Latest Drugwonks' Blog
According to Craig Kessler, professor of medicine and pathology at Georgetown/Lombardi, the absence of mandatory clinical trials for biosimilar drugs could compromise their safety and effectiveness.
He said that the difference in manufacturing processes between companies can alter the drugs "in ways that technology can't detect.”
The healthcare reform law outlined a pathway for FDA to approve next-generation biopharmaceuticals modeled on original breakthrough drugs. But the legislation leaves the agency with a great deal of leeway -- including the flexibility to decide whether clinical trials are necessary at all.
"If you don't have clinical trials to take a look at all of these other off-label uses," Kessler said during a Capitol Hill discussion hosted by the Congressional Health Care Caucus, "then you don't really know what the equivalency in dosing is going to be like, and what the safety — the long-term safety — [issues] will be."
We need to proceed with biosimilars – but with care and caution.
No profit grows where is no pleasure ta’en;
In brief sir, study what you must affect
Close the FDA Approval Gap
The extensive review by a panel assembled by the Food and Drug Administration of the diabetes drug Avandia highlights the critical importance of government regulation and oversight of the drug industry.
Questions have been raised about the safety of Avandia since 2007, and a process to assess these risks versus patient benefits was undertaken by the objective professionals at FDA. But one important question underscores all such inquiry: What happens when the drug safety cop is taken off the beat?
Even though our system of pharmaceutical review and approval is regarded as the most effective in the world, there exists an incredible -- and potentially deadly -- loophole: unapproved drugs.
Recent news stories regarding the recall of 1,500 lots of Johnson & Johnson's children's and infants' Tylenol, Motrin, Zyrtec and Benadryl due to bacterial contamination, and the subsequent suspension of the their manufacture, reinforce the importance of the US Food and Drug Administration's (FDA) regulatory oversight over drug products--even years after they have been approved for sale. But due in large part to grandfather provisions going back 50 years, unapproved drugs - those that have been marketed prior to the establishment of today's FDA - are actively promoted, prescribed and taken by millions of patients in the U.S. These drugs escape FDA scrutiny otherwise imposed for all approved prescription and over-the-counter medications.
Most alarming is the fact that unapproved drugs account for nearly 72 million prescriptions per year. Unapproved drugs lack the specific quality controls of an FDA-approved drug, including manufacturing oversight that ensures the appropriate amount of active drug in each tablet, the purity of ingredients and consistency from dose-to-dose. And perhaps equally troubling is the fact that - unlike every other medication available for human consumption in the United States - unapproved drugs are not required to be accompanied by dosing information supported by human clinical studies.
The consequences of this approval gap can be tragic. Hundreds of deaths have been linked to the more than 500 unapproved drugs that FDA eventually banned. Yet to this day dozens of unapproved drugs are marketed under the regulatory radar. As recently as this past March, FDA took action against manufacturers of unapproved sublingual nitroglycerin tablets for treating certain heart conditions. FDA stated that it had seen "significant quality and efficacy problems" with unapproved nitroglycerin products and, as a result, recalled them from the market. Meanwhile, an FDA approved version had been available for years right alongside the unapproved, unregulated, and we now know, unsafe versions.
And the front-line gatekeepers of the nation's prescription drug delivery system--America's pharmacists--are themselves largely unaware of this dual standard for safety among the products on their shelves. A 2006 nationwide study of 500 pharmacists found that 91% of them incorrectly assumed that all of the products they dispense are FDA-approved.
They should be approved, of course. That's why in June of 2006, when I was head of the FDA's Center for Drug Evaluation and Research, we launched an initiative to finally address unapproved drugs. The Agency issued a Compliance Policy Guide (CPG) to review the safety and efficacy of unapproved drugs that continue to be available, in an attempt to bring these products into the modern world of drug safety with clinical, regulatory and manufacturing oversight.
Certain medications that have never undergone FDA evaluation should continue to be available for patients--when no substitute exists--so long as there are no known safety concerns. Many patients simply have no alternative treatment. But as soon as an approved version becomes available, FDA needs to act immediately and enforce its policies by withdrawing all unapproved formulations from the market. Regulatory oversight alerted us all to the risks associated with certain products manufactured by J&J. If no one is watching, how can we be sure it will never happen again?
"Patients should continue taking all currently prescribed medications unless instructed otherwise by their healthcare provider," said Dr. Robert A. Vigersky, immediate past president of the Endocrine Society. "Stopping diabetes medications can cause significant harm and result in higher levels of blood glucose that may cause severe short-term health problems and could increase the risk of diabetes-related complications in the long term."
“Effectively, this drug is gone.”
U.S. sales of the drug have plunged from $2.2 billion in 2006 to $520 million last year because of fears generated largely by Nissen. Meanwhile Actos, made by Takeda, the company Nissen has consulted for, has seen sales of it's product soar from $1. 9 billion in 2006 to $3.4 billion last year.
I think they got their money's worth.
Whether patients did is another matter. During the same time, the combined number of scrips for TZDs declined overall by 40 percent and scrips for oral diabetes agents fell by 20 percent. (I am going to double check this figure..) Did cardiovascular events among diabetics decline by 25 to 43 percent as might be predicted? No.
While there was an effort to depict Avandia's problems as a matter of deadly risks purposely hidden by GSK the issue was really two-fold. First, the fact that the FDA had to react to the risks of Avanda as framed by Nissen rather than the overall risk and benefits of each drug in the class in the context of treating diabetes and all it's complications. It had to focus on heart risks and whether surrogate endpoints were reliable, etc. all of which were issues framed to undermine confidence in the FDA and shift power to Nissen and outside or rogue forces. Second, and only after wading through this thicket, was the FDA able even to carry out it's public health responsibility and provide the advisory committee with that task. To that end, Commissioner Hamburg's leadership on this issue, along with the stewardship of Drs. Woodcock, Temple, Jenkins and DelPan should be applauded. And once again David Graham demonstrated why he is best suited for getting coffee in the FDA's division of psychopharmacology..
The big question is whether the treatment and management of diabetes is better off after the fearmongering.
More people have diabetes and fewer people are taking drugs. Is that a good thing?
Maybe Nissen should worry more about patients instead of his publicity and his bank account.
The vote ended up not even being that close. Ten panel members voted to keep Avandia on the market but with serious revisions to its label as well as possible restrictions on its sale. Seven voted to simply add further warnings to the drug’s label. Three voted to allow further sales without change. Twelve members voted for market withdrawal.
To most Americans it means that it’s almost time for lunch.
Robust internal debate.
Reading the coverage of yesterday's Avandia adcomm, you'd think the FDA professsional staff never disagreed with each other and lived in perfect regulatory harmony. Nothing could be further from the truth. Also, statements like "Avandia has split the agency in two" is just laughable -- considering the issue exists in one division of one center. But, hey, hyperbole sells.
Robust internal debate. It's healthy and it's the rule rather than the exception -- media reports to the contrary.
Kudos to Peggy Hamburg who, once again, reminds everyone that the science is the only thing that counts.
And science, as those who know understand, is plenty contentious enough.
It’s got to be more than just “sign here.” And it’s about time.
The IOM report on ethical and scientific issues in post-marketing drug safety studies could very easily get lost in the frenzy over you-know-what. That would be a shame because its real value lies in an intelligent and thoughtful outline of how to restructure informed consent. And in our age of the digitally empowered healthcare consumer, this is welcome news
"When a substantial amount of information indicating that a drug to be studied may involve serious safety risks has already accumulated, there are heightened obligations to ensure that potential participants understand the risks posed by study enrollment," the IOM Committee on Ethical and Scientific Issues in Studying the Safety of Approved Drugs says in a letter report.
The IOM says the emphasis given to risk information in the informed consent process should increase with the severity of risk and the level of certainty about the causal connection between a drug and the adverse outcome. "At a minimum, risks that should be disclosed should include any black box warnings, the 'major statement' currently listed in television advertisements, any adverse event findings of an FDA advisory committee, and a summary of evidence from published peer-reviewed studies."
The committee notes that in addition to verbal disclosures and written consent documents, there is a growing set of additional tools, such as videos and interactive electronic presentations that can enhance potential study participants' understanding of risks they may face.
Bravo.
"Whatever efforts are employed to communicate with potential participants, it is key that they include information that is useful to participants about where the weight of the evidence falls with regard to serious risks and the level of confidence that experts have in drawing conclusions about the risks," IOM says.
Potential study subjects should understand how treatment they will receive in the study differs from the current standard of care. "This is particularly crucial in cases in which medical practice has shifted away from prescribing the study drug because accumulating evidence from passive surveillance, observational studies and small trials or meta-analyses suggests that another therapy is as effective and has a more favorable safety profile," IOM says.
And, of course, FDA must assure that the post-marketing study is appropriately designed to answer the public health questions at issue and minimize risk to participants. Risks should be judged acceptable by FDA, data safety monitoring boards and institutional review boards and the study and subjects should be continuously monitored. As always – but it’s certainly worth repeating.
“Ignorance is never better than knowledge”
-- Enrico Fermi
As a commentary in this week's Biocentury suggests, the FDA's public hearing on Avandia being held this week is stacked in favor of Steve Nissen and David Graham, the two most public and vociferous critics of the drug. Something tells me that forces within and outside the FDA are seeking to force FDA commissioner's Peggy Hamburg's hand.
If the advisory committee votes to pull Avandia it will be hard for the FDA not to concur. And that will be the beginning of the end of the FDA's science-based regulatory authority, at least under this administration. It will mean that that marauders who react to any safety signal can run to the media and members of Congress to slow down or delay a product's approval or kill it's sales. It's means that meta-analysis, which has become a powerful data dredging tool for generating risks and diverting attention from benefits by producing spurious statistical association will triumph over biologically based outcomes.
Fearmongering requires new and unexpected risks. It must eliminate efforts to individualize treatment based on risks and benefits.
Nissen and Graham along with their fellow travelers on the one side. Dr. Hamburg and the FDA's future is on the other.
The decision on Avandia will decision which way regulatory science and the FDA will go for years to come.
Center for Medicine in the Public Interest is a nonprofit, non-partisan organization promoting innovative solutions that advance medical progress, reduce health disparities, extend life and make health care more affordable, preventive and patient-centered. CMPI also provides the public, policymakers and the media a reliable source of independent scientific analysis on issues ranging from personalized medicine, food and drug safety, health care reform and comparative effectiveness.
