FDA’s Indifferent Attitude Towards the First Amendment

The FDA doesn’t care about the First Amendment rights of the companies it regulates. It cares even less about the “free speech” rights of those companies’ sales and marketing representatives.

And why should the agency care? One of FDA’s primary missions is to protect the public health and safety of the American people from illegal, adulterated and misbranded products. Doing so involves restraining food, drug, device and cosmetics companies from committing fraudulent and deceptive acts that are not protected by companies’ commercial free speech rights.  

Nonetheless, FDA Matters envisions opportunities for FDA and industry to broaden permissible product communications. The key is understanding history, not constitutional law.

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I recently participated in a forum at American University Washington College of Law on “Evolving First Amendment Protection of Commercial Speech” and offered up my mantra that constitutional analysis is largely irrelevant from FDA’s perspective. I said “largely” because FDA is still part of the federal government and can’t act arbitrarily. On the other hand, the agency mostly operates within the zone in which government is given the most leeway: where public health and safety is at stake and the threat is from commercial (as opposed to individual) speech.

History, not constitutional law, provides the best explanation. The sale of bad food and drugs—often accompanied by slick, deceptive pitches—goes back millennia and was even addressed as a problem in most ancient legal codes.

FDA’s own birth comes from a time when state regulation and inspection of food and drugs was minimal, inconsistent and often corrupt. It is hard for any of us to imagine what an unregulated market in food and drugs is like.  Yet, it is not so long ago.

The 1938 Amendments to the Food, Drug and Cosmetics Act gained popular support in part because of a traveling exhibit that portrayed the death and disability that resulted from patent medicines, counterfeit products, false medical and scientific claims, and adulterated and misbranded products. Lax to non-existent cosmetics standards were particularly singled out for their role in causing burns and blindness, as well as some deaths.

It is nice to imagine that this world is behind us, just an interesting piece of history. But it isn’t.

No industry regulated by FDA is immune from shoddy products, false claims, unscrupulous behavior and greed-induced threats to public health and safety.  I am sure that none of my readers count themselves among these “bad guys,” but they exist in the U.S., as well as globally.

Further, even the great and innovative companies—household names that we view with great trust—have often proven to be quite fallible. A certain amount of informal off-label promotion of drugs and devices is rightfully ignored--when good studies have been published, when the off-label indication is very close to an approved use, when assertions are made with great care about the extent of proven scientific knowledge.

In contrast, most of the off-label promotions that have resulted in billion dollar settlements with big-name drug companies have not been based on such close questions. Nor have they been the result of an individual salesperson crossing the line in some excess of enthusiasm.

Rather, the off-label promotions have been the product of marketing departments and sales managers who encouraged, empowered, or authorized the off-label promotion. There never seems to be a good answer as to who was supervising marketing and sales, which is why so many drug companies are now operating under government-negotiated corporate integrity agreements.

From FDA’s perspective, there are legitimate, well-documented reasons to scrutinize all companies: none are immune from the impulse to over-hype products to expand markets and sales beyond what FDA has approved. This is not a matter of FDA being over-fussy. It is the inevitable conclusion from about 4000 years of human commerce in food and drugs.

In the face of this, the First Amendment really has very little place. Commercial free speech does not extend to misleading statements, blatant fraud, or deception. FDA sees too much of this to ignore. 

FDA Matters believes the agency still has an obligation—but not a constitutional one--to clarify its standards, provide published guidance, and demonstrate acceptance that the Internet has fundamentally changed the nature of product promotion. The lack of FDA guidance on social media (first raised at an agency hearing 15 years ago) is particularly outrageous and the agency’s tendency to create de facto policy with enforcement letters is an abdication of responsibility.

The drug and device industry can also improve the situation. They need to stop looking at the current controversies in product promotion as noble causes involving sacred constitutional rights. If these industries have a claim to better treatment and clearer policies, it needs to be grounded in the contributions they make to improve public health and evidence of serious efforts to rid their companies of unscrupulous promotional practices.

Steven

I have written previously on some of the issues in drug and device promotion, as well as about opportunities for FDA and industry to reach accommodation:

Off-Label Promotion: Best Resolved by Congress, Not Courts     December 2012

On December 3, a federal appeals court ruled against one of the FDA’s untouchable restrictions on industry—thou shalt not promote the off-label use of pharmaceutical products. An industry that is little interested in constitutional law suddenly finds itself talking about the First Amendment. At stake: permitting off-label promotion undercuts the incentive for companies to thoroughly investigate the safety and efficacy of a drug for a second or third use.

Off-Label Uses Need to Become On-Label Indications  December 19, 2009

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

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

Creating an Internet communications policy for regulated medical product companies is so daunting that FDA has largely ignored the responsibility. November’s FDA hearing on social media was an important step, but offered no sign that new policy will be announced anytime soon. FDA needs a different approach. This is not a matter of a large, complicated problem with many facets. Rather, it is a number of smaller problems that can be addressed separately. 

Off-Label Promotion and Whistleblowing    September 9th, 2009

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

FDA Funding: Agency Mission "At Risk", Says Alliance President

FDA’s mission is “at risk” because of inadequate funding. So says Alliance for a Stronger FDA President Diane Dorman, testifying before the FDA Science Board. Her remarks come 5 years after the Science Board made a similar declaration, concluding that decades of underfunding had left FDA without the resources to fulfill its mandate and make science-based decisions.

Congress responded with more monies for the agency, but since then the FDA’s workload has increased even faster. The current threat to FDA comes from two sources: four major new laws to implement since 2009; and changes in the environment in which FDA operates, notably acceleration of globalization and increasing scientific complexity.

Ms. Dorman’s remarks are reprinted below. If you care about FDA, FDA Matters urges you to read her testimony, go to the Alliance’s site (www.StrengthenFDA.org) and join.

Testimony of Diane E. Dorman

President, Alliance for a Stronger FDA

Before the

Science Board of the U.S. Food and Drug Administration

February 27, 2013

Good afternoon and thank you for the opportunity to address the FDA Science Board.

My name is Diane Dorman and I am President of the Alliance for a Stronger FDA, as well as Vice President for Policy at the National Organization for Rare Disorders. The Alliance is a 200-member coalition of all FDA’s stakeholders—consumers, patients, health professionals, trade groups and industry. Our sole purpose is to advocate for increased appropriated resources for the FDA.

When we started in 2006, FDA appropriations stood at slightly less than $1.5 billion for an agency tasked with overseeing 100% of drugs, vaccines, medical devices, and personal care products and 80% of our nation’s food supply. Altogether, the products and industries regulated by FDA account for nearly 25% of all consumer spending in the United States.

In short, FDA was the victim of decades of underfunding. It was quite small, despite its vital, complex world-wide responsibilities. Presidents weren’t asking for nearly enough money for FDA and Members of Congress were responding by giving the bare appropriations that had been asked for.

The Alliance’s goal was to change this situation by galvanizing the FDA’s broad stakeholder community to focus attention on the consequences of underfunding. We never doubted the accuracy of our analysis or the importance of our cause.

Nonetheless, it was immensely helpful when--18 months after our founding--the FDA Science Board released its own report in November 2007. As the media described it---the FDA’s own Science Board evaluated the agency’s capacities and responsibilities and declared that the agency’s mission was “at risk.”  The word “crisis” was often used and was an appropriate description of the situation.

Subsequently—and with the Alliance’s broad stakeholder advocacy—the prospects for FDA improved. Policymakers acknowledged the underfunding and acted aggressively to reverse it.

Today, in FY 13, the FDA receives slightly more than $2.5 billion in appropriated funding. This amount, might have met the FDA’s funding needs in late 2007 when the Science Board report was issued…BUT NOT NOW.

Today, $2.5 billion is dramatically less than the amount the FDA needs. For reasons I will describe in my testimony, the agency’s mission is again “at risk.” Even without the possibility of funding cutbacks, the American people will lose if FDA does not receive increased funding.

FDA Responsibilities Grow Each Year Because Congress Enacts New Laws

Two months before the Science Board declared FDA to be “an agency at risk,” the FDA Amendments Act of 2007 was signed into law, renewing the prescription drug and medical device user fee programs. It added a slew of new responsibilities, notably in food and drug safety, regulatory science, clinical trial registries, and establishment of a program for risk evaluation and mitigation strategies for new drugs.

The new responsibilities--combined with delays in funding of existing and new programming--had severe consequences. For example, FDA’s efforts in the critical area of drug reviews and approvals were slowed substantially for nearly two years, as demonstrated by this CDER chart.

The message from this experience is clear, albeit not surprising: new laws take enormous resources to implement. Once implemented, they permanently increase agency responsibilities.

Since 2007, Congress has identified a number of new needs that fall within FDA’s jurisdiction. At least six new laws have been passed in the intervening five years:

• Family Smoking Prevention and Tobacco Control Act (2009)
• Biologics Price Competition and Innovation Act (2010)
• Secure and Responsible Drug Disposal Act (2010)
• Combat Methamphetamine Enhancement Act (2010)
• Food Safety Modernization Act (2011), and
• FDA Safety and Innovation Act (2012), including re-authorization of the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act

This is hardly the end of it. Congress is already looking at a number of legislative initiatives for 2013, covering topics such as:

• Bio-security
• Track and trace/counterfeit products,
• Drug compounding, and
• Drug shortages.

 In addition, this year’s legislative requirement--renewal of two Animal Drug User Fees--is widely seen as a vehicle for other legislative mandates that FDA will need to implement.

The problem is not solely Congress’ urge to legislate. While some of our Alliance members may quibble with some of the new programs and requirements, overall I believe there is strong public and stakeholder support for Congress addressing unmet needs and emerging challenges. We all want safe foods and safe and effective medical products.

Ultimately, the real problem is Congress’ failure to acknowledge FDA as a funding priority despite the austere budget environment. Transforming FDA’s mission and responsibilities needs to be met by the necessary resources to do the job well. The current appropriations level is totally inadequate to make up for decades of underfunding AND all of the new laws enacted since 2007.

FDA Responsibilities Grow Each Year Because of Globalization and Scientific Complexity

Even were Congress not active in legislating new mandates for FDA, the agency’s mission and responsibilities would grow enormously each year for reasons unrelated to new laws. While the list is long, my remarks will concentrate on two: globalization and increasing scientific complexity.

One of FDA’s highest priorities since the Science Board report has been to re-align to adjust for the accelerating globalization in all product categories overseen by the agency. While there is no one way to fully convey the enormity of this shift and the resources required, I offer the following sample of key facts:

•      Food Imports are growing 10% annually. Altogether, 10-15% of all food consumed in the U.S. is imported. This includes nearly 2/3 of fruits and vegetables and 80% of seafood.

•      Device Imports are also growing about 10% annually.  Currently, about 50% of all medical devices used in the US are imported.

•      Drug Imports are growing even more quickly, about 13% annually.  Approximately 80% of active pharmaceutical ingredients (API) are manufactured abroad, as are 40% of finished drugs.

Inspections at U.S. ports-of-entry are critical, but ultimately less than 2% of shipments can be inspected. The better alternative--the one encouraged by Congress and chosen by FDA--is to increase foreign inspections and to establish foreign offices to work globally to improve the standards and quality of products entering the U.S.

The value of this approach cannot really be quantified. We know that the cost of illness, death and lost markets--from just a single bad actor in a single food category--can cost as much or more than the entire investment we put into FDA’s food safety activities. Drugs and devices are harder to track for a variety of reasons, but there is no reason to doubt a similar effect.

In contrast to globalization, greater scientific complexity is diffused into every part of the agency and its mission. That makes dealing with it less visible, but doesn’t make it any less costly.

FDA has adopted several approaches, many from the FDA Science Board Report. These include creation of a commissioner-level science office, investment in regulatory science, expanded and more intensive training, changes in time and manpower allotments for complex assignments, and significant reworking of the drug and medical device approval pathways.

Specifically, we have identified five areas that FDA is working on to improve the review process and respond to more complex science. Each comes at a cost in additional dollars and manpower:

•      Sponsors Need More Meeting Time and Other Feedback from FDA

•      Product Applications Require More Patients, Study Sites and Analysis

•      Enhanced Timeliness and Consistency of Product Review is Paramount

•      Expansion of Pre-and Post-Market Safety is Essential

•      Sustain and Increase Core Programs That Enhance Innovation, Speed Approvals

Further, safety inspections have also become more complex—requiring more scientific training, more preparation and, often, more time during the inspection itself.

FDA: An Agency Still Very Much “At-Risk” for Lack of Adequate Funding

It is important to recollect that FDA is a staff-intensive organization. More than 80% of its budget is devoted to staff-related costs. Of the remainder, rent and utilities are fixed costs that must be paid first. There is little grant and contracting to cut.

Sequestration is the most immediate threat to the FDA’s already-inadequate funding. Just a few days from now, the agency faces a loss of 5.1% of its FY 13 (current year) budget. This is the nominal rate. The Alliance’s analysis, confirmed by OMB testimony, is that the actual impact will be close to 9%.

Even if sequestration is avoided, FDA faces challenging funding battles in FY 14 and beyond.

If cuts occur now or in FY 14—or even if the agency budget stalls and fails to grow over the next few years:

•      food will be less safe and consumers put at risk,

•      drug and device reviews will be slower, conflicting with promises made to consumers and companies,

•      problems with imports and globalization will become more numerous, and  

•      critical efforts to modernize the agency and improve its support for innovation will stall.

Is FDA’s mission again at risk? Absolutely, yes.

And those who have the most to lose are the American people.

FOR MORE INFORMATION: www.StrengthenFDA.org or contact Steven Grossman of the Alliance staff at (301) 539-9660, sgrossman@strengthenfda.org.

The State of the FDA---February 2013

FDA is the only federal agency that touches the lives of every American several times every day. Despite this, FDA will probably not be mentioned when President Obama delivers his State of the Union (SOTU) address to Congress on February 12.

Instead, FDA Matters provides its third annual “State of the FDA.” As reflected in last week’s column, I think that FDA did well in 2012. And 2013 is very promising. Potential funding cutbacks are the primary impediment to future successes.

Strengths. Once again, FDA’s most important strength is the dedication of the agency’s staff.   Last year, I viewed staff’s efforts as invisible and largely unappreciated. I believe that more recognition is being given to the staff—driven by a banner year for drug approvals, progress on implementation of the Food Safety Modernization Act (FSMA), and the narrowing of the FDA-industry chasm on medical devices.

Another key strength is a growing self-confidence within the agency that it can solve problems and not just tread water to survive. Over the years, FDA has often spent extended periods in a bunker posture—harassed, defensive, waiting to be forced to act, speaking too softly for fear of unleashing criticism.

Over the last year or so, there appear to be many more instances where the agency has taken the initiative. To be sure, they have talked to stakeholders and checked in with experts first, but then they have acted by making an announcement, releasing guidelines, creating new policies or intervening to solve a problem. 

Both of these strengths have been heightened by continuity of leadership. In May, Commissioner Hamburg will have held the job for four years, the longest tenure of a commissioner since the mid-1990’s. It also feels like there have been fewer top-level personnel changes. In the past, constant changes have undercut achievement and sapped morale and self-confidence.

Weaknesses. Congress has given FDA an ever larger role without providing the funds to do the job. As a result, and despite the agency’s best efforts, important initiatives and activities are not getting the resources they need. Inadequate funding is the most pressing weakness of FDA.

There are really three parts to the problem:

• three new laws over the last three years need to be implemented: food safety (FSMA), biosimilars (BPCIA) and user fee amendments (FDASIA).
• Congressional pressure to do more in complex, expensive areas, such as medical innovation, safety, medical countermeasures, track and trace/counterfeit products, drug shortages and compounding.
• FDA’s job is getting bigger, tougher and more resource-needy each year independent of whether Congress gives them new responsibilities. This emanates from greater scientific complexity, industry globalization, and increased workload (meetings, NDA’s, etc).  

 As will be discussed further under “threats,” there is a strong potential for cuts in funding that would take FDA far below even the current inadequate level.

Opportunities. Dr. Hamburg has made it a priority to improve the agency’s scientific bench strength—better credentials, better training and better tools. The next step—still very much a work in progress—is to integrate patients and human concerns into FDA decisionmaking.  

The agency understands the importance of this opportunity, but underestimates the tension between patient viewpoints and the scientific process. The task is more nuanced than current efforts suggest….and the risk is that patient-input becomes a box that gets checked, rather than a meaningful improvement to the agency’s science-based decisionmaking. 

In a different vein, FSMA is a well-conceived solution to achieving a safe food supply in the 21^st century. The opportunity is enormous, the blueprint largely drawn, and only the inadequacy of funding a substantial barrier to success. I don’t know if the American people will ever properly appreciate the effort required by FSMA or the value its implementation adds to protecting the food supply. Without that public feedback and support, the challenge for FDA will be to continue to see FSMA as the transformative opportunity it is.

Threats. The largest threat to FDA is the potential for immediate and long-term cuts to the resources available to the agency. On March 1, FDA may lose more than 5% of its current-year funding. Even if that cut is averted, funding for domestic discretionary programs is going to be under pressure for the next decade.  

The increasing reliance of user fees for agency funding is also a threat. Including tobacco and the new generic drug user fees, the FDA is now 40% funded by industry. Those fees are put to good use and are not, by themselves, a problem. Rather, American taxpayers need to preserve--if not actually increase--their stake in funding FDA. There are philosophic reasons for this (the integrity of the agency) and practical ones (a large part of FDA’s mission cannot appropriately be funded by industry).

Conclusion. FDA’s strengths and opportunities are immediate and powerful...perhaps more so than in many years. The challenge is to preserve and expand the funding, particularly taxpayer funding, to support the agency. Trying to “do FDA on the cheap” is both a weakness and a threat to the agency and the American people.

Steven

FDA Post-Election: Continuity and Progress Likely to Mark 2013

Looking back over the last 40 years at FDA (as I have), there are three characteristics that create a more progressive environment at the agency: continuity of leadership, presidential support, and increased funding. For FDA in 2013 (as the saying goes): 2 out of 3 ain’t bad.

In particular, medical innovation seems poised to flourish in an FDA environment where there is continuity of policy and leadership, instead of a new team learning the ropes. I explore this and other themes in the latest issue of Pharmaphorum.com. You can read my thoughts at: http://www.pharmaphorum.com/2013/01/29/fda-post-election-continuity-and-progress-likely-to-mark-2013/.

Steven

Off-Label Promotion: Best Resolved by Congress, Not Courts

On December 3, a federal appeals court ruled against one of the FDA’s untouchable restrictions on industry—thou shalt not promote the off-label use of pharmaceutical products. An industry that is little interested in constitutional law suddenly finds itself talking about the First Amendment and whether, and on what grounds, the case will be appealed. 

Meantime, the court’s decision left FDA Matters torn between cheering and booing. Patients are poorly served if their doctor is prescribing drugs without being able to tap into all sources of relevant knowledge. However, permitting off-label promotion undercuts the incentive for companies to thoroughly investigate the safety and efficacy of a drug for a second or third use.

Benefits and abuses of off-label use. Off-label use is a medical necessity--an acknowledgement that the current inventory of approved drug indications is woefully inadequate to deal with the breadth, complexity and individual idiosyncrasies of human disease. All patients—but particularly those with rare diseases—would suffer grievously if physicians did not have flexibility with regard to the off-label use of pharmaceutical products.

Some off-label uses are supported by extensive published scientific studies, but no corporate entity or individual has the financial incentive to underwrite the FDA approval process. Many other off-label uses are in the evidence-thin realm of “we tried it for lack of alternatives and the patient seemed to be better.” The benefits of specific off-label uses are evaluated by published collections of expert opinions (known as compendia). The practice of prescribing off-label is monitored and approved (inconsistently) by payers.

If doctors can legally prescribe a particular drug for a specific use (albeit off-label), then companies ought to be able to provide “truthful and not misleading” information that they possess. Arguably, they can do so now (via reprints of scientific articles), but only in response to a physician’s request. This is a very limited means of disseminating information.*

The Struggle to Incentivize Approval of Second and Third Uses of Approved Drugs.  As I have written previously, it is in the public interest for off-label uses to become on-label indications. The agency is remarkably positive about deferring to the professional judgment of physicians, but would like to see every off-label use get the scrutiny necessary to assure it is safe and effective.

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

Unrestricted promotion of off-label use would definitely undercut FDA. In such an environment, I believe that many companies will “game” the system by finding a comparatively easier first use for approval, then let sales for other uses build off-label. Nor do I think companies are universally concerned about “litigation commenced under states’ product liability laws for ineffective products and the resulting reputational harm from such lawsuits.”**

Congress, Not the Courts, Should Set the Ground Rules. By their nature, courts pick winners in these situations; they don’t create rules that maximize two competing public goods. I have been taught (and believe) that litigation is almost always the worst and most inefficient way to solve a problem. I consider this an example.

To achieve appropriate policy, Congressional action is needed.***  For many reasons, this may never happen. However, it is the only way to reconcile the competing and valid positions held by industry and FDA. I encourage Congress to try to bring peace to this area of contention.

Steven

*   Even without permissive policies, company sales and marketing practices are a source of constant problems, as discussed in Off-Label Promotion and Whistleblowing.

**  For those seeking a more legal and enforcement-oriented perspective on the court’s decision, including a number of critical nuances not covered here, I recommend  the FDA Law blog’s current analysis. The paragraph and the quote are based on that article’s description of why some commentators argue that off-label promotion is not a threat to FDA’s drug approval process.

***  A thorough and forthright FDA administrative proceeding (followed by guidelines or regulations) could also clear the air. This is unlikely because the agency generally lacks objectivity on a topic it feels so strongly about, plus the agency tends to respond to court directives, not act to break judicial deadlocks.  On a similarly thorny issue, the agency’s failure, after more than 15 years, to articulate sound policy (or any policy) on social media is indicative of why I don’t think the agency can resolve the “off-label promotion” issue by itself.

Drug Product Pricing 101: A Fundamental Issue Revisited

Eighteen months ago, FDA Matters wrote about the firestorm created by KV Pharmaceuticals’ decision to “charge $1500 per dose for Makena, a drug that reduces the risk of pre-term delivery in pregnant women. The same therapy has been compounded in pharmacies for years at a cost of $10 to $30 per dose.”

Three months ago, K-V Pharmaceuticals filed for bankruptcy protection. This week, a federal judge rejected the company’s last-ditch effort to save itself by ruling that FDA had discretion to permit continued compounding of the drug.  

No one knows the “right price” for this or any other drug, but there are ways to rationally evaluate and guide product pricing decisions. Apparently, not everyone in industry knows this.

Value/pricing analysis helps companies determine an appropriate and defensible price. Some large pharmaceutical and biotech companies have the in-house capacity. Generally, small and medium-sized companies will use external consultants or consulting firms to assure a professional, unbiased process. However, it seems clear that some companies don’t bother to undertake a sophisticated analysis prior to setting prices.

In recommending a particular price or a range of prices, the consultant or consulting firm will look at three or more approaches…and then work with the company to make judgments about “best fit” or achieving consensus among a range of possible prices. Here are three examples of the approaches a consulting firm might use:

·         “Value-added” pricing. This values the company’s product (and supports a price) based on replacement or enhancement of current treatments in the same clinical category. In the case of an asthma drug, a value-added pricing approach would look at “savings” achieved by the reduction in hospital days, emergency room visits, and disability. Other system savings might be considered, such as the benefit of added compliance, the reduction in concomitant drugs, fewer side effects, etc. Any system “costs” (e.g. loss of productivity, treatment of adverse events) are also included in the model.

·         “Cost plus” pricing. This values the company’s product based on the development costs and achieving a reasonable return on investment (ROI).  This may include real, imputed and opportunity costs. Thus, the “cost” component is likely to be greater than the company’s actual expenditures. Pricing in this approach is highly dependent on the ROI variable and the likely timeframe before newer products or generics cut deeply into sales.   

·         “Comparable value” pricing. This looks at the pricing of products that have comparable characteristics or benefits, but may be in different clinical categories than the company’s product. For example, a new recombinant vaccine might be compared to the pricing increment when another vaccine was “upgraded” to a recombinant version. In the case of a unique therapy or breakthrough (e.g. a new drug for Huntington’s disease), an analogy is drawn to the most relevant situations in other treatment areas.

The analytic models are adjusted for a host of variables, such as the size of the potential market, the degree and rate of market penetration, and the likely product lifecycle. As noted, there is usually a consensus-building process where the consultant works with the company to determine a price that factors in the results of the different analyses.

Each consulting firm has its own approach, a proprietary model to distinguish their services from competing firms. These models add value and reach far beyond the basics I have described above.

Now you have an idea of how it’s done….or should be done. This analytic process should reduce objections to the pricing of a product and also prepare a company to defend its pricing decision. Controversy cannot always be avoided, but shareholders, patients, and payers are always going to respond better to companies who have backed their pricing with sound reasoning.

Steven

Disclosure: I am not affiliated with any consulting firm that does pricing analysis, nor is this a service I provide. However, if you are interested in the names of a few firms that are in this business, please contact me by e-mail at sgrossman@fdamatters.com.

FDA and the Republican Platform: Harsh Words, Unclear Intent

Between “the FDA today” and the “FDA in 2013” stands a U.S. presidential election—one that appears to offer Americans a choice of philosophy about the size of government and the role of regulatory agencies.  FDA Matters’ previous blog laid out some very early comparisons between the candidates on regulatory policy and the role of Commissioner.

Along with nominating Mitt Romney as its Presidential candidate, this past week’s Republican Party convention produced the party’s 2012 Platform --a series of policy positions to guide the campaign. FDA reform commands about 180 words—laying out the case for aggressive (although unspecified) changes.

Campaigning vs. Governing. Before looking at the specific words and thoughts in the Republican Platform, it is worth providing some context. One of the enduring lessons of my 50 years watching American politics is that there is often a profound difference between campaigning and governing. The Platform is put together by party delegates from every state, working with subject-matter experts and overseen by the Presidential nominee’s team.

Mitt Romney would not allow a party platform with which he disagreed. However, should he be elected, he will not feel bound by the positions taken in it. That said, the Platform’s words on FDA reform appear to generally reflect other things that Mr. Romney (and his surrogates) have said on other occasions.  What he will want to do about FDA if elected (or even what he will be able to do) is unknown.

The 2012 Republican Platform on FDA Reform. The  platform report states:

America’s leadership in life sciences R&D and medical innovation is being threatened. As a country, we must work together now or lose our leadership position in medical innovation, U.S. job creation, and access to life-saving treatments for U.S. patients. The United States has led the global medical device and pharmaceutical industries for decades. This leadership has made the U.S. the medical innovation capital of the world, bringing millions of high-paying jobs to our country and life-saving devices and drugs to our nation’s patients. But that leadership position is at risk; patients, innovators, and job creators point to the lack of predictability, consistency, transparency and efficiency at the Food and Drug Administration that is driving innovation overseas, benefiting foreign, not U.S., patients.

We pledge to reform the FDA so we can ensure that the U.S. remains the world leader in medical innovation, that device and drug jobs stay in the U.S., that U.S. patients benefit first from new devices and drugs, and that the FDA no longer wastes U.S. taxpayer and innovators’ resources because of bureaucratic red tape and legal uncertainty.

While the rhetoric expressed in the platform is not new to FDA Matters—it has a certain menacing quality when it is “the voice” of an American political party as opposed to a “government is bad” Tea Party leader or a frustrated medical device executive.

It begs the question: didn’t America’s global leadership in the life sciences come in part from the FDA’s competence and high standards and not despite them? I would emphatically say “yes,” but there certainly seem to be others that would answer “no.”

Harsh Words for FDA: Consistent with the Overall Tone of the Platform. FDA definitely needs some improving—as past FDA Matters’ columns have made clear. I try to stay constructive and be mindful that complex problems rarely have simple solutions.

Perhaps more to the point, FDA—by itself and working with Congress—seems to have made enormous strides over the last few years. One could even argue that FDA is already working hard on implementing a “pro-innovation” and “create more predictability” agenda that Republicans should like.

This, perhaps, brings us full circle around to our prior warning not to read too much into campaign rhetoric.

FDA reform is two paragraphs in a 50 page document—one that stridently and broadly promotes smaller government and fiscal prudence, almost regardless of consequences. For example, on budget issues, the Platform calls for “Reining in Out-of-Control Spending, Balancing the Budget, and Ensuring Sound Monetary Policy.”

When government is cast as incompetent and out-of-control, it leaves little space to say good things about federal agencies, such as FDA, that work hard, are underfunded, and are committed to improving their performance. When it comes to FDA, we can be hopeful that Republican candidates are more judicious while campaigning…..and, if elected, more restrained in their actions than their rhetoric suggests.

Steven

Why Orphan Drugs are a Key Part of Pharma’s Future

I was recently interviewed about orphan drugs for the British website, “pharmaphorum” and thought my readers might be interested. Here is a sample:

HB: How has the orphan drug space changed since the introduction of the Orphan Drug Act 1983?

SG: There is really no way to compare the situation. When we passed the Act, we hoped to stimulate the development of a few drugs that would make a difference in people’s lives. No one foresaw that we were creating what would become a multi-billion dollar market segment in which companies might compete fiercely to be first. The timing was also fortuitous — in that the Act was adopted just as our capabilities in biotechnology began to grow and the two movements are closely intertwined.

The full interview is as at: http://www.pharmaphorum.com/2012/08/22/fda-matters-orphan-drugs-key-part-pharmas-future/.

Steven

2012 Mid-Year Report on FDA: Opportunities, Threats and Accomplishments

So much is going on at FDA right now, that it is difficult to pick just one topic for this week’s FDA Matters. Instead, we are going to take a quick tour of some “hot spots” at FDA and how they might affect the agency over the remainder of the year and beyond.

Please read on…there is something for everyone in the topics covered.

The “Lost” FSMA Regulations. At the very end of 2010, Congress passed the Food Safety Modernization Act (FSMA). The law was intended to fundamentally re-set the term under which FDA acts to assure a safe food supply. It focuses on preventing problems, rather than fixing or limiting them afterward. FSMA provides the agency with new authorities and additional resources consistent with FDA’s role of overseeing a global food supply.

The first provisions of FSMA went into effect in January 2012 and additional requirements become effective this month. To guide implementation of these requirements, FDA has produced four draft regulations. None have been published; all are stuck in the review process at OMB.

The mystery of the “lost” FSMA regulations prompted two reporters to call me this past week and ask: is OMB holding back these (and other) regulations until after the election, presumably for political reasons. I couldn’t see an electoral connection, plus the first of the proposed regulations was submitted to OMB in December 2011, a very long time before the election.

The “lost” FSMA draft regulations are worrisome by themselves, but especially with so much else going on at FDA that may require OMB review.  

FDA’s Drug Safety Monitoring Program Hits Target, Will Expand. We don’t read often enough about the successes that come from cooperation and hard-work at FDA. In the 2007 user fee reauthorization legislation, Congress directed FDA to construct a nationwide electronic post-market safety monitoring system that would allow FDA to examine tens of millions of patient records to discover or refute possible safety concerns about FDA-approved products.

In a recent edition of FDA Voice, the FDA’s own blog site, the agency reported that the monitoring system, called “Sentinel,” now has access to the de-identified medical and/or insurance records of about 126 million Americans, collected through 17 data sources (e.g. VA, Kaiser). Sentinel is definitely still a “work in progress” on a number of levels, but it will be of increasing value as medical products become even more complex and even more integral to medical care.  

Funding Ups and Downs. Despite Congressional reauthorization of the prescription drug and medical device user fee programs, the budget authority (BA) (taxpayer-funded) portion of FDA’s budget is still the bulk of the dollars. The Senate has included a small increase in BA funding for FDA for FY 13; the House has proposed a small decrease.

Of compelling concern is the strong potential that FDA (along with all federal discretionary funding programs) will be hit with a 7% to 10% “sequestration”—an across-the-board cut--on January 2, 2013. This would reduce the agency’s budget  by between $175 million and $250 million in FY 13. This is FDA’s "contribution" to saving the federal budget more than $1 trillion over the next 10 years. 

If sequestration occurs, FDA will try to avoid lay-offs by shifting more employees from taxpayer funding to user fees. In that case, increases in user fee income will be backfilling the BA cuts, rather than contributing to real agency growth. Yet, FDA will be obligated to undertake the user fee-driven activities and meet the law’s performance measures as if the new user fee money was paying for additional staff.

User Fee Reauthorization Will Drive, Not Disrupt, the Agency Agenda. Five years ago, the user fee reauthorization (PDUFA 4) didn’t become law until late September, a few days before fiscal year 2008. The combination of immediate deadlines, delays in collecting user fees, and insufficient trained personnel set off a series of problems that took three years to fully overcome.

This time, Congress finished the reauthorization in late June and FDA has been planning the law’s smooth implementation for months. Instead of panic, CDER in particular, seems to be feeling good about the path forward and the many changes called for in PDUFA 5. 

Dr. Janet Woodcock, head of CDER, has listed her priorities as, among other things: timely transition to new user fee requirements (including start-up of new generic drug and biosimilars user fees); dealing with drug shortages, moving forward on data standards and new IT support systems, and advancing regulatory science.

Results are still what matters and there are always critics….but a sense of optimism at CDER is always welcome.

 Steven

User Fee Reauthorization—Critics Come Out Before the Ink Is Dry

The House passed the final user fee reauthorization legislation last week and (as of this evening) the Senate has also passed the bill. It will now go to the President for signature. FDA Matters says: well done, Congress! Despite my fear of delays and bickering, you completed this process on time and with broad bipartisan support.

However, critics are already emerging, "before the ink is dry.” The advocacy group, Public Citizen, is complaining that drugs and devices will be less safe as a result of the legislation. At the same time, Dr. Scott Gottlieb, a former FDA official, has published an essay arguing the legislation doesn’t go far enough to expedite review of drugs for serious medical conditions.

The Public Citizen Health Research Group’s critique is to be expected. They were founded 40 years ago and have consistently been critical of the agency’s handling of drug and medical device approvals. Their continued opposition rests on three primary points:

1. User fees created by PDFUA have created a conflict of interest because the agency is funded in part by the industry it is supposed to be regulating.
2. This has led to poor quality reviews of drugs and thus the release of dangerous products. Since PDUFA, more drugs have been approved and then banned, causing needless deaths/injuries.
3. Working conditions at the FDA have plummeted since PDUFA, resulting in high staff turnover and sweatshop-like conditions.

I, too, wish that FDA were 100% taxpayer funded, but user fees are reality, a compromise that makes it possible for FDA to have the funds to operate. There is no evidence of bias generated by the fees, plus Americans would be far worse off if a quarter of FDA’s budget (user fees) were to suddenly disappear.

With regard to the quality of drug reviews, I see no evidence they’ve declined and the methodology of the PDUFA/drug approval study is suspect. Working conditions and staff turnover are definitely a matter of “compared to what?” I don’t think FDA does badly when you look at it that way.

Far more of a surprise is the essay by Dr. Scott Gottlieb, former deputy commissioner for medical and scientific affairs at FDA.  Using primarily examples of orphan drugs, he argues that FDA is over-focused on long-term safety and on reining in physician prescribing practices. As a result, the agency is stifling medical innovation and disregarding the needs of patients with serious medical conditions. I don’t agree with him on a number of points, but you can hit the link and judge for yourself.

His argument might be more compelling if he referenced large-market products, such as pain killers and obesity drugs. However, by using orphan drug examples, Dr. Gottlieb winds up attacking the new user fee reauthorization legislation as insufficient to expedite review of drugs that target serious medical conditions.

FDA Matters has already praised changes affecting orphan drugs and accelerated approval. My view is shared by much of FDA and the FDA stakeholder communities; for example: FDA and other leaders, BIO, the National Health Council and the National Organization for Rare Disorders.

So, why attack PDUFA’s bold new efforts on behalf of orphan drugs and patients with serious medical conditions? 

To Dr. Gottlieb, these “legislative fixes” are inadequate because “the agency’s staff will still have wide discretion in determining when to employ these [new] tools.” If overcautious, reluctant reviewers are still in charge, then even Congressional changes in the FDA law will not improve the review process to benefit patients with serious medical conditions.

His proposed solution is to remove the approval of drugs from the review divisions and give that authority to a panel of senior scientists with the “experience and stature to exercise the policy judgment required to make careful decisions about how to weigh risk and benefits…” An even better solution, in his mind, would be to follow the European Medicine Agency’s model in which staff does analysis and evaluation, but the final approval decisions are made by politically-appointed individuals.

I think both of these approaches would severely weaken—if not outright undermine—the existing FDA approval process. This would be particularly unfortunate now, when the new legislation empowers agency leadership to lower the barriers, so that review staff can be more flexible and apply new approaches to evaluating therapies for serious medical conditions.

Conclusions. Before more drastic actions are considered, let’s give the new user fee reauthorization legislation time to work. The ink isn’t even dry!

Steven

Many readers were out of town this past Friday and may have missed:

Biosimilars Update: Keys for the Next Year and Beyond   June 22nd, 2012

The biosimilars market in the U.S. will not grow large overnight. By a decade from now, sales of biosimilars will be creating new winners and losers in the overall biopharmaceutical marketplace. In light of this, I was recently asked: what should a developer or investor be looking to achieve over the next year in the area of biosimilars? What should they be looking to achieve in the years after that?  Read the rest of this entry

Biosimilars Update: Keys for the Next Year and Beyond

The biosimilars market in the U.S. will not grow large overnight. However, over the next 4 to 10 years, a lot of companies are going to become players. During this same period, health plans, pharmacy benefit managers, Medicare, and Medicaid are going to start reaping savings by buying less expensive biosimilars. By a decade from now, sales of biosimilars will be creating new winners and losers in the overall biopharmaceutical marketplace.

In light of this, I was recently asked: what should a developer or investor be looking to achieve over the next year in the area of biosimilars? What should they be looking to achieve in the years after that?

Over the next year: Assuming the U.S. biosimilar law survives the upcoming Supreme Court decision (concerning the constitutionality of the President Obama’s health reform program), then the last roadblock to creating a biosimilar marketplace in the U.S. will have been eliminated.

The key, then, becomes: how quickly can FDA complete the multiple steps  necessary to establishing a viable system for evaluating and approving biosimilars. Here are some key indicators to watch in judging the agency’s progress:

• the number of investigational new drug applications (IND's) being issued for biosimilars, which would be a “leading indicator” of slowdown or snags in FDA’s initial intake process;
• publication of draft policy guidances dealing with critical details such as nomenclature, label warnings, unique names, etc. (until these issues are settled, FDA will be reluctant to approve anything);
• revised estimates of how many fees the FDA expects to collect each year under the new biosimilars user fee program (a rough gauge of FDA’s view of its timeframe for approvals).

For those looking to be active in the biosimilars market, the next year provides an opportunity to build and strengthen relationships with payers (especially purchasing groups). Payers are going to be focused on the strength of clinical, animal and laboratory data comparing the biosimilar to the original biologic product. There will be a need for biosimilars to be offered at a discount to the cost of the original, but high-quality biosimilars with a 15%-20% discount will dominate the market over biosimilars of questionable quality with 30% to 40% discounts.

Similarly, it is not too soon for companies developing biosimilars to start working with practicing physicians—to calm their fears that they will be forced to use inferior biosimilar products that will result in treatment failures. While payers, not physicians, will drive this market—payers will avoid products likely to generate criticisms and resistance from physicians.  

Finally, for those interested in the biosimilars market--stay cool over the next year. Biosimilars are a sure bet for the long-term. However, it will (quite legitimately) take FDA some time to create the new complex approval pathway that is required.

Looking beyond one year. Stay cool is still good advice. Some companies are going to slip behind or drop their investments because of corporate pressures for short-term return on investment (ROI). The biosimilars market is a battle for the long-haul and will belong to those who are prepared to stay the course through the several years it will take for FDA to develop policies and implement them consistently.

Another potential restraint on developers’ and investors’ commitments over the next several years is the persistent allegation that the U.S. biosimilars market will be limited unless FDA makes a determination that a biosimilar is interchangeable with the original product. However, FDA has placed a low priority on establishing a pathway for determining that an approved biosimilar is also interchangeable with the original biologic product.   

This “controversy” is a throwback to the implementation of Hatch-Waxman in the 1980’s. At that time, substituting copies for originals was a new concept, quality was low, purchasing was decentralized, and doctors had no incentive to prescribe generics.  Allowing forced substitution of FDA-approved generic drugs because they were “interchangeable” was an important dynamic in the growth of the generic drug industry.

However, none of these same underlying conditions are present at the beginning of the U.S. biosimilars market—substitution is widely accepted, quality biosimilars will be available, purchasing is far more centralized, and physicians will have incentives to prescribe biosimilars. FDA designation of "interchangeability," key to generic drugs, is almost irrelevant to biosimilars.

As a final thought: the rise of generic drugs made it necessary for innovators to work harder to develop new, patent-protected products that were better than drugs available generically. The same dynamic is going to play out over the next 10 years for biologic products. The biosimilars pathway adds further urgency for innovator companies to be refilling their pipelines with products that are better than ones currently available.  
Steven

Spinal Cord Injury—Innovation Measured in Decades, Not Headlines

We are undergoing a supposed “national crisis” in medical innovation.  Congress, FDA, NIH, and industry are involved in multiple initiatives to “cure” this problem. This is particularly visible now because the user fee reauthorization process is underway, but the state of medical innovation is always relevant because of our headline-driven, crisis-oriented culture. 

To FDA Matters, this approach profoundly distorts medical accomplishment. You can’t use “where are we today” to judge the success or failure of a medical research process that is inherently broad, iterative, uneven, filled with false starts and driven by cumulative success more often than miraculous breakthroughs. As a case in point, I offer efforts to achieve spinal cord regeneration.  

In the mid-to-late 1970’s, I worked for an advocacy group that, among other things, represented the interests of medical research institutions. There was one Congressman on the right committee who was friendly to our cause and with whom we should have had a great relationship.

However, he had two key positions with which we could not agree. He was, simultaneously, the leading Congressional advocate for animal rights and perhaps the only Congressional advocate for spinal cord regeneration. We opposed his position on animal rights because we thought it would hinder medical research.

Surprisingly, we were also against his legislation that would stimulate medical research on spinal cord regeneration. We supported groups promoting the fight against cancer or cardiovascular disease because their proposals allowed NIH significant discretion to determine priorities. In contrast, we were against legislation that would require research on narrow and specific topics, such as spinal cord regeneration.

But our objection (and the vehemence of our objection) went well beyond that. The promise of biomedical research was so great, it was wrong to waste research monies on areas that held no promise.

After all, we thought, spinal cord regeneration was the stuff of science fiction. Despite the death and disability from spinal cord injury—an area of genuine unmet need—there was nothing that could be done. People could dream of a future world where medical science could achieve such miracles, but for the foreseeable future it was wasted money and unfairly gave hope to patients to suggest that spinal cord regeneration was possible.

Flash forward 30 plus years and the Congressman looks like a visionary….and the organization I worked for looks like unwitting advocates for the status quo. A rich base of scientific discoveries has improved supportive care, provided mechanisms for limiting the damage from spinal cord injuries and given reasonable hope that spinal cord regeneration is a possibility for humans in the next 10 to 15 years, maybe sooner. 

To gain perspective on this, along with a sense of NIH’s current commitment to this area of research, go to http://www.ninds.nih.gov/disorders/sci/detail_sci.htm and also follow some of the links from that site.

I don’t think we were fools in 1998 because we couldn’t see spinal cord regeneration as a promising research area. Despite the organization’s considerable expertise, we underestimated how far medical research could take us—given enough time, interest, commitment and funding. Also, in retrospect, it is remarkable how willing researchers are to contribute to a process of innovation and discovery for which someone else might eventually gain most of the credit.

Forgive me if I don’t see the crisis of “medical innovation” about which it is so fashionable to complain.

As a result of the user fee reauthorization legislation and other FDA and NIH initiatives, I foresee a more conducive regulatory environment for development and approval of medically-innovative products, particularly orphan drugs. The goal is to allow more flexibility, while maintaining rigor. However, these process enhancements are only valuable if there is a wealth of medical innovation, not a dearth of it.

There is more innovative medical research being done today than at any time in history. But the truly great achievements are usually built on many people’s work undertaken over many decades—and until near the end, they hardly ever rate a headline unless someone is intentionally hyping them. Look beneath the surface and you will find that medical innovation is alive and well and just needs our continued encouragement---via regulatory and funding support.  

Steven

PDUFA Reauthorization: Major Upgrades for Orphan Drugs

Congress is to be congratulated on its progress toward passage of user fee reauthorization legislation. House and Senate-passed versions are being reconciled by staff, with a few fairly tough issues yet to be resolved. There is no apparent barrier to a final piece of legislation later this month or during July.  

One of the big winners in this process has been the rare disease/orphan drug (RD/OD) community. Notwithstanding a few remaining (minor) disputes in the RD/OD space (more on this later), the final legislation will contain the strongest set of improvements for the community since the original 1983 Orphan Drug Act.

The RD/OD community had three overriding objectives during the multi-year process of hearings and negotiations that culminated in the House and Senate-passed legislation:

• FDA flexibility in reviewing orphan drugs
• Resources  and process improvements for development  of biomarkers/pharmacogenomics
• Overhaul of the humanitarian device program

The community achieved all three plus a number of additional items that will also be part of the final package.  

The Commissioner’s Commitment Letter. The user fee agreement is only partially contained in the law—much of the detail is in a commitment letter signed by the Commissioner. As part of this, FDA agreed to the Rare Disease Initiative, which includes:

• increased staffing of the CDER/CBER Rare Disease Programs (RDP) (which provides expertise in orphan drug development to the product review divisions)
• increased FDA efforts to assure that product reviewers, industry, and patients are working together
• broadening  research and programming in the areas of non-traditional clinical trial design, endpoints, and statistical analysis associated with orphan drug development
• enhanced staff training for reviewers with specific regard to approval of drugs for rare diseases
• better integration of RDP staff into review teams

When the PDUFA legislation becomes law, these will be firm commitments that FDA must carry out for Fiscal Years (FY) 2013 (starts October 1, 2012) through FY 17.

Other RD/OD Priorities.  A number of other proposals, critical to the RD/OD community are in both the House and Senate bills:

• establishing procedures for faster review and more flexibility for promising therapies for unmet (orphan) medical needs. This will be accomplished by:
  •  updating and codifying FDA’s existing accelerated approval process, and
  •  adding a new process to speed development of drugs demonstrating strong efficacy in the early stages of clinical development (the Breakthrough Act).
• encouraging greater use of the existing, successful Humanitarian Use Device (HUD) program. The reauthorization legislation expands the scope of HUD (adult and not just children’s devices) and allows companies to make a profit.

• permitting FDA to use a wider range of experts and to use the government-wide standards for assessing conflicts of interest
• re-authorizing and improving the Orphan Drug grant program.

The Remaining Issues. There are three RD/OD issues that differ between the bills.

The first is in the Senate bill and tries to expand and strengthen the patient voice in FDA discussions. FDA is already doing this. However, the agency has a weak understanding of how much risk some rare disease patients might be willing to bear in order to have even a small possibility of benefit. Patients need to be heard in this debate. I hope the House agrees to this provision.

The second provision is in the House bill. It would revise the accelerated approval process to allow its use when there is little or no data on a rare disease with a particularly small population. I think these represent situations where FDA can best judge each situation themselves rather than being prodded into what might well be an unscientific review process. I hope the Senate does not adopt this provision.

Finally, the House has included a pilot program to encourage development of drugs and biologics for rare pediatric diseases. There are some questions about how this will work, so making it a pilot program makes sense. I hope the Senate agrees to this provision.  

Steven

About once a year, I check on progress in bettering the lives of people with rare diseases:

• Orphan Drugs Return to Center Stage (2009) http://www.fdamatters.com/?p=239
• For Twenty-Five Million Zebras: New Hope for Therapies (2010) http://www.fdamatters.com/?p=1046
• Public Incentives and Drug Development: More is Usually Better (2011) http://www.fdamatters.com/?p=1361

Biosimilars and the U.S. Supreme Court: FDA Program Could Be Nullified

The U.S. Supreme Court will rule on the constitutionality of the Affordable Care Act (ACA) (also known as ObamaCare) no later than early July. One of the possible results is nullification of the entire Act, although FDA Matters thinks this is the least likely outcome.

Nonetheless, the U.S. biosimilars law—passed as a separate section of ACA—could be rendered void if the Supreme Court overturns the entire ACA. Where would that leave FDA? What about those companies that have invested hundreds of millions of dollars to be part of the emerging U.S. biosimilars marketplace?

Controversy over The Affordable Care Act. The ACA, passed in March 2010, creates a comprehensive national approach to the problems of access and affordability of health care.  While not a pure “national health insurance” program that would be recognizable in most of the world, it is more far-reaching than any prior U.S. health legislation since the creation of Medicare (for the over-65 population) and Medicaid (a federal-state program for the poor) in the mid-1960’s. Numerous cost-containment provisions are also included in the ACA.

The ACA nearly didn’t pass Congress at all….and heated opposition has not lessened since its passage. A number of lawsuits have attacked the constitutionality of the law—with the leading case being led by the attorneys general of about 20 states. The US Supreme Court listened to oral arguments earlier this year and will decide the case before it adjourns in early July.

Biosimilars at Risk.   The Supreme Court may uphold the entire law as constitutional. Or they might decide only specific parts of the law are unconstitutional, none of which relate to biosimilars.  In either scenario, FDA will proceed with its current plans to implement the biosimilars law.

However, the Supreme Court might decide that a constitutional problem with one part of the law (e.g. mandating that individuals buy health insurance) is so far-reaching that the entire law is unconstitutional. In this last situation, FDA might be stripped of its authority to implement the biosimilars program enacted into law as part of ACA.

Little Precedent on What Comes Next. The Supreme Court rarely rules that Congressional actions are unconstitutional. When it does so, the Court usually looks for the narrowest Constitutional grounds possible—trying to preserve as much of the legislation as it can. This makes it most likely that biosimilars will survive the Court’s review. It also means there is little precedent as to what would happen to the biosimilars program if the ACA is invalidated in its entirety.  

One possibility is that FDA has innate authority to create and regulate a category of biosimilar drugs and does not need a legislative grant of authority.  This was discussed when Congress was first considering biosimilars legislation seriously in 2007 and 2008. At the time, FDA wisely deferred on the question, stating that it wanted Congressional guidance (meaning legislation). 

Should the law be overturned, the “innate authority” question might be re-raised, allowing FDA to continue with little or no change in its plan. The agency might even argue that Congress has given the agency guidance—treating the language of the 2010 law as a directive rather than a mandate.*

There is no hint as to whether FDA is thinking along these lines. When I asked FDA, I was told: we are confident that the Affordable Care Act is constitutional.

Failing a decision by FDA that it has the innate authority to approve biosimilars, it would fall to Congress to find a way to restore the program by legislation.  According to the trade publication, FDA Week, biosimilars’ leader, Hospira, is gearing up to pursue a legislative re-enactment should the Supreme Court overturn the biosimilars program. The Biotechnology Industry Organization (BIO) and Congress would also want to assure there is a biosimilars pathway.**

The problem: legislative re-enactment might not be so easy. While Congress is generally happy with the current biosimilars law, it was the product of a series of compromises and political maneuvering that left winners and losers. Merely re-adopting current law might prove surprisingly difficult.

Meantime, we all await the Supreme Court’s decision. And it’s safe to say that no one in the bio-pharma community is looking forward to the possibility of a new fight over biosimilars.

Steven

* There is no lack of support in Congress for the biosimilars program. Both the House and Senate versions of the user fee reauthorization legislation contain a new user fee to cover part of FDA’s costs for reviewing applications for biosimilar products approvals.

** For those with subscriptions to FDA Week, the article can be found at: http://insidehealthpolicy.com/FDA-Week/FDA-Week-05/11/2012/hospira-to-pursue-biosimilars-bill-if-scotus-strikes-down-health-care-law/menu-id-721.html

Safety and Efficacy Standards: Innovative Approaches to Radical Ideas

FDA is in the midst of its quinquennial* (five year) review from Congress as part of the user fee reauthorization cycle. Lots of proposals are on the table and FDA Matters agrees with some and disagrees with others. So far though, there doesn’t seem to be anything that would pull FDA apart or create an agency that cannot act with integrity. 

In contrast, two key opinion leaders are talking about potentially radical changes in FDA’s safety and efficacy standards. While neither has seen their specific proposals become part of the Hill debate, there are redeeming qualities to what both of them are suggesting.

User Fee Reauthorization Legislation.  I have been expecting the worst from Congress. Five-years of FDA issues have accumulated and there are tight deadlines for action by summer. The Senate bill just passed subcommittee in late April and the House bill will be marked up starting May 8. So far, House and Senate negotiations have stayed within the bounds of acceptable disagreement and we might see final legislation on schedule.

Of course, there is no guarantee that the reauthorization process wouldn’t yet turn into a mess or that the early start won’t be frittered away in extended debate. However, at least so far, Congress is doing a good job with a tough task.   

Radical thinking, far from Capitol Hill.  In February, former FDA commissioner Andrew von Eschenbach wrote that maybe FDA was being too tough on efficacy in the face of proven safety. Specifically, he wrote:

Instead, after proof of concept and safety testing, the product could be approved for marketing with every eligible patient entered in a registry so the company and the FDA can establish efficacy through post-market studies.

Then, in late April, Dr. Eric Topol** of Scripps Institute and a leader on cardiovascular safety issues, suggested that FDA may be too tough on safety in the face of proven efficacy. Specifically, he said:

The whole concept of having “overwhelming efficacy” of a device, or a drug, or a diagnostic test hasn’t been embraced enough. If we have that, learning about safety could be done on a conditional approval basis…..under a probationary status [with] every single individual…monitored electronically to watch the device, the drug, the test in question.

If the goal was to shock as well as provoke discussion, they both succeeded with me. Each offers a proposal that violates at least two important norms: “all drugs have risks” and “the first obligation of physicians is ‘to do no harm.’”

FDA Matters and, I believe, FDA and most stakeholders believe that substantial evidence of both safety and efficacy are needed before drugs are made available in the marketplace. I imagine the American public would agree.  

Radical Thinking Re-channeled.  I respect both individuals for their intellect and achievements, so I tried to find more conventional ways of looking at their ideas, ways that wouldn’t place tens of thousands of patients at risk. I think I succeeded.

Dr. von Eschenbach’s central point is that we don’t squeeze enough therapeutic potential out of drugs that have been well-tested and have excellent safety profiles. In that case, NIH Director Francis Collins is thinking along the same lines.  

On May 3, he announced  a new initiative, called Discovering New Therapeutic Uses for Existing Molecules. The program “will direct researchers’ attention to [and provide availability for testing] a part of the drug development pipeline traditionally difficult to access: compounds that have cleared several key steps in the development process, including safety testing in humans.”

Dr. Topol’s central point is that seriously-ill patients should have access to therapies that demonstrate impressive efficacy, without delay by inflexible rules about proof of safety. In that case, the Senate is thinking along the same lines.  

As described in a recent column, Proposals to Speed Drug Approvals: Not Created Equal, the Advancing Breakthrough Therapies for Patients Act or the Breakthrough Act (S. 2236) would:

“provide more flexibility when a drug or treatment shows dramatic responses early in development, while still ensuring drug safety and efficacy. For patients, this proposal would allow FDA the ability to move towards more innovative clinical trials, such as minimizing the number of patients enrolled in trials and shortening the duration of trials, when scientifically appropriate.”

S. 2236 is part of the user fee reauthorization bill that passed in the Senate Subcommittee.

Radical ideas met with innovative but conventional solutions. Well done all around.

Steven

* Yes, there really is a word that means “once every five years.” http://www.merriam-webster.com/dictionary/quinquennial

** Dr. Eric Topol was recently named the “most influential physician executive in the U.S.” by Modern Healthcare magazine.

Medical Innovation: The Dream of More Cures and More Industry Success

Can we, as a society, stimulate medical innovation? If so, how? These are key questions facing Congress as it considers amendments to the FDA user fee reauthorization legislation. The answers are of central importance to FDA, patients and industry. So far, most of the “solutions” being considered by Congress (legislatively) and FDA (administratively) are worthwhile and likely to have a positive impact over time.

However, in FDA Matters’ view, the challenge of stimulating medical innovation mostly lies outside the policy sphere. Instead, achieving more cures and more industry success requires substantive and attitudinal changes inside the research and development process itself.

Simply put, most of what can be done externally to stimulate medical innovation is important, but marginal. The biggest changes must come from industry and academia.

  New biomedical knowledge   is being generated every day, some of it quite extraordinary. The challenge is aligning that knowledge into safe and effective medical products. That process requiring inspiration, ingenuity, luck, capital and incredible amounts of hard work. Unsurprisingly, success is hard to achieve.

Regulatory agencies, legislatures, patients, consumers and payers all have a role to play and can definitely influence the success of the research and development process and, thereby, stimulate medical innovation. However, all of those efforts come to naught unless there is:

• an initial discovery or insight from researchers and inventors
• followed by carefully planned development and clinical trials
• concluding with proof that a medical product is safe and effective for its intended use.

 It is the researchers, development teams, product managers, and corporate executives, along with investors and shareholders, who hold the key to medical innovation.

Numerous CEO surveys say otherwise, with a plurality and sometimes a majority asserting that FDA is a major obstacle to their company’s success. However, these CEO’s are hardly objective judges of their own product pipeline. Very few ever acknowledge that regulatory concerns might be justified.  When faced with slow-moving projects, failed trials and agency rejections, the natural response of many is to blame FDA.  

Reality can be hard for CEO’s to accept. Medical innovation is a tough business, as witnessed by the startlingly large numbers of drugs (and to a lesser extent, complicated devices) that don’t survive late stage development. However, with a few exceptions, the inability to prove safety and/or efficacy--not FDA policy or reviewers-- are the primary cause of product failures.

This does not absolve FDA, just places the focus on the companies, where it belongs. For its part, FDA knows it can do better and is committed to supporting medical innovation For example, the agency has already agreed (on its own initiative and through support of legislation) that:

• Some medical products should be moved along faster in the process than they are now.
• More early-stage meetings with companies would reduce late-stage problems.
• Greater flexibility is needed with particularly promising compounds.
• Areas of unmet medical needs and where trials are particularly challenging should be given more attention.  
• Development of new methodologies, such as  adaptive trials and proper use of patient-reported outcomes, is a key component of advancing regulatory science.

FDA and Congress seem to be doing a good job of working on these issues. We will see the results in the user fee reauthorization process and other amendments, as well as new policies and pathways being developed at FDA. Hopefully, we will also see Congress support these activities through increased appropriated funding of FDA.

These external changes planned by Congress and FDA are valuable in their own right and will certainly result in some good approvals that might not otherwise have occurred.

However, stimulating a significant increase in approvals of medically-innovative products requires industry to: support more biomedical and bioengineering discoveries, carefully plan development, and achieve proof of safety and efficacy. This past week, the CEO of Eli Lilly, which faces patent expirations and generic competition, stated “I don’t think we can save [cost-cut] our way out of the enormous challenge we face. The best course is to maintain our focus on advancing our pipeline.” 

Exactly so. While FDA and Congress are doing their part, our focus shouldn’t wander too far from where it belongs. The key to medical innovation is better and smarter drug and device development. Nothing will help patients or companies if medical innovators don’t innovate.

Steven

Proposals to Speed-Up Drug Approvals: Not Created Equal

An important part of the 2012 user fee reauthorization cycle is Congressional efforts to push FDA toward approving drugs and biologics more rapidly. Most of industry and a large number of patient groups agree. Proposals to speed up FDA are already in play.

Since these proposals have a common purpose, it is easy to think of them as alike. However, most are different from each other—in focus, intent, and likely impact on the agency’s existing decisionmaking process. This is FDA Matters’ analysis of why proposals to speed up drug approvals can’t be lumped together and why FDA may support some, but not others.

Is FDA really too slow? Efforts to speed up drug approvals start with an implicit assumption: FDA is approving drugs too slowly. The conventional wisdom is that FDA’s positioning swings over time like a pendulum. FDA allegedly gets "too easy" with its approvals, but then a few years later is faced with a major product recall over safety issues.

The FDA then hunkers down and the pendulum swings toward being slow and rigid. Finally, the bad experience becomes less immediate in the agency's mind and the pendulum swings back toward “too easy” and the cycle starts again.  

The FDA mindset. FDA hates this metaphor, but secretly fears it might be true. As a result, the agency has been working toward being more consistent....and less prone to the alleged pendulum swing. Among other things, the agency is trying to publish more official guidances and handle perceived blockages proactively (e.g. prospects for obesity drugs seem to have improved since the failure of three such drugs to gain approval in 2010).

Some of this spirit of change is reflected in the agency’s October 2011 white paper, Driving Biomedical Innovation:  Initiatives to Improve Products for Patients. Likewise, as part of the new user fee workplans, FDA and industry agreed to work together, particularly earlier in the development process, so that there are fewer surprises and more approvals. 

Proposals for speeding up drug approvals.  Improving the existing accelerated approval process is the goal of the Faster Access to Specialized Treatments or FAST Act (HR 4132) and section 301 of the Transforming the Regulatory Environment to Accelerate Access to Treatments or TREAT Act (S. 2113).

Accelerated approval allows surrogate endpoints as the basis for demonstrating efficacy. FDA uses this example: “instead of having to wait to learn if a drug actually can extend the survival of cancer patients, the 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.”

The two bills would broaden the means to demonstrate clinical benefit by encouraging use of emerging scientific methods and tools and allowing a wider range of surrogate and clinical endpoints. The bills would explicitly codify the accelerated pathway in law.

A different approach is taken in the Advancing Breakthrough Therapies for Patients Act or the Breakthrough Act (S. 2236).  This bill would “provide more flexibility when a drug or treatment shows dramatic responses early in development, while still ensuring drug safety and efficacy. For patients, this proposal would allow FDA the ability to move towards more innovative clinical trials, such as minimizing the number of patients enrolled in trials and shortening the duration of trials, when scientifically appropriate.”

This reflects a reality: FDA often feels constrained in situations where common sense dictates special handling. An example might be a new melanoma treatment that was approved in August 2012, after receiving significant assistance from FDA to move the drug forward rapidly. However, after reading an earlier NY Times article, it is easy to imagine that FDA might have been even more flexible, but felt constrained.

Finally, some commentators have included former FDA Commissioner Andrew von Eschenbach recent Wall Street Journal article in their discussion of “speeding up FDA approvals.” He advocated “creating FDA pilot programs to bring promising therapies to patients more quickly by allowing them to be approved based on safety, with efficacy to be proven in later trials.”

Speculation on FDA’s position. FDA is certain to oppose Dr. von Eschenbach’s proposal if offered as a legislative amendment. However, FDA is still deciding its position on FAST/TREAT and the Breakthrough Act.

In response to a Congressional question, FDA spoke favorably of the Breakthrough Act.  The key is that FDA is given discretion to provide more rapid and higher level process, but is not directed to change the standard of proof or the meaning of efficacy or safety.

FDA has been more hesitant about FAST/TREAT. Informally, it opposed a prior iteration because, among other things, it lowered standards by not requiring prior validation of a surrogate endpoint.  My understanding is that FDA is considering whether its concerns have been addressed by these later versions of the bills.

Steven

The FDA Matters “Guide to the User Fee Reauthorization Process”

The prescription drug (PDUFA) and medical device (MDUFA) user fee programs, which run for 5 years, must be renewed by September 30 of this year (last day of the current fiscal year).  House committee staff has just released a 205-page first draft of reauthorization legislation. The Senate has starting releasing drafts on specific issues and has a March 29 hearing scheduled.

Because the PDUFA and MDUFA provisions are pre-negotiated by FDA with industry and patient groups, they are likely to change little. Congress’ focus will be on the backlog of FDA-related legislative proposals that have accumulated while awaiting a “must pass” FDA legislative vehicle. This is FDA Matters’ guide to the process and likely amendments.

To understand the unfolding process for user fee reauthorization in 2012, it is useful to think in terms of four levels of legislative proposals that Congress will consider.

Level One: Renewal of Existing Legislation and Uncontroversial New User Fees. In addition to PDUFA and MDUFA, there are two other programs on the same 5-year reauthorization cycle. The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) are certain to be reauthorized and may be made permanent.

In this same level are two proposed new user fee programs: the Generic Drug User Fee Act (GDUFA) and the Biosimilars User Fee Act (BSUFA).  These have gone through an abbreviated version of the PDUFA and MDUFA negotiation process, meaning that the FDA proposals reflect input from industry, patient groups and other stakeholders.

Level Two:  Areas of Strong Consensus to Act; Specific Provisions Not Yet Agreed Upon. Despite Congress’ deep partisan differences, there are several areas in which both political parties appear to be in general agreement about adding programs or strengthening authorities at FDA. 

In this level are proposals dealing with drug shortages, incentives for antibiotic drug development, import safety, a core set of medical device process reforms, and some adjustment in the FDA “accelerated approval” pathway for drug and biological products. There is also consensus for dealing with drug supply chain integrity (e.g. anti-counterfeiting), which may be advanced as a separate bill this spring or be folded into the reauthorization legislation.

For the most part, the consensus to act in these areas does not yet include specific legislative language that has bi-partisan support in both the House and Senate. So negotiations are certain, may even be testy at times…but final agreements are near-certain.

Level Three: Areas of Disagreement Where Compromises Are Possible. Ultimately, committee leadership will have to deal with FDA amendments where there are sharp disagreements or a lack of consensus that action is needed.

The two most prominent such issues are the extent of medical device reform and the amount of change needed or appropriate for the drug approval process. In both areas, there is a more limited, core set of proposals that are in level 2.

As with all such areas of disagreement, compromises may ultimately develop. Unlike the issues in level two, these proposals start with disagreements that may lead to negotiations, but with no assurance of inclusion in final legislation.

Beyond those mentioned, the list of issues and amendments that might be offered (and controversial) is limitless, but it is possible that we will see Congress again debating drug re-importation, re-opening the 2010 biosimilars legislation or even considering amendments to Hatch-Waxman. There may also be food safety amendments.

Level Four: Proposals to Dramatically Re-shape FDA and Likely to Be Rejected. A small number of Members of Congress think FDA’s role should be significantly smaller. They see radical surgery on the agency mission as the necessary response to the restraints they feel the agency imposes on industry and on patient access to new therapies.

The possibility exists for amendments that might substantially reduce the agency’s jurisdiction over medical devices or significantly roll back the 1962 Kefauver Amendments that require drugs to demonstrate efficacy (not just safety) before entering the market. There is no reason to think there is a majority in either the Senate or the House for such radical reform or substantial reduction in FDA’s mission. Nonetheless, such proposals may be offered.

Conclusion.  In enacting a timely reauthorization of the user fee programs, Congress will need to consider a range of legislative proposals. As these are offered and discussed, this FDA Matters analysis provides a guide to understanding Congressional activities.

Steven

This blog column is a much-shortened version of an article I wrote that appears in the March 2012 issue of Scrip Regulatory Affairs, entitled “Reauthorizing US FDA User Fees: A Slow-Moving Train Wreck?” Readers interested in a copy of the longer article should contact me at sgrossman@fdamatters.com.

Biological Complexity and the Myth of the Low-Hanging Fruit

Two events persuaded FDA Matters to write another column on biological complexity and its implications for medical research, drug discovery, and personalized medicine. First was the release of a remarkable study on gene mutations in cancer tumors. It is a stellar and sobering example of how biological complexity confounds our expectations that rapid advances in science will quickly lead to cures. 

Second was the multiple comments from readers of last week’s columnsuggesting that drug discovery (and biomedical advances generally) are so hard because “the low-hanging fruit has been picked.” This is a persistent and dangerous myth that devalues past breakthroughs and distorts the challenges bio-medicine faces over the next decade. 

This past week’s New England Journal of Medicine contained an original article on cancer tumor heterogeneity. According to Reuters, the study showed:

 “about two-thirds of genetic mutations in samples from primary tumors of kidney cancer patients were different from one another, even if they were taken from the same tumor…Researchers also found even more genetic differentiation in biopsies of secondary tumors. The findings suggest that using samples from a primary tumor as a basis for treatment decisions may not be good enough, researchers said.”

An accompanying NEJM editorial, as well as a Wall Street Journal article and comments,  both pointed to this as a setback for matching treatments to the genetic make-up of a person’s tumors (i.e. personalized medicine). Their comments didn’t surprise me.

Over 2 ½ years ago, I put personalized medicine in perspectiveby comparing it to the long history of biotechnology. I didn't predict the cancer gene mutation discovery. I just pointed out what history tells us: biological complexity is greater than we imagine, making promising areas of discovery appear closer to maturity than they really are. The truth of this was on prominent display in these new research results on cancer tumors.

This provides a near-perfect context to respond to those who thought the answer to last week’s column, “Why is Drug Discovery So Hard (and Expensive)?” is “because the low-hanging fruit has been taken.” They suggested: what remains to be accomplished in human biology and drug discovery is incredibly difficult because all the easy questions have been answered and the easy drugs and biologics have already been developed.*

As near as I can tell, a great many very smart people believe this. And they could not be more wrong. The challenges ahead are, indeed, quite difficult….but so were yesterday’s challenges before we solved them.

The “low-hanging fruit theory” is truly insulting to a generation of bioscientists whose record of accomplishments over the last 50 years was achieved by their hard work and dedication, as well as their brilliance. If anything, they might argue that it is easier now—given the new knowledge and the new tools that researchers have to work with.

Beyond that, the view of the past as low-hanging fruit--“easy and less expensive”--distorts our view of the future…that somehow we face challenges greater than other people have faced before us. We don’t.

Human biology is complex and biomedical research is slow and time-consuming. Most new knowledge raises as many questions as it answers (as is certainly true with the new cancer tumor research). None of this is new.  And it is true no matter where you stand in the continuum of biological knowledge, whether you are Pasteur or one of today’s biotechnology “rock stars”.

I am not pessimistic or discouraged about biomedical discovery or opposed to personalized medicine, just concerned we see them in a realistic light. I conclude that:

·         More biological knowledge is always better than less.

·         Having more knowledge doesn’t tell you whether the next task is easier or harder (and often it is both).

·         Having more knowledge doesn’t tell you whether success is near or far.

These three observations are controlling principles in biomedical research’s quest to lessen the burden of disease and provide all of us with a higher quality of life.

Since this is FDA Matters blog, how does FDA fit in? The agency works closely with companies developing drugs and devices and is one of the final arbiters in whether biological knowledge has, indeed, been turned into benefit for mankind.

The agency needs the tools, the resources and the top scientific minds to stay ahead of the ongoing flood of new biomedical knowledge. It needs to be ready to stimulate, then evaluate, what we hope will be a torrent of new, ground-breaking drugs and devices that will, over time, arrive.

Steven

* Dr. John LaMattina, former President of Pfizer R&D, examines this same question in his recent column in Forbes. We agree that “low-hanging fruit” is a myth, but articulate the reasons differently. His perspective complements my own and I recommend reading it along with this column.

Why is Drug Discovery So Hard (and Expensive)?

Notwithstanding herbal medicines and the re-emergence of leeches as therapy, it is only in the last 70 years that physicians have had proven medical science to support “the healing arts.” Potions and procedures of dubious value have been replaced by powerful medicines that treat infections, heart disease, diabetes and mental illness.

While the benefits are clear, the difficulties and cost of creating new medicines are a source of widespread frustration to patients and industry alike. FDA Matters is impressed that current efforts to speed up drug discovery are gaining momentum.  At the same time, the nature of human biology dictates that the creation of new therapies will never be easy or inexpensive.

Recently, Matthew Herper of Forbes wrote about the “truly staggering cost of inventing new drugs”, a range he put at $4-11 billion per success! The point is that every success is bearing the cost of a staggeringly-large number of expensive failures.

The chart at the end of this column shows that about 10,000 compounds are screened to produce about 250 compounds that are promising enough for pre-clinical and early clinical testing. In turn, this produces five compounds in late stage clinical testing and only one approved drug. As a result, efforts to improve drug discovery have two goals:

• early identification of compounds with the highest  probability of proving safe and effective, and
• the ability to discern and discard promising-looking compound that are, nonetheless, likely to fail at later stages.

The growing consensus behind these goals has pushed collaboration and innovation much faster than would otherwise be expected. Identification and validation of biomarkers, pharmacogenomics, toxicology databases, and new compound screening methodologies are among the many approaches to enhance the discovery process.

NIH has committed to speeding early drug discovery through the just-launched National Center for Advancing Translational Sciences  (NCATS). I admit that I was skeptical when it was first proposed because it looked like NIH wanted to compete with industry. However, NCATS’ is appropriately focused on generating useful early-stage drug discovery tools, data and methodologies that will be made widely available and are complementary and supportive of industry efforts. (The advocacy group, Faster Cures, recently held an informative webinar with NCATS’ leaders. Here are links to the audio and accompanying slides.)

FDA has acknowledged the need to be more attuned to advancing medical innovation as an integral part of the agency’s role in promoting the public health.  This was reflected in FDA’s October, 2011 report, Driving Biomedical Innovation: Initiatives to Improve Products for Patients and by its willingness (during user fee negotiations and other venues) to commit to more early-stage meetings with companies. In addition, FDA has committed resources to creating and validating new tools and methodologies for drug discovery. Most important of all, FDA recognizes the need to act on the critical next stages after drug discovery by creating a more predictable regulatory pathway that minimizes the time that it takes safe and effective new medicines to gain approval.

All these activities taken together may produce dramatic improvements on the front end of drug discovery. This would provide the ability to focus on the “most promising, least likely to fail” compounds and reduce the number of expensive failures. In some cases, companies and regulators might know enough from the initial discovery screening to shorten or narrow pre-clinical and clinical testing.

The new focus and activity on drug discovery is reason to be hopeful....but these efforts will take time to bear fruit. The process of taking a compound “from bench to bedside” must still be measured in years.

Optimism should also be tempered by realizing that the human body is almost always more subtle than we can discern, even with the best predictive tools.  New uncertainties emerge, even as new biological information resolves old uncertainties about diseases and drug development.

No matter how much we know, there will always be clinical trials that fail, sometimes quite miserably, just when everyone is most sure that the solution is logical and success guaranteed. That’s why drug discovery will never be easy or inexpensive.

Steven

The last two links connect readers with earlier columns on biological complexity:  Is the Human Body Just An Exquisitely Intricate Machine? and Scientific Reductionism and the End of Medicine. For those interested, there is a third column on this topic: Personalized Medicine in Perspective.

Development of New Therapeutics is Slow, Expensive and Failure-Prone

http://www.fastercures.org/train/tools/documents/022712_NCATS.pdf  (slide 14)