FDA’s Fuzzy Funding Future

While not all of FDA’s problems are caused by a lack of resources, few of its problems can be solved without better funding. Money matters. “Safer foods” requires funding to implement the Food Safety Modernization Act. “Faster and safer drug and device approvals” are only possible with funds to pay additional reviewers and build improved regulatory systems.

FDA has an enormous job and its responsibilities grow every year. Funding increases over the last five years have not offset decades of underfunding and under-investment in the agency. FDA Matters believes the next 12 months will determine FDA's funding future.

The Outlook for Appropriations. FDA’s FY 12 funding is now set. The agency will have $50 million more to spend this fiscal year, for a total of $2.5 billion. While this increase is not large, FDA did quite well in the face of a possible $285 million cut. The agency was one of the few federal programs to receive more dollars than in FY 11.

 It’s too early to project next year’s appropriation. The President’s FY 13 request will be released in early February 2012. Because the Budget Control Act (BCA) of 2011 requires aggregate domestic discretionary spending to be lower than FY 12, competition for funding will become even more intense. Congress will need to be persuaded that FDA funding is a priority and needs to be an exception to funding constraints.

Also as a result of BCA, there is a very real threat to FY 13 FDA funding, as part of mandatory across-the-board cuts (“sequestration”) scheduled to take place on January 1, 2013. Unless Congress passes substantial deficit reduction legislation next year in lieu of sequestration, FDA must prepare for a possible cut in the range of $150 million to $250 million.   

Prospects for User Fees. In addition to appropriations, the Prescription Drug User Fee Act (PDUFA) provides FDA with supplemental funding from industry to support review of applications for new drugs and biologics. A similar program (MDUFMA) supports review of medical devices. There are also several smaller fee programs, as well as user fees that support the FDA’s tobacco center.  This chart shows the amount and growth of revenue derived from industry fees:  

All numbers approximate	FY 2009	FY 2010	FY 2011
PDUFA	$    512 million	$    573 million	$   667 million
MDUFMA	$      47 million	$      57 million	$     57 million
TOBACCO	------	$    235 million	$   450 million
All Fee Revenue (inc. smaller programs)	$    637 million	$    922 million	$ 1.224  billion

PDUFA and MDUFMA are expected to be renewed in FY 12 with higher revenue targets. With so much pressure on appropriations, Congress will be tempted to see user fees as the answer to FDA’s growing funding needs. However, user fees are only available for specific purposes and do not support FDA’s full mission.

Further, Congress has no qualms about increasing the amount of user fees, then bemoaning the agency’s increasing reliance on industry funding.  This is not a situation where “all money is green.” Increases in appropriated funding are still critical to a well-functioning FDA.

Delays in Enacting User Fee Legislation and the Possible Impact of Unfunded Mandates. FDA’s future funding is further obscured by the nature of the process of renewing the user fee programs. For example, delays in adopting legislation could result in funding shortages in early FY 13, making it harder for FDA to fulfill its obligations. In turn, this will contribute to Congressional concerns about whether FDA is spending monies efficiently and effectively.

Further, Congress “must pass” renewal of user fee programs in 2012, creating a situation where multiple FDA-related amendments are certain to be considered. Such amendments, if they become law, are likely to expand the agency’s responsibilities without adding additional funds for implementation.

Steven

Here are November 2011 columns you may have missed:

Animal Research: An Update on One of FDA’s Core Values     November 22nd, 2011

Bold Discussions: Possible New Approval Pathways for Breakthrough Drugs November 14th, 2011

By Whose Standards: FDA’s Identity Crisis and the Level Playing Field  November 7th, 2011

Animal Research: An Update on One of FDA’s Core Values

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

Animal research is the 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.

For understandable reasons, we tend to focus on the human part of new products. Which patients will be helped and by how much? By the time a company files a New Drug Application (NDA) or the equivalent in biologics and devices, the headline is the human data. While the animal data is always relevant, it has largely served its purpose as the gateway for human trials.

We talk about the people part without recognizing that the pipeline of innovative drugs and devices would collapse if a broad range of research on animals (e.g. non-human primates, pigs, sheep, dogs, rats, mice, zebrafish, fruit flies, worms) was heavily restricted. Over 96% of the animals used in biomedical research are rodents, birds, fish and invertebrates. As background, there is an excellent summary on the need for animal research available from the advocacy organization, Americans for Medical Progress.

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. Laboratories should be accredited and subject to inspection. Problems should be addressed within a facility under the watchful eye of government, accrediting and licensing agencies and in accordance with the Animal Welfare Act.

Since I last wrote on this topic two years ago, the nature of the animal rights movement in the United States has shifted. Successful prosecutions under the 2006 Animal Enterprise Terrorism Act (AETA) have purged some of the more violent elements of the movement and discouraged others from engaging in destructive acts. However, a small number of activists still use tactics of harassment, intimidation, and vandalism against some research scientists and veterinarians involved in working with laboratory animals.

Many of the research advocacy groups say a greater threat to medical progress is proposed state and federal legislation, often authored by animal rights lobbyists, that has little to do with animal welfare but rather seeks to restrict or raise the cost of animal-based research. An example is The Great Ape Protection and Cost Savings Act legislation, which continues to draw strong support in Congress. As of April 29, 2012, the House version (HR 1513) has 165 sponsors and the Senate version (S 810) has 14 sponsors.  

These bills would virtually eliminate chimpanzee research, which includes work in vaccines, hepatitis, HIV/AIDS, malaria and some types of cancers. Although we use only a comparatively small number of chimpanzees in animal research, I am told that the work often provides essential information that cannot be obtained in any other way.

While the legislation is purportedly about animal welfare, these bills are really designed to limit the biomedical research that we all support and which, we hope, results in FDA-approved medical products.

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.

The importance of animal research needs to be a core value for FDA. Those who benefit from animal research (including patients and industry) need to provide the manpower and financial resources to counter the animal rights movement in America and its threat to medical progress for humans.

Steven

Bold Discussions: Possible New Approval Pathways for Breakthrough Drugs

For discussion purposes, let’s assume that there is a broad consensus that patients would benefit if new drugs and devices could get to the US market sooner. Current market barriers can be fearsome: long timeframes, high cost and regulatory uncertainty.  How can we fix this problem? What costs and risks are involved in getting products to patients faster?

These are old questions, renewed this year by the Biotechnology Industry Organization’s (BIO) proposal to create a “progressive approval” process. This is controversial, but also worthy of widespread discussion. FDA Matters finds itself interested and open-minded about ways to permit earlier market-access if patients will benefit and the safety risk minimized.

Currently, FDA has several mechanisms for helping drugs move faster through the approval process, but only one might be said to be an alternative pathway. FDA describes it as follows:

ACCELERATED APPROVAL:  [I]n 1992 FDA instituted the Accelerated Approval regulation, allowing earlier approval of drugs to treat serious diseases, and that fill an unmet medical need based on a surrogate endpoint….For example…FDA might now approve a drug based on evidence that the drug shrinks tumors because tumor shrinkage is considered reasonably likely to predict a real clinical benefit [e.g. prolonged survival].

Since creation of the program, FDA has granted an average of about four accelerated approvals to drugs each year, sometimes for more than one clinical indication. More than half of these indications have been shown subsequently to have clinical benefit and FDA has converted the approval from accelerated to regular. Others accelerated approval drugs are still being studied and a few have been withdrawn.  

FDA has itself shown interest in moving beyond accelerated approval. Early this fall, FDA released a report, Driving Biomedical Innovation: Initiatives to Improve Products for Patients. In a section entitled “Expedited Drug Development Pathway,” the agency observes:

Sometimes during the development of a new drug to treat a serious or life-threatening disease that has few therapeutic options, the new treatment performs much better than standard-of-care in the early trials. While there is general agreement that such a drug should be developed quickly, there is not a common understanding of how to appropriately speed up development while simultaneously gathering adequate evidence about the performance of the product.

FDA envisions a series of meeting with stakeholders to develop this concept and answer a number of difficult questions about the nature of a new pathway and how it could be implemented.

Consistent with this, BIO had already been talking about transforming the FDA approval process by permitting a “progressive approval” and market access for innovative products that:

• treat an unmet medical need,
• significantly advance the standard of care, or
• are highly targeted therapies for distinct sub-populations.

The November 11, 2011 BioCentury reported that Senator Kay Hagan (D-NC) will be circulating draft legislation to create two new FDA approval pathways, presumably beginning the process of providing details for BIO’s concept. Here are the new approaches:

• Progressive approval would require data "reasonably likely" to predict clinical benefit, the standard currently used for accelerated approval. Unlike accelerated approval, drugs could receive progressive approval without data from a surrogate endpoint.
• Exceptional approval could be granted when the data necessary to satisfy the standard for approval "cannot ethically, feasibly or practicably be generated."

Much more needs to be said about how these would be implemented. In particular, it is not uncommon for a drug to produce solid safety data and/or startlingly good efficacy data in phase 2 (preliminary human trials), then fail in phase 3 (clinical trials to support approval).

Even after we see the bill text, the BIO/Hagan effort must still be seen as a conversation starter. But it is a discussion well worth having.

Steven

Of possible interest to readers:

While the accelerated approval approach has been successful, it also raises a host of methodological questions. One of the best critiques is Professor Tom Fleming’s Surrogate Endpoints And FDA’s Accelerated Approval Process (Health Affairs, 2005).

By Whose Standards: FDA’s Identity Crisis and the Level Playing Field

FDA advances public health, protects consumers, regulates products and is an important force in our national economy. Now, FDA is being challenged by Congress and the President to justify itself as a positive force in the advancement of American innovation and as a contributor to US competitiveness.

This is precipitating an identity crisis at FDA. The agency is constantly establishing new standards (and revising old ones) that will protect consumers and bring new therapies to patients. Now it must also consider whether it is unduly impeding American industry.  As this forces FDA to rethink who it is and what it stands for, FDA Matters believes a different FDA will emerge.

The Need for Standards.  Most of FDA’s authority has been granted by Congress in response to marketplace abuses that had led to harmful products becoming commonplace. In each case, FDA has used that authority to set standards that all products must meet, creating a level playing field for industry. As a result, producers of quality products are assured that their competitors will also have to meet standards. 

How important is this effect? A manufacturer in a highly-competitive, FDA- regulated industry once told me: to survive as a business, our upper boundary is limited by what our most foolish competitor offers for sale. FDA standards (and enforcement of those standards) are what assures that both the well-intended and the foolish deliver products that are at or above a defined level of quality and surety.

We mostly take the benefits of a level playing field for granted. Yet, greed, carelessness and malevolence are always at work behind the scenes trying to create a profitable advantage out of substandard products (e.g. counterfeiting, ingredient substitution).  

Abuses aren’t limited to product manufacturing and distribution. Unsafe and ineffective products also result if standards aren’t created and enforced for clinical trial management, proof of efficacy, acceptable clinical trial designs, food additives, data reporting integrity, post-market surveillance and so on. Having these standards also assures fair competition among companies.

The Standards Crisis. By creating, applying and enforcing the highest standards, FDA wants to be seen as the primary force in assuring that Americans have the safest food supply and the safest and most effective therapies anywhere in the world. The agency aspires to always be “the gold standard” for the world.

Two sets of circumstances are forcing the FDA to rethink this particular sense of purpose and self-image. As a result, an identity crisis is slowly building within the agency. 

First, the “highest” standard is rarely the best way to stimulate innovation. If FDA had chosen the toughest, most protective and most restrictive standards in the late 1970’s and early 1980’s, the biotechnology industry might not exist today. (see FDA and Things that Might Go Bump in the Night).

The agency faces this same challenge in creating the highest standards that nonetheless help advance nanotechnology, open new vistas in diagnostics and genomics, and encourage breakthroughs in drugs or medical devices. The tension between the “highest standards” and “reasonable and appropriate standards” is a visible and palpable part of the current controversy over revising medical device categories and approval standards. (see Medical Device Melodrama: A Great Story With a New Plot Twist)

Second, there is no global force that levels the playing field among each nation’s regulatory agencies…the way FDA levels the playing field for companies and products in the US market. Efforts at international harmonization of regulatory standards have stretched into decades. Without global standards, there are differences in requirements and even greater differences in interpretation in each national marketplace.

FDA knows that setting standards substantially higher than other nations creates the risk that other countries will introduce new products first. It also makes it more likely those countries can attract more industry, capital and jobs in the global economy. Apart from the issue of bragging rights over whether a drug or device was approved first in the US, considerations of international competition (versus cooperation) have been peripheral, at best, to FDA’s identity.

Conclusion. Right now, FDA is struggling to show that it can be all these things: the gold standard, the toughest, the best, the stimulator of innovation and the advocate for companies and products that meet American standards.

Ultimately, FDA will reconcile these roles because it has no choice. The resulting FDA will not necessarily be better or worse. The change may be dramatic or subtle. The only certainty is FDA’s identity will be different.  

Steven

In Praise of Predictability: A Virtue Revisited

More than two years ago, FDA Matters suggested that one of FDA Commissioner Hamburg’s goals would be making it easier for stakeholders to anticipate agency actions. I was looking beyond transparency (see what FDA is doing and has done). I hoped the agency would focus on the larger virtue of predictability (being able to anticipate FDA’s standards and actions).

The task has proven larger than I imagined and the volume of issues facing the agency has made progress hard. However, the agency has taken many steps forward, even as it has been pushed backward on a number of occasions. Is the glass half empty or half full?

I believed that, after the initial stage of setting new policies and assembling her team, one of Dr. Hamburg’s priorities would be to provide more guidance (published and spoken), explain more actions, and rationalize and coordinate more regulatory processes. With regard to this goal of predictable, science-based regulation, progress has definitely been made.

Once completed and enacted, the 2012 round of user fee legislation will further contribute a degree of predictability. The five-year renewal cycle allows industry and FDA to re-work ground rules for the product review process (note: these negotiations are intended to change process, not standards).  

So why doesn’t it feel like FDA is making more progress in becoming predictable and science-based in its regulatory decisionsmaking?

First, a degree of uncertainty is inherent in the nature of FDA’s work. I’ve explored this theme in two recent columns. One discussed the role of FDA staff and the necessity that People, Not Science, Make Decisions. The other examined the biological complexity that makes it impossible to provide guidance that anticipates all situations and outcomes (FDA Approvals and the Failure of the “Human Body as Machine” Metaphor).

Second, certain well-publicized areas of conflict between FDA and industry have tended to exaggerate the overall degree of unpredictability. For example, FDA faced a decision last year on three weight-loss drugs—and approved none, despite credible claims that the drugs met FDA standards.  The agency’s reasons satisfied some observers, but not others. This particular situation became something of a poster-child for critics who say that FDA is unpredictable in its decisionmaking.

The ongoing struggle between FDA and the medical device industry has also focused attention on claims that FDA’s regulatory decisions are not predictable. I have chronicled the often-heated debate in a number of columns, most recently Medical Device Melodrama: A Great Story With a New Plot Twist.

Medical devices were a conflict waiting to happen. It is not because FDA is disinterested in improving predictability in this area. Rather, the approval process is uniquely adapted to the nature of medical devices (wide range of risks, short innovation cycle for product improvements) and almost impossible to explain to someone not already familiar with medical device regulation. Ironically, the two years spent (thus far) on improving the medical device process began with FDA unexpectedly approving a device based on irregular agency procedures.  

Increasing predictability and science-based decisionmaking are still hallmarks of Dr. Hamburg’s agenda. A recent example is FDA’s new initiative to spur biomedical innovation and improve the health of Americans. Streamlining and reforming FDA regulation is one of the initiative’s goals. 

If FDA has not become more predictable in your area of interest, keep encouraging FDA to make it so. The agency is listening and making progress. They need feedback on where processes have broken down or do not produce predictable decisionmaking. In the quest to achieve this goal, I believe the glass is half-full.

Steven

A Salmon on Every Plate

President Herbert Hoover supposedly promised Americans “a chicken in every pot” during his 1928 campaign. Chicken was an expensive delicacy then, so his message was about raising living standards, not ending hunger. Today, chicken is a low-cost source of protein and a mainstay of the American diet.

FDA Matters hopes that salmon (and other fish) will also become sources of low-cost protein over the next two decades. FDA is nearing the end of a long regulatory process, the outcome of which could be approval of a faster growing genetically-engineered Atlantic salmon. FDA must overcome opposition from environmental groups…and politicians and companies trying to protect the market for Pacific salmon.

The health benefits of fish are well-known. They are also a valuable source of dietary protein. However, our oceans are over-fished and aquaculture is now the source of almost 50% of the fish consumed worldwide. Expanding the availability of fish products meets a growing demand and is an important component of improved nutrition for Americans.

The proposal before FDA is for a genetically-engineered (GE) salmon that is biologically and chemically identical to the Atlantic salmon that is served in restaurants and at our own tables. The only difference is the inclusion of a Chinook salmon gene that provides the potential to grow Atlantic salmon to market size in about half the time.

Opponents have labeled the product as “Franken-fish.” It’s a catchy slogan that tries to vilify over a decade of scientific research and discredit several years of FDA review. Ultimately, the appeal is to emotion—that something dramatically new and different must automatically be dangerous. Decisions about new and different products are hard for FDA, as I wrote a few week weeks ago in a column entitled: “FDA and Things that Might Go Bump in the Night.”  

Approval of genetically-engineered animals will always require serious consideration of safety, environmental and ethical issues.  In this case—FDA’s first application for approval of a GE food product--the agency has been fortunate to have what might be considered a favorable factual context. No one questions the legitimate demands for more plentiful, high quality supplies of salmon. Further, the sponsor has agreed upon multiple redundant safeguards. For example, the GE salmon will be only sterile females and will be grown in inland fisheries with no access to either wild or farmed salmon stocks.

FDA has done its homework—digging deep into the relevant science and taking the time to consider all aspects of the issue. An agency decision is considered imminent and likely to be favorable….unless Congress tells it otherwise. A showdown may occur this week when the Senate considers the FY 12 appropriations bill for the Agriculture Department and FDA.

The House version already contains restrictive language forbidding the agency from spending any of its FY 12 monies to approve the application. However, according to some reports, only about a dozen Representatives were present when the amendment was adopted by voice vote during floor consideration.

In contrast, when the issue comes before the Senate this week, there will be debate and almost certainly a vote. Currently, about a dozen Senators are known to support the ban, with most of them from Alaska, California, Oregon and Washington, states that are the primary sources of Pacific salmon sold in the United States. 

Healthy, affordable high-protein food is always a desirable dietary option. At some time in the future, salmon could be as affordable as chicken if we allow the development of salmon that can be grown faster.  

The current fight is not just about “a salmon on every plate.” It is also about whether Congress will substitute its political judgments for FDA’s scientific decisionmaking. FDA Matters hopes that enough Senators will vote for FDA and against regional economic interests that want to protect existing sources of salmon production.

Steven

More information about salmon, aquaculture regulation of genetically-engineered foods and the current controversy can be found at: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/VeterinaryMedicineAdvisoryCommittee/ucm222635.htm and http://www.aquabounty.com/PressRoom/#l7

FDA and Things that Might Go Bump in the Night      September 18th, 2011

FDA’s everyday business requires balancing risk and benefit as these might apply to a particular medical product or a new food. Occasionally, FDA is faced with a much larger responsibility: judging a breakthrough technology that could bring great benefit or great sorrow to humankind. Who can confidently know in advance which it will be?

Still, FDA must decide. If they say “yes,” whole new industries and benefit may be created for patients and consumers. Or, the world and humankind may be subject to devastation. Today, the agency is faced with just such challenges in dealing with nanotechnology, genetically-engineered (GE) animals, and synthetic biology. Read the rest of this entry

Should Money Have a Seat at the FDA Table?

FDA’s traditional stakeholders are patients, consumers, health professionals, and industry.  Add Congress, media and other government agencies and you have the full set of FDA audiences. What they all have in common: a commitment to the public and individual health of Americans.

While FDA’s focus is health and safety, almost every decision has economic consequences.  Money is never far from the surface. Yet, to my knowledge, Wall Street has never been treated as a stakeholder or an audience of FDA. Now a variant has emerged: organized efforts by venture capitalists (VC) to affect how FDA evaluates drugs, biologics and devices.

Why do VCs care about FDA? Venture capital is financial capital provided to early-stage, high-potential, high risk, growth companies, usually start-ups. Such funding plays a critical role in a large number of medical products that FDA reviews for market approval.

If FDA is more open to innovation and new technology, venture capital firms are more likely to invest in medical product companies in the United States. Conversely, a hesitant, overly cautious FDA makes it more likely that venture capital monies will be used to fund information technology, telecommunications and software companies, rather than life-sciences companies.

What is the VC community doing now about FDA?  Last week, the Medical Innovation and Competitiveness Coalition held a press event, releasing a survey they had conducted in partnership with the National Venture Capital Association. www.nvca.org/vital_signs_data_slides.pdf

In attendance were Senators Michael Bennet (D-Colo.) and Richard Burr (R-North Carolina), both members of the Senate Committee with jurisdiction over FDA. The Senators’ interest is the prominent role that small companies and venture capital play in economic growth and job formation.

The survey of venture capital firms found a significant decreased commitment to investment in life sciences over the past 3 years, with more dollars aimed at overseas projects. According to the Wall Street Journal:

The chief reason [for decreased investment], according to most of the 156 venture firms surveyed, is dysfunction at the Food and Drug Administration, an agency investors say is so unpredictable and risk-averse that young companies are now inclined to merely give up on trying to get on the market in the U.S.

This is definitely attention-getting, but needs to be seen in context. VCs are the FDA’s natural critics. Having invested millions of dollars (and sometimes hundreds of millions of dollars) in a company’s science and product pipeline, VCs are more likely to see product failures as a result of FDA deficiencies than their own failures to back successful products.  

However, the survey may still have a point….and VCs can be a powerful voice for a stronger, more predictable, science-based FDA.

How has FDA responded?  The Obama Administration has emphasized the importance of innovation in building the US economy. There is some question about the effectiveness of that effort overall, but it has been a serious theme at FDA under Commissioner Hamburg.

Last week, Commissioner Hamburg unveiled FDA’s new initiatives to spur biomedical innovation and improve the health of Americans. According to FDA’s press release, this is FDA’s blueprint for addressing “concerns about the sustainability of the medical product development pipeline, which is slowing down despite record investments in research and development.”

Should “money” have a seat at the table among FDA stakeholders?  Companies and individuals seeking “return-on-investment” are significant contributors to making medical progress possible. VCs are the natural allies of an FDA that wants to be a strong, science-based agency and is willing to admit that its process and judgments can always be made better.

FDA needs to carefully consider the critique being offered by the VC community. FDA Matters supports FDA in its willingness to do so.   

Steven

Why is it so hard for investors to pick winners? Why is it so hard for FDA to be flexible?    

Complexity, Uncertainty, Unpredictability: Not Necessarily Bars to FDA Approvals   July 17th, 2011

In most discussions of science and medicine, there is an implicit assumption that the human body is a machine—complex and biological, but still a machine. “The human body as a machine” is a metaphor, not a fact. Once we accept this, FDA Matters believes we can become liberated from unrealistic expectations about medical discovery and FDA’s role as a gatekeeper for new products that benefit patients.  Read the rest of this entry

FDA Should Consider Cost in Some Decisions

FDA decides whether drugs, biologics and medical devices are safe and effective and can be marketed legally in the United States. The agency analyzes risk-benefit, but never cost. In contrast, public and private insurers, along with physicians and pharmacists, have the responsibility for cost-benefit decisionmaking.

FDA Matters has always felt quite strongly that this was the right way to allocate roles. Safety and efficacy determinations are difficult enough without weighing cost, so keeping a barrier between them makes sense. Two events this past week have left me wondering whether there are certain limited circumstances when FDA should be able to take product cost into consideration.

On September 26, 2011, The Oncology Commission of the British medical journal, Lancet, released a report entitled: “Delivering Affordable Cancer Care in High-Income Countries.” The 40-page report is wide-ranging, but its conclusion straightforward: as cancer care grows more expensive (and it is doing so at a rapid pace), affordability, accessibility and value are issues that need to be confronted aggressively.

Medicare, Medicaid and private payers are undoubtedly looking at this report, hoping to glean insights on cost containment strategies that can mesh with improved cancer care. They may also be looking for support and better rationales for tough decisions they may need to make in the near future.  

FDA also has a stake in affordable cancer care. The growing problem of drug shortages in the United States is heavily skewed toward oncology drugs (mostly generic injectable products). Patients suffer, research is delayed, and more expensive drugs are often substituted (or patients do without).

While ingredient shortages and manufacturing problems play a role, there are also economic drivers. In many cases, it is not sufficiently profitable for manufacturers to produce older oncology drugs. FDA cannot hope to  improve the shortage situation without considering cost—and may need to find ways to favor less effective or riskier products only because they can be made available at a market-driven price.

FDA also plays a role (however unintentionally) in exacerbating the crisis in affordable cancer care. Oncology is one of the hottest areas at FDA, with a large number of new products added to the market over the last few years. More are coming. Increasingly, they are being priced at about $100,000 per cycle. Some patients may need multiple cycles or multiple expensive drugs, all of which contribute to further cost escalation.

This brings us to the second event that occurred last week. I was asked the seemingly naïve question, what would FDA do if a drug was only 90% as good as the safest and most effective therapy on the market (the standard of care), but would be available for only 10% of the cost? I gave the stock answer: FDA only approves therapies that are as good as or better than the existing standard of care. The cost aspect is irrelevant and would never be considered or even discussed.

But then I thought about the Lancet Oncology Commission report. Wouldn’t patients benefit if FDA had some room to consider standards of care, risk-benefit and comparative cost? It scares me to write this….the whole notion of FDA putting cost on the table seems like an abandonment of principles, as well as fraught with potential misuse. Certainly, FDA should not be rejecting therapies because they would be expensive.

In a sense, there are already two possible exceptions. To demonstrate bio-equivalence, generic drugs must have a bio-availability profile within the range of 80% to 125% of the innovator drug. For potentially expensive new products, there is the possibility of approval based on clinical trials that show the product is “non-inferior” to the best therapy on the market. It is possible that a product could be approved as non-inferior with a 10% margin of error, setting up a “90% as good” paradigm. 

But neither of these situations gives FDA explicit permission to say: we are approving a drug, biologic or device that is not quite as effective or safe because it will make care more affordable and accessible. I am not yet an advocate for this….but I think it is one of the possibilities that we need to be discussing. 

Steven

The Lancet Oncology Commission Report is available only as a reprint from Lancet, which charges for it. http://www.thelancet.com/commission/delivering-affordable-cancer-care-in-high-income-countries. If any reader knows of a site where it is available without charge, please let me know.   

US press coverage of the Lancet Oncology Commission Report was thin. Here is the Reuter’s story: http://www.reuters.com/article/2011/09/26/us-cancer-costs-idUSTRE78P26B20110926

A prior column with some relevance:

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

Can FDA Survive the Next Round of User Fee Legislation?

If FDA is to have sufficient money to operate in fiscal year 2013 (and thereafter), drug and device user fee legislation must pass Congress next Spring. That is the immovable object of the agency’s future. To pass legislation, Congress will need to plow through dozens of amendments touching every aspect of FDA and the industries it regulates. This is the irresistible force of Congress.

What happens when this irresistible force meets this immovable object? Something will need to give. FDA Matters hopes it will not be FDA’s ability to carry out its mission.   

The threat to FDA is created by two constraints imposed on the legislative process to reauthorize drug and medical device user fees.

First, the legislation needs to pass at least 90 days before the existing user fee programs expire on September 30, 2012 (i.e. by June 2012). During the last renewal cycle five years ago, the legislation wasn’t signed into law until September 21. As a result, FDA had to delay hiring new staff and the agency was compromised in its ability to implement the new law during the first year of the cycle.  

This time, there may be greater awareness by Congress of the problems created by delayed passage of the user fee legislation. However, this Congress has (thus far) a poor track record of reaching compromises on even simple matters and has demonstrated serious problems meeting deadlines.

Second, the user fee legislation is likely to be the only FDA-related legislation that “must pass” during this Congress (2011-2012). It provides Members of Congress a “one-time only” opportunity to advance their favorite issue or concern about FDA.

A partial list might include: drug re-importation; the exclusivity provisions of the new biosimilars law; approval of genetically-engineered salmon; regulation of dietary supplements; changes in the way that medical devices are regulated; and the use of Bisphenol A (BPA) in consumer products.  In addition, Congress now has some Members who might offer more fundamental amendments, such as revising FDA’s authority to review the efficacy of drug products.

The user fee reauthorization legislation will essentially have two parts. The core bill (“the inner bill”) will include renewals of drug and device user fees and adoption of new fees for generic drugs and other programs. In the best case, disagreements on these programs will be negotiable and compromises found.

Any additional amendments (“the outer bill”) are problematic. There may be some areas of agreement, such as new authority for drug import inspections, incentives for development of antibiotics, and provisions for addressing drug shortages.

However, as mentioned above, the outer bill will face a pent-up demand for resolution of controversial FDA-related issues. The House and Senate committees and leadership are going to have to deal with the onslaught—by allowing votes, negotiating compromises or adopting procedural barriers to prevent consideration of their colleagues’ amendments.

The risk for FDA is twofold. Even if “the inner bill” can be moved without problems, a lot of time will be required to deal with “the outer bill.” The clock will be ticking and June 2012 will arrive quickly. If Congress misses, FDA will be hurt. The longer it takes, the greater the damage.

Second, no one can predict which of the items proposed for “the outer bill” might be adopted. Some may make important and possibly undesirable changes in the agency’s mission and activities.   

Reauthorization of FDA’s user fee programs is essential, but difficulties are unavoidable and extend well beyond the fees themselves. FDA needs to be talking now with its many Congressional friends—not just about the details of the inevitable clash, but how to control the battle so it doesn’t get out of hand.

Steven

“Must-Pass Legislation” Key to FDA’s Future     December 12th, 2010

FDA Matters believes that the 2010 election will profoundly affect the FDA’s mission, priorities, funding, standards and work flow. Eighteen months from now, FDA’s leadership team will probably be the same, but the agency won’t be.

Identifying and understanding the likely changes to FDA requires examining the meaning of “must-pass legislation” and its escalating importance as a quarrelsome Congress turns into a divided Congress. At the moment, there is only one “must-pass” item on Congress’ FDA agenda: the next round of user fee renewals that will come before Congress in the Spring of 2012.  Read the rest of this entry

It’s Time to Change CDER Funding   September 17th, 2009

I did some crunching of FDA budget numbers for my column earlier this week on the Office of Regulatory Affairs (ORA). A by-product of my efforts was an analysis of how the Center for Drug Evaluation and Research (CDER) is funded. 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 entry

FDA and Things that Might Go Bump in the Night

FDA’s everyday business requires balancing risk and benefit as these might apply to a particular medical product or a new food.  Occasionally, FDA is faced with a much larger responsibility: judging a breakthrough technology that could bring great benefit or great sorrow to humankind. Who can confidently know in advance which it will be?

Still, FDA must decide.  If they say “yes,” whole new industries and benefit may be created for patients and consumers. Or, the world and humankind may be subject to devastation. Today, the agency is faced with just such challenges in dealing with nanotechnology, genetically-engineered (GE) animals, and synthetic biology.   

Thirty years ago, FDA gave a cautious “yes” to the first biotechnology studies that eventually became important medical products to treat cancer, arthritis, MS and many other diseases. The world is a better place as a result.

In retrospect, the decision was right, but at the time, it wasn’t clear. Scary visions of mad scientists and technology run amok were powerful forces in the early days of biotechnology. In response, FDA took great care in setting up an appropriate regulatory environment.[1]

Not surprisingly then, FDA proceeds carefully when new areas of science and technology have great potential, but could also be the source of great harm.  

One such area is nanotechnology, “the science involving manipulation of materials on an atomic or molecular scale.” The agency is concerned because: “materials at the nanoscale can have different chemical, physical, or biological properties compared to their conventionally-scaled counterparts.” What we consider safe may not be safe if made from nano-particles.[2]

FDA responded in 2006 by forming a Nanotechnology Task Force, which still exists. It released an assessment and recommendations in 2007 that have guided FDA’s subsequent actions. These include the first draft guidance on nanotechnology in regulated products, published earlier this year. More extensive guidance is expected in the future.[3]

Yet another science with great potential for benefit, but also possible risks, is genetically-engineered (GE) animals. FDA has been monitoring this field for two decades and accelerated its efforts over the last 5 years as GE animal products have gotten closer to filing for approval.[4]

Currently, the agency is working (slowly and carefully) on GE Atlantic salmon that have been modified to grow faster.[5] If approved, it would also be the first GE animal to become part of our food supply. Opponents call it “Franken-fish” and allege that it will be dangerous to humans and the environment.

The agency has held hearings, sought feedback from advisory committees and tried to solicit all viewpoints. When it finally decides, it wants to be certain that the result will be beneficial and not harmful to our society.

While nanotechnology and GE salmon are well-along in the decisionmaking process, the FDA is only just beginning a similar cycle regarding “synthetic biology.” While “synthetic biology” can be defined a number of ways, it is generally considered to be “the use of molecular biological techniques and chemical synthesis to mimic and even redesign natural biological systems.”[6]

Synthetic biology raises the specter of artificial life (more mad scientists running amok?). The Presidential Commission for the Study of Bioethical Issues released a report in December 2010[7] and NIH is also deeply involved. FDA is watching, adding staff with appropriate backgrounds and planning carefully, knowing that product-specific questions about synthetic biology are coming its way.

As with biotechnology thirty years ago, FDA continues to make tough decisions about dramatic new technologies that can alter our way of life—for good or bad. Some fear will always be with us, if only because a wrong decision might be catastrophic. Past experience shows us the agency will be appropriately deliberative before coming to a conclusion.

Steven

 [1] http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SelectionsFromFDLIUpdateSeriesonFDAHistory/ucm081964.htm

 [2] “There is a virtual consensus among scientists that the toxicology of engineered nanomaterials is largely unknown, and that toxicity data cannot be extrapolated from existing toxicology studies conducted on larger-scale materials.” http://www.fda.gov/ScienceResearch/SpecialTopics/Nanotechnology/NanotechnologyTaskForce/ucm118910.htm

[3] http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm258377.htm

[4] http://www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/GeneticEngineering/GeneticallyEngineeredAnimals/default.htm

[5] For more information on GE salmon: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/VeterinaryMedicineAdvisoryCommittee/ucm222635.htm

[6] Testimony of Dr. Anthony Fauci on synthetic biology: http://www.hhs.gov/asl/testify/2010/05/t20100527a.html

[7] http://www.scribd.com/doc/47350129/NEW-Directions-the-Ethics-of-Synthetic-Biology-and-Emerging-Technologies

FDA’s Busy Summer of 2011

Once upon a time, Washington slowed a little over the summer. Those days are long gone…and this was a particularly busy summer. Congress went down to the deadline on the debt limit/deficit reduction legislation, then left town for August. There was a continuous stream of FDA headlines in June, July and August.

FDA Matters focused on a number of the most pressing issues: post-market safety and surveillance; barriers and opportunities for increased drug discovery and approvals; the rising tide of imports; prospects for biosimilars and medical devices; FDA funding; and various crises facing the agency.

Here is a recap of the summer’s stories:

FAQ: How Biosimilars Will Transform the Marketplace      August 21st, 2011

Biosimilars will be a huge success--used by most prescribers at least some of the time. Much of the current negativity about the market for biosimilars is fed by a mismatch of expectations: the Biologics Price Competition and Innovation Act (BPCIA) is barely 18 months old, while the transformation of the marketplace will take a decade or longer. FDA Matters explores the likely evolution of the marketplace in a set of FAQs.  Read the rest of this entry

FDA Funding Prospects Altered by the Budget Control Act     August 14th, 2011

The Budget Control Act of 2011 (BCA) will have a heavy impact on FDA’s future. Under this new law, most discretionary spending programs will shrink—not merely cease to grow. Yet, FDA’s growing responsibilities and resource needs are not diminished because federal spending is being reduced. Our nation is less safe and less healthy if FDA cannot excel at its mission. Read the rest of this entry

People, Not Science, Make Decisions  August 8th, 2011

To FDA Matters, the people making the decisions at FDA are its strength. They are smart, conscientious and committed. Yet, when asked about bottlenecks at FDA, I have to admit that people slow the process down. There are good reasons why this is so. Read the rest of this entry

Medical Device Melodrama: A Great Story With a New Plot Twist  August 1st, 2011

Two years ago, FDA Matters urged FDA and Congress to review the 510(k) approval process for moderate-risk medical devices and predicted meaningful changes that would work for FDA, industry and consumers. FDA and industry have been proceeding along these lines (albeit with some tough negotiating and lots of rhetoric)…until the Institute of Medicine (IOM) declared that the current system is so flawed that a new regulatory framework is needed.  Read the rest of this entry

FDA, Reorganization and the Four Crises    July 24th, 2011

Dr. Hamburg’s reorganization plan addresses four crises that beset the agency: industry discontent with the medical product review process; public concern about import safety; implementation of the Food Safety Modernization Act; and Congressional concerns that the agency is inefficient in its use of resources. The new structure should drive better decisonmaking and greater productivity…. at a time when the agency is struggling to fulfill its growing mission and faces the potential for budget cuts.  Read the rest of this entry

Complexity, Uncertainty, Unpredictability: Not Necessarily Bars to FDA Approvals      July 17th, 2011

In most discussions of science and medicine, there is an implicit assumption that the human body is a complex biological machine. “The human body as a machine” is a metaphor, not a fact. Once we accept this, FDA Matters believes we can become liberated from unrealistic expectations about medical discovery and FDA’s role as a gatekeeper for new products that benefit patients. Read the rest of this entry

Should FDA Have an Independence Day?     July 4th, 2011

FDA Matters thinks that making FDA an independent agency will not make FDA more effective or more efficient. Although the idea is not truly harmful, proposing independent agency status is a seductive distraction from the tough job of improving FDA. Read the rest of this entry

Imports: FDA Issues a Cry for Help   June 26th, 2011

 No challenge to FDA’s mission looms larger than the rapid globalization of the world markets for food, drugs, medical devices and other FDA-regulated products. By way of making this point, the FDA released a special report, entitled “Pathway to Global Product Safety and Quality.”  FDA Matters read the report carefully and heard a cry for help, if not an actual primal scream. Read the rest of this entry

Post-Market Safety: Getting the Most Out of Inferences That Aren’t Proofs   June 21st, 2011

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.  Read the rest of this entry
Steven

FAQ: How Biosimilars Will Transform the Marketplace

FDA Matters thinks biosimilars will be a huge success. FDA-approved products similar to off-patent biologics (“biosimilars”) will be available in the US by 2014 or 2015, with more added each year. There will eventually be price competition in the range of 20% to 40% discounts. Biosimilars will be used in most health care settings with most prescribers using them at least some of the time.

Much of the current negativity about biosimilars is fed by a mismatch of expectations: the Biologics Price Competition and Innovation Act (BPCIA) is barely 18 months old, while the transformation of the marketplace will take a decade or longer.

Will the biosimilar market be similar to the generic drug market? Over the last 25 years, generic drugs have grown from 12% of all prescriptions to nearly 75%. Discounts can be as great as 80% off the original innovator price. Because of their greater complexity and higher production costs, biosimilars will never achieve similar market penetration nor sell at such a steep discount.

However, generic drugs and biosimilars share a common premise: the willingness of physicians and pharmacists to use alternative products (generic and biosimilars) instead of the innovator (or reference) product with which they are most familiar. As generic drugs have become accepted by prescribers, so too will biosimilars.

Will biosimilars fail if they don’t generate substantial discounts?  Biological products are more expensive than drugs and at the extreme end may cost $100,000 to $300,000 in a year. In order to gain market share, biosimilar manufacturers will have to provide discounts to purchasing groups, wholesalers and benefits managers of at least 20% off the originator’s prices. Deeper discounts are likely if there is more than one biosimilar competing for sales. To payers and purchasers, saving $20,000 on a $100,000 medication is both substantial and significant.  

If physicians and pharmacists don’t accept biosimilars, how will the market grow? It took more than 25 years for generic drugs to reach 75% of all prescriptions. As with generics, physicians will gain experience with biosimilars as they become available. Meantime, powerful forces of change--led by payers, purchasing groups and formulary committees--will start to narrow the choice of products easily available to physicians and pharmacists. This will become evident by 2015, although it may take as long as a decade for the pace of new biosimilars to transform the marketplace.

Why is therapeutic substitution important in understanding the market for biosimilars?  Increasingly, payers and purchasing groups have treated drugs within a therapeutic class (e.g. statins) as interchangeable and insisted on use of the least expensive one or two. Similarly, biosimilars are eventually going to be judged in the marketplace by safety and efficacy within a therapeutic class, rather than the degree of similarity to the reference product. FDA will create the basis for this approach by looking at the totality of the evidence before deciding the testing requirements for a biosimilar….but has already made clear that some clinical trials (i.e. more concrete proof of safety and efficacy) will be needed as part of the first generation of biosimilar applications.

Why does the success of biosimilars seem so certain to FDA Matters, even in the face of their slow evolution and the many unanswered questions about details? Knowing that it may be months before the first guidance is issued, key FDA leaders are making clear that they are active and serious. Agency leaders recently authored a “perspectives” article, published in the New England Journal of Medicine, that explains their approach.  In June 2011, the head of CDER’s Office of New Drugs indicated that FDA had already held 15 drug development meetings with representatives of 21 companies interested in nine different biosimilar products.

Bio-pharmaceutical companies are not just asking for meetings with FDA. Large sums of money are being invested in the belief that a substantial and profitable biosimilars market will evolve. For example, a large pharmaceutical company recently closed a deal worth up to $720 million for the rights to a biosimilar version of another company’s blockbuster biologic product.

Biosimilars will transform the drug marketplace. We are just in the early stages, which makes it hard for some to see the degree of change that is coming.  

Steven

The FDA’s August 3, 2011 article on biosimilars in the New England Journal of Medicine is at: http://www.nejm.org/doi/full/10.1056/NEJMp1107285.

FDA Funding Prospects Altered by the Budget Control Act

The just-passed Budget Control Act of 2011 (BCA) will have a heavy impact on FDA’s future.  Under this new law, most discretionary spending programs will shrink—not merely cease to grow.  Yet, FDA’s growing responsibilities and resource needs are not diminished because federal spending is being reduced. Our nation is less safe and less healthy if FDA cannot excel at its mission

FDA Matters urges Congress and the President to see that increased funding of FDA is the only option.  Ultimately, the pressures created by the BCA will test the government’s commitment to FDA’s essential role in our society.  

Appropriations Caps and the Impact on FY 12.  The BCA limits discretionary federal spending for every fiscal year from 2012 through 2021. By capping annual appropriations growth, federal spending will be reduced by more than $900 million over 10 years.

For FY 12, the House and Senate appropriations committees cannot spend more than $1.043 trillion. Within this total, the ceiling for non-security programs (e.g. FDA, NIH, education, etc.) is slightly below the FY 11 appropriations level.

The ceiling is also substantially above the level the House has been using to mark up FY 12 bills. This is particularly encouraging because the House-passed Ag/FDA appropriations bill would cut FDA by $285 million below FY 11 (-11.5%) and $572 million below the President’s FY 12 budget request (-21%).

Senate staffs are currently preparing FY 12 appropriations bills using the aggregate spending levels in the BCA. Subcommittee and then full committee mark-ups are expected to start in early to mid-September.  Advocates, notably the Alliance for a Stronger FDA and its members, have been encouraging the Senate to put more money into FDA. The goal is to provide the agency with an increase in its FY 12 appropriation, not merely undo the cuts proposed in the House bill.

FY 13 Appropriations and Beyond.  A second part of the BCA requires a further reduction of the federal deficit by $1.2 trillion over the next 10 years. This can be achieved by any combination of changes in entitlements, revenues and appropriations.  

To pull together this deficit reduction plan, a so-called “super committee” has been appointed. It is composed of 12 members—3 each from the majority and minority parties in the House and the Senate. The group’s work must be completed by November 23, 2011. Any resulting bill will not be amendable and must pass Congress by December 23, 2011. If no legislation passes or the President fails to sign it, then across-the-board cuts (“a sequester”) will occur during  fiscal year 2013, which starts on October 1, 2012.

The general consensus in Washington is that the super committee appointees are too divided ideologically to pull together the needed deficit package. Democrats will only accept entitlement changes if there are new tax revenues. Republicans are pledged to oppose any tax increase.

Predictions of failure may be premature because the super committee will be under intense public and political pressure to find a compromise. In addition, sequester cuts would fall heavily on defense programs that most of Congress supports.

FDA is vulnerable in the “super committee/sequestration” process in two ways.

• If the super committee produces a plan, it may include further cuts in discretionary spending. There is no guarantee that Congress would allocate those cuts in a way that would protect FDA and other essential programs.
• If the super committee does not produce a plan, then the sequester would go into effect in FY 13.  If the entire 10-year $1.2 trillion in savings must be found through sequestration, then FDA is likely to sustain an across-the-board reduction in FY 13 of at least 8% to 10%.

Conclusion. Over the last five years, FDA has been one of few discretionary programs to receive substantial funding increases. This reflected both Congressional and Executive Branch recognition that the agency was dramatically underfunded for its growing responsibilities in an increasingly complex world. FDA still needs more resources, even though the downward budgetary pressures have become significantly greater.

Steven

Imports: FDA Issues a Cry for Help          June 26th, 2011

No challenge to FDA’s mission looms larger than the rapid globalization of the world markets for food, drugs, medical devices and other FDA-regulated products. By way of making this point, on June 20, the FDA released a special report, entitled “Pathway to Global Product Safety and Quality.” FDA Matters read the report carefully and heard a cry for help, if not an actual primal scream. Read the rest of this entry

FDA “Exceptionalism” at the Funding Crossroads       May 2nd, 2011

Congress returns at the beginning of May to start the FY 12 appropriations process. Downward pressure on federal spending will intensify. If, despite this, the FDA receives another increase, then it will move closer to establishing itself as an exception to the budget cutting process. Thus, FDA Matters sees the coming funding battle as a crossroads for FDA.  Read the rest of this entry

People, Not Science, Make Decisions

People constantly make decisions. We choose vanilla instead of chocolate or a job in DC instead of a job in Texas. Can’t decide? Then, maybe, flip a coin.

Yet, the most important decisions—such as FDA approvals--can’t be treated so cavalierly. While scientific evidence and good judgment are necessary to make these choices, people make the decisions.

To FDA Matters, the people making the decisions at FDA are its strength. They are smart, conscientious and committed. Yet, when asked about bottlenecks at FDA, I have to admit that people slow the process down. There are good reasons why this is so.  

FDA lacks sufficient resources.  FDA has been dramatically understaffed for decades. Better funding in recent years has improved the situation, but not nearly enough. Also, it seems like new demands on FDA are increasing faster than staff can be added.

Many FDA employees have overwhelming workloads and inadequate time to refresh their scientific knowledge or broaden their thinking. As a result, higher levels of evidence and “certainty” become necessary to reach decisions. Getting to “yes,” particularly for product approvals, often consumes a great deal more time than telling a sponsor “no” or asking for more information. Hiring more staff would reduce or at least stabilize workloads*.

FDA’s culture promotes intensive scientific discussion.  Objective science-based decisionmaking is a goal, not a reality. People arrive at decisions with a bundle of perceptions and experiences that render their judgment subjective. On the flip side, they probably wouldn’t have much to contribute to the decisionmaking process without those experiences.

This is true for FDA, where agency staff—all with subjective views--interact and struggle to come to a clear decision.  If six or seven well-trained, highly-disciplined FDA scientists examine a pre-clinical or clinical trial, there are certain to be multiple views about the meaning of the data It is a slow path to a consensus, if one can be forged at all.   

Delay can increase further if the agency—as it has in the past—expects a single conclusion to emerge from such staff engagement. One of Commissioner Hamburg notable efforts has been to manage dissent (and let it be expressed in public), rather than always force consensus decision-making.

Science has become more complex and results often unpredictable. Life sciences’ products are increasingly based on cutting edge discoveries. It takes more time, more thought and more knowledge on FDA’s part to make a good decision about them. No sponsor feels good when FDA doesn’t know the science behind their product. Delays are inevitable while FDA catches up.

Medical and scientific information is rarely simple. Sometimes a protocol has a sound hypothesis, great supporting science, and logical inferences from similar studies, etc. It feels like running the clinical trials is merely a formality. …and yet the product ultimately turns out to have little efficacy or unexpected safety problems. Every FDA reviewer knows: assumptions based on early data can often be wrong. Biological complexity can, indeed, lead to surprises.

Conclusion. There is much that can be done to improve the FDA regulatory pathways, particularly for approvals, even though bottlenecks are inevitable.

FDA staff makes the decisions, which is how it should be. As individuals, their decisions cannot be isolated from workload, culture or complexity. Faster is possible, but it is important that people slow the process enough to be sure that decisions are both scientific and sound.

Steven

*   Adding new staff eventually helps. However, it can take upwards of two years for new hires to be trained, integrated, knowledgeable and experienced enough to lessen the workloads of others.

Complexity, Uncertainty, Unpredictability: Not Necessarily Bars to FDA Approvals        July 17th, 2011

In most discussions of science and medicine, there is an implicit assumption that the human body is a machine—complex and biological, but still a machine. If we could only understand all the mechanisms, processes and parts of that machine, then we could prevent and cure disease. Yet, the further we travel into the biology of life, the more complexity we find and the less certainty and predictability.

“The human body as a machine” is a metaphor, not a fact. Once we accept this, FDA Matters believes we can become liberated from unrealistic expectations about medical discovery and FDA’s role as a gatekeeper for new products that benefit patients.  Read the rest of this entry

The State of the FDA—January 2011      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. Read the rest of this entry

Medical Device Melodrama: A Great Story With a New Plot Twist

Two years ago, FDA Matters urged FDA and Congress to review the 510(k) approval process for moderate-risk medical devices. It was recognition that medical devices are different and that the review process had not been thoroughly re-examined in two decades.

I imagined tweaks, possibly substantial ones, to the 510(k) process. I also predicted that those working with the current system would be comfortable with the changes. FDA and industry have been proceeding along these lines…until last week when the Institute of Medicine (IOM) declared that the current system is so flawed that a new regulatory framework is needed.  

The FDA and industry discussions are being played out on several fronts: industry proposals, FDA proposals, and negotiations over a five-year extension of the Medical Device User Fee Modernization Act. FDA and industry both think the existing system can be improved.

They have different viewpoints. Industry wants a more predictable process that allows applications for moderate-risk devices to be submitted, reviewed and approved more quickly. FDA admits that evolving requirements and standards may be slowing reviews, but also feels the quality of company submissions is a major impediment to faster reviews.

The medical device industry has played its hand well. At their behest, Congress has sent a message to FDA: go slowly as you revise the medical device approval process, avoid mistakes, and do not create any unintended consequences.

FDA has been deft in its responses. It has talked about changes in abbreviated review processes, has proposed a new speedy “high innovation” review track, and been appropriately attentive to Congressional concerns that the process not be rushed. They have been forthright that user fees will need to increase significantly over the next 5-year period for the agency to meet its growing workload and keep pace with 510(k) reviews.

Industry is reluctant to pay increased fees, given their perception that FDA has failed to meet performance targets in the current user fee program. Industry has suggested that maybe a two-year user-fee reauthorization may be preferable to five-years, giving FDA a chance to implement reforms that would, in turn, justify the increased user fee revenue.

The back and forth discussions between industry and FDA have been heated at times, but always mixing disagreement with civility. That is not to minimize the degree of conflict or occasional harsh words. But by government standards, the two sides are working together well and there is reasonable hope of a satisfactory conclusion that will protect the interests of the American public and stimulate innovation in the medical device industry.

Enter the Institute of Medicine. This branch of the National Academy of Sciences had been commissioned by FDA to study the 510(k) approval process. Its long-awaited report was issued on July 29.

Surprisingly, IOM’s report didn’t provide any insights that would help the negotiating process. Instead, they concluded that: FDA should invest in developing a new regulatory framework to replace the flawed 510(k) medical device clearance process. An effective system could not be built on the current framework.

FDA immediately declared: “FDA believes that the 510(k) process should not be eliminated but we are open to additional proposals and approaches for continued improvement of our device review programs.” Industry, too, has a strong interest in improving, not replacing, the 510(k). They agreed with FDA’s rejection of the IOM report.

FDA and industry will continue working and disagreeing with each other, trying to reach agreement. They now have a common enemy: an IOM that insists that a perfect medical device review system should be created….while FDA and industry know that patching the existing one is the only realistic possibility. 

Steven

All FDA Stakeholders Affected by Medical Device Reforms      October 31st, 2010

There are so many visible, contentious FDA issues right now….that reform of the medical device approval process has received only a fraction of the attention it deserves. Other centers at FDA and non-device stakeholders need to be watching more closely. FDA Matters is. Read the rest of this entry

“No Surprise” That Medical Devices Are Under Scrutiny           October 1st, 2009

Five weeks ago, I wrote a column entitled, “Re-Evaluating the Medical Device Approval Process.” It 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

Re-evaluating the Medical Device Approval Process        August 27th, 2009

Earlier this year, a GAO report concluded that many high risk medical devices have not been adequately reviewed. In June, the House Health Subcommittee held the first of what may be a series of hearings on medical devices. The media appears increasingly interested in medical devices and is raising more questions.

All these events are a prelude to FDA and Congress undertaking a major re-evaluation of the product approval process for medical devices. It would be a relief if FDA could diagnose and treat its own medical device problems, leaving the Congress and the media to watch. Read the rest of this entry

FDA, Reorganization and the Four Crises

In previous posts, FDA Matters has expressed its disdain for efforts to solve problems by reorganizing government agencies. So, it may be surprising that I am giving Commissioner Hamburg an “A” for her recent reorganization of FDA’s senior management.

In the reorganization, she is addressing four crises that beset the agency: industry discontent with the medical product review process; public concern about import safety; implementation of the Food Safety Modernization Act; and Congressional concerns that the agency is inefficient in its use of resources. The new structure should drive better decisonmaking and greater productivity…. at a time when the agency is struggling to fulfill its growing mission and faces the potential for budget cuts.  

Until the beginning of this year, Dr. Hamburg has relied upon Dr. Joshua Sharfstein, a trusted deputy and alter-ego, to assist in managing the agency. In addition, he had served as a buffer between the agency and external forces, particularly Congress.  Instead of replacing Dr. Sharfstein, the Commissioner has chosen a new organizational approach that responds to the agency’s most difficult challenges:

Crisis #1: Growing discontent among the medical product industries. They allege that unreasonable FDA requirements and the agency’s overly-cautious approach to potential safety issues are keeping innovative and effective products from becoming available to patients. For more details, see my columns at:  http://www.fdamatters.com/?p=1428 and http://www.fdamatters.com/?p=1401.

Response: Create a new Deputy Commissioner for Medical Products and Tobacco and appoint Stephen P. Spielberg, MD., PhD, a distinguished physician and researcher and former dean of Dartmouth Medical School. He also spent 11 years in industry, working for Merck and then J&J.

In his new role, Dr. Spielberg will oversee the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research, the Center for Devices and Radiological Health and the Center for Tobacco Products.

The intent is for him to serve as a “senior partner” to the four center directors, facilitating decisions that might otherwise wait for the Commissioner. When appropriate, he would also stand-in for the Commissioner on their behalf. Right now, these center directors can’t be getting very much of Dr. Hamburg’s time and they are quite vulnerable on the Congressional side.

In addition to the stature he brings, Dr. Spielberg’s bio describes his research interests as: mechanisms of idiosyncratic adverse drug reactions, human pharmacogenetics and personalized medicine, and pediatric clinical pharmacology. This background is germane to the areas of industry concern about pre- and post-market review of medical products and also positions him to be one of the agency’s chief advocates for improvements in regulatory science.

Crisis # 2: The safety and quality of imported food and medical products.  The American people and Congress want safe products and expect FDA to use its very limited resources to make it so. For more details, see my column at: http://www.fdamatters.com/?p=1408.

Response: Create a new Deputy Commissioner for Global Regulatory Operations and Policy and appoint Deborah Autor, now Director of CDER’s Office of Compliance. Her “directorate” will oversee the Office of Regulatory Affairs (ORA) and the Office of International Programs.

The intent is to increase coordination and greatly reduce the number of decisions that would otherwise wait for the Commissioner’s availability. Just as importantly, the new structure brings together FDA’s overseas relationship and capacity-building successes with a tougher, more regulatory posture to assure that imports meet the same standards for safety and quality as domestic goods.

Crisis #3: Implementation of the new Food Safety Modernization Act to create a sophisticated risk-based food safety system. This is a complex multi-faceted task being made more difficult by inadequate funding.

Response: Continue the existing position of Deputy Commissioner for Foods, which oversees the Center for Food Safety and Applied Nutrition and the Center for Veterinary Medicine. Michael Taylor, who will continue in this post, has already demonstrated the advantages of Dr. Hamburg’s new organizational approach….by his general leadership and his representation of the agency with Congress on food issues.

Crisis #4: FDA’s ability to sustain and grow its FY 2011 funding level is being challenged in the Congressional appropriations process.

Response: Create a new Office of Operations, headed by a Chief Operating Officer (COO) to oversee human resources, facilities, information technology and finance. This will strengthen the agency’s ability to respond to Congress on administrative matters and, in particular, assure Congress that the agency is under tight fiscal management.

Conclusion: FDA has many problems, some of which are reaching crisis-proportion. While more resources are necessary, good leadership is essential.

Regardless of the demands, Commissioner Hamburg can never have more than 24 hours each day to address the agency’s needs. The new organizational arrangement—with four deputy commissioners providing span of control over most of the agency--seems well-suited to address this limitation.

Steven

Here is a link to read the Commissioner’s message to agency employees conveying the new organizational structure:  http://carl1anderson.wordpress.com/2011/07/14/major-reorganization-at-fda/.

I would hope in the future that FDA would post these types of communications directly onto the agency website, rather than relying on the Commissioner’s messages to be reprinted in newsletters and blogs.

Is the Human Body Just An Exquisitely Intricate Machine?

In most discussions of science and medicine, there is an implicit assumption that the human body is a machine—complex and biological, but still a machine. If we could only understand all the mechanisms, processes and parts of that machine, then we could prevent and cure disease.  Yet, the further we travel into the biology of life, the more complexity we find and the less certainty and predictability.

“The human body as a machine” is a metaphor, not a fact. Once we accept this, FDA Matters believes we can become liberated from unrealistic expectations about medical discovery and FDA’s role as a gatekeeper for new products that benefit patients.

Medical progress is the direct result of basic and clinical research conducted according to rules of scientific evidence and proof that have been refined over several decades. Our knowledge grows and our methods of discovery improve through our nation’s support for medical research at NIH and regulatory science at FDA, as well as billions invested by industry. 

Even still, we can’t consistently or logically explain why good scientific hypotheses tested in well-controlled trials often produce unimpressive clinical outcomes. Or why some medical products are clearly helpful for some patients in a clinical trial, but of no benefit to other patients who appear indistinguishable in baseline characteristics.  

Researchers, medical products companies and FDA would love to know the answers to these questions. Until we do, we are powerless to explain, predict or prevent the persistent and expensive discovery failures that are frustrating patients (and investors) who are desperate for medical successes.

We imagine the failures come from the imperfection of our knowledge. This is certainly true, but not a complete answer.

For several hundred years, physicists assumed the world was a machine, a so-called clock-work universe. This was logical and worked remarkably well to explain and predict physical phenomena. Then quantum mechanics demonstrated unpredictable, random, counterintuitive outcomes in the physical world. Ultimately, quantum mechanics increased our knowledge of the physical world, but only after its uncertainty and inconstancy became part of the calculations.

Similarly, there is no clock-work biology just waiting for us to discover all the mechanisms, processes and parts. Some complex biological responses may prove to be “explainable” only through unpredictable, random, counterintuitive activity.*

This may be true of individual responses, as well. If each of us has a unique fingerprint and a unique personality, why should it be hard to imagine that we each have our own biology that can never be fully defined or predicted, even if we could identify all the unique machine-like (e.g. genetic) elements?

If the metaphor (man as machine) is incomplete--and some degree of biological response is inherently unpredictable, uncertain, unknowable, as well as individualized—then FDA’s current standards of evidence and proof are not optimum for stimulating medical discovery. Many products that would benefit patients may not reach the market.

FDA Matters believes the FDA understands this is a problem, at least at the senior management level. However, the agency currently lacks the culture or impetus to incorporate complexity, uncertainty and unpredictability into its approaches to approving medical products. Admittedly, it also operates in an environment where it is gently praised for approvals when they occur….and harshly vilified later if an unresolved or unexpected issue (i.e. uncertainty) is a source of clinical problems.

Patients, physicians, researchers and medical products companies want an environment where a higher level of patient benefit can be achieved, even at the cost of a slightly larger degree of uncertainty and unpredictability. FDA needs to accept and act on this challenge or face rising discord with those stakeholders.

Steven

* Note: there is some work specifically on how quantum mechanics may explain certain biological processes, such as photosynthesis, but the analogy here is only that random, unpredictable biological responses play a very large confounding role in biological discovery, even greater than commonly attributed. See also: “Biology faces a quantum leap into the incomprehensible” http://www.guardian.co.uk/science/blog/2010/nov/12/biology-quantum-leap

Earlier columns from FDA Matters that are related:

Post-Market Safety: Getting the Most Out of Inferences That Aren’t Proofs  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. Read the rest of this entry

Scientific Reductionism and the End of Medicine      December 27th, 2009

“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.   Read the rest of this entry

Should FDA Have an Independence Day?

Years ago, while helping an incoming administration evaluate the public health service agencies at HHS, I became captivated by the idea that a series of reorganizations would solve many of the problems. I eventually snapped out of my trance and learned a life-long lesson: redrawing organizational boxes and altering reporting relationships are rarely effective solutions.

FDA Matters thinks that making FDA an independent agency will not make FDA more effective or more efficient. Although the idea is not truly harmful, proposing independent agency status is a seductive distraction from the tough job of improving FDA.    

Making FDA an independent agency has been proposed many times before. The issue has come up now because Jim Greenwood, CEO of the Biotechnology Industry Organization (BIO), included it last week among a number of proposals in his “state of the industry” speech. The industry is to be applauded for its commitment to new thinking, which focuses on ways to stimulate investment in biosciences, as well as improve FDA. While I think there may be some great ideas in BIO’s proposals, an independent FDA is not one of them.

An” independent agency” is a federal government organization that is not located within one of the 15 executive departments.  While most independent agencies are commission-type organizations run by a board, some are structured in a manner similar to the executive departments.  Examples include the Environmental Protection Agency (EPA), the National Aeronautics and Space Administration (NASA), and the National Science Foundation (NSF).

Being independent sounds great, but would it really help FDA become a more effective or better-resourced agency?

Independent agencies do not run independently of the President and the Executive Branch. Whether part of HHS or independent, FDA’s authority derives from the President, its money comes through the Office of Management and Budget (OMB), its manpower is cleared by the Office of Personnel Management (OPM), and its office space and purchases are controlled by the General Services Administration (GSA).

The chief advantage to FDA of being independent would be the ability to by-pass HHS leadership and bureaucracy. While HHS may be a problem, does anyone want to argue that it is so bad that it requires FDA to be uprooted? Historically, it is OMB that has pushed FDA budget requests downward and objected to FDA regulations. That wouldn’t change.

Being an independent agency does not necessarily improve access to the President. Because only heads of executive departments are cabinet members, the HHS secretary currently speaks for FDA when the cabinet meets.  The head of EPA has the status of “cabinet-rank,” along with OMB. I am not sure whether EPA gets much out of this honor, but similar standing for FDA would seem unlikely.  

Being an independent agency does not move an organization to a different appropriations committee. EPA is funded by the Interior, Environment and Related Agencies subcommittee. NASA and NSF are funded by the Commerce, Justice, Science and Related Agencies subcommittee. Independent or not, FDA will be funded as part of the Agriculture appropriations bill.

Independent agencies haven’t necessarily prospered, either. NASA had a good track record while it embodied a national aspiration, but it is clearly on the decline now. The National Science Foundation has never enjoyed the level of support given the National Institutes of Health.

That leaves us, perhaps, EPA as the embodiment of an independent agency with regulatory and scientific responsibilities. Has science triumphed at the agency because its independent status shields it from politics? It seems unlikely that anyone would make that argument. EPA, too, appears to be an agency on the decline.  

Maybe FDA would benefit from being an independent agency, although I don’t think so. At best, it would take enormous political effort to accomplish….energy that could be applied toward more effective ways to improve the agency.

Steven

Jim Greenwood, President and CEO, 2011 BIO STATE OF THE INDUSTRY ADDRESS. “Unleashing the Promise of Biotechnology to Cure Disease and Save Lives”  http://www.bio.org/news/speeches/2011_greenwood_convention_speech.pdf

A more in-depth description of the BIO proposals is at: http://www.bio.org/aboutbio/promiseofbiotech.pdf

List of independent agencies: http://www.usa.gov/Agencies/Federal/Independent.shtml 

Imports: FDA Issues a Cry for Help

No challenge to FDA’s mission looms larger than the rapid globalization of the world markets for food, drugs, medical devices and other FDA-regulated products.  By way of making this point, on June 20, the FDA released a special report, entitled “Pathway to Global Product Safety and Quality.”  

FDA Matters read the report carefully and heard a cry for help, if not an actual primal scream.

The report provides startling statistics on the recent and future growth of imports. A decade ago, 6 million shipments of FDA-regulated goods passed through our nation’s 300 ports; this year the number will quadruple to 24 million shipments.

The impact is across all areas of FDA responsibility. Currently, 60% of fruits and vegetables and 80% of seafood consumed in the US are imported. About 80% of active ingredients found in pharmaceutical products (not finished products) originated abroad. More than 35% of the US medical equipment market is imported devices.

The world is an unsafe place. Despite that, Americans are not going to restrict themselves to seasonal and locally grown food. Nor will we limit ourselves to the drugs and devices that can be developed and manufactured using only ingredients and parts that come from within the US.

We count on FDA to be sure our foods are safe and medical products safe and effective, regardless of origin.  However, imports inspire less confidence because there are hundreds of thousands of products made under local laws and business practices. We have much to be concerned as these numbers continue to grow.  

Even with additional resources, new legal authorities, international cooperation, improved strategies, complex databases and a bunch of good luck…keeping the American people safe will require the agency to invest several times more effort than it has in the recent past.

FDA’s plan is logical and appropriate:

1) FDA, in close partnership with its foreign counterparts, will assemble global coalitions of regulators dedicated to building and strengthening the product safety net around the world.

2) With these coalitions, FDA intends to develop a global data information system and network in which regulators worldwide can regularly and proactively share real-time information and resources across markets.

3) FDA will continue to expand its capabilities in intelligence gathering and use, with an increased focus on risk analytics and thoroughly modernized IT capabilities.

4) FDA will effectively allocate agency resources based on risk, leveraging the combined efforts of government, industry, and public- and private-sector third parties.

In short, FDA’s strategy is: let’s build the food, drug, and device equivalent of Interpol, then “let’s get the bad guys before they get us.”

This seems like a good approach, but it is not enough. In a speech in April, Dr. Murray Lumpkin, Deputy Commissioner for International Programs, referred to FDA-regulated products as coming from “roughly 200 countries, using 825,000 importers through over 300 US ports-of-entry.” How do you possibly manage that?   

I can’t claim to know the answer. Significantly increased funding for import safety is essential. A larger FDA overseas force is necessary to work with other governments and set up international standards. Tougher US laws are needed. We have learned, however, that it is hard to prevent problems when one or two business owners are prepared to willfully neglect standards and heedlessly adulterate food and drug products.

Our only choice is to respect what FDA has accomplished.....and give them the support and funding (and maybe some out-of-the-box ideas) to do an even better job.

Steven

FDA’s Report on Imports: http://www.fda.gov/AboutFDA/CentersOffices/OC/GlobalProductPathway/default.htm

Dr. Lumpkin’s presentation:  Viewing the world through the FDA international lens: Advancing domestic public health through international engagement. Slides from presentation given to membership of the Alliance for a Stronger FDA, April 26, 2011.

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

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