Introduction: Despite the launch of indirect, “proximity” talks between Palestinians and Israelis, Palestinian President Mahmoud Abbas continues to resist a resumption of direct negotiations with Israel absent a full settlement freeze. As chairman of the Palestine Liberation Organization (PLO) and president of the Palestinian Authority (PA), Abbas also insists that any new negotiations pick up where previous talks left off in December 2008 and that the parties spell out ahead of time a clear “endgame,” including a timetable for concluding negotiations. While these may seem like unreasonable preconditions, Palestinian reluctance to dive headfirst into yet another round of negotiations is rooted in some genuine, hard-learned lessons drawn from nearly two decades of repeated failures both at the negotiating table and on the ground.

Not only have negotiations failed to bring Palestinians closer to their national aspirations but the peace process itself has presided over (and in some ways facilitated) a deepening of Israel’s occupation and an unprecedented schism within the Palestinian polity. Such failures have cost the Palestinian leadership dearly in terms of both its domestic legitimacy and its international credibility. While it remains committed to a negotiated settlement with Israel based on a two-state solution, the PLO/PA leadership has been forced to rethink previous approaches to the peace process and to negotiations, as much for its own survival as out of a desire for peace.

Haunted by past failures, Palestinian negotiators are now guided, to varying degrees, by six overlapping and sometimes conflicting lessons:

1. Realities on the ground must move in parallel with negotiations at the table.

2. Don’t engage in negotiations for their own sake.

3. Agreements are meaningless without implementation.

4. Incrementalism does not work.

5. Avoid being blamed at all costs.

6. Don’t go it alone.

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On April 10th and 11th, the heads of state and government from nearly every state in the Americas will meet in Panama City for the Seventh Summit of the Americas. The leaders present in Panama preside over a region that has advanced far and fast on key political and economic indicators since the first of these meetings was held in Miami in 1994. At the Miami Summit, the legacy of the Cold War was very much present, and the specter of war, military dictatorship, armed revolution, financial crises, and political instability still hung in the air. 

In 2015, the region is by and large more democratic, economically prosperous, free from war, and the last insurgency in the region—Colombia’s—is winding down as peace is discussed between the government and its opponents at talks hosted by Havana. The beginning of a rapprochement between the United States and Cuba in December 2014 broke down one of the last remaining obstacles to an event that is truly inclusive of every country in the Western Hemisphere. 

In comparison to the rest of the world—where in the past year we have witnessed terrorist attacks in Paris, war in Ukraine, insurgency in Yemen, and saber-rattling around the South China Sea—the Western Hemisphere appears to be relatively better off. While there are a small number of countries that face challenging circumstances, especially among the fragile states of the Caribbean basin, these problems mostly threaten local rather than regional order. Given this picture, what lessons can we learn from the Western Hemisphere, and from U.S. policy towards the region, as we contemplate how best to improve global order?

Drawing the right lessons from history

The Americas have a long history of developing regional norms that promote the peaceful resolution of conflicts. Since the founding of the Panamerican Union in 1890, which transformed into the Organization of American States (OAS) in 1948, the countries of the hemisphere have embedded these norms of peace into their multilateral institutions. While frequently criticized, it is important to remember that the OAS has presided over the elimination of inter-state conflict in the Americas. 

Today, Latin American states resolve territorial disputes at the International Court of Justice rather than on the battlefield. The last war in the region, between Peru and Ecuador in 1995, occurred two decades ago. Given how rare militarized disputes are at home, Latin American soldiers frequently serve as peacekeepers in United Nations missions around the world. Latin Americans have become good at peacemaking and peacekeeping, something that other regions of the world would do well to emulate.

When it comes to domestic politics, most leaders in the region now understand the political and economic principles that contribute to stability. Governments have become much better about economic governance, which means that as South America’s economy cools off this year, fiscal problems will be manageable and localized rather than region-wide and existential, a sharp contrast with the 1980s and 1990s. 

Leaders in the region have learned that promoting polarization for short-term political advantage is all too likely to produce instability, coups, and revolution. To minimize the risk that domestic political violence might reoccur in the future, states in the region have self-consciously examined the legacy of their authoritarian pasts, using innovative processes such as truth and reconciliation commissions—initially in Argentina in 1983—but also drawing on traditional courts to prosecute perpetrators of past abuses.  

In the 21st century, successful coups d’état have become rare, and when they do occur, as was the case in Honduras in 2009, the region collaborates to ensure a return to democracy. Here again is an area where Latin America has led the way through policies that reduce the likelihood of domestic conflicts that threaten internal stability or global order.

The importance of revisiting unworkable U.S. policies 

At this Summit in Panama, President Barack Obama will be able to credibly claim that he has listened to his Latin American counterparts and has begun to change policies that had become obstacles to improving regional order. At the 2009 and 2012 Summits (they occur every three years), U.S. policies on drugs, immigration, and Cuba had made President Obama the target of growing criticism from other leaders. In fact, many governments had made it clear that they would not attend the 2015 Summit if Cuba was not invited. 

Since 2012, the Obama administration has taken steps to address these concerns. It has taken executive action to reform immigration policy, signaled greater openness to drug policy liberalization by states such as Uruguay, and initiated a historic normalization of relations with Cuba. In each of these areas, the United States has shifted from policies that were largely unilateral towards its neighbors to policies that emphasize collaboration and partnership. This reflects U.S. learning that unilateralism produces blowback, strengthens its political adversaries in the region, and undermines its interests in the long run. This is a lesson worth considering as we think about our policies towards troubled regions of the world.

The risk of forgetting lessons learned

Yet not all countries and all politicians have remembered these lessons, and some of them have learned the wrong ones. In Argentina, macroeconomic stability is at risk due to a feud between the government and its international creditors. The result is a country cut off from international capital markets at a time when its economy is suffering the effect of declining commodity prices. Venezuela faces a deep crisis that has at its heart the highly polarizing politics practiced by the governing party and an unreasoning attachment to an unworkable economic model. Key countries such as Brazil have lost interest in hemisphere-wide institutions, as indicated by their refusal to appoint an ambassador to the OAS or pay their membership dues. And the region as a whole has become so attached to multilateralism and politics by consensus that is has forgotten how to work together when individual member states deviate from regional norms of democracy and human rights, as is occurring today in Venezuela.

So while the recent history of the Americas offers insights into policies that contribute to a peaceful and stable regional order, it also illustrates that these achievements are not irreversible. Let us hope that future generations do not have the relearn these lessons anew. At this and future Summits, there must be a commitment to preserving the gains made in peace, democracy, human rights, and economic prosperity, but also a new emphasis on developing workable mechanisms to address deviations from the norms and practices that have contributed to making the Americas a relative safe and orderly region of the world.

For more information, check out Emily Miller's post on U.S. priorities at the Seventh Summit of the Americas.

For nearly fifteen hours between Wednesday morning and early Thursday, Senator Chris Murphy (D-CT), along with his Connecticut colleague Senator Richard Blumenthal (D) and Senator Cory Booker (D-NJ), led a filibuster on the floor of the Senate aimed at addressing gun control issues in the aftermath of last weekend’s mass shooting in Orlando. Other than learning that Wednesday is pizza night in the Murphy household, what else should we take away from this Mr. Smith Goes to Washington­-style exercise? Here are three lessons:

1. The real meaning of “I” in “I hold the floor until I yield the floor.”

Anyone who tuned into yesterday’s filibuster joined Senate procedure wonks (and faithful viewers of the West Wing) in the knowledge that a senator who holds the floor can yield to another senator for a question without yielding the floor. Indeed, 38 of Murphy’s 45 Democratic colleagues (as well as two Republicans, Senators Ben Sasse (R-NE) and Pat Toomey (R-PA)), came to the chamber yesterday to ask “questions.” In many cases, these were lengthy speeches—Senator Tammy Baldwin (D-WI), for example, read brief biographies of all 49 Orlando victims—in which the speaker satisfied the question requirement with a conclusion that asked Murphy for his reactions to their statement.

This kind of teamwork on extended speech-making is not unusual. When Senator Ted Cruz (R-TX) took the floor to talk for 21 hours about the Affordable Care Act in 2013, he took questions from nine fellow Republicans (as well as two Democrats). Last May, Senator Rand Paul (R-KY) got an assist from ten colleagues, including seven Democrats, during his filibuster of a bill extending the PATRIOT Act. The depth of Murphy’s bench not only reduced the energy he had to expend speaking, but also helped guarantee that the entire discussion was on-message and focused on the topic at hand; Murphy did not have to resort to reading the phone book to fill the hours.

2. In policy terms, it’s hard to know if the filibuster was a success…

When Murphy left the floor early Thursday morning, it was reported that Senate leaders had agreed to consider two gun control amendments: one that would address the ability of suspected terrorists to purchase guns and a second that would expand background checks for gun purchases. Details of the deal ensuring consideration are still emerging, but it is difficult to know if Murphy’s filibuster caused Senate leaders to agree to hold votes on them. It is possible that, had Democrats simply threatened to object to the motion to proceed to debate on the underlying spending bill, Republican leaders would have been forced to agree to consider the amendments for which Murphy and his allies were pushing. In the contemporary Senate, this is often how obstruction proceeds: without extended speeches and off the floor, with the two sides negotiating behind the scenes.

3. …but the political victory is perhaps more important

As my colleague Sarah Binder and her co-author Steve Smith wrote in their 1997 book on the filibuster, “encouragement from external groups…has given senators an incentive to exploit their procedural rights, sometimes leading them to block legislation with the filibuster or with holds and at other times leading them to use procedural prerogatives to force the Senate to consider issues of importance to parochial, partisan, or national constituencies.” On these grounds, Murphy’s filibuster was unequivocally a success in the eyes of its supporters. As the filibuster neared its end, Murphy reported that his office had received 10,000 phone calls supporting his efforts, and the hashtag #filibuster was trending on Twitter for much of the day. Even if the underlying amendments are not adopted—a real possibility that Murphy acknowledged in one of his final speeches of the evening—the visibility of the exercise is likely to pay political dividends for Democrats in the coming weeks.

In 2015 the international community agreed on a set of ambitious sustainable development goals (SDGs) for the global society, to be achieved by 2030. One of the lessons that the implementation of the Millennium Development Goals (MDG s) has highlighted is the importance of a systematic approach to identify and sequence development interventions—policies, programs, and projects—to achieve such goals at a meaningful scale. The Chinese approach to development, which consists of identifying a problem and long-term goal, testing alternative solutions, and then implementing those that are promising in a sustained manner, learning and adapting as one proceeds—Deng Xiaoping’s “crossing the river by feeling the stones”—is an approach that holds promise for successful achievement of the SDGs.

Having observed the Chinese way, then World Bank Group President James Wolfensohn in 2004, together with the Chinese government, convened a major international conference in Shanghai on scaling up successful development interventions, and in 2005 the World Bank Group (WBG ) published the results of the conference, including an assessment of the Chinese approach. (Moreno-Dodson 2005). Some ten years later, the WBG once again is addressing the question of how to support scaling up of successful development interventions, at a time when the challenge and opportunity of scaling up have become a widely recognized issue for many development institutions and experts.

Since traditional private and public service providers frequently do not reach the poorest people in developing countries, social enterprises can play an important role in providing key services to those at the “base of the pyramid.”

In parallel with the recognition that scaling up matters, the development community is now also focusing on social enterprises (SEs), a new set of actors falling between the traditionally recognized public and private sectors. We adopt here the World Bank’s definition of “social enterprises” as a social-mission-led organization that provides sustainable services to Base of the Pyramid (BoP) populations. This is broadly in line with other existing definitions for the sector and reflects the World Bank’s primary interest in social enterprises as a mechanism for supporting service delivery for the poor. Although social enterprises can adopt various organizational forms—business, nongovernmental organizations (NGOs), and community-based organizations are all forms commonly adopted by social enterprises—they differ from private providers principally by combining three features: operating with a social purpose, adhering to business principles, and aiming for financial sustainability. Since traditional private and public service providers frequently do not reach the poorest people in developing countries, social enterprises can play an important role in providing key services to those at the “base of the pyramid.” (Figure 1)

Figure 1. Role of SE sector in public service provision

Social enterprises often start at the initiative of a visionary entrepreneur who sees a significant social need, whether in education, health, sanitation, or microfinance, and who responds by developing an innovative way to address the perceived need, usually by setting up an NGO, or a for-profit enterprise. Social enterprises and their innovations generally start small. When successful, they face an important challenge: how to expand their operations and innovations to meet the social need at a larger scale. 

Development partner organizations—donors, for short—have recognized the contribution that social enterprises can make to find and implement innovative ways to meet the social service needs of people at the base of the pyramid, and they have started to explore how they can support social enterprises in responding to these needs at a meaningful scale. 

The purpose of this paper is to present a menu of approaches for addressing the challenge of scaling up social enterprise innovations, based on a review of the literature on scaling up and on social enterprises. The paper does not aim to offer specific recommendations for entrepreneurs or blueprints and guidelines for the development agencies. The range of settings, problems, and solutions is too wide to permit that. Rather, the paper provides an overview of ways to think about and approach the scaling up of social enterprise innovations. Where possible, the paper also refers to specific tools that can be helpful in implementing the proposed approaches. 

Note that we talk about scaling up social enterprise innovations, not about social enterprises. This is because it is the innovations and how they are scaled up that matter. An innovation may be scaled up by the social enterprise where it originated, by handoff to a public agency for implementation at a larger scale, or by other private enterprises, small or large. 

This paper is structured in three parts: Part I presents a general approach to scaling up development interventions. This helps establish basic definitions and concepts. Part II considers approaches for the scaling up of social enterprise innovations. Part III provides a summary of the main conclusions and lessons from experience. A postscript draws out implications for external aid donors. Examples from actual practice are used to exemplify the approaches and are summarized in Annex boxes.

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Economist Albert Hirschman’s marvelously perceptive little book with big ideas written in 1970 titled “Exit, Voice and Loyalty: Responses to Decline in Firms, Organizations and States” provides a cornucopia of insights into understanding Brexit and the current state of global governance.  When it emerged American economist Kenneth Arrow marveled at its extraordinary richness, and political scientist Karl Deutsch, in his presidential address to the American Political Science Association, called it an “outstanding contribution to political theory.”

Economists assume exit to mean dissatisfaction with an organization’s product or the service leading to decline in demand for it. The value of exit lies in the certainty it provides in terms of the relationship between the customer or member and the firm. Political scientists think of how a firm handles its response to customer dissatisfaction as the exercise of voice by stakeholders. The value of voice is that it can lead to reform that ultimately determines the firm’s revival, an idea also advanced by scholar Clayton Christiansen in his book “The Innovator’s Dilemma.” An understanding of the conditions under which exit and voice are exercised requires the incorporation of the concept of loyalty. Loyalty makes voice more probable and exit less likely. But loyalty does not by itself make the exercise of voice more effective. That depends on the extent to which customers or members are willing to trade off the certainty of exit against the uncertainties of improvement in the deteriorating product, and their ability to influence the organization.  

Applying these ideas to Brexit suggests that the option of a U.K. exit was made more likely because of the limited voice of the U.K. in achieving reforms, coupled with the fact that Britain’s loyalty to the European Union was mixed at best. Its self-perception as “special people” was accompanied by long-standing skepticism about foreigners, including other Europeans.

Some have attributed Brexit to misjudgment by Prime Minister David Cameron about holding a referendum, poor management of migration policy by the EU including procrastination and downright misjudgment on migration, and they have termed the historic vote as nothing short of the beginning of the end of the post-World War II institutional frameworks, including the Bretton Woods institutions. They fear that the longest and most prosperous period of sustained peace in modern human history, enabled by post-war global architecture, may have come to an end.

The Economist is one proponent of this view, describing Brexit as multiple calamities. The British economy and polity are wildly off the rails, the newspaper notes. The prime minister has resigned with no obvious successor. The leader of the opposition is struggling to survive a coup. The pound hit a 31-year low against the dollar and banks lost a third of their value before stabilizing. Meanwhile there is talk in Scotland and Northern Ireland of secession.

But my own English friends, some of whom favored Brexit, talk about the high tax payments to the EU, oppressive overreach of the EU bureaucracy, and the fear of open borders leading to uncontrollable immigration from Eastern Europe, Turkey, and the Middle East. In short they see EU membership as all pain and no gain. On the surface Brexit has all the flavors ranging from nostalgia of self-rule to xenophobia.

There are already signs that exit is becoming the preferred option in various global governance organizations. Global loyalties are split, not just among great powers, but also between developed and developing countries. Voice and reform have not been effective.

Hirschman mentions leadership and timely action in sharing power with the next generation as a behavioral trait (often found in the animal kingdom) favoring voice. He contrasts that with exit, which he describes as a human behavior which assumes markets, including political markets, will solve problems.

Hirschman’s chapter “Exit and Voice in American Ideology and Practice” helps us to better understand the U.S. role in global governance. He notes that exit has been accorded “an extraordinarily privileged position in the American tradition” founded in its very creation as a land of immigrants, who, he reminds us, were opting for exit.  Indeed, like in Britain, “the neatness of exit over the messiness and heartbreak of voice” has persisted throughout U.S. history. In his last chapter, “Elusive Optimal Mix of Exit and Voice,” he does not come up with a recipe for some optimum mix of the two, nor does he recommend each institution has its own optimum mix, instead arguing conditions are seldom ripe for their optimum and stable mix—although it is possible to say there is deficiency of one or the other at a given point in time.

Today, it seems that the dominant mode of the post-World War II era, namely voice, is plainly revealing its inadequacy, so the other mode, exit, will eventually be injected once again.

Having had a leading role in founding the global architecture of the United Nation, Food and Agriculture Organization, and Bretton Woods institutions, the U.S. has had a strong voice in and loyalty to the Bretton Woods institutions as well as leadership roles commensurate with its historic roles. U.S. loyalty to the U.N. outside of the Security Council has varied among administrations, since voice in U.N. organizations is distributed more equally. The U.S. has opted for exit from specific U.N. organizations from time to time when it has disliked the dissenting views of other members. 

Others are also choosing to exit. China’s slightly increased shares in the International Monetary Fund and the World Bank after the financial crisis are nowhere near its weight in the global economy, thanks to European reluctance to accept a reduced voice. China and other emerging countries have exercised a partial exit option by establishing the Asian Infrastructure Investment Bank and the New Development Bank to meet the investment needs of developing countries.The U.S. considered the establishment of the two as a threat to its leadership and to the Bretton Woods institutions, viewing the acts as verging on disloyalty, whereas most U.S. allies have embraced membership in both. And yet the Asian Infrastructure Investment Bank is following on the footsteps of the Bretton Woods institutions as regards norms and rules.

To strengthen global governance requires strengthening “voice” and weakening incentives for “exit” from the U.N. and Bretton Woods institutions and other forums of global governance. The U.S. needs to also lead the effort to increase the rewards and reduce the cost of exercising voice. This would be a timely reminder, when politics seems to thrive on divisions, that leadership means forging inclusive institutions that serve all members. 

In 2015 the international community agreed on a set of ambitious sustainable development goals (SDGs) for the global society, to be achieved by 2030. One of the lessons that the implementation of the Millennium Development Goals (MDG s) has highlighted is the importance of a systematic approach to identify and sequence development interventions—policies, programs, and projects—to achieve such goals at a meaningful scale. The Chinese approach to development, which consists of identifying a problem and long-term goal, testing alternative solutions, and then implementing those that are promising in a sustained manner, learning and adapting as one proceeds—Deng Xiaoping’s “crossing the river by feeling the stones”—is an approach that holds promise for successful achievement of the SDGs.

Having observed the Chinese way, then World Bank Group President James Wolfensohn in 2004, together with the Chinese government, convened a major international conference in Shanghai on scaling up successful development interventions, and in 2005 the World Bank Group (WBG ) published the results of the conference, including an assessment of the Chinese approach. (Moreno-Dodson 2005). Some ten years later, the WBG once again is addressing the question of how to support scaling up of successful development interventions, at a time when the challenge and opportunity of scaling up have become a widely recognized issue for many development institutions and experts.

Since traditional private and public service providers frequently do not reach the poorest people in developing countries, social enterprises can play an important role in providing key services to those at the “base of the pyramid.”

In parallel with the recognition that scaling up matters, the development community is now also focusing on social enterprises (SEs), a new set of actors falling between the traditionally recognized public and private sectors. We adopt here the World Bank’s definition of “social enterprises” as a social-mission-led organization that provides sustainable services to Base of the Pyramid (BoP) populations. This is broadly in line with other existing definitions for the sector and reflects the World Bank’s primary interest in social enterprises as a mechanism for supporting service delivery for the poor. Although social enterprises can adopt various organizational forms—business, nongovernmental organizations (NGOs), and community-based organizations are all forms commonly adopted by social enterprises—they differ from private providers principally by combining three features: operating with a social purpose, adhering to business principles, and aiming for financial sustainability. Since traditional private and public service providers frequently do not reach the poorest people in developing countries, social enterprises can play an important role in providing key services to those at the “base of the pyramid.” (Figure 1)

Figure 1. Role of SE sector in public service provision

Social enterprises often start at the initiative of a visionary entrepreneur who sees a significant social need, whether in education, health, sanitation, or microfinance, and who responds by developing an innovative way to address the perceived need, usually by setting up an NGO, or a for-profit enterprise. Social enterprises and their innovations generally start small. When successful, they face an important challenge: how to expand their operations and innovations to meet the social need at a larger scale. 

Development partner organizations—donors, for short—have recognized the contribution that social enterprises can make to find and implement innovative ways to meet the social service needs of people at the base of the pyramid, and they have started to explore how they can support social enterprises in responding to these needs at a meaningful scale. 

The purpose of this paper is to present a menu of approaches for addressing the challenge of scaling up social enterprise innovations, based on a review of the literature on scaling up and on social enterprises. The paper does not aim to offer specific recommendations for entrepreneurs or blueprints and guidelines for the development agencies. The range of settings, problems, and solutions is too wide to permit that. Rather, the paper provides an overview of ways to think about and approach the scaling up of social enterprise innovations. Where possible, the paper also refers to specific tools that can be helpful in implementing the proposed approaches. 

Note that we talk about scaling up social enterprise innovations, not about social enterprises. This is because it is the innovations and how they are scaled up that matter. An innovation may be scaled up by the social enterprise where it originated, by handoff to a public agency for implementation at a larger scale, or by other private enterprises, small or large. 

This paper is structured in three parts: Part I presents a general approach to scaling up development interventions. This helps establish basic definitions and concepts. Part II considers approaches for the scaling up of social enterprise innovations. Part III provides a summary of the main conclusions and lessons from experience. A postscript draws out implications for external aid donors. Examples from actual practice are used to exemplify the approaches and are summarized in Annex boxes.

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The breakthrough therapy designation (BTD) program was initiated by the U.S. Food and Drug Administration (FDA) in 2012 to expedite the development of treatments for serious or life-threatening illness that demonstrate “substantial improvement” over existing therapies. The program has since become a widely supported mechanism for accelerating patient access to new drugs. As of March 2015, FDA has received a total of 293 requests for BTD. However, it has granted just  82 (28%), which indicates an ongoing lack of clarity over what exactly meets the criteria for the designation.

On April 24, the Center for Health Policy at Brookings convened a public meeting to explore the designation’s qualifying criteria and how FDA applies those criteria across therapeutic areas. Panelists used real-world and hypothetical case studies to frame the discussion, and highlighted major considerations for the application process, the FDA’s evaluation of the evidence, and the key factors for acceptance or rejection. The discussion also identified strategies to ensure that qualifying criteria are well understood. Here are the five big takeaways:

1.  The BTD program is viewed positively by drug companies, researchers, advocates, and others 

Across the board, participants expressed enthusiasm for the BTD program. Industry representatives noted that their experience had been extremely positive, and that the increased cooperation with and guidance from FDA were very helpful in streamlining their development programs. Receiving the designation can also raise a drug company’s profile, which can facilitate additional investment as well as clinical trial patient recruitment; this is particularly important for smaller companies with limited resources.

Patient and disease advocates were likewise supportive, and expressed hope that the early lessons learned from successful breakthrough therapy approvals (which have been mostly concentrated in the oncology and antiviral fields) could be translated to other disease areas with less success. However, while BTD is an important tool in expediting the development of new drugs, it is just one piece of broader scientific and regulatory policy landscape. Accelerating the pace of discovery and development of truly innovative new drugs will depend on a range of other factors, such as developing and validating new biomarkers that can be used to measure treatment effects at an earlier stage, as well as establishing networks that can streamline the clinical trial process. It will also be important to develop effective new approaches to collecting, analyzing, and communicating information about these treatments once they are on the market, as this information can potentially be used by FDA, providers, and patients to  further improve prescription drug policy and medical decision-making.

2.  BTD requests far outnumber those that actually meet the qualifying criteria

Since the program began, less than 30 percent of requests have received BTD designation. A substantial majority were denied at least in part due to either a lack of data or problems with the quality of the data, or some combination of the two. For example, some sponsors requested the designation before they had any clinical data, or submitted the request using clinical data that was incomplete or based on flawed study designs. Many requests also failed to meet the Agency’s bar for “substantial improvement” over existing therapies.

One reason for the high denial rate may be a lack of a clear regulatory or statutory bar that could be used as a definitive guide for sponsors to know what is needed to qualify for the designation. BTD denials are also confidential, which means that sponsors effectively have nothing to lose by submitting a request. Going forward, manufacturers may need to exercise more discretion in deciding to request the designation, as the process can be resource- and time-intensive for both sides.

3.  There is no single threshold for determining what defines a breakthrough therapy

About 53 percent of the 109 total BTD denials were due at least in part to the fact that the drug did not represent a substantial improvement over existing therapies. During the day’s discussion, FDA and sponsors both noted that this is likely because the criteria for BTD are inherently subjective. In practice, this means there is no clear threshold for determining when a new therapy represents a “substantial improvement” over existing therapies. Designation decisions are complex and highly dependent on the context, including the disease or condition being targeted, the availability of other treatments, the patient population, the outcomes being studied, and the overall reliability of the data submitted. Given the multiple factors at play, it can be difficult in some cases to determine when a new product is potentially “transformational” as opposed to “better,” especially for conditions that are poorly understood or have few or no existing treatments. In making its determinations, FDA considers the totality of the evidence submitted, rather than focusing on specific evidentiary requirements.

4.  Early communication with FDA is strongly recommended for BTD applicants

Roughly 72 percent of the BTD denials related at least in part to trial design or analysis problems, which led several people to suggest that sponsors engage with FDA prior to submitting their request. Though there are several formal mechanisms for interacting with the agency, informal consultations with the relevant review division could help sponsors to get a better  and much earlier sense of what kind of data FDA might need. This early communication could both strengthen viable BTD requests and reduce the number of frivolous requests.

5.  FDA may need more resources for implementing the BTD program