Animal Welfare and FDA

A coalition of animal rights organizations has filed a lawsuit to force FDA to address issues about animal testing that were raised in its 2007 citizen petition (FDA Law Blog, www.fdalawblog.net). The animal rights organizations want FDA to mandate that companies consider non-animal tests before using animals. This is apparently the standard in the EU.

It would be nice if FDA answered their citizen petition. A "no" with explanation is all that is required. And FDA Matters believes that "no" is the right answer.

FDA now encourages the use of alternative, non-animal tests for pre-clinical safety, but most drug and biologic applications rely heavily on animal data. But what's the big deal? Is "mandating consideration of alternative tests by sponsors" really much different from "encouraging sponsors to use non-animal alternatives?"

According to the animal rights organizations, the new language would reduce or eliminate "ineffective and costly animal testing methods that fail to identify the dangerous and lethal effects of drugs and devices on humans, and yet needlessly inflict pain and suffering on millions of animals each year."  And therein, their real agenda is revealed. They want to discredit animal research in order to force use of alternative tests. You can hear them shouting: get rid of animal testing, even if it means an increased risk to humans.

Thankfully, FDA doesn't see it that way. Along with other government agencies and industry, it is working on the development, validations, and utilization of alternatives to animal testing. But this is hard work and progress does not appear to be rapid. Meantime, unlike the activists, FDA believes that animal testing provides critical information that could not be gotten any other way.

In an earlier column, I wrote that animal research and testing is one of FDA's (unacknowledged) core values. Using animals to gain insight is a vital first step in the development of new medical products. Before any safety or efficacy testing is permitted in humans, FDA must be satisfied with animal testing data submitted by the product sponsor. Pick any medical breakthrough and you will find animals were tested prior to humans.

Everybody should be for protecting the welfare of animals. Any means to lessen our dependence on research animals should be welcome. Animals should always be treated ethically and pain reduced or eliminated. The fewest number of animals should be used to reach a conclusion that can be relied upon.

There are elaborate arguments about whether animals should have rights or just have their welfare protected. For me, the choice is easy. I want a product or procedure tested in animals before it is given to me or my loved ones. I believe in protecting animals, but human rights come first.

In the face of animal rights activism, FDA seems willing to stand its ground. The FDA stakeholder community needs to "seize the day" and make clear where its stands. Those who benefit from animal research and testing (including consumers and patients) need to provide the manpower and financial resources to counter the animal rights movement in America and its threat to medical progress for humans.

The value of animal research in the life sciences is usually considered an NIH issue. FDA Matters believes that the FDA and its stakeholders need to be equally concerned.

Steven

The link to the FDA Law Blog article on the lawsuit is: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2010/04/fda-sued-by-animal-rights-advocates-and-ear-holistic-candle-advocates.html

My earlier column that relates to this topic:

Animal Research: One of FDA's Core Values

November 5th, 2009

Earlier this year, ABC's Nightline did a story about alleged abuses at the nation's largest primate research center. Fueled by this, the Great Ape Protection Act (HR 1326) now has 95 co-sponsors, compared to 29 sponsors on a similar bill in the last Congress.

The bill would virtually eliminate research using chimpanzees, even where there is no other animal model that could serve to predict safety in humans. This is a threat to animal research and, ultimately, to ourselves. The loss of chimpanzees would be a serious blow to research and would encourage animal rights activists to push for even more restrictions. Read the rest of this entry »

Clinical Trials: Gold Standard In Need of Improvement

There is an emerging crisis in the development of drugs, biologics and complex new medical devices. Clinical trials take too long, cost too much and often produce imperfect knowledge. Many promising medical products are not developed because of the difficulty and expense of proving safety and efficacy—a loss that is costly to society.

FDA Matters believes that the key lies in developing new approaches to generating rigorous data and analysis. Ultimately, this will require the re-invention of the clinical trial.

Clinical trials produce the knowledge that makes FDA approvals possible. Without them, we would all become test subjects in a dangerous game of medical trial and error. FDA (and patients) want a reasonable level of certainty about safety, efficacy and risk-benefit before medical products are marketed. Except in extraordinary cases, FDA should never be put into a position to accept less.

The clinical trial is, and must remain, the gold standard. To understand why, it is useful to look at another type of medical knowledge that is increasingly in vogue: analysis of real-world data. The Medicare Claims database would be an example. Another would be patient data compiled by large health plans. Analysis of real-world data sets is becoming a cornerstone of reimbursement policy and plays a significant role in comparative effectiveness determinations.

The supposed advantage is the ability to look at hundreds of thousands of patients and discern patterns that might not be seen in clinical trials. However, the association of data points tells us nothing about causality. It only signals where additional analysis is needed. Real-world datasets also lack rigor:

Real-world data sets → post-hoc analysis using uncontrolled variables + inconsistent definitions + incomplete data collection + questionable data accuracy

By comparison, clinical trials produce a wealth of reliable knowledge (albeit far from infallible). This can be expressed as:

Clinical trial data sets → prospectively-defined analysis using controlled variables + randomization of patients + double-blind protocol + placebo controlled + pre-defined standard for data collection and data integrity

"Prospectively planned" means a drug or device sponsor must declare in advance the precise findings that will determine whether the treatment caused a beneficial outcome. Sponsors are limited in their ability to go back afterward to "data dredge" for positive correlations that might be spurious. To some extent, all analysis of real-world data sets is data dredging.

"Controlled variables" means that the outcomes of patients in the clinical trial can be compared with some degree of reliability. In real-world data sets, you can never be sure.

"Randomization" and "double blind" work together to assure there is no bias in patient selection (e.g. putting healthier patients in one arm of the trial) and that neither patients nor medical staff knows who is getting the study drug.

"Placebo controlled" allows a reliable determination of the impact of treatment. Since some patients will improve regardless of whether they are getting treatment or placebo, treatment effectiveness is the differential between those who improve in one study arm over the ones who improve in the other.

"Pre-defined protocols for data collection and data integrity" assures that definitions stay constant and results from different trial sites and different investigators can be combined. In real-world data sets, no one has yet figured out why medicine is practiced differently in Boston compared to Hartford.

Taken together, these features of the clinical trial serve to produce reliable data that support a conclusion (or not) that the treatment caused the benefit. The challenge is to improve upon this gold standard while maintaining confidence in the results.

Future columns will explore how this might be done. Meantime, readers are encouraged to post their thoughts or send me their ideas.

Steven

Here are two earlier columns that partially address this topic:

Long-term Challenges Need Short-term Attention

December 13th, 2009

We are less than 7 months into the new Commissioner's tenure. Three or four years from now, she will be judged by whether she moved the agency forward in these areas. I think she has gotten off to a very good start, but there is immense amount of work still required. Read the rest of this entry »

Turning Data into Knowledge

June 2nd, 2009

Through statute and directive, FDA has been asked to collect, analyze, interpret and utilize massive amounts of data. This includes biological, clinical, adverse event, production and distribution data, medical and food product tracking, and the Sentinel system for early discovery of potential drug safety problems. The systems are not in place to do any of this, at least not at the required level of sophistication. Even if they were, sifting valuable information from background noise is extraordinarily hard. Read the rest of this entry »

It’s 12 Years of Data Exclusivity

For an updated analysis, go to the May 2, 2010 column: Data Exclusivity and Bio-Similars: Both More and Less Than It Seems.Read the rest of this entry »

On several occasions, FDA Matters has asked Congressional staffers: how many of the Senators and Representatives understand that the follow-on biologics debate is about the amount of data exclusivity, not market exclusivity? In reply, I always get a smile that confirms my suspicion.

The confusion is not limited to the Hill. The New York Times referred to "market exclusivity" in its article on industry winners and losers on the day of the key House vote. A prominent industry trade publication—whose staff clearly knows better—referred to "bullet-proof market exclusivity" in a story the next day. The San Francisco Chronicle got it right—perhaps because of the concentration of bio-pharmaceutical companies in the Bay Area.

None of this would matter if data and marketing exclusivity were similar to each other…or even of roughly equal value. They are not. The future of bio-similar products cannot be understood without grasping the difference.

Intellectual property (IP) protection comes in several forms—the more types you have for the longest possible time, the less likely you will have competition.

The most familiar is patent protection. You own a product, formula or process for a number of years set by law and subject to various other considerations. For example, Hatch-Waxman provides for patent extensions to cover part of the time that pharmaceutical products are delayed in regulatory review.

On the other hand, patents can be challenged both as to their legitimacy and when they expire, thus negating or shortening the patent. At the end of the patent's life, the product, formula or process is (at least potentially) in the public domain, available for copying.

Another form of intellectual property protection is market exclusivity. For a period of time, a regulatory approval agency (FDA) will not accept another application for the same drug and indication. The best-known example is the seven years of market exclusivity granted to orphan drugs.

Market exclusivity runs independently from the patent. It can also protect the ability to market a product that is unpatentable or for which the patent has expired. With some exceptions, market exclusivity cannot be challenged in court….meaning that there are situations where it is better than a patent. Note that market exclusivity is primarily about regulatory forbearance, not ownership.

Data exclusivity under the new law is about ownership of the safety and efficacy data that supported the reference (originator) product when it received regulatory approval. Specifically, for a period of 12 years, FDA cannot approve a bio-similar product using the data (owned by a different company) that supported the original approval.

Data exclusivity does not prevent a second company from generating their own data. Nor does it prevent FDA from deciding that a 200 person trial is sufficient when the original approval was based on 2000 patients. Further, the science of characterizing biological substances is likely to advance rapidly over the next few years, providing the potential for additional ways for a bio-similar product to satisfy FDA requirements.

Data exclusivity is valuable. The investment community's enthusiasm for the 12 years of protection is appropriate. However, patents and market exclusivity are extremely powerful barriers to competition….and data exclusivity is not.

In a future column, I will further explore the implications of these distinctions…particularly, my view that the new law will lead to significant growth in the biopharmaceutical marketplace for both innovator and bio-similar products.

If you are not a subscriber and don't want to miss that column and future analysis of FDA and bio-pharmaceutical issues, I recommend going to www.fdamatters.com to register for free updates.

Steven

Two earlier columns on this topic:

Follow-on Biologics: 1-2-3-GO

March 21, 2010

The long fight is over for follow-on biologic (FOBs). The Senate-passed version of health reform will become law, even while the larger fight continues over the reconciliation package. Within 10 days, FDA will be busy implementing an approval pathway for FOBs.

The world of biopharmaceuticals will never be the same, but not in the ways that many players expect. Here is FDA Matters' guide to understanding the next phase. Read the rest of this entry »

The Follow-on Biologics Market
June 23, 2009

Since the debate began several years ago, the policy and politics of follow-on biologics (FOB) have been driven by assumptions and projections of the anticipated market. There has been a lot of fuzzy thinking about what type of companies will be players and how they will position themselves. Read the rest of this entry »

Wrestling for the Soul of FDA

User fees are acceptable if they pay for processing passports or extra services at national parks. I don't worry that the American public will lose confidence in the State Department or the National Park Service. This doesn't translate to every user fee and every government department.

User fees are a bad way to fund FDA, a public health regulatory agency that oversees nearly a quarter of all consumer spending. It's not that user fees are corrupting. FDA is capable of making good and bad decisions without regard to where the money comes from. But user fees have the potential to erode public confidence in the agency.

FDA Matters gets it. The agency needs more money to fulfill its mission and the Congress won't pay for all of the costs. In FY 10, nearly $700 million came from user fees charged to drug and device manufacturers and a few others. (This total and the remaining discussion omit tobacco user fees. No one thinks tobacco companies are getting favorable treatment for their monies!).

FDA received $2.345 billion from public funds in FY 10, more than three times the amount from user fees. It would take a long-time and a lot of user fees for the overall balance in the agency to be threatened.

The real story (and the worry for the future of the rest of the agency) is the Center for Drug Evaluation and Research (CDER). It receives about $750 million to run the drug approval process and other CDER activities (other than inspections and enforcement). Of that total, about $335 million comes from public funds (45%); $415 million from user fees (55%). How can it be good for industry to provide the predominant funding for CDER or any of the other FDA centers?

Nothing wrong is occurring. But the overreliance on user fees is confidence-eroding for Congress, media and the American public…and dispiriting for FDA staff.

Now is the time to raise and debate these issues.

• FDA has begun the public hearing process for the next drug user fee act (PDUFA V). Another round of user fee increases could push CDER into even greater dependence.
  
• The appropriations committees have started consideration of the agency's FY 11 appropriation. Under the President's request, existing user fees (excluding tobacco and proposed new fees) will grow about 15%, while public funds only 6%.
  
• Congress may pass new food safety legislation and the House version includes $220 million in new user fees to pay part of the costs of new responsibilities. This is about 20% of the food monies in the President's FY 11 budget request. This percentage could increase if Congress doesn't provide several times this amount from public funds to implement the law.
  

For fiscal and political reasons, user fees are here to stay and FDA will never be funded entirely from public monies. This should not blind us to the risk of FDA slipping into dependence on user fees. Nor should it blind us to how user fees are a drag on public confidence in FDA.

I believe that FDA, regulated industries, Members of Congress and other stakeholders agree with FDA Matters. Yet, you are unlikely to hear them say so. Each fears that FDA would shrink without user fees. Someone needs to go first and say: we will find public monies to keep FDA from becoming dependent on user fees.

The soul of the FDA may not be at stake. But we should not underestimate the damage to the agency from a public perception that user fees are darkening its soul.

Steven

At the March 10, 2010 House Appropriations Committee hearing, Commissioner Hamburg addressed the relationship between user fees and FDA decisionmaking:

…. [E]xamining the integrity of our decision making and ensuring that it is free from conflict of interest and other concerns is one of the most essential elements of FDA being able to do its work, being able to have the trust and confidence of policy makers and the public and certainly one of my highest priorities.  So we take it very seriously. We have established firewalls in terms of the use of user fees. We are committed to a science-driven decision making process, and it's a dynamic concern. We can't just sit back and say our systems are in place, move onto the next issue. It's something we have to continually be monitoring, continually responsive to concerns as they're raised and ensuring that we have the right checks and double checks.

My earlier blog column on this topic:

It's Time to Change CDER Funding

    September 17th, 2009

As most readers know, bio-pharma companies pay user fees, based on activities (such as submitting a New Drug Application) and on the number of their manufacturing facilities. The amounts are set by law. As part of the arrangement, FDA agrees to certain performance goals, which are also specified in law.

We often hear how dependent CDER is on user fees. The actual numbers are startling and deserve to be well-aired. Read the rest of this

Messages to the FDA-Regulated: Seven Columns to Re-read for 2010

This past year has been a tumultuous one for FDA-regulated industries as they struggled to provide new and safer medical products and safer foods, while weathering much criticism.

FDA Matters has explored a number of industry issues in 2009. As they evolve in the new year, I will continue to provide readers with my analysis and commentary. Meantime, here are seven columns that provide insight about FDA-regulated companies. They provide useful background for 2010:

The Follow-on Biologics Market

Since the debate began several years ago, the policy and politics of follow-on biologics (FOB) have been driven by assumptions and projections of the anticipated market. There has been a lot of fuzzy thinking about what type of companies will be players and how they will position themselves. Read the rest of this entry »

"No Surprise" That Medical Devices Are Under Scrutiny

My column entitled, "Re-Evaluating the Medical Device Approval Process" was not widely-read. I assumed it was because everyone already knew that a review was underway at FDA with more activity coming. Apparently, I was wrong. Read the rest of this entry »

The Beatings Will Continue…

….until the biopharmaceutical and medical device industries clean up their act.

It has been an expensive year for pharmaceutical companies. Billions of dollars have been paid to federal and state governments and whistleblowers in settlement of allegations and lawsuits. The complaints include off-label marketing and overcharging Medicaid, but there are many others. Read the rest of this entry »

Patients Come First

It is a distracting time for the biopharmaceutical and medical device industries. All this frenzy makes it a good time to stop, draw a breath and remember why seriously-ill patients care about the success of biopharmaceutical and medical device companies. Read the rest of this entry »

Black, White, Shades of Gray

Civil and criminal investigations are becoming more prominent in the world of FDA-regulated industries. Being FDA-regulated means "always worrying that you will have to say you're sorry." But it matters whether you are apologizing to FDA or trying to apologize to investigators. Read the rest of this entry »

FDA: Invisible Arbiter of What Constitutes Disease

The nature of disease and constantly changing definitions are pertinent to FDA, which often makes decisions on behalf of society that reshape our understanding of disease. Read the rest of this entry »

Internet Communications: FDA Needs to Divide the Issues to Conquer the Problem

Creating an Internet communications policy for regulated medical product companies is so daunting that FDA has largely ignored the responsibility. FDA needs a different approach. This is not a matter of a large, complicated problem with many facets. Rather, it is a number of smaller problems that can be addressed separately. Read the rest of this entry »

Steven

Scientific Reductionism and the End of Medicine

"For the last 400 years, science has advanced by reductionism ... The idea is that you could understand the world, all of nature, by examining smaller and smaller pieces of it. When assembled, the small pieces would explain the whole." (John Holland).

Have you ever heard someone accused of "reductionist thinking?" You probably will in 2010 because scientific reductionism is a critical, but rarely articulated, foundation of personalized medicine.

Reductionism is an attempt or tendency to explain a complex set of facts, entities, phenomena or structures by another, simpler set of constituent parts. Historically, scientific reductionism has held that all biology can be explained in terms of chemical reactions. In turn, these chemical reactions can be explained at the atomic level by physics.

An example of scientific reductionism is the belief that a blueprint for understanding and curing all disease will result from mapping genomes (human, bacteria, etc.). In effect, the complexity of biology ultimately yields to a much simpler paradigm based on de-coding the meaning of each component in the human genome and then delivering medical therapy personalized to the individual's genetic make-up. To oversimplify a little, biology then becomes a predictable "machine," subject only to additional reductions that yield smaller pieces and even more insight.

In contrast, many scientists believe that the complexity found in biology is more than just the inability of scientists to simplify the tangle of life and disease. No matter how much we know about genomic causation and associations, we will never have a full picture of life nor unlock the secrets to all diseases. These scientists believe that life is more than the sum of its parts. To them, reductionism is not wrong; it just produces an incomplete vision of biology because it cannot account for systems effects. A new field, systems biology, is trying to develop ways to understand the complex, irreducible biological qualities of life.

FDA Matters views scientific reductionism as a source of actionable knowledge. But just as the book, "The End of History," was more provocative than predictive, there is no "end of medicine" where human biology is reduced to the point of near-total knowledge and flawless cures.

Thus, personalized medicine will not defeat biological complexity. Further, the reductive process will incorporate knowledge from the human genome, but then take us past it into even more difficult and unpredictable challenges to understanding biology and curing disease.

Meantime, public policy is being shaped by the belief that biology and medicine will eventually yield answers that are concrete and totally reliable. But even when personalized medicine provides better targeted therapies, there will still be phase II and phase III clinical trials that inexplicably fail to show patient benefit. After approval, even the most well-documented and logical therapies may prove harmful and require modification or recall. FDA will need to constantly manage the expectations of Congress, the media and the general public to be sure that they understand that no amount of knowledge or evidence renders a medical therapy certain or riskless.

One prominent futurist has said: if we can just live long enough, progress in medicine will allow us to live forever. I say: not so.

The nature of medicine will be quite different 20 years from now, but unpredictability will still be common. As we develop vast amounts of new biological and medical information, old uncertainties about diseases and drug development will be resolved. New uncertainties will emerge.

Steven

Off-Label Uses Need to Become On-Label Indications

A friend asked: what advice would you give a pharmaceutical company in the late stages of developing a new product that will be widely used off-label? The company's concern was that FDA might hold the first use to a very high, perhaps unrealistic standard to protect patients that might receive the drug off-label after approval.

In thinking about how FDA views this type of situation, I realized there were two very concrete things the company could do. Here is the FDA Matters analysis:

FDA controls the availability of prescription medicines and devices in the US. It does not control the practice of medicine. Once a drug/device is approved for marketing, any doctor can prescribe it for an indication that is not on the label of the drug or device. For example, narcolepsy drugs are often prescribed to enhance concentration and wakefulness in individuals without the disease.

The agency is remarkably positive about deferring to the professional judgment of physicians. Even still, FDA's mission is to protect the public health. It would like to see every off-label indication get the scrutiny necessary to assure it is safe and efficacious.

One of FDA's great fears is that off-label prescribing will become dominant in clinical medicine (as I am told it has in certain areas of oncology). FDA is concerned that companies will get approval for a first use, then (directly or subtly) encourage doctors to prescribe off-label. If this strategy is profitable, FDA worries that fewer and fewer companies will commit the time and money to get approval for additional indications. If a company can't promote off-label, then it is more likely to invest in clinical trials to gain approval of the additional indications.

There are two components to FDA's concerns.

First, does the company intend to do the studies to support additional indications for their product? FDA has been promised much by companies and often receives very little back.

Companies can address this FDA concern by having a clinical trial plan in place for any additional indication(s). Where FDA will permit subsequent trials to be initiated prior to first approval, doing so will further strengthen the company's case. A clear commitment to seek FDA approval for additional indications will reassure the agency that the first indication should be judged on its own merits; not elevated to a higher level by the agency's angst about subsequent off-label use.

Second, will the company try to build the market by promoting the off-label uses? By all appearances, companies often decide that off-label use will be so profitable and supplemental indications so expensive that it does not "pay" to do clinical trials for additional indications. And since companies have paid billions of dollars in fines over the last few years for off-label promotion, FDA assumes that such marketing will occur.

The path is open for a company to announce that they will be implementing the strictest possible controls on marketing and sales practices to prevent promotion of off-label uses of their product(s). In the case of a first approval of a product with multiple uses, such an announcement could assuage FDA's fears that the first use is the only indication that the company will seek.

There is a larger issue here, apart from the strategic and psychological aspects of getting a first approval for a specific product.

Getting more indications on-label should be a public health priority. FDA and industry need to discuss how to accomplish this.

Steven

Two prior columns touched on off-label use and off-label promotion:

Internet Communications: FDA Needs to Divide the Issues to Conquer the Problem
December 2nd, 2009

Creating an Internet communications policy for regulated medical product companies is so daunting that FDA has largely ignored the responsibility. November's FDA hearing on social media was an important step, but offered no sign that new policy will be announced anytime soon.

FDA needs a different approach. This is not a matter of a large, complicated problem with many facets. Rather, it is a number of smaller problems that can be addressed separately. Read the rest of this entry »

Off-Label Promotion and Whistleblowing
September 9th, 2009

Whistleblowing and off-label promotion of drugs and devices have become hot topics because of the September 2 Pfizer settlement with the federal government. While none of my views are specific to Pfizer, the company's settlement provides an opportunity to comment on off-label promotion….and to encourage bio-pharma and medical device companies to engage in deeper soul-searching. Read the rest of this entry »

Long-term Challenges Need Short-term Attention

Most current readers of FDA Matters were not receiving these posts during June, when we examined seven long-term challenges for FDA. Some of these challenges may take years to accomplish; all need to be started now.

We are less than 7 months into the new Commissioner's tenure. Three or four years from now, she will be judged by whether she moved the agency forward in these areas. I think she has gotten off to a very good start, but there is immense amount of work still required.

Here are the seven challenges:

Integrating new science into traditional clinical trials. Constructing real-world clinical trials has never been more difficult. In many clinical areas, we are moving from targeting disease symptomology toward a new paradigm of altering fundamental biological processes. These issues need a broader, more systemic examination. More resources need to be applied to Critical Path and other clinical trial improvement initiatives.

Balancing safety with patient risk and need. All FDA approvals represent a balance between risk and benefit. There is a lot of variability in what the agency views as acceptable risk for patients with life-threatening conditions. There may be even more variation in their response to the needs of patients with severely disabling conditions that are not life-threatening.

In most FDA activities, medical and scientific expertise and insight is the key to decisions. Creating better risk-benefit judgments is different: patients are the experts on what they feel and believe and on what risks they would accept for what benefit. Meaningful dialogue requires that patients lead this process, not be an afterthought.

Sifting valuable information from background noise. Through statute and directive, FDA has been asked to collect, analyze, interpret and utilize massive amounts of data. This includes biological, clinical, adverse event, production and distribution data, and medical and food product tracking. FDA lacks the sophisticated systems it needs. Once these systems are developed, it is still a difficult, highly iterative process to distinguish meaningful patterns from background noise and to create actionable intelligence.

Managing globalization, rather than just responding to it. There needs to be a comprehensive, multi-year plan for managing globalization, including a budget for Congress to consider and fund. Tomorrow's problems need to be identified and addressed before they become even bigger issues. Food and drug tracking, recall authorities and overseas offices are necessary, but they are not sufficient to meet this challenge.

Resisting the bias toward negative decisions. Uncertainty is inherent in all positive decisions. Taken to the extreme, excess caution could force the whole world of food and drugs to slow down, and then stop. The correct balance is not achieved by a memo or a speech, but by day-to-day actions and enhanced communications. Systematic review of all decisionmaking processes could be an important corrective.

Staying focused on priorities. FDA's responsibilities greatly exceed its resources. Some mission creep is inevitable and some new responsibilities may be needed to benefit society and the public health. But sometimes FDA needs to say "no." Such moments are difficult. "No" will never be accepted by policymakers or the public unless FDA is clearer in defining, justifying and explaining its priorities. This must be addressed comprehensively.

Keeping the Best and the Brightest. FDA cannot succeed without a high-quality and committed workforce. Public service is an important attraction of working at FDA. It cannot be allowed to go out of style. Increased appropriations provide the opportunity to rationalize workloads, reduce burn-out, and build morale.

Do you have items you would add to this list? If so, post comments with your suggestions…or e-mail me at sgrossman@fdamatters.com.

Steven

The Perils of Living in a Bubble

This past week, the US Preventive Services Task Force (USPSTF) issued its revised recommendations for breast cancer screening and mammography and set off a firestorm of criticism. Among the controversial items was changing initial mammography screening from 40 to 50 years of age, recommending mammography every two years instead of one, and urging an end to the teaching of breast self-examination.

There is a valuable lesson for FDA in how the announcement and aftermath unfolded.

FDA Matters is amazed at how unprepared the Task Force seemed to be for criticisms from individual patients, health professional groups and Members of Congress. It is as if they were unaware of how much comment, confusion, and dissent their views were going to generate. The Agency for Heathcare Research and Quality (AHRQ), which provides support for the Task Force, seemed no better prepared.

There may be a number of reasons why the Task Force didn't see the need to prepare better or didn't care about the responses they would receive. One possibility is that the USPSTF is made up of primary care doctors and statisticians and doesn't reflect the broader perspective of medical specialists, who provide much of the nation's care.

There is also a deep schism between those relying on statistical modeling (such as the Task Force) and those believing that common sense, patient need and clinical experience should be weighed before decisions are made. Ultimately, the Task Force conducted its business in a bubble, isolated from public discourse and perceptions and with no accountability to the women whose lives will be impacted.

In contrast, the American College of Obstetrics and Gynecology (ACOG) released its recommendations later in the week, calling for less frequent screening for cervical cancer and for screening to be initiated at a later age. Their views received appropriate attention, but generated very little controversy.

ACOG supported their position with analyses that pointed to when and how cases are identified in this slower growing cancer. They documented clinical consequences (not just cost impacts) of additional unneeded diagnostic and treatment activities. Clearly, they had engaged practitioners and other organizations in their process…and had taken their input seriously.

There is a constant tension between high-minded decisions and the realities of clinical diagnosis and care. FDA must balance these every day. Some days they do better than others.

Risk Evaluation and Mitigation Strategies (REMS), a relatively new FDA patient safety and communications initiative, represents an area that will constantly challenge the agency's ability to balance stringent purity with "real world" practicality. Under a REMS agreement with a biopharmaceutical company, FDA tries to assure that the risks of approved products are properly communicated to healthcare professionals and patients and that systems have been put into place to reduce potential adverse events and treatment failures.

To date, most REMS programs appear to reflect the complexity of drug information and distribution. Greater challenges lay ahead….and FDA may struggle to communicate its decisions and rationale well.

If FDA lives in a bubble, unprepared for people's perceptions and needs, then REMS will become a major area of controversy. As ACOG demonstrated this week, it is possible to communicate the value of new approaches to good medicine, without losing sight of what is understandable and useful for patients.

I think that Drs. Hamburg and Sharfstein have made a good start at opening up FDA's insular world. Their experiences in running big-city health departments have taught them to value real-world solutions, geared to the majority of Americans who live outside the bubble and want to understand decisions that affect them.

Steven

FDA: Invisible Arbiter of What Constitutes Disease

According to Wikipedia, "disease" refers to any condition that causes pain, dysfunction, distress and social problems. (http://en.wikipedia.org/wiki/Disease). What constitutes disease is more varied and changeable than this definition might suggest.

The nature of disease and its constant changes are pertinent to FDA, which often makes decisions on behalf of society that reshape our understanding of disease.

Some diseases are culturally-defined. Homosexuality has long been treated as a disease or medical disorder. Scientific knowledge and societal attitudes have shifted over the last 25 years. Homosexuality is increasingly viewed as a variation on human behavior, rather than a disease or condition. FDA would never consider an "anti-homosexuality pill."

In the opposite direction, obesity has long been a symbol of wealth and well-being. Today, it is being redefined as a disease, complete with claims that it is an epidemic. FDA decided obesity was a "disease" years ago and has considered a number of "anti-obesity pills."

Other diseases reflect new thinking about what constitutes illness. Examples would include post-traumatic stress disorder, attention-deficit hyperactivity disorder and restless leg syndrome. FDA has approved drugs that treat each of these.

The Food Drug and Cosmetics Act provide the agency some leeway in how it looks at disease. The term "drug" means, among other things:

• "articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and
  
• articles (other than food) intended to affect the structure or any function of the body of man or other animals." (FD&C Act, Section 201(g)(1)).
  

This dual definition has allowed the agency to finesse the issue of pregnancy. I assume that birth control and fertility drugs are viewed as affecting the structure or function of the body. The agency would not want to claim that pregnancy is a disease or that preventing (or causing) it constitutes disease treatment.

FDA seems to make these judgments without any fanfare. My own benchmark is the formalization of erectile dysfunction (ED) as a disease. I expected FDA to go through some extra, visible steps, to show that it had considered whether ED was a disease for which therapies were appropriate. I did not see this occur during the FDA review or at the time of approval.

The question "is this a disease" doesn't come up every day at the agency. When FDA does make judgments, it appears embedded in the work rather than a notable event.

One of the great future challenges will be for FDA to decide if "anti-aging" drugs are possible. The answer may be "yes," pointing to the function and structural changes that are clearly made by aging and the opportunity to stabilize and reverse them. This would allow anti-aging to be a drug's formal indication for prescribing and would be allowed as a label claim.

If "no," then sponsors of anti-aging drugs will need to show a direct link between their drug and an aging-related disease, such as diabetes or dementia. My understanding is that most anti-aging pipeline drugs are being developed on the assumption that FDA is not ready to decide and that "anit-aging" may never be an approved indication.

When the aging issue becomes timely, FDA will be there to decide. It will bring more experience to the process than most FDA watchers realize.

Steven

Personalized Medicine in Perspective

We are told that personalized medicine will transform drug development and bring about the end of blockbuster drugs. If you believe the hype, this will all happen soon. More realistically, personalized medicine is at least a decade away from having any substantial impact. Blockbuster drugs are not going to disappear anytime soon.

"Personalized medicine" involves managing a patient's healthcare with therapies based on patient-specific characteristics. It is often defined as part of genomics, although there are and will be non-genomic therapies that fit within personalized medicine. Personalized medicine is seen as individualized treatment and "the future of drug development."

In contrast, most of our current therapeutic options are drugs and biologics intended for large cohorts of patients. This creates a focus on developing "blockbuster drugs" that will be used by hundreds of thousands and even millions of patients. It is said that the rise of personalized medicine will bring an end to "the era of blockbuster drugs."

To understand the status of personalized medicine, it is instructive to look at the history of biotechnology. As with all great transformative achievements, latecomers might imagine that success was inevitable and progress was smooth and relatively trouble-free. The reality has been quite different.

Biotechnology began in confusion, uncertainty and opposition. In 1975, the scientific community gathered at Asilomar, CA to consider the future of biotechnology. They were operating in an environment of apprehension and believed restrictive legislation might be adopted. In part because of principles, guidelines and restrictions adopted at Asilomar, biotechnology lasted just long enough to quell the worst fears that uncontrolled experiments might change the fundamental nature of man, animals and plants.

Here is my history of how biotech developed into a force:

• Rocky childhood (1970's)
  
• Became "the next big thing" (1980's)
  
• Finally had a significant impact (1990's)
  
• Some biotechs mature and big pharma swallows small biotechs for their knowledge, capacity and pipeline (2000's)
  

Notice that there is almost 20 years between childhood and impact. Fortunately for the health of the American people, biotechnology still has plenty of room to grow.

I expect something of a similar pattern for personalized medicine. The movement is, at best, in late childhood. It is not yet the "next big thing," except rhetorically. It will be at least 2020 before more than a handful of products are making an impact….and we can't know whether it will be a significant impact. The death of the blockbuster is at least 10 to 15 years away and may never occur.

One expectation is that genomic information will spur "drug development by design." This will allow the discovery of better drugs more quickly and with many fewer developmental failures. This is a much harder road than it may seem. History shows us that clinical trials can fail, sometimes quite miserably, just when everyone is most sure that the solution is logical and success guaranteed. The human body is almost always more subtle than we can discern, even with the best tools.

Deservedly, there is lots of excitement about personalized medicine. It will eventually transform drug development. However, as you read and listen, remember that:

• excitement is not the same as impact, and
  
• investment is not the same as success.
  

Steven

FDA and NIH: Natural Allies

Tension between CMS and FDA is a fact of life at HHS. This is not surprising because they have fundamentally different missions and world views. An analysis of the FDA-CMS relationship leads to an interesting conclusion: FDA should be doing a lot more with NIH because they have complementary missions and similar world views. They are natural allies.

FDA's mission is the approval of safe and effective therapeutic agents. It believes that actionable knowledge comes from prospective, randomized, double-blind controlled clinical trials. Its view of individualized patient treatment: it should be based on the results of rigorous clinical trial information. Yet, they do not impose this on physicians, who may practice medicine as they see fit. FDA will consider information from observational trials, natural history controls and medical literature, but these generally supplement information derived from clinical trials.

In contrast, CMS' mission is to pay for the health care of individuals eligible for coverage through statute. They try to assure health care access that maximizes quality and minimizes public cost. To them, actionable knowledge is retrospectively derived: therapies approved by FDA and treatments reviewed favorably in compendia and having support in a broad cross-section of medical literature. Increasingly, CMS is interested in supplementing these sources with more retrospective data: population studies and analysis of claims data and electronic medical records. Ultimately, CMS' target population is beneficiaries, not patients. Knowledge about the needs of classes of beneficiaries is usually thought sufficient without reference to individualized needs.

While my FDA vs. CMS comparison involves some sweeping generalizations, it also explains a lot of behavior. For example, CMS kept offering its Medicare claims data to FDA and, for a long time, FDA wasn't interested. FDA has now accepted the Medicare data from CMS. However, the dialogue will always be limited by CMS' perception that they are giving FDA an extremely valuable tool and FDA's perception that it is potentially useful, but of limited value. As noted in an earlier post: FDA believes that retrospective "real world" data sets = uncontrolled variables + inconsistent data collection + questionable data accuracy. In short, nothing that FDA would base a safety or efficacy decision on…unless it had no choice.

If you look at what type of knowledge counts to FDA, its natural ally is NIH. They both believe in the virtue of prospective clinical trials as the basis of actionable knowledge. NIH generates more clinical trials—directly or through grants—then any other entity in the world.

FDA and the National Eye Institute provide a model of cooperation that should be fostered FDA-wide and NIH-wide.  NEI had started to work with endpoints based on medical imaging and biological evidence of disease progression. FDA's standard endpoint was still: how many lines on an eye chart had the patient improved or regressed. From working together, both NIH and FDA have advanced knowledge in the field and moved closer to standards appropriate for an increasingly sophisticated therapeutic area.

NIH-funded trials often have to be re-done because FDA won't accept the endpoints or some other aspect of the clinical trial design. In many of those instances, NIH should be running trials with different endpoints to advance clinical knowledge or validate those endpoints. Many times though, early coordination would reduce the chances that expensive trials will need to be repeated….and patients might get beneficial therapies quicker.  A high level of coordination should be possible because NIH and FDA share similar values about the importance of knowledge derived prospectively. There are differences between them, but they are ones of degree, not kind.

Access to Experimental Drugs: Hard Cases Make Bad Law

I oppose open access to early-stage therapies. However, hard cases make bad law. This was amply demonstrated by the riveting front-page article in Sunday's New York Times, "Months to Live: Fighting for a Last Chance at Life." This is a must-read for anyone concerned about terminal illness or early access. Definitive rules are hard to develop, especially while heart-strings are pulled hard.

The reporter, Amy Harmon, follows the agony of a family whose son/husband/father has ALS (amyotrophic lateral sclerosis). There is a product previously on the market for a different use that allegedly provides relief from progression of the disease. Unfortunately, the firm that was developing it was restrained by a patent settlement. The company that won the patent dispute did not want to acquire responsibility for a population/use it had no intention of serving.

As is usually the case, FDA was torn between compassion today and assuring that clinical trials can still be undertaken in the future. The two companies and FDA also know how rare it is for internet-hyped medicine to prove useful.

To the reporter's credit, she doesn't blame either of the companies or FDA. The story is impactful and honest in chronicling the family's frustration--without choosing good guys and bad guys.

I have had my own lessons in this. It was a crisp New England morning almost 20 years ago. I was helping a company prepare for a "shut the plant down" demonstration by AIDS activists determined to gain access to an experimental therapy. The drug had never been tested in humans. Nor, as I recollect, did it have significant animal testing to back it up.

Given these factors, it seemed like a particularly poor choice for early-access. Understandably, the activists saw this as a dire situation where taking on extraordinary risks was a choice they should be able to make for themselves. There are no good guys or bad guys in this type of situation.

The ALS situation is more nuanced than the one I faced 20 years ago. There appears to be safety data, but probably not at the dose levels that ALS patients would use. There is anecdotal support for the drug's use, although such reports are notoriously unreliable. The ALS case does not necessarily raise what I consider a fundamental issue: should totally untried drugs be available on open access.

Generations of law students have been taught: hard cases make bad law. This certainly applies here. And FDA can never win. One recommendation would be to upgrade the review function and include some outside ethicists and scientific advisors in the process. However, the publicity that would come from doing so might have the effect of doubling or tripling the number of requests, many totally baseless.

The NY Times logged 165 comments in less than 2 days. Clearly the story (and the underlying issues) touched people. What advice would you give FDA in handling demands for early access where there is some data, but not enough to be sure of anything?

The article and the comments posted to NYT website: http://www.nytimes.com/2009/05/17/health/policy/17untested.html
http://community.nytimes.com/article/comments/2009/05/17/health/policy/17untested.html?nl=health&emc=a7