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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.

Steven

Posted in Drug Approval and Access, FDA and Industry, FDA Leadership, Planning for FDA's Future | No Comments »

Forget the Hype: Change Takes Time

Monday, 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. (more…)

Posted in FDA and Industry, FDA Leadership, Follow-on Biologics, Food Issues, Planning for FDA's Future | No Comments »

Will the Real FDA Please Stand Up?

Sunday, January 23rd, 2011

This e-mail grabbed my attention this week:

TAKE ACTION: FDA Whistleblowers being Fired – HELP THEM.

[Organization] has received an appeal for help to prevent the firing of courageous, honest FDA scientists who risked their careers to save lives by informing Congress about serious safety concerns involving dangerous, FDA-approved drugs and medical devices.

FDA employees should not be afraid to speak honestly and freely about misconduct that threatens the health and safety of all Americans.

This isn’t the FDA that FDA Matters has known and followed for 30 years. Yet claims like the one in this e-mail are persistent and come from many sources.

Many FDA critics—inside and outside the agency—believe the FDA is corrupt, industry-beholden, and arbitrary in its decisions. They allege that the agency is insufficiently concerned about safety and that managers have too much power to overrule staff and suppress dissent.

FDA Matters has itself raised questions about workplace problems at FDA. There are links below to columns on "Dissent and Efficiency: Difficult Trade-offs for FDA," "Why Do Some People Dislike the FDA?" and "FDA: A Hit and a Miss" (about Avandia). Nobody would take the position that all 12,000 FDA employees are happy, fulfilled or satisfied with their work.

Nonetheless, I have always found FDA employees to be committed to the American people and dedicated to the public health needs of patients and consumers.

After spending four years as a government manager in the 1980’s and over a decade as a manager in the private sector, I believe FDA is like most companies or organizations: encompassing a broad range of competency and commitment and having its fair share of job dissatisfaction. From my government experience, I also remember how hard it can be to re-assign government workers who lack commitment or are incompetent or disruptive.

So, would the real FDA please stand up? Is it my very positive experiences or the dark accusations of ethical lapses, industry coziness and harmful suppression of disagreements? How can two such disparate views co-exist?

Forming a consensus and "speaking with one voice" are logical and sensible for FDA, but not an accurate reflection of what usually happens when well-trained, analytically-oriented people with different perspectives gather to make a decision. For example, reviewers focused on the risk-benefit of a medical product are often at odds with reviewers whose focus is safety.

The situation can become more confused when data is open to different interpretation. In such a clash, some people will feel they were not heard or that their views were not considered seriously enough. This is understandable and inevitable. Further, no one can deny that FDA has made some bad decisions and might have done better if it had listened to dissenting views.

However, aggrieved employees may also feel that malicious agency thinking and dictatorial managers have kept their views from becoming the FDA’s position. It is this generalization–from a single instance to the entire agency–that fosters the corrupt image of FDA propounded by agency critics.

I am not persuaded that these critics are right. FDA is making progress in handling dissent and in encouraging managers to be more open-minded. As happened with the Avandia decision, the agency is trying to be honest about disagreements. I am still impressed by the FDA’s self-evaluation of its poor performance in the ReGen medical device approval.

To me, these are hopeful signs, as well as indications that FDA values the nation’s public health above all other interests. FDA makes mistakes, but there is no conspiracy. The agency is fully committed to serving the American people.

Steven

Some related columns:

Dissent and Efficiency: Difficult Trade-offs for FDA
May 9th, 2010

FDA has a reputation for being tough on dissent, whether it comes from employees or regulated companies. It is often alleged that FDA employees with contrary views are re-assigned, marginalized or ousted. Within the regulated industries, there is a widespread belief that arguing with FDA has adverse consequences for a company.

Whatever the truth has been in the past, FDA is trying to develop an institutional cultural that welcomes and accepts dissent from employees, industry and other stakeholders. It is difficult, even messy, to do this. Yet, FDA’s reputation and authority rests on showing that it listened to all competing views–without unreasonably slowing the decisionmaking process. Read the rest of this entry

Why Do Some People Dislike FDA?
October 15th, 2009

Yesterday, I received separate posts from three organizations that are anti-industry, one of which dislikes FDA and one of which hates FDA. They are not alone in these feelings. There are many groups and individuals who believe that industry and physician professional societies run FDA. I don’t accept their premise or the “facts” from which they launch attacks. Read the rest of this entry

FDA: A Hit and A Miss
September 26th, 2010

FDA Matters has watched FDA handle the Avandia decision differently from any prior controversy. I like the new approach. In the same week, FDA provided a status report on its long-overdue social media and Internet communications policy. Because the agency’s efforts have been glacial, the prospect of useful guidance is dim. I think this is a serious problem. Read the rest of this entry

Posted in FDA Accountability and Transparency, FDA Leadership, Planning for FDA's Future | 1 Comment »

The State of the FDA—January 2011

Sunday, January 16th, 2011

FDA’s touches the lives of every American at least 6 to 10 times each day. The agency oversees 80% of the nation’s food supply, all of human/animal medical products and cosmetics, and almost all radiation-emitting devices. Altogether, the agency is responsible for about 20% of all consumer dollars spent in the United States.

With the President set to deliver his State of the Union address to Congress in 10 days, it seemed a good time for FDA Matters to provide its view of the "State of the FDA." At the beginning of 2011, the agency is doing well, but has a lot of catching-up to do and faces a number of threats. (more…)

Posted in FDA and Congress, FDA and Industry, FDA Appropriations, FDA Leadership, Planning for FDA's Future | No Comments »

Success is Uncertain for FDA’s Regulatory Science Initiative

Sunday, October 10th, 2010

FDA Matters was an early advocate for regulatory science. It has been exciting to see the concept grow from the Commissioner’s first public speech to the President’s request for $25 million in FY 2011. And now, FDA has released a White Paper describing the Regulatory Science Initiative (RSI).

It is an excellent report and I applaud those who worked hard to create it. Still, I have misgivings about the way the White Paper characterizes regulatory science, leading to concerns about whether RSI will develop the necessary political and public support to be a long-term, permanent part of FDA. (more…)

Posted in FDA and Congress, FDA and Industry, FDA Appropriations, FDA Leadership, Planning for FDA's Future | 1 Comment »

FDA: A Hit and A Miss

Sunday, September 26th, 2010

Posted in FDA Accountability and Transparency, FDA and Industry, FDA Leadership, Insight on FDA-regulated Industries | No Comments »

ACRA: Little Attention to an Important Appointment

Sunday, September 19th, 2010

For more than a year, FDA Matters has talked about the position of Associate FDA Commissioner for Regulatory Affairs (ACRA), who is the agency’s chief officer for inspections, enforcement and compliance. Of FDA’s appropriated (non-user fee) budget, the ACRA oversees one-third of the agency’s monies and more than 40% of the staff. It is FDA Matters that dubbed the ACRA the “uncrowned prince” of FDA.

Because of the importance of ACRA and the level of resources it receives, we have been awaiting a new appointee to this long-vacant position. This has now occurred, but the announcement was so unassuming as to raise concerns. (more…)

Posted in FDA and Congress, FDA and Industry, FDA Leadership | 1 Comment »

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…)

Posted in Drug Approval and Access, FDA Leadership, Planning for FDA's Future | 1 Comment »

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…)

Posted in Drug Approval and Access, FDA and Congress, FDA Leadership | No Comments »

Late Friday Afternoon: FDA, Politics, and Scientific Integrity

Sunday, August 15th, 2010

When my Smartphone delivered an e-mail at 5:12 p.m. on Friday: “FDA approv…,” I knew that FDA had just announced something controversial. All public relations people (including those at FDA) have been taught that late Friday is the time to release stories you don’t want to receive much attention.

Indeed, it was the 5-day emergency contraceptive pill, Ella, that was approved. So far, FDA seems to have achieved its goal of less coverage. But I was left wondering if the announcement required that treatment and why it led one advocate to describe the decision as “further evidence that the FDA is committed to restoring scientific integrity in its decisions.” (more…)

Posted in Drug Approval and Access, FDA and Industry, FDA Leadership | 1 Comment »

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