Integration of the effects of multiple medications are a challenge.
Jardiance is a recent diabetes medication that initial trials indicate that it not only improve the diabetes, but will also reduce cardiac events in diabetes. It also reduces blood pressure.
Tramadol is used for chronic pain, and is claimed to have less addiction potential. It also lowers blood glucose and blood pressure.
Self monitoring revealed these “side effects”, so adjustment of existing medication was required.
Tramadol like other narcotics (Eg endone, OxyContin) is metabolised by the body in one of three groups, all genetically controlled.
There are normal metabolisers, fast metabolisers, and no metabolisers.
This vital information is neglected so patients are at risk of receiving the wrong medication or the incorrect dose.
Perhaps the risk of addiction is related to the genetic profile?
I hope that better education on these neglected issues will help doctors and patients understand the complex interactions of their own personal drug metabolism.
1
Good thing big pharmaceutical companies have been lobbying to keep cannabis prohibition in place for nearly a century, or we might actually have empirical evidence which properly demonstrates the plant’s medical efficacy.
Assuming that maximizing profit is universally ‘good’, at least.
https://www.denverpost.com/2016/08/28/what-is-marijuana-patent-6630507/
1
I was in my local French hospital recently for a colonoscopy as a follow up to an internal bleeding issue when I was given a routine blood test.
Both the initial blood test and a follow up indicated positive results for methamphetamines. When the head nurse confronted me with this result my firm denial was met with consistent disbelief.
I had given a complete list of meds and supplementals when admitted to the hospital which included pain killers and SamE for arthritic discomfort.
My colonoscopy was negative for problems and I left the hospital with this cloud hanging over my medical record.
This pharmaceutical misunderstanding left me with a feeling of frustration and being disbelieved despite my innocence.
The next routine blood test with my g.p. will provide an opportunity to clear the record!
2
The FDA approves generic drugs as long as certain chemical similarities to known effective brand name drugs exist, without the "burden" and expense of clinical trials for the generic. This endangers patients who are successfully treated by brand drugs, as they are being forced by insurance coverage to switch to the generic. Even with strong letters from internationally-recognized expert MDs, appeals are overturned by insurers like Cigna. Often the savings are minimal, as generic prices rise inexorably, approaching brand prices and markedly improving the insurance and generic drug companies' stock value. To hell with safety and good health of patients if Wall Street is happy. Randomized controlled clinical trials should be MANDATORY for FDA generic approval.
3
@PAT
from a retired FDA attorney:
Or put price-controls on generics roughly equal to the cost of innovators' safety+efficacy trials across all three Phases of study? And make it easier for treating MDs and prescribers to write for branded, no generics, dispensing.
If you eat fewer calories than you burn each day you can drop your weight to any desired number. Who needs meds? Truth is, it is almost impossible to achieve long term compliance with behavior modifications. If you have diabetes, take your metformin. You already know you should diet and exercise.
2
@Epistemology Your point is well taken that if people get to a healthy weight, the need for so many drugs just goes away.
However, calorie counting just doesn't work if you don't address carbohydrate consumption. Overweight people can go as low as 1000 calories and not lose weight if they're snacking a lot and eating carbs and sugar. On the other hand people can eat 2500 calories a day and lose weight if carbohydrates are low and they don't snack between meals.
Just a simple understanding that blood sugar drives weight gain and weight loss can help a lot. Just avoid eating things that spike your blood sugar.
But instead, Americans are told to count calories and exercise -- which fails close to 100% of the time.
3
@Epistemology - Recently I got my 85+ yo mother with Type 2 diabetes (and other health issues) a bottle of spray on magnesium oil with aloe vera to try for her nightly leg cramps. After massaging about 20 sprays onto her legs for 10 days, she told me that her blood sugar had dropped from 142 to 116 (normal being 120 or below). She couldn't recall how many years ago it had been so low. And it has stayed low! Ranging from 105 - 117 for the past month. She asked me if it could be the magnesium oil? (She had already been taking a daily capsule orally.) I looked online and found that- yes! - there have been a number of (NIH and other funded -)studies that showed that magnesium oil could be used to sucessfully treat or prevent Type 2 diabetes.
But at $20/bottle, who's going to tell your Dr. to prescribe that? Non of their Big Pharma reps, that's for sure!
Oh - and one of the long term side effects of using metformin? LEG CRAMPS!
2
I always enjoy reading Dr. Carroll's critiques of studies and medical advice. I hope he takes a look at a recent article in the Journal of the American Medical Association about nutritional epidemiology. I'll bet his article would be excellent!!
1
The problem with all trials, be it against placebo or active treatment, is that we still analyze them according to the statistical rules of the average. All these trials can tell us is that on average one treatment is better than another or better than placebo (or worse). We know that for some patients treatment A is better while for others treatment B is better, and some it does not matter. If at the end more people benefited from treatment A, hen we conclude that A is better. Same applies if we compare A to placebo. Even though some patients may be harmed we still go with what the overall data shows. That is a sad state of affairs. We should be moving towards more precise treatments based on biologic criteria. It is happening somewhat is cancer therapy but needs to be adopted in other fields.
The other problem with comparative effectiveness trials is that they are usually large enough to detect differences in benefit but not large enough to detect differences in adverse outcomes or serious side effects.
One way to address both of the above limitations is to continuously evaluate response in real life. Something that the AllofUs study at NIH is supposed to attempt.
3
from a retired AMA attorney:
how many would be surprised to learn that the "most read" section of the Journal of the American Medical Association/JAMA is the front-end "News." Over decades of asking and answering the identical question of physicians, the answer never changes:
Q. "Where do you get information you can use in your practice?" A. "From local news/daily news."
No inconsistencies there so companies reach physicians where they--and their patients--are literally tuned in: prime time News shows at night.
1
Apart from the influence profitability bears on the approval process, one of the things that disheartens me most is relative ignorance of the consequences of long-term use.
All drugs have side effects. For approved drugs, most of the side effects are tolerable in the short run, and may greatly outweigh the consequences of not using the drug.
But in the long-term things change. The human organism evolved to function in a particular, delicately balanced, fashion. Drugs disturb that balance, often in ways that can't be anticipated. Lower cholesterol may affect brain function; hormones given for allergies may affect bone density, etc.
It seems to be that consideration of long-term consequences might be useful after a period of time following approval. Even a statistical study might be sufficient to reveal problems.
2
Aaron - your thoughts on the MI-FREEE trial are far too optimistic. Waiving co-pays for important medications after MI in fact did NOT have meaningful effects on compliance. Compliance is improved only when patients are convinced that taking the medications is meaningfully important to them.
3
First, eliminate drug advertising, again, including the notorious drop-in drug reps. Think of the money the companies will save on advertising! Second, require that any drug using any government-funded research be priced affordably. Third, require insurance plans to cover what the doctors prescribe. Fourth, take testing out of the hands of Big Pharma and test under real-life circumstances; they can pay into a blind fund instead of running their own testing with predictable results. Testing should include safety, efficacy, and comparative value/effectiveness, right from the start. And if an old drug gone generic is still the best answer, done let that get buried in the new drug hype.
9
@Barbara Lee
see Matt's comment--below.
We move from abstract ideas such as you suggest to concrete costs to appreciate what is called "the identified life." And "willingness to pay." Think of the boys trapped in the cave in Asia. Now change that story to very young soccer players under water, likely to drown soon, if not rescued from a cave in Thailand. The closer we get to fully "identified" lives, like the first pictures out of the Thai cave brought by divers to world media, the more each of us and all of us are "willing to spend" to get to a good outcome.
That rule doesn't apply in science and medicine, including drugs. Where would we be now if 20 years ago no companies had invested in learning how to target chemotherapy for breast cancer patients only to those we know can benefit? Seventeen years to create Genomic Health and validate Oncotype Dx tests for cancer patients. You can read their story online.
Capital spent well before there is any possibility of return-on-investment and ideas well beyond what our NIH/public sector can manage from bench-to-bedside. All ways always pharma and device companies mantra is "Skate to where the puck is going. Not to where it's been." Gretsky
Owners' capital, company shareholders, is at-risk for all ideas that fail and huge investments to show "intended uses" and dosing and safe & efficacy for useful Rx.
Generic another time, but know that a generic version of a drug is not necessarily less expensive than originals.
@Barbara Lee Pharma already spends more on advertising than they do on R&D. TV advertising beyond medical journals has been a source of overprescribing since it began. There is no reason to advertise drugs on TV or popular press, not because research is a big secret, but most people aren't well versed the methods, statistics and outcomes of clinical trials.
1
At this point there can be no doubt that social media is a failed experiment. The Russians have used pure diabolical genius to weaponize these platforms against us, effectively transforming them into vast cesspools of lies and hatred-provoking inhumanity. KILL YOUR SOCIAL MEDIA ACCOUNTS BEFORE IT IS TOO LATE!
3
In addition to trials looking at performance compared to placebo (as opposed to other therapies), we have a host of other problems. Proxy measure is one mentioned in the article: some drugs have been shown to reduce blood pressure or blood glucose level but actually raise the probability of death. It would be nice if studies looked at outcomes that actually matter to patients, but often that's not in the drug manufacturer's interest. Studies also enrol people who are not taking other drugs, are generally (other than the condition being studied) healthy, etc. and they need to for methodological reasons. But patients in the real world, out in the wild as it were, often, indeed usually, have multiple conditions and take multiple drugs. That means we know exactly nothing about how a particular drug will affect them. Finally, and this point is crucial, trials study the trend in outcomes in the enrolled population. That is not at all the same thing as the response of each participant. Some participants respond favourably to the drug, some unfavourably, some not at all. If the preponderance of data is favourable -- more good outcomes than bad ones -- the drug is a success. But this tells you virtually nothing about how an individual person prescribed the drug will respond. It could be good, it could be bad, it might be not at all. So doctors have to monitor carefully how each patient reacts -- but very few do so & no one collects the data once the drug is licensed.
5
A practical but important point overlooked in the article is the expense of comparative effectiveness trials. Because the size of the difference between two proven therapies will always be MUCH smaller than between an effective treatment and a placebo, the size of the sample needed to detect this effect grows exponentially. While 100 cases might demonstrate effectiveness for a therapy against a placebo, it might take 1000 cases to demonstrate that one effective treatment is superior to another. Who will pay for a study that's 10 times more expensive? Certainly not the companies making the drugs. Moreover, learning that one treatment is slightly better than another in a large group would not really inform treatment decisions absent information about side effects, costs, dosing frequency, interactions with other medications and individual differences in response. Again, who's going to come up with the 10s of millions of dollars to do such a study when there is so little to be gained?
9
Yes! It should also be noted that many NDAs coming into the FDA are utilizing active control arms like physician's choice or current standards of care (SOT) rather than classical inactive placebos. A similarly overlooked point is that the FDA cannot require proof of superiority in comparison to already approved drugs. Rather, they require noninferiority to drugs within the same class. It should also be noted that we are finding more and more often that drugs work much better for some patients than others, and implying that there should be a gold standard for every indication would require that all drugs work the same for all patient populations, which is ridiculous.
This article is a good thought, but the FDA is already on it. Promise
4
With all the many drug options, and the equally large numbers of ways to combine them in a treatment protocol - God help the solo Cardiologist! I mean, God help the patients who are treated by the small Cardiology practice.
2
FDA approved psych drug that helped 14% of patients somewhat. It was "40% more effective" than drug that helped 10%.
Placebo effect (typically about 40%) is strong medicine compared with many Rx drugs.
4
In the UK we have NICE. The National Institute for Clinical Effectiveness. It’s not perfect and has its detractors, but it aims to do just this and produces guidelines on a whole range of treatments based on panel based expert review of all the available evidence.
It’s necessary because our free to all system is woefully underfunded and new therapies/treatments are usually more expensive and it aims to standardise treatment across the country to ensure everyone has access to effective, safe as possible, properly evaluated healthcare.
It is also extremely useful in ensuring substandard care in medical negligence cases, the area in which I work.
There are millions of patients and clinicians in the US. With the full support of the medical profession and all the associated practitioners that make up the team of people who deliver healthcare, proper funding and a non profit organisation to collect and collate the information with rigorous data protection the benefits to patients and improvements in standards, innovation and affordability of healthcare could be almost unlimited.
Sadly, partly because profit is so much a part of healthcare in the US, (something that is increasingly so affecting us in the UK), because big pharma is so powerful, competition is so fierce, and partly because it’s such a huge undertaking that would cost millions, it’s never likely to happen.
It would be amazing if it did though.
8
40+ years work on two questions: What works in medicine? How do we know? Cool name: Evidence-Based Medicine.
Dr. Carroll and I are colleagues. I use his easy-to-read analyses in teaching outcomes research. That said, as a non-physician engaged in asking and answering these questions, I always emphasize what EBM can miss. What remains outside our study designs and always all ways affects study results . . .as it can affect individual patient outcomes when they are not what studies/treating physicians would predict?
The element that too often escapes, often goes unasked by physicians, is what "self-care" decisions are patients making? Decades ago, two U MD sociology students decided to approach this question working with MDs and NPs and patients in one university clinic.
Published results over three years of follow-up: 98% of patients reported to the students that they had self-care additions to their treating physician's regimen/drugs and 94% attributed "equal efficacy" to both physician-prescribed treatment and self-care choices.
Those numbers provide stunning insight into what lay people consider reliable "evidence."
One more data point added about a year into this study: Did treating clinicians ask and include in a patient's records any self-care measures? By report of patients corroborated by a random sample of individual records, zero clinicians asked about self-care measures. None.
2018 EBM? We're a long way from comparative efficacy outcomes research.
6
"Compared to what?"
Who cares about comparisons if
1. it works
2. is accessible
3. is safe.
1
One might care if alternatives are less expensive or more beneficial or less harmful (i.e., has fewer adverse side effects, which all health interventions pose for patients).
7
The most telling ... and frightening statement ... in the article is "All the guidelines and practices we have are best guesses."
When we consider that the costs involved in bringing a new drug onto the marketplace and the incentives for "cooking the books" our physicians have a daunting task in attempting to effect a cure or improve the quality of life of patients.
Alas, there is no incentive for making a safe, effective treatment and providing a comparative analysis of a drug or treatment's effectiveness. Not to mention that there is very little data exchanges. The physicians have little time to spare and no reward if they did exchange information.
1
We watched an episode of the old original Star Trek the other night.
At one point Dr. McCoy said "I can do more for you if you just eat right and exercise."
True surely back in the 1960's when the episode was filmed, and probably still true in 200 years, where the episode was placed.
5
900 days of headache amid other wretched side effects from BP meds. I'm not waving any flags for Pharma. Friend from CA sent CBD oil in a vape. It was effective. But, can't get it in NY without a script. My Dr. is now inundated with patients and reports if he signed up for permission to write a script, the phone wold ring off the wall because his name goes on a public register. Light a fire under NY politicians to make this available. Spineless creatures.
7
There's a game I and a few friends made up: count all the side effects (including death) that are rattled off in a blur at the end of all those commercials for the new "wonder" drugs that you see on tv nightly, with people fra la la-ing in flowery fields. The counts of these "side effects" are astounding! They usually average around the mid twenties, too many times even more. I'd rather suffer from the conditions than take any of them. And the FDA is worried about opioids? They're practically safe compared to many of these products!
3
@Mike OD To be open and transparent, FDA requires any negative effect ever seen in a clinical setting to be listed on the drug label. Usually there is a chart listing the percentage of the effects and very often the numbers are exceedingly low. This is because the effects would have been seen in a Phase I study where healthy volunteers are trying the drug at various levels to establish the limits of a tolerable dose. The listing on TV does not distinguish in what setting an effect was observed nor its likelihood
3
@Mike OD I take a drug now for central neuropathy* that has a whole bucketful of side effects including being drowsy most of the time. It works, and to me that makes it worth the side effects. If I still worked it probably wouldn't be.
* Picture living with constant 'buzzing' like you sat wrong and your leg 'fell asleep' or you've been to the dentist and the injected pain killer is wearing off. And your arms and legs feel like that 24/7.
1
For approval in Europe, a new drug can only be compared to an existing treatment (if one exists). And if it is not substantially better in some dimension it may not be approved. Comparison to placebo is not acceptable. Drug companies cannot simply run one study and submit it everywhere - every regions requires something different US/Eu/Japan, etc
14
it seems that another question to answer would be if drug A restricts the amount of blood flow, then would giving that drug A give rise to another drug to thwart the side effects? For example, 'Lisinopril blocks the enzyme angiotensin, which tightens blood vessels, leading to lower blood pressure.' Would males taking that medication experience more ED issues and require Viagra, and perhaps an anti-depressant medication as well?
So who benefits from prescribing Lisinopril to an over 55 year old man. . . psychiatrists, physicians, pharmacists, perhaps even the legal system when that man goes off the deep end, but certainly not the patient. Perhaps that over 55 year old patient should be taking a water pill? IDK and it seems I am not alone.
3
@Rita Harris
I'm clarifying a statement in the article which is a trifle ambiguous:
"Lisinopril blocks the enzyme angiotensin, which tightens blood vessels, leading to lower blood pressure"
What the author means is that it is actually angiotensin (more accurately angiotensin II) that causes 'tightening' of blood vessels (vasoconstriction) thus elevating the blood pressure.
Lisinopril is among a class of drugs that blocks the formation of angiotensin II from its precursor angiotensin I by blocking the enzyme ACE (angiotensin converting enzyme). Hence these drugs fall into the category of ACE inhibitors or simply ACEI.
When there is less angiotensin II around, the blood vessels are more 'relaxed ' causing a reduction in blood pressure.
4
Thank You! I noticed this too. I was appalled. Diuretics work quite well for many. Electrolytes should be monitored closely. Even Potassium sparing ones can lead to low Potassium which can truly aggravate heart muscle.
6
As more and more patient records move from paper to computer files, the "big data" necessary to perform comparative effectiveness studies at low cost will become available.
The government must demand interoperability and easy data exchange from every medical records product in order to facilitate effectiveness studies.
I hold no hope for near term progress as Big Pharma spends more on lobbying than any other industry.
5
@Boston Barry
Please keep a few items in mind. Firstly, a large proportion of patients present with multiple medical conditions, various life styles and behaviors, and genetic backgrounds. Physicians currently can't spend much time with indiviual patients, so some of this information (even if it were available) doesn't factor into devision-making. No amount of data can eliminate the risks of non-response due to multiple factors. Secondly, we have to move beyond the progressive bias that a poor or undesirable medical result is someone's fault. Sometimes we do the best thing possible and still obtain a poor resulty for reasons that we don't know or understand. Finally, the life science products companies in biotech, pharma, medtech, etc. have greatly contributed to the imrprovement in life expectancy of recent decades. (better nutrition and safety have also contributed greatly). When the Social Security Act was passed in 1936, the average life expectancy for white males was 63 years; it is now about 80. That's an enormous improvement in a relatively short period of time, produced largely by private corporate initiative. PS - largest lobbying efforts are (in order of decreasing magnitude) by the legal profession, AMA and public sector unions.
Appreciate this comment and agree that interoperability is an important part of the equation, but it is also worth noting that data in electronic medical records are not automatically "research ready." Quite often, significant cleaning, curation, and standardization is needed before the data are of sufficient caliber and dependability to stand up to the rigor needed for high-quality research. Vendors have a big role to play here as well, and have not stepped up to the plate to facilitate the use of "big data."
2
It might be best to avoid diuretics in males with being prostatic hypertrophy.
However, there are drugs that relax the prostatic capsule and dilute blood vessels.
This gives you positive effects on both conditions, for the price of one.
Yes, no doubt some drugs are better than others.
But if they or some of their ingredients are made in China, all bets for any of them are off.
The fewer drugs we take, the better. I am not anti-drugs or anti-vaccines; but for many years now I have been wary of anything manufactured in China.
Blood-pressure and thyroid meds, anyone?
5
I totally agree! I will not purchase any med manufactured in China. I'm not a fan of India-based firms either, but I relax a bit for the few I know. (20+ years in pharma.) I live in a 55+ community and friends start rolling their eyes when I get on my soapbox about the quality of ingredients, non-active "fillers" and the number of well trained inspectors in places like China and India. Of course, they're the first to call me when their new low-priced generic doesn't work the same as the branded...
5
@B. In the aftermath of the valsartan scandal I have been trying to get information from drug and supplement companies on the countries of origin of their ingredients (active and inactive). As a medical researcher as well as a concerned mother and grandmother, I want to avoid drugs and supplements with ingredients from China which seems to be the worst offender. I have contacted several drug manufacturers as well as Consumer Lab and the People's Pharmacy with this goal in mind. The information has been difficult or impossible to ascertain thus far with the exception of the Gaia company which lists country of origin for their supplements on their website. I also learned that the platelet inhibitor
1
@B. Or India. Or Pakistan. The third world is awash in fake and ineffective drugs coming from these hypercorrupt countries, killing millions of people annually. It is appalling that theFDA permits importation of any drugs from Asia.
2
"Comparative effectiveness research can.. involve more than drugs".
Well said but will West allow this sensible suggestion, go for complementary and alternative medicine (CAM)?
West is highly biased towards rational evidence-based system. Any new approach need open mind away from dualistic and reductionist approach of Cartesian mind and matter dualism and Newtonian determinism taught that the physical world is governed by iron laws and everything in the physical world is predictable ultimately controllable.
" Whether rational evidence-based clinicians like it or not, many people like CAM, and their justifications align with criticisms of the shortfall of Western medicine in providing a fully effective and satisfying system of healthcare. In the current climate of evidence-based medicine underpinning national recommendations for care, it is unlikely that the commissioning of CAM by health services will reflect its popularity. A fruitful way forward for health care systems may be to use the justifications that people have for using CAM as a framework to address the shortfalls and problems of their own systems. The extent to which CAM itself should be included in national policy and clinical practice to address those gaps in health care remains a topic for debate, including about nature of evidence that should underpin choice of care for long-term conditions such as chronic musculoskeletal pain". http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200879
@N.G. Krishnan Rhino horn? Tiger wine? Snake soup? Pangolin scales? Shark fins? If nothing else, traditional Chinese medicine is curing the world's wildlife infestation.
Both as a prescriber and a patient, I also want better data, but the the question of why we don't have it has already been answered by the example given in the article: $100 million was spent and 4 years were spent coordinating 623 centers to generate data that saved zero lives and still faced questions about methodology. By nearly any measure, expecting comparative effectiveness data on all of the 10,000 drugs in use today is insanity. We can make strides by making clinical research cheaper and more efficient and by instituting higher standards for researchers, but what we truly need is better treatments, not better data.
10
Medical Writer, Beverly
Don't agree that all physicians and patients really care about every day is how effective and safe drugs are compared to one another. What I care about is the safety and effectiveness of my drugs for me. Look forward to the day when genetic and genomic testing will personalize drug choice for each of us. Also wonder what studies support the supposition about what physicians and patients really care about.
2
I think it is also worth mentioning that the Advisory Committees that the FDA uses to review new drugs and devices have been, and still are, tainted by conflicts of interest.
In many, many cases, the committee members have received large amounts of money from the very companies whose products they are reviewing... And have every expectation of receiving even more money in future.
I believe there was a analysis done on drugs that, having received FDA approval, were subsequently taken off the market for being dangerous and harmful. The analysis found that if the experts on the Advisory Committees who had been paid by the manufacturer had recused themselves, the drug would never have been approved in the first place.
3
I can't agree with Carroll more about the importance of comparative effectiveness studies. "Safe and effective" often is virtually meaningless in today's world and is more a marketing shibboleth than a reflection of science. Unfortunately, in medical research, even comparative drug studies have the flaw of just comparing one drug to the next. When it has been well established that 80% or more of contemporary illnesses are the result of lifestyle issues such as poor diet, lack of exercise, overexposure to EMR, vitamin and mineral deficiencies, or other noxious environmental influences, the comparison of one drug to the next is irrelevant.
A comparative study, if there even was a point in doing one, would more sensibly be between using a suppressive drug to treat the symptom of an illness and the treatment of the underlying cause of the illness. I say if there even is a point in doing such a comparison study because treating the cause of problems should be the true mission of medicine, not treating symptoms and ignoring the perpetuating factors underlying those symptoms. Yet, Carroll's article illustrates, this continues to be where mainstream medicine places its emphasis.
3
A company can develop a drug that doesn't need to be more effective than what's already available. They spend those many billions and provide no net benefit to society. Only market share matters to them. That's a waste of resources that could be devoted to new or better treatments.
15
Real life. You go to the Doctor, he finds something that requires more specific test. The lab work comes back, or maybe an ultrasound, and a drug is prescribed. Few of us ever heard of the drug. You go to the pharmacy and get your prescription filled. You go home and go to a reputable web like Mayo Clinic, to read about side effects. What I learned is 90% of side effects pretty much read the same. Physicians usually don’t talk about side effects until you experience a side effect. Blockbuster drugs side effects listed are often lethal. Point being tuff for the Doctor and no mans land for the patient.
7
This is why it behooves pharmacy benefit managers (PBMs) to invest in comparative effectiveness research. Health insurers use PBMs for a lot of reasons to lower drug costs, but they should keep in mind the long-term treatment costs as well.
Couple of things I learned from interviewing pharmacists who do this research:
you don't want to take the newest thing - it's the least proven.
Safe is a relative term, and can be assessed only against the potential risks.
A critical part of the "approval" process is doctors telling the FDA when new drugs have bad outcomes -yet these doctors are wooed by PhARMA to say nice things.
PhARMA cherry-picks research to "prove" safety and effectiveness.
You want "safe and effective?" Wait till the newest thing has been on the market a few years. The risk of another Vioxx--which killed 60,000 people--is just one FDA hasty approval away.
19
@Kilroy71....PhARMA cherry-picks research to "prove" safety and effectiveness.....Every piece of data from a clinical trial is reported to the FDA. Pharmas may be selective in the data that they choose for publication, but every piece of data is reported to the FDA, and the FDA independently makes the decision on safety and effectiveness.
6
@W.A. Spitzer Not according to pharmacists I know who conduct comparative effectiveness research that includes data far beyond what the FDA requires. If research goes south, drug companies just end the trial early and don't report.
@Kilroy71
Names and data or you're over-matched in this cohort, my friend.!
How is statistical significance achieved when individual responses vary so widely? I'm on my third statin and fourth BP med. Both work fine (judging by the test results) and both are inexpensive.
The answer to "Compared to what?" should be "doing nothing."
2
@JimmyMac
When individual responses vary widely, statistical significance is achieved by using large sample sizes.
6
@JimmyMac Statistical significance means that if you happen to be in the middle of the bell curve you're likely to be okay. Less likelihood of being okay as you deviate from the mean. How do you know where you fall in the distribution population? You take a pill and find out!
2
Scientists have a bias against studies that depend too much on participants’ awareness and judgment. Stated that way, it sounds silly, but you can understand why it would not be objective.
@Ed....Which is why most clinical trials are double blind, and where ever possible results are reported by physical rather than subjective measurements - blood pressure, temperature, blood glucose levels, cholesterol levels, etc.
8
A well written article about an important issue. There are a number of caveats to consider. The notion of “safe drugs“ is misleading. Which people? What is their general health status as well as the quality and levels of their living conditions? It is useful to remember that any “drug“ is an active chemical which effects the structure and function of any living organism; human or other. From that perspective all “drugs“ have outcomes which are uncertain, unpredictable, random, and over which we have no total control. Research, which determines a drug’s relative safety, is often based on extremely large data sets. In theory their outcomes should help us to know/understand potential or actual patterns, trends, cause-and-effect relationships, associations,side effects,etc., Relating to human behavior, treatment outcomes, and other outcomes.A caveat: this type of result relates to a virtual person or system. Not to the specific individual, at THAT TIME with his or her known and unknown, measurable and untestable diversities for whom a treatment plan is being made or an emergency medical response is needed. In addition the research data sets may be so big and complex that the analytic techniques being used are inadequately effective to meaningfully deal with them.Drug safety validity problems can can include insufficient replication studies, lack of diversity about relevant characteristics of the study population, unethical stakeholder behaviors and failure “blindness.”
1
The problems are manifold.
Observational studies are difficult to remove bias, are long term, and expensive.
Much of medical research presents little value to the practicing physician.
Like all grant funded research, the fight is in to get funding.
Much medical research is funded by the industry which it is studying making the results questionable.
Many if not most practicing physicians do not understand statistics nor do many researchers themselves.
Most medical journals are supported by pharma also making the results published dubious.
16
@John Ghertner …. "Much medical research is funded by the industry which it is studying making the results questionable".....Funded by and employed by are two very different things.
"Most medical journals are supported by pharma also making the results published dubious.".....How does your conclusion square with peer review?
Who do you think is going to fund medical research, clinical trials, and medical journals, the tooth fairy?
10
@W.A. Spitzer medical research that is funded by the very beneficiaries of that research is questioned. Having been a physician for ~40 years I have seen this as a very clear issue which journal editors have tried to address by forcing authors to state their financial relationships. This does not however remove the implicit and real bias. Just read the NYT article about vitamin d, go back and study the VIOXX debacle and that Celebrex remained on the market.
The editors of the journals are not immune to bias anymore than you or I. Peer review does not remove this bias totally either. Read the bios of the peer reviewers.
The response to your last question cannot be answered in this short dialogue but cute little statements adds nothing to this important conversation.
@John Ghertner….The results that you site are notable precisely because they are exceptional. What are they one in a thousand? One in ten thousand? The point of the cute little statement is serious - funding of clinical trials is enormously expensive, and there is no way in your wildest imagination they will every be funded except by economically invested parties.
The problem is really exacerbated when Big-Pharma decides to market their new drug directly to the potential patient. The patient doesn't know, or really want to know, all the particulars. They just want what they think (having been told in the commercial) is the best/ greatest/ newest/ fantastic/ unbelievable/ top of the line medication. That can put the MD at odds with the commercial, even if the new drug isn't the best for the patient. Then the MD faces the individual who wants what he wants when he wants it of he will find somebody who will prescribe it for him.
It's much more than just doing the research, it's dealing with the direct marketing campaigns.
17
Actually diet, exercise, attitude are more important the meds in supporting health, especially for those over sixty. Alzheimer's is a case in point. While Big Pharm is spending its time looking for the magic bullet to cure this scourge, Dale Bredesen
and his lab at UCLA spent twenty five years studying the disease from a different standpoint. The rest is his book "The End of Alzheimer's" which gives a clinically tested and scientifically solidly based protocol for reversing mild to moderate Alzheimer's. The protocol involves much more than taking a pill, but is so much cheaper than the disease !
All this assumes that the patient can afford to see the doctor, pay for medication, and can pay for the continuing care. And let's not forget the insurance company's formulary and their "best practices" when it comes to putting a patient on medication.
I do agree that the right questions and studies need to be asked and done. But I also believe that pharmaceutical companies ought not to be allowed to advertise to the public any longer. Too much money is spent on market research and not nearly enough on researching the drug(s).
20
Is there no requirement for all prescriptions to include country of origin? Clothing must be labeled, why not drugs? I take Levothyroxine, which was recently recalled, and discovered it is made in China and potentially contaminated, with what wasn't revealed. Melamine, maybe? My health insurance company has changed my prescription several times over the years, but is the different medication always "comparatively" safe and effective for patients? This is the second time my meds have been subject to recall, so I guess the answer is very clearly NO.
6
The article is excellent in its recommendations. It does not address the endless advertising on television of drugs which in some cases may be safe and effective, in other cases there is always the proviso "May cause death" spoken very fast when all the happy patients are not seen. I particularly want to BAN the Prevagen ads promoting an expensive drug which has been clinically proven to be ineffective. Placebo effects not withstanding. Why allow the maker to advertise?
12
@JCT...." I particularly want to BAN the Prevagen ads promoting an expensive drug"....Prevagen is classified as a dietary supplement, not as a drug; and as such is not subject to FDA trials which require proof of safety and efficacy..
2
@JCT
now retired FDA attorney:
1984 Waxman-Hatch law dictates that FDA has ZERO control over "dietary supplements" and its kin for premarket safety and efficacy OR for checks on advertising claims made. Last year, for the first time in many years, a handful of "herbal supplement" manufacturers were targeted for action by the Federal Trade Commission on referral from the FDA because their claims included prohibited "medical" healing or fixes.
FTC=truth-in-advertising federal oversight . . .albeit rare. With supplement companies, monetary penalties paid and promo changes to get back to business-as-usual. Which usually means they morph back to medical claims and nobody goes to jail.
No surprise that many of the biggest and wealthiest supplement manufacturers are headquartered in Utah . . .staying close to their creator and protector, Senator Orrin Hatch.
Excellent article although I would value Dr. Carroll's thoughts about how the safety and efficacy of drugs are advertised to the public. Regardless of the quality of clinical trials leading up to FDA approval, it appears that the pharmaceutical industry has become very sophisticated at presenting the positive side of new drugs by hyping with clever visuals and sounds while a voice ticks off potential side effects. The patient then goes to the physician armed with propaganda.
Is this a good way to facilitate the best discussions between patients and physicians? I think not.
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The effectiveness of EVERY drug should be featured in the pharmaceutical's advertising campaign in big, fat letters for all to see.
Is the drug 20% effective? 90%? The only drug on the market today that advertised efficacy rates with any regularity is Gilead's cure for Hep C. And why do they highlight it? Because the drug is over 95% effective and costs nearly $100,000 for a pill a day 12-week treatment.
"Live Longer!" cancer drugs are the most offensive commercials. Some might give a patient an extra month or two of sheer inhumane agony in order to raid the patient's wallet of more than six figures.
Our government is in a coma when it comes to pharmaceuticals, in large part because they're bought and paid for by pharma lobbyists.
As patients, we've been figuratively and literally left for dead.
67
@Sarah "Effective" is pretty well defined for acute illness, not so much for "chronic". Is a cancer drug that adds a week to a sufferer's life "effective"? If one cancer drug competely cures 25% while the 1-week life extension does this 100% of the time, the "25% effective" claim will get swamped by the "100% effective claim.
4
@Sarah I can understand how a person could be left to feel as you do, especially about the benefits of some cancer treatments, but I think you are under informed on the subject compared to many other medications, not related to oncology. The FDA does a very good job ensuring drugs are safe and effective. They balance benefit and risk before allowing any medication on the market.
1
Excellent points.
Also if there is something better than a pill to correct the problem ie if you have aches and pains, do exercise before taken a pain killer.
Most of the above points and others are compromised by our de facto criminal health care system where the wealth of billionaire HMO and big PHRAMA execs. come over the health of the patient.
20
We pay our taxes so that billionaires don’t have to. TheIr goal is your total impoverishment so that your wealth doesn’t go to your children. Thus we are gouged by big Pharma and big medicine, particularly at the end if life. The question is not safe and effective “compared with what” it is: “for whom”. Who is benefitting from the opiod epidemic, the outrageous cost of drugs, etc. it is not the patient.
This corruption starts at the top, he spouts an anti-elite mantra to his sycophants but he ONLY favors billionaires.
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@SW Our legislators are the people who facilitate our being gouged by big Pharma and big medicine. We allow this. Would be helpful to voters for major news media to publicize correlations of donors, donations and votes by legislators.
1
Comparative studies don't answer all of the questions and can be misleading. Imagine a drug that proves better and safer at treating hypertension than a second drug. What if this new drug causes cardiac events during strenuous exercise, a factor that wasn't considered in the study? Now imagine millions of primary care doctors switching to the "better drug".
The point? Comparisons between two drugs or devices is useful but doctors should change prescription patterns with caution.
13
There are strict ethics involved in clinical trials - it is required that all the patients in a given study receive the best available medical treatment. This means that in the clinical trial of a new drug, unless all other available treatments have already failed, the new drug will be added on to an already existing treatment. This complicates the picture and makes the comparison of one drug to another more difficult.
1
This isn't quite right. Ethics require that there be equipoise between the treatments offered. That means that if true uncertainty exists as to which of two or more treatments is the best, it is acceptable to randomize between or among the treatments.
9
Good points as far as they go. Some further needs:
1. Better and mire rigorous trials—and fewer small, short, poorly designed ones that do not have the power to answer the questions that need answering.
Forget nonexperimental, observational studies, generally speaking, that cannot address these comparative effectiveness issues.
2. A much stronger approach to dealing with harms (ie, adverse events and negative side effects), and not simply “benefits.” All interventions, from operative procedures to drugs to psychological or behavioral treatments, pose rusks to patients. We need “net benefits,” that is, data on benefits minus harms.
3. More trial data on a full range of patients across important sociodemographic and health characteristics. Not just middle-aged white men, as things used to be!
4. One-off trials are an inadequate basis for decisionmaking. We need systematic reviews and adequate synthesis of all relevant data, and application of modern statistical methods to combine those data, like the work done by the federal Agency for Healthcare Research and Quality, to give clinicians and policymakers actionable information.
And, we need to return to a political and educational environment that believes in science and knowledge—lacking that, as is too much the case today in the USA, threatens to render moot all the research scientists and clinicians now do.
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@Kathy
" .. And, we need to return to a political and educational environment that believes in science and knowledge .."
Left out how trial lawyers advertise on TV 24x7. offering to sue everyone. You want to fight them, be our guest. Thanks.
And who is going to pay for these huge experiments? And who is going to run them? The average researcher can't afford to get involved with such a huge study because it takes years for the publications to come out.
As an informed patient with Type 1 diabetes, I regularly scan journals for relevant articles, reading abstracts and, when warranted, research articles. I have often found it absurd when drugs are compared to outdated and absurd therapies. Even when the new drug is flawed, even if only minimally less good on some dimension, the researchers twist the conclusion to support a positive, diminishing the negative. This is all part of the pipeline to generate positive publication as part of the marketing effort for new drugs. It's is disheartening, and also why we need to be skeptical of any new treatment comparisons.
21
What is not addressed the article is the side effects for the different classes of drugs and age. I wonder how many of these studies were done on people over 75, probably few and then over 80 maybe none.
Also we are learning more about how differently women and men respond to medications yet the studies rarely look at these differences, most of all drug research is done on men.
Amliodipine has the serious risk of angiodema, diuretics can be dangerous for the elderly as they have to get up more frequently at night when most falls occur in bathrooms.
It would be great to know which drug is more effective but then there are also so many other variables to consider.
Watson where are you?
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@Chelsea
"Watson where are you?"
Watson "locks up" on the complexity of human differences.
IMHO, Dr. Carroll's point is -- medicine is complex. Case in point: medical MJ. How does it interact with Lipitor? Metformin? Both? Simple "answers" can beget giant disasters, like the Flint Water disaster.
1
"To get approval from the Food and Drug Administration, drugs must be proved both effective and safe. The costs of doing this are significant, and they are most often borne by the pharmaceutical industry."
When asked to justify huge price differences between drug costs in the U.S. and other countries, the industry cites R&D and regulatory costs as major reasons. So the industry does not bear those costs; they pass them along.
With the enormous amounts of money at stake in the drug business, the lobbying and campaign contributions made by the industry, and the revolving door between government and industry, we can only hope that some unbiased science makes it through once in a while.
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@Pat
Sad and cynical. You do know that Scott Gottleib, MD, took an 80%+ pay cut when he left Duke Medical faculty for FDA Commissioner?
Those who want to understand the medical innovators in this country and world, including "pharma" companies, and the array of costs and benefits essential to reach informed judgements about regulatory policies, should read Dr. Gottleib's Duke Economics faculty colleague Henry Grabowski, PhD. And John Eisenberg's work while based in academe and first Director of the National Center for Health Statistics and Research (NCHSR).
Lots of "unbiased science" PLUS unbiased economic assessment using widely shared methodologies.
I came away from my experiences in practice, at FDA and the pharmaceutical industry with the following general notions:
1. “Drugs are simple; patient’s are complex.” A drug that works well for many, may fail or have intolerable or severe/dangerous side effects for some. (Or to paraphrase Lucretius, “One man’s meat is another’s poison.”)
2. Clinical trials are very different routine practice. Both the type and frequency of drug associated adverse events may be markedly changed once a drug has been administered to a larger number of patients with morbidities and characteristics not well tested in the relatively small number of patients exposed in trials.
Dr. Carroll’s mention of the need for basic research is critical. Such research in normal biological systems is grossly overshadowed by applied research, simply because of the desire to develop a therapy. Until we understand organismic self maintenance and repair better, we are stuck trying to make “magic bullets” that turn out to be less than predictable in their positive and negative effects.
Stephen Rinsler, MD
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@Stephen Rinsler…..You cannot emphasize enough that people are not averages. They are individuals and will respond to drug treatment as individuals. What is the best of a class of drugs for one person may not be the best for another, which is why your personal physician is critical.
1
@Stephen Rinsler As I understand it NIH will not grant funds for research that is strictly empirical; applicants need to show that a hypothesis will be tested. This can be an obstacle to broadening our understanding as above.
1
“Safe and effective”?
Seems like a very low standard, a minimalist standard, to reach. In my problem solving and problem prevention research and work, “safe and effective” seems a far cry from really effective SOLUTIONS and/or PREVENTATIVE measures. I see that drugs do both solve problems and prevent them (and reduce impacts of problems).
Surely the FDA is bound by budgeting constraints, so the best scientific evaluation they can make is “safe and effective”. Is it really?
Can we get “Consumer Reports” to do the product effectiveness evaluations? Not likely - far too expensive, but that kind of thinking is needed here.
I am accustomed to think of “binary choices”: Does the solution work, or does it not work? I don’t work in the quality step just above, “does no harm”, which is what “safe and effective” seems to improve upon.
2
So, “effective” means the drug, the “solution”, WORKS. How does THIS one work, solving the problem, compared to all the others in its class that also WORK?
Ahh...