I haven’t followed the goings-on about the FDA appointee Dr. Robert Califf and his industry connections. I’ve been tangled up in other things. To be honest, my beefs about the FDA aren’t as strong as many who are interested in these matters. I accept that the mandate of the FDA was originally Safety and that Efficacy was an add on. I don’t too much mind that their standards are so low for efficacy approval. Drug usage is traditionally determined by doctors, not the government and that’s as it should be. I have been impressed by the majority of the NDA Reports I’ve read [to my surprise]. And I don’t mind Califf’s familiarity with industry. It could just as well be an asset as a problem.
My complaint about the FDA is that they protect the drug companies claim of Clinical Trial data being private property, and they are slow as molasses with FOIA requests on newer drugs. We should at least be able to get the NDA medical reports when the drugs are approved, and we can’t. The lag time is forever because they vet them – and I vehemently object to that. The other thing is that they respond to the pressure to get new drugs on the market. It reminds me of the "body counts" from the Viet Nam days as if that number mattered. The safety and efficacy of a drug has nothing to do with the other drugs being evaluated. A drug is either approvable or not, and that rate of approval is a measure of nothing worth knowing. I don’t particularly like approving drugs for "diagnoses" because our DSM-III, IV, & 5 diagnoses suck, but I can’t think of an better alternative. The thing I don’t like Califf’s resume is that he directed a Translational Program. I’m not keen on the "translational" concept. What’s the hurry? But other than that, my criteria for FDA Director are simple – honesty and common sense.
This article in the Boston Globe does give us something to think about. Why did he withdraw his name from some articles in a series he edited? First I’ve linked the news article, then the abstracts of the articles in question, including the three he "un-authored." All of them are available full text online. So take a look:
Nominee to lead agency wrote series examining clinical trialsBoston GlobeBy Sheila KaplanOctober 07, 2015This story was produced by STAT, a national publication from Boston Globe Media Partners that will launch online this fall with coverage of health, medicine, and life sciences. Learn more and sign up for STAT’s morning newsletter at statnews.com.
President Obama’s nominee to lead the Food and Drug Administration recently coauthored a series of scientific papers raising concerns about the agency’s oversight of clinical trials but asked that his name be removed before publication, according to other authors. Dr. Robert Califf, the Duke cardiologist first named a deputy commissioner in January and then nominated for the top post last month, was the driving force behind the series, which was published in the October issue of the journal Clinical Trials.
The heart of the series is an examination of what are known as pragmatic clinical trials — an increasingly popular type of study that seeks to compare two or more treatments in a real-world setting instead of in a traditional clinical environment. Portions of the papers are critical of the agency and recommend policy changes that would be highly divisive. Califf, who completed most of the series before he joined the FDA, remained as an editor of the publication but asked that his name be removed from the three articles he had co-written, according to other authors and the publisher of the series. He also remained a coauthor on the brief introduction to the series.
It’s unclear what prompted Califf to remove his name — a decision that could raise ethical concerns. It is highly unusual for authors of scientific papers to have their names removed before publication. A spokeswoman for Califf said he declined to comment. A coauthor on one paper, speaking on condition of anonymity because of the sensitivity of the matter, said Califf had been told to mask his authorship by the FDA. A spokeswoman for the agency suggested it was his decision. “Dr. Califf requested that his name be removed as a coauthor from these three articles out of an abundance of caution to avoid any perception that he would be commenting as an FDA official through these articles,” the spokeswoman said in a statement to STAT…
by Robert M Califf and Jeremy SugarmanClinical Trials. 2015 12[5]:436-441.
The need for high-quality evidence to support decision making about health and health care by patients, physicians, care providers, and policy-makers is well documented. However, serious shortcomings in evidence persist. Pragmatic clinical trials that use novel techniques including emerging information and communication technologies to explore important research questions rapidly and at a fraction of the cost incurred by more “traditional” research methods promise to help close this gap. Nevertheless, while pragmatic clinical trials can bridge clinical practice and research, they may also raise difficult ethical and regulatory challenges. In this article, the authors briefly survey the current state of evidence that is available to inform clinical care and other health-related decisions and discuss the potential for pragmatic clinical trials to improve this state of affairs. They then propose a new working definition for pragmatic research that centers upon fitness for informing decisions about health and health care. Finally, they introduce a project, jointly undertaken by the National Institutes of Health Health Care Systems Research Collaboratory and the National Patient-Centered Clinical Research Network [PCORnet], which addresses 11 key aspects of current systems for regulatory and ethical oversight of clinical research that pose challenges to conducting pragmatic clinical trials. In the series of articles commissioned on this topic published in this issue of Clinical Trials, each of these aspects is addressed in a dedicated article, with a special focus on the interplay between ethical and regulatory considerations and pragmatic clinical research aimed at informing “real-world” choices about health and health care.
In the popular book, Big Data [see two points…], the author discusses the advances in data analysis increasingly possible with the vast explosion of data available and the massive increases in computational capacity in today’s digital world. We are used to approaching data analysis by collecting a sample, then generalizing about the whole from our results on the sample. In a modern world, we can come close to having the whole at our finger-tips moving in real time. In terms of something like medical interventions, it’s easy to fantacize collecting information from electronic medical records that would give us ongoing interactive feedback on interventions in the real world. This series addresses that future in a limited way. For the moment, they’re focusing on post-marketing comparative research conducted in existing health systems. Our clinical trial procedures are ill suited for such Patient Centered Trials – needing a revamp in terms of the meaning of things like informed consent. So they’re trying to define how to define "low risk" comparisons, what level of consent is required, and interestingly what level of confidentiality is guaranteed. Reading these three papers was like fingernails on a chalk-board for me. I’m glad they’re discussing such matters. I’m equally glad I’m not. But in terms of red flags, I didn’t see anything that worried me along the way. Your turn…
by Monique L Anderson, Joseph Griffin, Sara F Goldkind, Emily P Zeitler, Liz Wing, Sana M Al-Khatib, Rachel E Sherman,
«and formerly Robert M Califf»Clinical Trials. 2015 12[5]:511–519.
Pragmatic clinical trials can help answer questions of comparative effectiveness for interventions routinely used in medical practice. Pragmatic clinical trials may examine outcomes of one or more marketed medical products, and they are heterogeneous in design and risk. The Food and Drug Administration is charged with protecting the rights, safety, and welfare of individuals enrolled in clinical investigations, as well as assuring the integrity of the data upon which approval of medical products is made. The Food and Drug Administration has broad jurisdiction over drugs and medical devices [whether or not they are approved for marketing], and as such, clinical investigations of these products are subject to applicable Food and Drug Administration regulations. While many pragmatic clinical trials will meet the criteria for an exemption from the requirements for an investigational new drug application or investigational device exemption, in general, all clinical investigations of medical products that fall under Food and Drug Administration jurisdiction must adhere to regulations for informed consent and review by an institutional review board. We are concerned that current Food and Drug Administration requirements for obtaining individual informed consent may deter or delay the conduct of pragmatic clinical trials intended to develop reliable evidence of comparative safety and effectiveness of approved medical products that are regulated by the Food and Drug Administration. Under current regulations, there are no described mechanisms to alter or waive informed consent to make it less burdensome or more practicable for low-risk pragmatic clinical trials. We recommend that the Food and Drug Administration establish a risk-based approach to obtaining informed consent in pragmatic clinical trials that would facilitate the conduct of pragmatic clinical trials without compromising the protection of enrolled individuals or the integrity of the resulting data.
by Danielle M Whicher, Jennifer E Miller, Kelly M Dunham, Steven Joffe,
«and formerly Robert M Califf»Clinical Trials. 2015 12[5]:442-448.
To successfully implement a pragmatic clinical trial, investigators need access to numerous resources, including financial support, institutional infrastructure [e.g. clinics, facilities, staff], eligible patients, and patient data. Gatekeepers are people or entities who have the ability to allow or deny access to the resources required to support the conduct of clinical research. Based on this definition, gatekeepers relevant to the US clinical research enterprise include research sponsors, regulatory agencies, payers, health system and other organizational leadership, research team leadership, human research protections programs, advocacy and community groups, and clinicians. This article provides a framework to help guide gatekeepers’ decision-making related to the use of resources for pragmatic clinical trials. Relevant ethical considerations for gatekeepers include [1] concern for the interests of individuals, groups, and communities affected by the gatekeepers’ decisions, including protection from harm and maximization of benefits; [2] advancement of organizational mission and values; and [3] stewardship of financial, human, and other organizational resources. Separate from these ethical considerations, gatekeepers’ actions will be guided by relevant federal, state, and local regulations. This framework also suggests that to further enhance the legitimacy of their decision-making, gatekeepers should adopt transparent processes that engage relevant stakeholders when feasible and appropriate. We apply this framework to the set of gatekeepers responsible for making decisions about resources necessary for pragmatic clinical trials in the United States, describing the relevance of the criteria in different situations and pointing out where conflicts among the criteria and relevant regulations may affect decision-making. Recognition of the complex set of considerations that should inform decision-making will guide gatekeepers in making justifiable choices regarding the use of limited and valuable resources.
by John D Lantos, David Wendler, Edward Septimus, Sarita Wahba, Rosemary Madigan, Geraldine Bliss,
«and formerly Robert M Califf»Clinical Trials. 2015 12[5]:485-493.
Institutional review boards, which are charged with overseeing research, must classify the riskiness of proposed research according to a federal regulation known as the Common Rule [45 CFR 46, Subpart A] and by regulations governing the US Food and Drug Administration codified in 21 CFR 50. If an institutional review board determines that a clinical trial constitutes “minimal risk,” there are important practical implications: the institutional review board may then allow a waiver or alteration of the informed consent process; the study may be carried out in certain vulnerable populations; or the study may be reviewed by institutional review boards using an expedited process. However, it is unclear how institutional review boards should assess the risk levels of pragmatic clinical trials. Such trials typically compare existing, widely used medical therapies or interventions in the setting of routine clinical practice. Some of the therapies may be considered risky of themselves but the study comparing them may or may not add to that pre-existing level of risk. In this article, we examine the common interpretations of research regulations regarding minimal-risk classifications and suggest that they are marked by a high degree of variability and confusion, which in turn may ultimately harm patients by delaying or hindering potentially beneficial research. We advocate for a clear differentiation between the risks associated with a given therapy and the incremental risk incurred during research evaluating those therapies as a basic principle for evaluating the risk of a pragmatic clinical trial. We then examine two pragmatic clinical trials and consider how various factors including clinical equipoise, practice variation, research methods such as cluster randomization, and patients’ perspectives may contribute to current and evolving concepts of minimal-risk determinations, and how this understanding in turn affects the design and conduct of pragmatic clinical trials.
No answers, just a question. I have heard Ben Goldacre sing the praises of one type of “real-world” comparative effectiveness trial, in which regular patients coming into the clinic with Condition X are randomly assigned to one of two approved treatments. It makes me really uneasy, because it prohibits the doctor from using their own judgment in ways that could put patients in danger.
Say your clinic was assigned to compare two antidepressants: Celexa and Cymbalta. And in comes old Ralph, saying Doc, I’m ready to try an antidepressant. And the random number generator says he gets Cymbalta. But you happen to know old Ralph drinks more than he lets on, and his liver tests are kind of screwy already — and Cymbalta can be hazardous for this type of person. Do you give him Cymbalta anyway?
Goldacre would seem to say Yes, because if you let doctors follow their own ideas about which sort of patient gets which sort of drug, you destroy the blessed randomization. God forbid, you could make Celexa look bad because you’re giving it to all the heavy drinkers, who will have a harder time beating depression anyway! I think such a trial is unethical — and I’d avoid any clinic that engaged in such shenanigans.
But is this what Califf & Co. have in mind? Or do they just want to study the records of un-manipulated clinical practice?