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Archive for the ‘Drug Approval and Access’ Category

Post-Market Safety: Getting the Most Out of Inferences That Aren’t Proofs

Tuesday, June 21st, 2011


In the FDA-regulated world, success is often defined as approval of a new product or indication based on two, well-controlled clinical trials. However, the scrutiny doesn’t end there. FDA’s mission includes determining whether already-approved drugs perform safely and effectively when used by large numbers of patients in routine medical practice. 


To understand what happens under these “real world conditions,” FDA has expanded its post-market  efforts, including development of a monitoring system (called Sentinel) that will be able to track drug usage and medical history information on tens of millions of patients. Although such information will be useful, it can only provide post-hoc inferences, not proof of causation. Even with this limitation, FDA Matters thinks developing the system is worthwhile and may provide multiple benefits. 


There are multiple tools for assessing post-approval safety and efficacy that fit loosely under the rubric of pharmacovigilance. When approving medical products, FDA mostly relies on data that comes from pre-specified hypotheses that are tested through randomized, placebo-controlled, double-blind clinical trials. In contrast, the data that comes from pharmacovigilance is inherently less rigorous; indeed it constitutes a form of “data dredging” that FDA abhors. The heart of the problem is that:  

Real world data sets = uncontrolled variables + inconsistent data collection + questionable data accuracy.

When FDA and manufacturers collect adverse events reports, they know there will be underreporting of incidents, as well as limited ability to judge whether problems are drug-related. When FDA looks at the Medicare database, they know that information submitted as part of medical claims is unreliable and subject to systemic bias (e.g. medical coding is designed to support reimbursement, not public health analysis).

The Sentinel database should be superior because it incorporates medical records and patient registry information, along with claims data. Still it provides inferences, not proof.

Active surveillance—continuously monitoring millions of health records—is only worthwhile if these limitations are acknowledged. It can never provide certainty about whether drugs are safe and effective. It can tell you what is worth further examination…but can never tell you the cause of any problem that is identified.

As the FDA mantra goes: association is not causation. No matter how many health records and claims data are reviewed, this is still true.

Clinical trials have limitations, also. Trials don’t tell us how a drug will be used by prescribers. They can never provide complete information about patient outcomes for those individuals with several medical conditions (i.e. multi-morbidity) or who take many medications simultaneously (i.e. poly-pharmacy).

By inference (although not with certainty), pharmacovigilance and active surveillance could bring us closer to addressing potential problems that can’t be resolved by clinical trials. For example, many years ago, I worked on a drug to treat pre-term labor. As I recollect, there were two instances of respiratory problems in a trial of several hundred women. No one could say for sure whether this effect was caused by the drug or occurred at random. A study large enough to find out was infeasible.

Based on the potential respiratory problem, FDA rejected the drug despite the benefits it might have provided to women experiencing pre-term labor. If this same situation were to come up today…maybe FDA would decide differently, knowing it could collect patient outcomes information through pharmacovigilance, particularly active surveillance.

Ideally, FDA would know everything it needs to know about a drug at the time of its approval. Information derived from review of real world data sets can never be as good. But properly understood and carefully analyzed, the inferences derived from pharmacovigilance can add to our understanding about safety, efficacy, drug interactions and side effects.


Instead of just using that capacity to identify post-approval problems, FDA needs to incorporate pharmacovigilance into its thinking about when to approve drugs and with what conditions. FDA’s capacity to do pharmacovigilance and active surveillance should lead to a greater willingness by FDA to approve drugs, particularly those with otherwise solid benefit-risk equations, but burdened by questions that cannot be resolved prospectively or through clinical trials (even in phase 4).


Patients would benefit if FDA made this one of the Sentinel priorities.




Lies, Damned Lies and Statistics

Thursday, May 12th, 2011


FDA’s regulations, policies and actions are multi-faceted and complicated. Oftentimes, it is hard to interpret what the agency is doing and why. We all depend on good analysis to understand where the agency has been and where it is headed. Unfortunately, some of what we read about FDA is poorly reasoned or distorted by the media and others.  


Three recent analyses have particularly troubled FDA Matters. They claimed to draw broad and important conclusions about FDA behavior and were uncritically circulated through mainstream and trade press. Yet, the analyses they offer are unremarkable or misleading.



My first example is a recent analysis from a healthcare research firm analyzing the number of FDA refuse-to-file (RTF) letters over the last dozen years. These involve situations where companies file drug and biological applications for approval and the FDA returns them to the company rather than accepting them for evaluation.


There is a methodological problem: FDA does not disclose RTF’s and traditionally companies have not disclosed them. Thus, any analysis of trend data (“more now, fewer a decade ago) is speculative.



Likewise, not knowing which companies received RTF’s means there is no basis to conclude that RTF’s were previously associated with small, inexperienced firms, but now are being received by larger companies. The shift, we are told, might reflect the agency’s enforcement mentality under the new commissioner. And maybe standards have been raised. A commentator (not the author) even suggests that the alleged uptick may be FDA maneuvering to improve its success rate under the user fee program (while, presumably, returning meritorious applications?).



To its credit, the analysis does mention that “the wave of RTF’s” may be related to FDA’s 21st Century Review Initiative. One aspect of that initiative is for FDA to weed out applications that are likely to be rejected later in the process. This is more efficient for companies, as well as FDA.



Front-loaded reviews are going to create more RTF’s. This seems obvious, if not unassailable. But trying to embellish this with time/trend data and allusions to changing standards raises issues that have no bearing on the question of whether RTF’s are becoming more important in the review process…and whether this is a good trend.



However, the implication picked up by the media was that increased industry interest in orphan drugs was not being met by increased commitment by FDA to get these drugs approved. But is that really the case? I don’t know and, despite appearances, the numbers don’t answer the question.



Showing same-year data for applications, designations and approvals implies that they relate to each. However, any given year’s orphan drug approvals reflect designations that were made 2 to 6 years previously. The meaning of the surge in the number of designations in 2010 cannot be assessed until we see if there are more orphan drugs approved in a few years.



Lastly, there is this week’s headline that: Biopharmaceutical Product Approvals in the U.S. Rose Dramatically in the 2000’s.” As a result of a Tufts University study, we are told that “during the 2000-09 period, 65 biopharmaceutical products received U.S. marketing, approval, up from 39 in the 1990s and 13 in the 1980.” Media seemed to treat this as a revelation. 


However, there was no biotechnology industry to speak of in 1980 and no products. As chronicled in previous columns (link below), the growth of this new industry has occurred over several decades. Is anyone surprised there were more approvals in the 2000’s?  


These three examples are a reminder that those of who write about and critique the FDA have an obligation to be accurate and not misleading. All of us, including myself, will fail sometimes. The media that report on our analyses rarely check to see if our conclusions are valid or make sense. 






The first analysis is at: http://portal.leerink.com/IRPDocumentViewer/Web/DocumentViewerCache.aspx?docId=4E2F752B612F6B5646706F3D&pad=52384B6E6E74573478656F45317951416D4B6A506E673D3D&userId=52636261346B39577A34343D


The second analysis is at: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2011/01/orphan-drug-designations-and-applications-took-off-in-2010-while-orphan-drug-approvals-tapered-off.html


The third analysis is at: http://csdd.tufts.edu/files/uploads/may-june_2011_ir_report_summary.pdf



Forget the Hype: Change Takes Time     March 21st, 2011

FDA Matters is always impressed by how much FDA does. The everyday tasks are overwhelming: reviewing, approving, monitoring and inspecting the products and facilities responsible for 80% of our food supply and 100% of drugs, biologics, medical devices, vaccines, and animal drugs. Then there are the policy issues, big and small, that must be tended to.

These are largely functional tasks—someone has a job (or several) and does them. Yet, FDA has another life, as the bridge to the future of foods, drugs and devices. This responsibility is vitally important to our nation. It also takes time to bear fruit. Read the rest of this entry

Public Incentives and Drug Development: More is Usually Better

Tuesday, April 5th, 2011


A former colleague often declared: life sciences companies have no alternative to re-investing in developing more drugs, biologics and medical devices. I always thought this naïve because of its implication that life sciences research is self-perpetuating and does not need encouragement.  


Currently, Congress seems primed (through oversight and possibly legislation) to consider the role of companies and government in medical product development. This week, FDA Matters explores the nature and need for incentives to conduct life sciences’ research; last week’s column looked at issues surrounding the pricing of medical products.


The government’s goal in incentivizing certain life sciences research is to stimulate activity that meets or resolves societal needs (e.g. drugs and devices for cancers, therapies for rare diseases, treatments for tropical diseases). Idealistically, the incentives encourage vital, new activity without providing subsidies for research that would have occurred without incentives.  


The reality is different. If the rules (statutory or administrative) for receiving incentives are drawn too tightly, then many research projects will not be undertaken, losing the benefits that society would otherwise receive.


To explain this better, I have identified three broad categories of public incentives for research:


Ordinary research incentives. These are the incentives available for all corporate-supported research. These include the research and development (R&D) tax credit, access to government technology transfer programs and patent protection. For most industries, and even most life sciences research, these seem sufficient to stimulate a high-level of research investment.


Upgraded incentives.  Ordinary research incentives are sometimes not enough to stimulate life science research that will benefit society. As a result, Congress has created a number of upgraded incentives for medical product development.


For example, Congress has provided partial patent term restoration for drug companies experiencing particularly long delays in receiving marketing approval. This has led to increased research investment (as well as boosting the generic drug market as part of the same legislation).  


Also, Congress created the Orphan Drug Act to provide incentives for research on drugs for rare diseases/small populations. This law incorporated a number of incentives, notably up to seven years market exclusivity for any new orphan indication on a drug.  


FDA also provides a number of upgraded incentives for particular types of research through its expanded access and accelerated approvals programs. User fee waivers granted to first products from new companies also stimulates research investment.  


Extraordinary incentives.  Sometimes even upgraded incentives aren’t enough to stimulate vitally important research. In those cases, Congress may consider incentives designed to dramatically alter the normal risk/reward/certainty calculation that usually precedes research investments.


Thus far, I can think of only one instance of extraordinary incentives. In 2007, Congress enacted a program that awards a “priority review voucher” for successful development of a new treatment for a neglected tropical disease. Owning a voucher entitles a company to ask for a priority review (6 months) by FDA of an unrelated product that would otherwise be granted a normal review (10 months). Currently, Congress is looking at legislation (S. 606) that would extend this voucher program to developers of products to treat pediatric rare diseases.


It is up to Congress to decide whether to encourage particular life sciences research beyond the ordinary incentives. When upgraded or extraordinary incentives are under consideration, the goal is stimulating substantial additional research….and the development of many new drugs that are particularly beneficial to society.   


In all such situations, there is a risk that incentives will be provided to research that would have occurred anyway. My own experiences suggest that overly tight restrictions on program eligibility result in understimulatoin of needed research. When creating incentives and, also, assessing their impact later, Congress needs to take the broad view of the societal good that can be achieved by upgraded and extraordinary incentives for research.




Drug Product Pricing 101                 March 26th, 2011

A thousand good deeds of the pharmaceutical and biotechnology industries have been washed away by the decision of K-V Pharmaceuticals to charge $1500 per dose for Makena, a drug that reduces the risk of pre-term delivery in pregnant women. There is an easy comparator: the same therapy has been compounded in pharmacies for years at a cost of $10 to $30 per dose. Congressional and public reaction has, quite understandably, been one of outrage.

No one knows the right price for this drug, but there are ways to find out. In conversations this week, FDA Matters discovered that many knowledgeable people don’t know that there are tools to rationally evaluate and guide product pricing decisions. Read the rest of this entry

FDA Is Fighting on Two Fronts

Sunday, February 27th, 2011

FDA is still a 20th century agency. It lacks the databases, technologies and tools to do its work. It does not have the depth of manpower to be experts in all the increasingly complex sciences associated with medical products and foods. It lacks the confidence to consistently make decisions based on risk-benefit analysis, rather than leaning toward the highly restrictive Precautionary Principle.

FDA Matters can’t see any downside to the FDA gaining the technology, the manpower and the confidence to transform itself into the 21st century FDA that our nation needs. Yet, Commissioner Hamburg has to fight on two fronts to preserve her ability to make the necessary changes. (more…)

NIH and Drug Development: Dr. Collins’ New Initiative

Sunday, January 30th, 2011

Dr. Francis Collins, director of the National Institutes of Health (NIH), wants to create a new National Center for Advancing Translational Sciences (NCATS) at NIH.  The new Center would combine $700 million in existing NIH projects with, perhaps, an additional $300 million from new monies or other NIH programs. NCATS is intended as NIH’s “response” to the biopharmaceutical industry’s failure to produce more new drugs.

FDA Matters doesn’t see the sense of creating a public sector drug development company. Nothing suggests that government has either the requisite knowledge or experience to succeed. Yet, several people I respect are supportive of Dr. Collins’s initiative. (more…)

FDA: An Honest Broker on the Slow Path to Biosimilars

Sunday, October 24th, 2010

FDA Matters‘ enthusiasm for biosimilars is a matter of public record. The market will build slowly, but 10 years from now the new law will be seen as ushering in a new age of biopharmaceutical product development. FDA will present the next glimpse of the future on November 2 and 3, 2010, when it holds hearings on implementing the new approval pathway.

The key to the future will be the FDA’s strong commitment to expanding prescriber and patient choice among biological products. FDA will be satisfied (and successful) if the new law stimulates biosimilars, bio-betters, and innovative new biological products, along with a dramatic increase in knowledge about the nature and characterization of biologic products. (more…)

FDA and Quran Burning: Trouble Can Start With a Tweet

Sunday, September 12th, 2010

Bravo! Florida Pastor Terry Jones has decided not to burn a copy of the Quran. The next danger is that the Pastor’s “success” will be seen narrowly as the unique confluence of 9/11, the Ground Zero mosque, and the readiness of millions to take to the streets at signs of American intolerance toward Muslims.

FDA Matters thinks the lessons are larger and urges FDA to pay attention to how this reflects changes in the way crises develop and decisions are made. (more…)

FDA’s “Summer of Safety Concerns”

Sunday, September 5th, 2010

One of industry’s great fears is that FDA will become obsessed by theoretical or miniscule safety concerns and ignore the difficult realities of providing consumers with a varied and plentiful food supply and providing patients with effective medical therapies.

It is even possible to think this has occurred. It has been a long summer of media and Congressional attention to safety: whether drug manufacturing, medical products already on the market or Salmonella contaminated eggs. A closer look suggests to FDA Matters that theoretical safety risks and inappropriate FDA concerns about safety are not the issue. (more…)

FDA’s Pivotal Role Fighting Bioterrorism and Emerging Infectious Diseases

Thursday, August 26th, 2010

With Congress out of session until September 13, the Executive Branch has the opportunity to gain extra column inches and media bandwidth. Thus, last week’s report on medical countermeasures (MCM), released by HHS Secretary Sebelius, drew a lot of interest and a minimum of Congressional comment.

The Secretary released the findings and recommendations from a top-to-bottom review of the Department’s efforts with regard to the development of MCM. In the view of FDA Matters, the report thrusts FDA back into its rightful place as a key agency deserving more resources and respect for its national security responsibilities. (more…)

For Those Who Don’t Work With Patients: A Reality Check

Friday, August 20th, 2010

Guest Column: Summer, Camp, Kids, Cancer

By Margaret Anderson, Executive Director, FasterCures

While we focus on improving the efficiencies of the system that discovers treatments and cures for disease, there are untold numbers of people taking a medical treatment journey right now. For the kids partaking in the 28th year of Camp Fantastic in Virginia this week, they get to focus more on the fun, and less on the challenges of coping with a cancer diagnosis and with treatment. Camp Fantastic is a program of a nonprofit called Special Love that gives cancer families support. (more…)

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