Posted by Gary Schwitzer in FDA
“Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012,” by Dr. Joseph Ross and colleagues, concluded that the quality of clinical trial evidence used by the FDA as the basis of approving new drugs varies widely. A couple of interesting data points:
- in the seven-year period of analysis, 37% of drugs were approved on the basis of a single pivotal trial.
- trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 45% of drugs approved. (See our primer, “Surrogate markers may not tell the whole story.”)
In an opinion piece, “Opening the FDA Black Box,” Drs. Steven Goodman and Rita Redberg said the study:
“…raises a host of questions needing further exploration. Despite the FDA requirement for evidence from a minimum of 2 randomized clinical trials supporting an effect on health outcomes, 37% of product approvals were based on only 1 trial, 53% of cancer trials were nonrandomized, and an active comparator was used in only 27% of non–infectious disease trials. Surrogate end points were used in almost all approvals via the accelerated approval process and in 44% of nonaccelerated approvals. Trials were comparatively short, with most lasting less than 6 months, even those assessing chronic treatments for chronic diseases. Cancer drugs, perhaps predictably, were more often approved via the accelerated process and with weaker designs.”
Another paper looked at the reasons that FDA marketing approval for new drugs was delayed or denied.
And a fourth paper looked at FDA regulation of medical devices, “a process that has received relatively little attention,” according to Goodman and Redberg, who continued:
In USA Today, Liz Szabo wrote a good summary of the JAMA papers under the headline, “Not all FDA-approved drugs get same level of testing: Evidence behind FDA-approved drugs and devices often has major limitations.”
ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world.
When available, study results information is included in the study record under the Study Results tab. See How to Find Results of Studies for more information on finding results entered in the results database.
Results (after 2008, only those required by US federal requirements) include
–Participant data (how many started the trial, dropped out, etc)
– Information about participants (age, gender, blood pressure readings, etc)
[Speaking of gender…]
Good to know, most drugs can affect women and men differently
— Outcome (results of taking the drug plus any placebo), with statistics
–Adverse effects , serious and other (this was not required before 2008)
Evaluating Health Information (from my personal Google site)
Another take on the “relaxation of standards”
British physician and writer Ben Goldacre is on a North American tour. His book, “Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients,” is released in the US on February 5. The book has been discussed in The Economist, The Public Library of Science blogs, The Guardian, and elsewhere. (Addendum one day later: Carl Elliott also reviewed the book in the BMJ.)
He also has an op-ed in the New York Times, “Health Care’s Trick Coin.” Excerpt:
“…the entire evidence base for medicine has been undermined by a casual lack of transparency. Sometimes this is through a failure to report concerns raised by doctors and internal analyses…. More commonly, it involves the suppression of clinical trial results, especially when they show a drug is no good. These problems would be bad enough on their own, but they are compounded by a generation of “fake fixes” that have delivered false reassurance, and so prevent realistic public discussion.
The best evidence shows that half of all the clinical trials ever conducted and completed on the treatments in use today have never been published in academic journals. Trials with positive or flattering results, unsurprisingly, are about twice as likely to be published — and this is true for both academic research and industry studies.
If I toss a coin, but hide the result every time it comes up tails, it looks as if I always throw heads. You wouldn’t tolerate that if we were choosing who should go first in a game of pocket billiards, but in medicine, it’s accepted as the norm. In the worst case, we can be misled into believing that ineffective treatments are worth using; more commonly we are misled about the relative merits of competing treatments, exposing patients to inferior ones.”
On average, new treatments perform better in clinical trials only slightly more often than existing treatments, according to a new systematic review published in The Cochrane Library. The fact that experimental treatments are not more effective may seem disappointing, but the authors of the review say their findings satisfy an important ethical requirement for clinical trials.
Randomised trials compare the effects of one treatment to another. In a randomised trial patients are randomly allocated to different treatment groups to ensure that like will be compared with like. When a new treatment is being tested, it is hoped or even expected that it will be better than the established treatment with which it is being compared. These expectations lead to an ethical dilemma. If the researchers already know that one treatment is better, they would be knowingly allocating some people to an inferior treatment. If randomised trials are to be ethical, therefore, only half of new treatments should turn out to be better than existing ones.
Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognised as the highest standard in evidence-based health care. They investigate the effects of interventions for prevention, treatment and rehabilitation. They also assess the accuracy of a diagnostic test for a given condition in a specific patient group and setting. They are published online in The Cochrane Library.
- Browse Free Summaries Looking for the full text of these Cochrane Reviews? They may be available at your local public, academic, and medical libraries. Call ahead and ask for a reference librarian. Many academic and medical libraries do serve the public, providing at least some basic services.
ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world.
- Clinical trials: Around half of new treatments perform better than existing treatments (medicalxpress.com)
- Cochrane Review finds no benefit from routine health checks (engineeringevil.com)
- Don’t call CAM “cost-effective” unless it’s actually effective (sciencebasedmedicine.org)
- Clinical Trials (cancerwhattodoorsay.wordpress.com)
- Clinical trials better than before (wlfi.com)
Legal Drug-Pushing: How Disease Mongers Keep Us All Doped Up – John-Manuel Andriote – Health – The Atlantic
By manipulating our fear of suffering and death, big pharmaceutical companies are able to keep us coming back for expensive medications
Excerpts from this article from the 3 April 2012online edition of The Atlantic
.Pharmaceutical giants, like small-town pizza parlors, have two options for making more money: convince regulars to buy more of what they obviously like, or find ways to persuade more people that they will be happier with this drug or that thin crust with extra cheese.In the case of the drug companies, it’s not our taste buds they’re appealing to. Instead, they market prescription drugs directly to consumers — a practice legal only in the United States and New Zealand — by, basically, manipulating our fear of suffering and death.These “disease mongers” — as science writer Lynne Payer in her 1992 book of that name called the drug industry and the doctors, insurers, and others who comprise its unofficial sales force — spin and toil “to convince essentially well people that they are sick, or slightly sick people that they are very ill.”Changing the metrics for diagnosing a disease is one reliable technique. Dr. Adriane Fugh-Berman, associate professor of pharmacology and director of the industry watchdog group PharmedOut.org at Georgetown University School of Medicine, pointed to how the numbers used to diagnose diabetes and high cholesterol have been lowered over time. “The very numbers we use have been reduced to the point of absurdity,” she said. “120/80 was considered normal blood pressure; now it’s considered ‘pre-hypertension.’”Entirely new diseases can be, and have been, invented to extend a manufacturer’s patent on a highly profitable drug. Fugh-Berman said Eli Lilly stood to lose a lot of profits once the patent expired on its hugely popular antidepressant Prozac. “So they positioned this new condition, PMDD (Pre-Menstrual Dysphoric Disorder), and then went to physicians and the FDA with their highly paid experts who said PMDD is a tragic disease, and they got approved for Sarafem, the same drug. It’s an on-label use for a repackaged drug; they created the disease and then got a drug re-approved that was going off patent.”..
The article goes on to outline one feature of the “medical industrial complex” – the expansion of disease categories to include precursor conditions as psychosis risk syndrome. These categories are included in professional manuals, making it easier for drug companies to develop and market new drugs associated with conditions recognized by medical associations.
The authors also asks if Americans are being overdiagnosed through an overly medicalized drug culture partly created through aggressive prescription drug advertisements. Responsibility for addressing this issue is in the hands of consumers, professional health care providers, government regulators, and all who contribute to our culture (as artistis, writers, and journalists).
- ClinicalTrials.gov -up-to-date information for locating federally and privately supported clinical trials for a wide range of diseases and conditions. A clinical trial (also clinical research) is a research study in human volunteers to answer specific health questions. Interventional trials determine whether experimental treatments or new ways of using known therapies are safe and effective under controlled environments.
A growing number of clinical trials publish at least some of their results at ClinicalTrials.gov
Use the Advanced Search and use the Search Results to limit to Studies with Results
- Cochrane Systematic Reviews
(Click here for the free summary version)Cochrane Reviews are systematic reviews of primary research in human health care and health policy, and are internationally recognised as the highest standard in evidence-based health care. They investigate the effects of interventions for prevention, treatment and rehabilitation. They also assess the accuracy of a diagnostic test for a given condition in a specific patient group and setting. They are published online in The Cochrane Library.Each systematic review addresses a clearly formulated question; for example: Can antibiotics help in alleviating the symptoms of a sore throat? All the existing primary research on a topic that meets certain criteria is searched for and collated, and then assessed using stringent guidelines, to establish whether or not there is conclusive evidence about a specific treatment. The reviews are updated regularly, ensuring that treatment decisions can be based on the most up-to-date and reliable evidence
- Drug Information Portal
A gateway to selected drug information from the US government. It links you to information on over 12,000 drugs from trusted consumer drug information sources (as MedlinePlus Drug Information), the US Food and Drug Information (as Drugs @FDA), LactMed (summary of effects on breastfeeding), and more.
Clinically important safety information and reporting serious problems with human medical products.Safety information includes drug information, recalls & alerts, drug shortage information, and medication guides.
Drugs, Supplements, and Herbal Information (from MedlinePlus.gov)Learn about your prescription drugs and over-the-counter medicines. Includes side effects, dosage, special precautions, and more.Browse dietary supplements and herbal remedies to learn about their effectiveness, usual dosage, and drug interactions.
- We should treat diseases not create diseases to treat (medrants.com)
Pop. Snort. Parachute.(New York Magazine, 2005))
To many New York teenagers, all the world’s a pharmacy. There is a vanishing distinction between pills for medication and for recreation, and the much-touted risk of suicide misses the point.By David Amsden Published May 21, 2005
“….Drug companies, though, have plenty of incentives to market their drugs to kids. Adolescents represent a relatively untapped (but rapidly growing) market for drugmakers, something any successful business looks to exploit. And they’re generally encouraged to do so by the government. A federal law passed in 1997 allows a drug company to keep its patent an extra six months by performing clinical trials on children, which translates into enormous profits. Zoloft, for instance, grossed about $3.1 billon in sales last year, so that additional time is hugely lucrative.
Meanwhile, the shame associated with psychotropic meds continues to dissipate as doctors write more prescriptions and the diagnosed “disorders” become less severe-sounding. First there was depression, then social-anxiety disorder; now we have general-anxiety disorder, which Xanax’s Website defines as having “vague feelings that something bad is going to happen,” an apt description of what it’s like to be an adolescent. Zoloft’s Website describes social-anxiety disorder as often starting in the “mid-teen” years, and yet the drug’s television ad campaign, with its cartoon powder puffs, looks like a Sesame Streetouttake. And while Pfizer denies targeting kids, teenagers themselves aren’t so sure. “That’s so geared toward children,” Timothy told me. “It’s like, ‘You’re not happy anymore? Here, take some pills and you’ll be appreciating butterflies left and right!’ ”
“What’s really changed is that now they market medical conditions,” says Marcia Angell, a member of Harvard Medical School’s Department of Social Medicine and author of The Truth About the Drug Companies, the just-published indictment of big pharmaceutical firms. “It’s simple—there will always be more healthy people than sick people, so they need to make more people think they’re sick. Teens are naturally going through an intense period of ups and downs. The marketing makes them think the downs are unacceptable, that they’re a disorder.”
What such marketing cannot take into account is that kids are cynical, reluctant to take the word of adults at face value. When this attitude mixes with prescription drugs, it turns into a desire to reinvent their intended uses in a manner that’s not necessarily ill-intentioned. Because the taboo truth is that illicit use can be legitimately helpful, which makes the dangers that much easier to overlook….
- Many NIH-funded clinical trials go unpublished over two years after completion (with ClinicalTrials.gov link for many trial study results) (jflahiff.wordpress.com)
- Pharmaceutical Companies Turn to Checklists to Sell More Drugs (labsoftnews.typepad.com)
- Painkiller sales soar across U.S., spread to new areas (usatoday.com)
- Tony Bennet Says Legalizing Drugs Could Prevent Deaths Like Whitney Houston’s; Prescription Drugs Aren’t Safer (blisstree.com)
- The billion-dollar battle over premenstrual disorder (salon.com)
Unnecessary reliance on screening tests and the underuse of personalized medicine are two major concerns I have with the present practice of medicine. Hence the selection of this article for a blog item.
Mayo’s Dr. Victor Montori and his team argue that medical intervention success is best be measured in holistic terms as death, quality of life, and ability to function. This is in direct opposition to current industry and professional guideline standards which emphasizes narrow (and often misleading) outcomes as blood pressure reduction, lipid levels, and glucose levels.
The team’s analysis with “10 commandments” for physicians is published in the 28 December 2011 article The idolatry of the Surrogate. The article, unfortunately, is only available through paid subscription through the BMJ (British Medical Journal – Helping Doctors Make Better Decisions).***
The commandments basically encourage physicians to be careful with statistical results from clinical trials, information from industry experts, and to treat and respect the patient as individual with treatment related statistics as guides.
On a related note, I am very impressed with folks who empower themselves in treatment decisions by keeping up with biomedical breakthroughs, new treatments, and new ways of looking at diseases. I have posted related blogs as ePatients: The hackers of the healthcare world and Meet e-patient Dave – a voice of patient engagement.
Here is the abstract of the article
Easier to measure surrogate outcomes are often used instead of patient important outcomes such as death, quality of life, or functional capacity when assessing treatments. John Yudkin, Kasia Lipska, and Victor Montori argue that our obsession with surrogates is damaging patient care
Diabetes care is largely driven by surrogates. The US Institute of Medicine defines surrogates as “biomarker[s] intended to substitute for a clinical endpoint [and] expected to predict clinical beneﬁt (or harm . . .) based on epidemiologic, therapeutic, pathophysiologic, or other scientiﬁc evidence.”1 In diabetes, concentrations of glycated haemoglobin (HbA1c) are used as a surrogate marker for outcomes that are important to patients, such as blindness or amputation. Other surrogates such as blood pressure, lipids, albumin excretion rates, and C reactive protein have been used to predict outcomes of cardiovascular disease and to guide clinical practice in people with or without diabetes. Much of the evidence for clinical interventions is based on their effect on surrogate outcomes rather than those that matter to patients such as quality of life or avoidance of vision loss or renal failure. Moreover, because these “hard” end points generally show much smaller responses to interventions than surrogate markers, many of the widely accepted strategies for diabetes may be based on artificially inflated expectations.
Recent studies have challenged the assumption that reliance on surrogates can accurately predict the effect of treatment on hard outcomes. There are the oral hypoglycaemic drugs that reduce HbA1c but increase the risk of cardiovascular events,2 antihypertensive drugs that do not reduce the risk of stroke,3 and drugs that improve cholesterol profiles but do not reduce cardiovascular events.4 Explanations for such phenomena include unwanted effects of the drug or an incomplete understanding of the pathophysiology of the disease.5 But why have …
Below are listed the the ten commandments**** with definitions and paraphrasing. I have forgotten much more than I have remembered from a college statistics class 30+ years ago! The “explanations” are a result of finding quality information on the Internet.
(For a great “translation” with less math, please go to the blog posting …Get Your Doctor to Treat You Right)
The New Therapeutics: Ten Commandments
- Thou shalt treat according to level of risk rather than level of risk factor.
Level of risk - these levels are experienced by everyone, not just those having the disease being treated [good summary of risk levels (minimal, less than minimal, greater than minimal) ]
Risk factor -anything that makes it more likely you will get a disease, either something you do (smoking)or something you have no control over (as being over 50 makes it more likely you will get colon cancer. People should be given treatments based on the risks associated with the treatment on anyone,not individual factors (age, blood pressure, other conditions)
- Thou shalt exercise caution when adding drugs to existing polypharmacy.
Polypharmacy - (poly is Greek for many) Whenever a person is taking a drug, any additional drugs may interact and cause bad reactions, including death.
- Thou shalt consider benefits of drugs as proven only by hard endpoint studies.
Endpoint study – research study involving humans where the outcomes (results) directly address the question. For example, if a drug was tested on how it reduced heart disease, the hard endpoint would be the reduction of heart disease. However, hard endpoint studies are usually not accomplished in short periods of time, because it takes time for diseases to develop. This paragraph sums up endpoint workarounds well.
From Deciphering Media stories on Diet (Harvard.edu)
4. Did the study look at real disease endpoints, like heart disease or osteoporosis? Chronic diseases,
like heart disease and osteoporosis, often take many decades to develop. To get around waiting that
long, researchers will sometimes look at markers for these diseases, like narrowing of the arteries or
bone density. These markers, though, don’t always develop into the disease.
- Thou shalt not bow down to surrogate endpoints, for these are but graven images.
Surrogate endpoint – a substitute endpoint in a clinical trial. It is not the item being measured directly (as heart disease), but an item related to what is being studied (as blood pressure). During the study these substitutes will be used to check on the health of the people in the clinical trial, the usefulness of the drug being treated, and if there are any complications. Surrogate endpoints are substitutes for (true) clinical endpoints (as survival for 5 years after the treatment). Surrogate endpoints don’t always guarantee a clinical endpoint (just because blood pressure goes down, heart disease may not be treated). However studies with good endpoints are expensive (require testing on many people) are take long periods of time. [Adapted from an eHow article with good references]
- Thou shalt not worship Treatment Targets, for these are but the creations of Committees.
Correlation doesn’t always meant causality!A treatment target is a goal of a treatment intervention. An example would be to reduce a specific protein in order to prevent a specific cancer (Potential New Treatment Target for Retinoblastoma, 13 January 2012 Medscape article) . The “cause/effect” relationship between something measurable (as a protein) and a disease may not truly exist. It is also possible that the presence of the protein and the onset of a disease may be due to other factors in a web of events.
- Thou shalt apply a pinch of salt to Relative Risk Reductions, regardless of P values, for the population of their provenance may bear little relationship to thy daily clientele.
Relative Risk - The number of times more likely (RR > 1) or less likely (RR < 1) an event is to happen in one group compared with another. [From the BMJ glossary] P value – a number used to show how a variable (as a drug treatment) has a different result thano variable (no treatments). So, a high P value would seem to point to an effective drug treatment.
- Thou shalt honour the Numbers Needed to Treat, for therein rest the clues to patient-relevant information and to treatment costs.
The Numbers Needed to Treat (NNT) tells how many patients need a specific treatment in order to prevent an additional bad outcome (as a heart attack or stroke). So if a drug has an NNT of 10, 10 people have to be treated with the drug in order to prevent one additional bad outcome.
For example, if a drug is found to reduce the risk of a bad outcome from 50% to 40%, the absolute risk .1 (the difference). And the NNT is the inverse of the absolute or 10. [From Numbers Needed to Treat (Patient.co.UK)
- Thou shalt not see detailmen, nor covet an Educational Symposium in a luxury setting.
Detailmen are pharmacy representatives who present doctors with their company's drug information with the aim of persuading the doctor to presribe their drugs. These representatives often sponsor educational talks (often "focusing" on conditions rather than drugs) at physician meetings. These "luxury settings" may included free buffets and hospitality rooms. [From Influencing Doctors :How Pharmaceutical Companies Use Enticement to 'Educate' Physicians (ABC News)]
- Thou shalt share decisions on treatment options with the patient in the light of estimates of the individual’s likely risks and benefits.
- Honour the elderly patient, for although this is where the greatest levels of risk reside, so do the greatest hazards of many treatments.
*** Click here for suggestions on how to get this article for free or at low cost.
In past blogs I have posted items on initiatives for the wider sharing of scientific articles to the public with subsidies, open access, etc.
****Richard Lehman’s Journal Review – 3 January 2012
Many NIH-funded clinical trials go unpublished over two years after completion (with ClinicalTrials.gov link for many trial study results)
[Flahiff's note: It is possible that many of these unpublished clinical trial results would have made a positive difference in many people's lives. These unpublished results have the potential of aiding many researchers. They can prevent unnecessary duplicate trials, point to areas needing more research, and potentially provide groundwork for collaboration.
On another note, it is good to see that published research papers are now more accessible to all. As of 2008, research papers based on NIH grants must be submitted to PubMed Central (PMC) when those papers are accepted for publication in a peer-reviewed journal. PMC will then make the papers freely available to the public within 12 months of publication.
I look forward to the day when all research papers are freely available to the public. There are a myriad of issues, as who pays for the publishing, the peer review process, and where the research papers should be "housed". However, I believe the more scientific research results are disseminated in easily accessible format, the more we can advance in technology applications and filling in knowledge gaps.]
In a study that investigates the challenges of disseminating clinical research findings in peer-reviewed biomedical journals, Yale School of Medicine researchers have found that fewer than half of a sample of trials primarily or partially funded by the National Institutes of Health (NIH) were published within 30 months of completing the clinical trial.
These findings appear in the January issue of the British Medical Journal, which focuses on the topic of unpublished evidence.
“When research findings are not disseminated, the scientific process is disrupted and leads to redundant efforts and misconceptions about clinical evidence,” said Dr. Joseph Ross, first author of the study and a Yale assistant professor of medicine. “Such inaction undermines both the trial in question and the evidence available in peer-reviewed medical literature. This has far-reaching implications for policy decisions, and even institutional review board assessments of risks and benefits associated with future research studies.”…
Ross said that there may be many reasons for lack of publication, such as not getting accepted by a journal or not prioritizing the dissemination of research findings. Still, he said, there are alternative methods for providing timely public access to study results, including the results database at ClinicalTrials.gov** that was created in response to Federal law.
[From the About Page at Clinical Trials.gov
US Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 or FDAAA), Title VIII, Section 801 mandates that a "responsible party" (i.e., the study sponsor or designated principal investigator) register and report results of certain "applicable clinical trials" that were initiated or ongoing as of September 27, 2007...]
ClinicalTrials.gov offers up-to-date information for locating federally and privately supported clinical trials for a wide range of diseases and conditions.
ClinicalTrials.gov currently contains 118,682 trials sponsored by the National Institutes of Health, other federal agencies, and private industry.
**Here is how one can check for study results
(remember, researchers are not mandated to submit study results to ClinicalTrials.gov, they are voluntary)
ClinicalTrials.gov records with published results listed via the PubMed medical literature search service.
- Use the Advanced Search with the search phrase clinicaltrials.gov[si]
Use the Builder limit results by topics (as a disease, medical device), year(s), name of researcher/invesitator)
- Need help searching? PubMed has tutorials , including a YouTube at the Advanced Search Page
Ask for assistance from a reference librarian at your local public, academic, hospital, or medical library.
Many academic, hospital, and medical libraries offer at least basic search help to all. Call ahead and ask
about their services. You may be pleasantly surprised.
- Many NIH-funded clinical trials go unpublished over 2 years after completion (eurekalert.org)
- The White House Calls for Information on Public Access to Publications and Data (The Scholarly Kitchen)
- How to obtain free/low cost medical and scientific articles(jflahiff.wordpress.com)
- Patients want to understand the medical literature (with links to resources for patients) (jflahiff.wordpress.com)
- Missing trial data threatens the integrity of medicine (eurekalert.org)
- Poor patient recruitment cited in call for trial disclosures (fiercebiotechit.com)
- A Present for NIH: President Signs Law Creating New Translational Center (news.sciencemag.org)
- NIH and Non-profits Sign Research and Development Agreement (kauffman.org)
- NIH establishes National Center for Advancing Translational Sciences (jflahiff.wordpress.com)