Latest Drugwonks' Blog
Immaturity is the incapacity to use one's intelligence without the guidance of another. -- Immanuel Kant
Is "Kant" in the FDA vocabulary?
Here’s the latest House PDUFA discussion draft being circulated by the House Energy and Commerce Committee.
As pointed out in the Pink Sheet, guidance development would take on a much larger and likely more extensive role at FDA if provisions in the draft are ultimately approved. The draft, would require FDA to give at least three months’ notice before it intends to issue a certain type of draft guidance and solicit public comment.
New, more rigid guidelines for public participation prior to issuing some draft guidance documents, as well as a requirement that they be finalized within a year, likely would require an increase in agency resources devoted to those efforts.
The more predictable schedule also would favor industry by ensuring the waiting period for FDA thinking on a subject would not be potentially unending. Industry typically complains about the uncertainty of FDA policy on many subjects.
The rule would apply to a guidance that “sets forth initial interpretations of a statute or regulation, sets forth changes in interpretation or policy that are of more than a minor nature, includes complex scientific issues, or covers highly controversial issues,” according to the draft.
A clause in the proposal allows the agency to skip the advance notice if it is impracticable, unnecessary or contrary to public interest, but it would still be required to meet with stakeholders during a three-month period beginning the day the guidance is issued.
Once a draft guidance is released, FDA would be required to finalize it no more than 12 months later or it would be considered null and void, according to the discussion draft.
Comprehensive reviews of final guidances also would be required every five years under the bill to ensure they are not “outmoded, ineffective, insufficient or exceedingly burdensome.”
The provision would subject FDA to a much more formal schedule of guidance development. While the intention appears to exclude routine guidance updates from the rule, it would be easy to place most, if not all, new agency guidance, into one of those categories, especially “highly controversial” and “more than a minor nature.”
The schedule would create more pressure on the agency to finalize guidances before the one-year deadline, which could leave them incomplete or rapidly outdated. A more structured guidance development process ideally would prevent situations where industry has been penalized for violations of FDA policy, yet still waited for years to receive formal agency thinking on the subject.
Sponsors have complained the agency changed its guidance on clinical trial endpoints in the midst of a development program, making continuation more complicated.
FDA is clearly being forced to battle against congressional efforts to adjust its mission to focus more on issues of innovation … and PDUFA’s first principle of predictability.
A provision would add to FDA’s mission that it would strive to establish a regulatory system that “protects the public health and enables patients to access novel products while promoting economic growth, innovation, competitiveness, and job creation among the industries regulated by this Act,” according to the draft.
The package includes reauthorizations of the prescription drug and medical device user fees, as well as new programs for generic drugs and biosimilars.
The four user fee cycles would run from FY 2013 through FY 2017.
The user fee package is expected to be ready for passage soon. Health Subcommittee Chairman Joe Pitts, R-Pa., already has stated he wants the bill signed by President Obama by June.
He alone is free who lives with free consent under the entire guidance of reason. -- Baruch Spinoza
Abbott Laboratories’ pharmaceutical spinoff will be called AbbVie and will debut by the end of the year.
Abraham Lincoln wrote that patents, “add the fuel of interest to the passion of genius.”
The Supreme Court of the United States has just doused a lot of that passion – and, along with it, the hopes that personalized medicine (via advanced diagnostics) can become reality sooner rather than later.
Or, as the Wall Street Journal judiciously puts it, “The ruling sparked uncertainty about the booming field of personalized medicine, in which some of the world's largest drug companies are vying to tailor treatments to patients' unique makeups by using diagnostic tests.”
The Supremes have rules that telling doctors of a new scientific discovery and recommending they use it to treat patients is not patentable. Per Justice Stephen Breyer, that’s all Prometheus Laboratories did when it patented a test to help doctors set drug dosages for patients with Crohn's disease. The inventions claimed in the patents "consist of well-understood, routine, conventional activity already engaged in by the scientific community.”
Justice Breyer said the Prometheus patents recited laws of nature connecting the level of certain chemicals in the blood to a thiopurine dosage that is too high or too low. Then, he said, the patent walked doctors through several obvious steps—such as measuring the chemical levels—to turn that natural law into recommendations for particular patients. He rejected the company's contention that, taken together, the steps represented a patentable method for treating patients.
But isn’t that what “intellectual property” is all about?
Justice Breyer emphasized that patent law should not inhibit future innovations by "tying up the future use" of natural laws. He said Prometheus's patent claims "threaten to inhibit the development of more refined treatment recommendations."
But where there is no patent protection there is no investment. And where there is no investment there is no development.
The only people who are going to love this ruling are those who agree with Jamie Love that separating the markets for innovation from the markets for physical goods will ensure that everyone, everywhere, will have access to new medical technologies at marginal costs.
Baloney.
Prometheus Bound is, after all, a Greek tragedy.
According to Alan Ashworth, head of the Institute of Cancer Research in London, "Today, despite the best efforts of the drug companies, we still use medieval methods to attack most cancers: cutting [surgery], burning [radiotherapy] and poisoning [non-specific chemotherapy]." But, says Ashworth, "Once we understand the Darwinian process by which cancer cells evolve in the body, we should be able to control even advanced disease through combinations of specific drugs."
Last week in Boston I was honored to give a presentation at the 10th Biosimilars America conference. But, as is often the case at good events, it was more about what I learned than what I had the chance to say.
Or, as my father used to remind me, “Listening is not just waiting for your turn to talk.”
Of the many fine presentations, I refer specifically to the talk given by John Pakulski, head of US Biopharmaceutical Regulatory Affairs at Sandoz, and the current chair of the GPhA Biologics Task Force.
John made many interesting and important points, but the one that resonated the most was that, in an age of technology, we must use technical data more and rely on clinical trials less. In short – when it comes to understanding the complicated concept of biosimilarity (from both regulatory as well as clinical perspectives) it’s a brave new world. But will we have the courage to move beyond “the gold standard.” Perhaps we should say, “the 20th century gold standard.”
Claude Debussy said, “Music is between the notes.” And the same can be said for biosimilarity. We now have many thoughtful guidance documents but, in many respects, it’s just theory. And just like with music theory, the words on the page are one thing – but when talented performers sit down at different pianos in disparate venues the result is both similarity and uniqueness.
In other words – creativity happens.
Another difference between biosimilars and small molecule generics is that the developers of biosimilars are very much in the innovation business.
Innovation happens.
A couple of weeks ago I posted on the 'statin scare', and referred to a study that discussed the increase risk of diabetes for people taking cholesterol lowering meds in primary prevention.
I was skeptical of a single study as the basis for concern (and certainly panic). Eric Topol's recent videoblog on the issue is underscores the need for careful review of all data, tailoring treatment to patients to maximize benefits and the urgent need for whole genome research on response and metabolism of all statins.I am on a low dose statin. I monitor my liver enzymes pretty regularly (normal for someone who works out as regularly as I claim to!). It never occured to me that the slight elevation in my glucose levels -- something my doctor has always kept an eye on -- was a 'side effect' of statin use. Since we have a family history of high cholesterol and heart attacks statins are indicated and my risk of a heart attack were probably greater if I didn't take statins compared to taking them and getting diabetes. But a more precise and individualized measure of risk and benefit would be greatly appreciated!
Dr. Topol raises important questions about the risks and benefits of using statin in primary prevention absent other risk factors. And he again makes a persuasive case about the value of genomic testing. As he notes in his excellent book The creative destruction of medicine: How the digital revolution will create better healthcare 30 percent of people being treated for diabetes are non-responders to metformin, which is pushed as first line therapy. Why not a test that measures response and reaction to statins and diabetes meds. Why not make that test available to consumers in the most convenient way possible?
The impact on compliance and health outcomes would be significant in my opinion. And as for my use of statins, I will be a bit more careful going forward.
Thanks Dr. Topol.
http://blogs.theheart.org/topolog
Many tough questions. No easy answers.
From the latest edition of the British Medical Journal ...
Speeding up access to new drugs
Nigel Hawkes
The prime minister promised at the end of last year to give some patients quicker access to new drugs. Was this just an empty aspiration?
No. A lot of thought has been given to a faster access scheme since David Cooksey recommended it in his review of UK health research funding in December 2006. A working group from industry and government produced a plan by November 2009. It sat on a shelf until resurrected two years later.
How would it work?
Medicines that have completed phase III trials (or in exceptional circumstances phase II) and that will treat or prevent life threatening, chronic, or seriously debilitating conditions that lack adequate existing treatments would qualify. Manufacturers would have to apply, and a decision would be promised in 75 days.
How would that be any quicker than licensing, if phase III trials have already been completed?
It usually takes a year or more to get licensing approval after a successful phase III trial. The new process is expected to get these medicines to patients a year earlier than otherwise would be the case.
But doesn't it mean that proper risk assessment will be skimped?
There's a danger of that. The burden of risk will be shifted towards the doctor and the patient and away from the manufacturer. Good information will be vital; patients will need to be fully informed and give active consent. Legally, the position will be the same as that for any unlicensed medicine, and the working group believes-but cannot guarantee-that primary care trusts or clinical commissioning groups will not be liable should anything go wrong. And it says that if the decision by a doctor to treat a patient was reasonable in all the circumstances and all relevant information was provided, a successful claim for negligence is unlikely.
If unlicensed medicines can be marketed and sold, what's the point of licensing?
The medicines under this scheme would be exceptional and few in number, perhaps only one or two a year. The NHS already uses unlicensed or off-label medicines in some cases, on the authority of the prescribing doctor (for example, bevacizumab for age related macular degeneration). Patients consulted by the working group were confident that they were competent to make a proper assessment of the risks. Doctors were not so sure.
What happens when the medicine is licensed?
The approval will last a year and can be renewed if necessary. When the medicine gets a licence it will become part of the normal process and the National Institute for Health and Clinical Excellence (NICE) will examine its cost effectiveness. Arrangements for continued funding of early access patients will need to be agreed for each medicine in advance.
So these fast access medicines will bypass NICE?
Yes. NICE deals with licensed medicines; these are unlicensed, so NICE does not have a role.
So how can we tell if manufacturers are overcharging?
We can't. They will set the price. It will be up to commissioning organisations, without NICE input, to decide if it's a price they want to pay.
Where's the money coming from?
An important question, the answer to which could yet put a spanner in the works. Since these medicines will not be approved by NICE, there will be no obligation for primary care trusts or clinical commissioning groups to pay for them. There will be no additional money available, unless the Department of Health or the drug companies provide it. Commissioning bodies will have to fund the drugs out of their normal allocations and in hard times may be reluctant to do so. This could lead to "postcode prescribing," as the working group conceded. But it hoped that if the process were applied only to medicines providing "significant clinical benefit in areas of current unmet need" the variation could be minimised.
Has anybody else attempted a similar scheme?
Yes, the French Temporary Authorisation for Use (ATU) scheme is quite similar and has operated for 15 years. To qualify for this, the medicine must have no satisfactory alternative and patients cannot access the scheme if they could become part of a clinical trial of the same medicine. The scheme is restricted to hospital specialists, and companies must agree to submit an application for a full licence, usually within a year, of the temporary authorisation being granted.
Experience shows that companies usually set high prices, but if the price fixed after market authorisation is lower they can be asked to refund the difference.
What about surveillance of side effects?
Applications for faster access would have to include plans for drug surveillance. "Collecting safety data is essential to protecting patients receiving the medicine," the working group concluded and is also an important way of developing a better understanding of the medicine. But the demands should not be so burdensome as to discourage companies from applying; nor should data gathering be seen as a clinical trial.
What's next?
The Medicines and Healthcare Products Regulatory Agency plans to launch a consultation on the scheme at the end of March. It will allow 12 weeks for responses.
Russia: Russian Companies Receive Lowest Number of Permits for Clinical Research in Seven Years
Russian companies have received the lowest number of permits for clinical research in seven years, according to a report from Remedium. In 2011, the Ministry of Public Health issued 571 permits for clinical studies, of which 369 were for multicenter studies (an increase of 49% from 2010), and 117 for local studies (a decrease of 27% from 2010).
The share of research by Russian sponsors was below average for the last seven years, with domestic producers receiving 14.1% of permissions for drugs research testing—against the seven-year average of 20.6%. According to the report, the number of local studies has fallen following the 1 September 2010 "law on treatment of drugs", which specified that local studies be included in the registration of medicines, meaning that Russian companies must apply for a drug's registration and pay a state fee before testing. There is no such requirement for foreign companies in Russia.
The Federal Antimonopoly Service (FAS) is currently preparing an amendment to the law proposing that the requirement to register be cancelled. They are also proposing to cancel the obligation for foreign companies in Russia to conduct local research if not including the country in a multi-center trial.
Significance: Russia's healthcare and pharmaceutical industry is currently going through regulatory changes that aim to simplify the registration process and speed market entry for drugs, among other goals. The report will come as a setback to Russia's efforts to expand the pharmaceutical industry and stimulate domestic manufacturers. The changes proposed by the FAS are likely to form a part of the regulatory reforms that are currently being formulated.
PCORI has devoted 9 million taxpayer dollars and nearly two years focusing exclusively on figuring out what patient-centered outcomes research is. That's like the Department of Homeland Security or Defense Department doing nothing but trying to define what "security" and "defense" is.
Here's the full defintion of patient-centered outcomes research:
Patient-Centered Outcomes Research Working Definition
Patient-Centered Outcomes Research (PCOR) helps people and their caregivers communicate
and make informed health care decisions, allowing their voices to be heard in assessing the
value of health care options. This research answers patient-centered questions such as:
1. “Given my personal characteristics, conditions and preferences, what should I expect
will happen to me?”
2. “What are my options and what are the potential benefits and harms of those options?”
3. “What can I do to improve the outcomes that are most important to me?”
4. “How can clinicians and the care delivery systems they work in help me make the best
decisions about my health and healthcare?”
(Note that for all the hot air about personalized medicine, there is no specific mention of genetic characteristics)
By way of comparison, it took less time to draft and ratify the Constitution of the United States. The excuse given for this over-cost and over-due delivery of a definition that leaves everyone more confused than ever is the following: " the difficulty in managing large numbers of healthcare providers with busy schedules and divergent interests." You see, these board members are much, much busier than Benjamin Franklin, John Adams, and Thomas Jefferson ever were.
And patient centered outcomes research is supposed to timely and scientifically up to date? If it took all this time just to agree on a definition, what can we expect about the effort to develop a research agenda that meets the definition?
As I have noted before, it will take less time to commercialize whole genome sequencing systems that produce same day results for clinical use then it will for PCORI, AHRQ, etc to decide what to study and to pay the groups who control the PCORI and AHRQ apparatus to do the research for the very same organizations. Did I forget to mention the incredible amount of cronyism involved in the entire CER process? But more on that in a future post.
A couple oversight hearings on what PCORI is really doing, how it's being done and whether it should be abolished would be beneficial. I mean, what's a couple more meetings and two days on the Hill when you spend two years defining what your organization should do. And I bet all those busy providers could clear their calendars pretty quick if called to testify.
Last November, the Center for Medicine in the Public held a confab entitled, “PDUFA without the Politics.” Many of the predictions from the event’s expert panelists seem to be coming true.
AS PREDICTED, the current conversation surrounding the reauthorization of the Prescription Drug User Fee Act (PDUFA) must focus on (among other things) the First Principle of Predictability as well as ensuring that the FDA can fulfill its role as an important ally in advancing healthcare in America.
The draft bill extends FDA's mission to include: advancing medical innovation; promoting economic growth and job creation; promoting predictability and allowing flexibility; identifying and using the most innovative and least burdensome tools for achieving regulatory ends; and incorporating a "patient-focused benefit-risk framework that accounts for varying degrees of risk tolerance, including for people living with a life-impacting chronic disease or disability."
AS PREDICTED, the House Republican discussion draft incorporates the Generating Antibiotic Incentives Now (GAIN) Act, which would extend market exclusivity by five years for drugs that treat antibiotic-resistant pathogens
AS PREDICTED, by Representative Michael Burgess at the CMPI conference, the bill also completely removes limits on issuance of conflict-of-interest waivers for FDA advisory committee participation that were enacted as part of the FDA Amendments Act.
The discussion draft also includes language intended to expand accelerated approval. The accelerated approval provisions are similar to those in the FAST and TREAT acts.
Is there still room for a few more Christmas Tree ornaments? Perhaps permanent renewal of the Best Pharmaceuticals for Children’s Act and PREA?
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.
