themselves. Very important for trainees, an essential read.

The only downside is that I've been following Vinay's work since 2019, so some parts of this book were a bit repetitive.

But otherwise, an excellent read.

[Sarah · Rating 5 out of 5]

As a student— 1. Feeling more prepared to read clinical trials with an eye towards deriving meaningful benefit for patients 2. Feeling inspired thinking about the ways I can use my masters thesis as a platform. Thank you for writing this cohesive, necessary read

[Lauren Birmingham · Rating 5 out of 5]

I really enjoyed this book. It is a quick and easy to digest read-- but still technical enough to be thorough and useful. I want to incorporate some of these things into my cost benefit analysis class! Definitely some great examples in here.

[Kate E · Rating 5 out of 5]

Excellent in-depth review of clinical trials and the flaws and considerations for interpreting the results of those trials. He speaks though the lens of Cancer trials but can be applied across other diseases.

[Chaitalee Ghosalkar · Rating 3 out of 5]

When I was reading the book, the author was still in charge of Centers for Disease Control and Prevention aka CDC. Now, he's resigned (or more likely ousted). The points he puts forth are valid, but his stance bordering on being an anti-vaxxer out me off.

[Ben · Rating 5 out of 5]

While Dr. Prasad could have gone further in depth in parts, this book provides a comprehensive, insightful, and alarming overview of the current gaps in cancer policy & research.

[Grant Barton · Rating 5 out of 5]

A book every medical trainee should read, whether they're interested in oncology or not.

[Caroline Yoo · Rating 5 out of 5]

Very interesting and engaging read that highlights problematic practices in current cancer clinical research but also proposes realistic solutions. I learned a lot, and this book also provoked a lot of reflection/thought on the way things are currently done and how they can be improved. I was especially drawn to discussions on ethical aspects. Would recommend to anyone working in the cancer clinical research space (the topics of this book are so important but may not be as digestible or interesting to everyone).

[Fate's Lady]

Untrustworthy source; mocks high risk patients and dismisses Covid dangers on Twitter.