What’s Real in Rare Disease: A Pharm Exec Roundtable

Roundtable Participants

Indranil Bagchi, Vice President and Head, Payer Insights and Access, Global Health and Value, Pfizer Inc.

Monica Martin de Bustamante, Managing Director, CB Partners

Doug Danison, Global Pricing and Market Access Head, Oncology & CNS, Takeda Pharmaceuticals

Sandeep Duttagupta, Principal and Vice President, CB Partners

Ted Haack, Managing Partner, Haack & Associates

Cindy McDonald-Everett, Executive Director and Oncology Global Therapeutic Head, Amgen

Mark Rothera, Chief Commercial Officer, PTC Therapeutics

Philip Ruff, Global Value Strategy Lead, Shire

William Looney, Editor-in-Chief, Pharm Exec

William Looney, Pharm Exec: Rare diseases are life-threatening conditions affecting fewer than 200,000 patients. This may seem definably small, but in the aggregate, rare diseases are hardly rare: some 350 million people worldwide have a rare disease, more than the total for cancer and AIDS combined. We also know that 7,000 diseases are classified as "rare," yet only around 400 are currently treatable with medicines available in the clinical setting. In light of this daunting hierarchy of need, what stake has your organization taken in rare disease research and therapy, and why?

Philip Ruff, Shire Pharmaceuticals: Shire has undergone a significant strategic realignment in the last year or so, but our commitment to rare diseases remains at the very heart of the company. Conditions like Hunter Syndrome, Gaucher's, and Fabry Disease are priorities, and our pipeline portfolio promises many additional growth opportunities in this space. All of us at Shire are aware of the intensely personal nature of rare diseases-as parents, we can relate to the fact that rare diseases affect children disproportionately. Shire also has a strategic focus on conditions where we know our scientists can make a difference. At present, we have 28 pipeline assets for rare disease in development.

Photos: John Halpern

Shire is shifting its organizational approach to rare diseases, from concentrating our work on rare diseases in a single business unit to one where rare disease products will be integrated with other products along therapeutic lines. For example, Gattex, the inflammatory bowel drug obtained through our recent acquisition of NPS Pharmaceuticals, will now sit in our GI business unit.

Mark Rothera, PTC Therapeutics: PTC is a biotech with a nearly two-decade commitment to the discovery and development of treatments for patients with rare disorders, utilizing our expertise in RNA biology and post-transcriptional control mechanisms. Our lead compound, Translarna, has been approved in the EU to treat patients with Duchenne muscular dystrophy (DMD) due to a nonsense mutation and we are in Phase III trials for its use in cystic fibrosis patients with the same mutation. It is estimated that 10-15% of an estimated 2,000 monogenetic rare diseases are caused by a nonsense mutation. We are assessing additional indications for Translarna for patients with the same underlying mutation. From an organization standpoint, in the last two years, PTC has moved from being privately held to a publicly traded company, providing the capital base to pursue our R&D goals as well as establish an international commercial presence. Our experience demonstrates that in the rare disease field, it's gratifying to advance patient-focused innovation for such high unmet need.

Indranil Bagchi, Pfizer: Pfizer has a robust presence in rare diseases, with 22 approved molecules that treat such conditions or carry status as an "orphan" drug. For example, we have a major presence in hemophilia as well as products for polyneuropathic conditions and Gaucher's disease. At Pfizer, our strategic focus in the areas of hematology, neuromuscular, and pulmonary has allowed us to find opportunities internally and externally to develop these franchises.

Doug Danison, Takeda Pharmaceuticals: I lead the regional pricing and market access team for Takeda Oncology. At Takeda, we aspire to make a difference in lives of cancer patients worldwide. My team is responsible for ex-US and ex-Japan regions, including EUCAN and emerging markets. As for rare disease, my team focuses on "rare" cancer. We are in the process of launching ADCETRIS, a CD30-targeted antibody drug conjugate in relapsed refractory Hodgkin lymphoma and relapsed refractory systemic anaplastic large cell lymphoma.

We try to focus our internal operations to deliver greater clarity, agility, flexibility, and focus around oncology, recognizing the different data requirements for many products in this segment as well as the growing importance of speed-to-market performance-which rests on our being able to anticipate the needs of market access decision makers at an early stage of development.

Cindy McDonald-Everett, Amgen: Throughout our 35 years as a company, we have focused on areas of high unmet medical need, including orphan therapies and indications through an integrated approach to commercialization that maximizes the potential market opportunities as well as benefits to patients. For example, we have a product with official orphan-drug status for chronic immune thrombocytopenia, a serious blood disorder. In oncology, we recently launched a product for a type of acute lymphoblastic leukemia (ALL), which by standard definition would qualify as an ultra-orphan therapy.

Overall, our approach in oncology combines both therapeutics and supportive care. There is a lot we can learn from companies that have built an exclusive franchise around rare diseases, but we also see that companies like Amgen, with a more diverse product portfolio, can leverage opportunities from this broader commercial presence, through the full product life cycle.

Ted Haack, Haack & Associates: I currently work as a consultant to the industry on various pricing, reimbursement, and access issues around the world. Most recently, I headed the Market Access function for Genzyme's rare disease business unit. Prior to joining Genzyme, I was Pfizer's head of pricing & reimbursement, primary care business unit, and acted as interim head of market access for PCBU from November 2011 through July 2012.

Looney: The common thread is that many diseases are now moving toward the "rare" category due to the impact of personalized medicine and the enhanced targeting options available through companion diagnostics. How does the work that CB Partners is conducting on rare diseases conform to these company assessments of the "state of the art" on rare diseases?

Monica Martin de Bustamante, CB Partners: The definition of rare disease has evolved. It is more fluid today-even in chronic conditions one can find a rare disease indication, especially as pharma and biotech companies work to differentiate their target populations for a particular therapy with clinicians and payers.

The central question is why rare diseases have attracted strong interest from the industry. One factor is the high level of unmet medical need, which drives the focus on innovation. There is the reward derived from treating people who have few options, with special emphasis on the plight of vulnerable children whose lives can be cut short literally before they begin. Approval requirements and pricing and access challenges are markedly different, dependent on geography and the motivations of the various disease stakeholders interacting with industry. The small patient numbers place a premium on recruiting the right people for clinical trials as well as finding professionals with the knowledge to lead this work; both tasks get harder the larger the geographic remit in readying a global launch plan.

Standout factors

Patient advocacy is a distinguishing characteristic of the rare disease space. Patients are a force of nature in rare diseases. Because many rare diseases are complex and the community of victims is often obscure, it falls on active patients to set the terms of engagement on everything from trial recruitment to access and reimbursement. Productive partnering with patient groups is central to market success.

Much of the global agenda around rare disease was established with passage of the US Orphan Drug Act in 1983. The law sparked a surge in interest in these therapies, with more than 300 orphan drugs approved by the FDA after 1983 to date compared to only 34 during the decade prior to passage of the Act. Many countries have followed suit with their own rare disease legislation, including the EU, Japan, and, most recently, the emerging market countries-precisely where the industry is pinning most of its hopes for future growth. These are countries where payment conditions for medicines are difficult across the board, and especially so for rare diseases due to their association with nose bleed prices in the US and other affluent countries. Yet the long-term opportunities there are quite promising, if you do the required homework; each country is different.

Another critical element is finding that sweet spot with payers. Here the landscape is shifting, from a situation where payers remained willing to accept a high price point due to the small size of the covered population. Pricing aside, rare disease drugs were considered to be products of "low budget impact." Today, payers are rewriting the contract with the patient, shifting costs to individuals through higher co-insurance, bigger deductibles, and tiered co-pays, with the highest contribution pegged to the most costly brands. Other tactics include heavy use of prior authorization to slow access as well as outright exclusions from drug formularies-we estimate that about 15% of rare disease therapies are currently not available to US patients enrolled in the Medicare Part D drug benefit program.

In addition, the popular notion of "value" in drug therapy raises significant challenges in building the evidence base for a rare disease. It's frequently impossible to include an active comparator in your trial. Instead, you have to rely on a single-arm trial, probably at Phase II, due to the pressure that exists from patients to get the product to market quickly, because there is nothing else available. Yet that only makes dealing with payer expectations for metrics to demonstrate such "value" even harder. How can you prove a rare disease therapy is actually cost-effective when there is no accepted ICER (incremental cost-effectiveness ratio) to set a control group baseline against current treatments, where none such treatment exists?

Three paths to access

Overall, the access environment seems to be coalescing toward three destinations. The first is through establishing an incremental clinical benefit, which is what France and Germany are seeking to do, where products obtain access when patients experience a clinical gain against what is currently in the market. The value/unmet need consideration must precede a discussion on price. Next, you have the budget impact environment, which has traditionally been a positive path to access in rare disease because price times small volume sales limits exposure to payers. The challenge here is that more rare disease products are reaching the market just as payers are placing caps on drug spend. If you keep adding new products, while the overall budget fails to keep pace, cutbacks in access are inevitable. While it is commonly assumed that a rare disease drug justifies a high -even six-figure-price tag, is this a sustainable model going forward?

The last-and toughest-environment is among those with a formal cost-effectiveness hurdle. The health technology assessment community is more comfortable with policies that earmark resources around broad chronic conditions like diabetes and CVD, when in rare diseases what works best is taking into account the level of unmet medical need. If a payer allows a discussion to focus on demonstrating clinical value, that's where you will see the best chance for access to a rare disease medicine. I see the cost-effectiveness argument being applied less rigidly, at least for ultra-orphan drugs that really have no alternatives. If such drugs offer a better quality of life, expressed over a five to 10-year span, that has to mean something to a payer.

All of this leads to a key strategic question, which is whether the distinctive characteristics of rare diseases require they be addressed through a separate regulatory channel or, alternatively, be evaluated much the same way as drugs for other conditions. Based on what I just said, do we need a tighter definition of what is "ultra-orphan?" It is worth noting that while most countries have opted to recognize rare diseases as deserving of special consideration and support, this does not guarantee an accommodating stance on P&R and access. Likewise, is it a good idea to press emerging country governments to prioritize a commitment to rare disease? If we put ourselves in the shoes of governments, with high public health expectations and limited resources, does that make sense? In some markets we might say yes, while in others it might prove to be a non-starter.

Finally, is it time for biopharma companies to refine their institutional approach to this part of their business? Do rare diseases require specialized expertise centered in a dedicated business unit or is it preferable to address the category through a therapeutic model?

I am not sure the group can resolve these questions today but they, nonetheless, carry important implications for future success in this space.

Time for new models

Looney: Any comments on this overview of the issues? Will payers keep on paying?

Bagchi: We might be too complacent about budget impact. Even if we present decent cost-effectivencess data, if you cannot convince the authorities the budget will not bleed, you will not get access to reimbursement. More flexible analysis of cost-effectiveness should be adopted that balances other considerations such as equity, the rule of rescue, community values, patient needs, and the long-term costs avoided as a result of access to treatment. The process for assessing new therapies for rare diseases should be efficient, fit-for-purpose, transparent, and informed by community and patient values.

Ruff: There is a basic disconnect between the pace of medicine innovation and the way our health systems register the cost of innovation. Technology is advancing to the point where, for example with the emergence of gene therapy, we are potentially close to being able to provide a cure for some rare diseases that originate in genetic abnormalities. The cost for such a cure in a rare disease would tend to be very highly priced. US payers then have to face investing a significant sum in a patient who may not remain within their plan long enough for them to accrue the full long-term financial benefits of such therapies. Patients in a US healthcare plan typically remain with that plan only for two to three years on average. Such new technologies are likely to have a profound effect on our healthcare system.

Haack: The average annual profit margin in US managed care is about 1.5%, after tax. A big ticket, big population drug like Sovaldi suddenly enters the picture, so what happens to United Healthcare, with its $110 billion of revenues? It just lost a full percentage point off its profits.

Bustamante: This is a reality for all approaches to financing healthcare. The UK NHS touts its lifetime cost of care health model, but the financial commitment is always contingent on the annual budget cycle. There is no systematic attempt to balance current liabilities against lifetime savings.

Bagchi: The industry must work harder to develop new payment models. An amortized risk exposure model is one interesting approach. It certainly has application to gene therapy, whose effects are truly long-term-if you can't amortize the cost, there is no sustainable way for society to pay. This is clearly on the radar screen, as a new gene therapy costing in excess of a million dollars per course of treatment is becoming a reality.

Opportunity knocks where?

Looney: Rare diseases do not conform to geography. Given the structural financing issues we have just highlighted, which country markets represent the most compelling market opportunities? Is it still the US and the European Big Five?

Rothera: Japan has to be included. It recognizes orphan indications and is willing to reward innovation for small patient populations. I also see potential in key emerging country markets, especially Brazil.

Bustamante: To the extent R&D investment drives the rare disease space, pharma companies must rely on markets where pricing is sufficient to finance it. That includes, in addition to the US, the EU five, Japan, Canada, Australia, Brazil and Turkey. Despite the buzz, it remains difficult to build a core rare disease business around emerging countries.

Ruff: It really depends on the profile of each rare disease; in some countries, the incidence of a rare disease is disproportionately high due to the confluence of many factors, from epidemiology to the environment shaping the gene pool. The attention these diseases get from governments also matters.

Haack: The epidemiology profile is important. When I was at Genzyme, we looked carefully at the numbers for one of our key rare drug therapies, indicated for treatment of Gaucher's disease. The global population with this condition is estimated to be around 35,000, of which a good number are located in China, a market that presents significant challenges to diagnosis. We estimated that only 8,000 patients worldwide were being treated, despite decades of enzyme replacement therapy (ERT) availability. So where was everybody? The discrepancy led us to conclude the size of the affected population is probably overinflated. We had the opposite situation with Fabry's, another inherited genetic disease that is usually fatal at an early age. After diagnostic screening began for Fabry, we learned very quickly that the epidemiology data was lower in many places than what the diagnosis rate showed. The screening of newborns showed that this rare condition was actually quite prevalent in some countries. Maximizing market potential depends on getting the epidemiology right, at the start so that budget impact can be better determined.

Ruff: The challenge in rare diseases is that our understanding of epidemiology is constantly evolving, which complicates our ability to meet payer expectations about budget impact.

Haack: It also affects the calculation of the payer: are we on the right side of the lump sum versus annuity equation? If a drugmaker treats a child with a rare disease at 18 months and that child goes on to live a normal life, that's an awesome annuity-for the child and for the drug company. But the good deal may not be seen as such by the payer, who has to bear the full cost of treatment over that lifetime.

Rothera: I'd also like to point to the increasing reliance on clinical trial enrollment criteria in determining the label for treatments. Even in rare diseases for very small populations, epidemiologic data allows us to identify sub-populations with a distinct clinical phenotype that can lead to a restriction of access to therapy when a larger population may benefit but were unable to be included in the clinical trial. An example is treatment for certain patients with ERT. Because ERT's are unable to cross the blood brain barrier, they do not address the CNS component of the disease. If CNS symptoms develop significantly, it can force the discontinuation of treatment. Again, how do you build that into the predictable budget impact scenario demanded by payers?

McDonald-Everett: Finding balance around pricing for diverse indications on the same product is another issue. Payers tend to apply a blunt tool when it comes to pricing. Establishing value in each indication and negotiating the right price point for a later indication can adversely impact pricing for the broader population-how do we ensure there is equitable access, at the right price, for both groups? It requires a lot of internal debate about the exposure risk if you don't get this right with payers. There are various mechanisms that could be considered: forgo seeking a high price tag for the smaller rare disease population, or promote access through patient assistance programs and donations, to minimize the effect that a high ex-factory price might have on price negotiations for the much larger indication? There is no easy way to address this.

Bagchi: Looking at the geographic spread, it's hard to make generalizations about rare diseases. I agree that the main market potential remains in the mature industrial markets, but there are some interesting twists. In sales of our hemophilia business, the US and the UK are at the top, but right up there with them is Iraq. And the Iraqis pay on a national tender basis; it's all government money and of course that also means some subsidization through independent donors and foreign aid.

Kickstart financing

Looney: This implies a much wider range of stakeholder groups are involved in facilitating access to drugs for rare diseases-similar to vaccines?

Bagchi: Yes. Our outreach has to involve NGOs, foundations, international organizations, and governments. As innovators, we have to be creative in finding these non-traditional sources of funding.

Haack: Actually, creative funding is as critical as producing the studies to demonstrate clinical relevance and cost-effectiveness. You have to establish where the local funding stream is going to come from, right at the start of your commercialization strategy; certainly well before registration.

Looney: We have spoken a lot about price and access, but what about issues that relate to development, particularly cycle time to registration? Aren't you living in a charmed world? Certainly there is a perception that regulators like the FDA are very supportive of rare disease medicines.

Bustamante: The FDA is usually quite flexible in the design and end point designations on clinical trials for rare diseases. It knows that reality requires some departure from the typical standard large population trial for CVD or diabetes. The key challenge is how this activity relates to the next step, which is obtaining patient access for an approved product.

Trials and tribulation

Ruff: It is widely assumed that, because rare disease trials usually involve a small group of subjects, it is cheaper to run them. That's not really true. Most trials that Shire conducts on rare disease have to be managed at numerous locations, across geographies. Finding qualified investigators is hard, especially outside the US, where major hospitals and other centers of expertise are often scarce. Here in the US, a patient we recruit might live 60 miles from a study center. In Latin America, that person can be two days journey or more away from the site. And as our trials often require children, there is extra overhead in including parents and other care-givers in the mix. Sometimes we have to move entire families to a trial site be able to get a patient to take part in a trial. This can be a complicated and costly process.

Rothera: Determining the proper endpoint for a rare disease trial is a process in itself-what are you actually testing? You cannot depend on the FDA to make that call for you. It has to be built by you, with the help of top experts in the field, with a design that can be validated through to final regulatory approval. We had to pioneer the development of a validated clinical endpoint for DMD-the six-minute unassisted upright walk-working with the DMD community. The endpoint has since become the standard for other DMD clinical trials.

Bagchi: Most rare disease patients lack treatment alternatives; usually, their condition is life threatening, and many of these patients are children, too. The result is strong resistance to being in a controlled blinded study where there is an even chance of the patient getting the placebo. What does this mean for the sponsoring company? Your trial is essentially competing with compassionate use programs. That's the goal for a desperate parent-you don't want your sick child to be in the placebo cohort. From an approval perspective, it carries a real implication. The access you give to a half dozen children can skew the findings and delay getting the test drug to market, where ultimately many thousands of children will benefit.

Looney: Is there an easy fix from regulators to allay such an outcome?

Rothera: The early access model applied in some European countries-like France or Italy-is an approach I'd like to see adopted in the US. Your ROI begins a little earlier, patients get quicker access, and it facilitates finding a sustainable price level, while not compromising the implementation of fully validated trials required for regulatory approval.

Bagchi: The other approach being tested in the EU is adaptive licensing, which is now the subject of a pilot program-involving several rare disease compounds-administered through the European Medicines Agency (EMA). The essence is to merge the interests of regulators and payers by granting contingent marketing rights to a drug developer in return for a commitment to additional testing-in short, coverage with evidence development (CED). So the company gets access, it conducts studies according to protocols approved by payers, and the payer can apply the results to negotiate a final market price or change the terms of access. I would say discussions are still tentative, largely because national reimbursement authorities are hesitant to devolve their responsibilities on price and reimbursement.

Haack: It's hard to see any real incentive for industry to play the adaptive licensing card. Most government participants view it as a way to short producers on price. Certainly, prices are never going to rise in response to real-world evidence that proves a medicine delivers what it promised. There has been discussion by certain governments of allowing the price to come up to an appropriate level, but the "launch price" would be lower than that.

Does France do it better?

Looney: Is there any market where we agree the stars are aligned toward doing things right in supporting rare disease innovation that delivers for patients? (Editor's note: the entire group agreed that France presents "an interesting dynamic.")

Bustamante: The French ASMR rating system puts a metric value around societal unmet need in a way that other markets do not. It accepts the idea that if there is no treatment available for a rare disease, and your medicine offers a chance for clinical benefit to the patient, then value is demonstrated.

Rothera: France was one of the first countries to single out rare diseases with a comprehensive national action plan. That plan has been amended several times to keep pace with the science.

Bagchi: In France, there have also been some new developments. The most important is a new rule requiring that any medicine costing more than €50,000 a year per patient undergo an intensified budget impact review. This is a key consideration in developing an early access plan.

Looney: Is this trend likely to spread to the US? Will the Patient Centered Outcomes Research Institute (PCORI) end up serving as a cost-effectiveness watchdog on rare disease drugs?

Ruff: I sit on PCORI's rare disease panel. PCORI is not authorized to consider any issue relating to pricing or cost of therapy, except when it relates to direct patient out-of-pocket costs. There would need to be a significant political shift in the US to introduce cost-effectiveness criteria as used by many other other countries.

Power points on pricing

Looney: Is the industry neglecting any useful arguments to justify the pricing of rare disease medicines and strengthen the value proposition behind them to patients and payers?

Rothera: Medicines for rare diseases amount to only about 2-5% of overall drug costs in the US and Europe. The budget impact is manageable and it supports a lot of innovation in areas of high unmet medical need, whose benefits are incalculable over time.

McDonald-Everett: The improvement in quality and productivity from medicines innovation, including the life years gained, as well as the general societal benefits that derive from this, are components of value that are usually overlooked. The math is always built around the next budget cycle. This is the psychology that we have to change.

Danison: We need to consider how we communicate the price of our products. We have seen the Sovaldi example where there was pushback about "a thousand dollars per pill." However, when you consider the cost to treat HCV it may have been perceived differently. Communication and framing of the drug price may have helped them. In an ideal world, it would be great if we could move away from such a focus on price per pill, per vial, etc. We must think about what it takes to have better health outcomes for patients more than counting up vials and pills. However the existing infrastructure is focused on units, so a lot of work would be required to remove the limitations of existing billing and coding systems, especially in the US. But, at the end of the day, the focus should be on delivering results for patients.

Haack: There is another issue hiding in plain sight-soaring company valuations and the rich premiums being paid for licensed products. Pharmacy benefit managers (PBMs) and insurers think that if a drug company has just paid several billion dollars essentially to acquire one new product, that company is going to have make a lot of money very quickly. True or not, it's a perception.

Practice with patients

Looney: The patient can serve as an important intermediary to this discussion. Clearly, patient organizations are critically important in focusing attention-and research dollars-on rare diseases. What is the current state of the industry's relationship with patient advocates? Are we in the midst of any significant changes in the way the two of you interact?

Duttagupta: A trend is the discomfort of some payers about overt efforts to mobilize patients as advocates for rare disease treatment. This is particularly evident outside the US. In Europe, for example, patients are still not perceived as a social partner in health, deserving of a seat at the negotiating table. Despite this, patients have in fact become far more global in orientation. In the hemophilia space, chapters of the Hemophilia Foundation have spread to virtually every major country. Local groups can be mobilized quickly on behalf of issues that impact patients.

Rothera: Our experience in DMD underscores the critical importance of patient advocacy. Organized patient involvement clearly helped push our technology over the registration line by highlighting the enormous unmet need and the natural history of this fast progressing disease. That in turn spurred support for the widest possible access to the drug. I would add that we were able to leverage the passion and awareness of the Duchenne patient community to accelerate recruitment to our clinical trials on the basis of the right genotype.

Bagchi: Rare diseases are an exception to the fact that in most of the large therapeutic areas, patients remain an afterthought. Patients have not been fully integrated to the FDA approval process, even though recent legislation mandates more consultation. There is a need to apply the positive lessons we have learned in rare diseases to the broader arena.

Rothera: The Parent Project Muscular Dystrophy, a family-centered network, recently funded a benefit-risk assessment survey-involving approximately 120 caregivers-that was designed to measure their tolerance for potential benefits and risks of emerging therapies for DMD. Most patients with this relentlessly progressive and terminal disease will die in their 20s or 30s. Preserving patients' muscles and abilities at any stage of the disease is valuable to the caregivers. The insights from the survey have gotten the attention of the FDA and may inform its decision making as it reviews potential therapies that slow or stabilize progression of the disease.

Danison: Patient insight is particularly critical as we move toward a financing system that relies more on individual contributions to the cost of care. These insights are particularly important, for example, in the US, when there are both oral and IV alternatives with different out-of-pocket responsibilities for the patient. Patients have preferences; we should understand them.

Bagchi: Again, I see a disconnect between reality and intent. Patient reported outcomes (PRO) are seen as a valuable source of insight, but when such data is collected in a study trial, how much of it ends up on the drug's label? Do payers consider the data when mulling reimbursement? It's not clear that they do. Standardized PRO instruments exist, but acceptance into wide use requires endorsement by all parties, including regulators and payers, which is not the case. The burden usually falls on the investigator to develop the PRO and then ensure its dissemination-an expensive task.

Ruff: The absence of a uniform PRO standard is a problem. Much is left to interpretation: is it really a PRO? Or is it a caregiver-reported outcome? Or a physician-reported outcome? You also cannot expect a child to fill in a questionnaire, so the parent does it. Is that a parent-reported outcome? I think an FDA regulator would tell you that a response from a physician carries more value than that of a patient, especially if mom and dad are really doing the reporting. There are clear guidelines around PROs in general. The issue is which type of instrument will capture the most appropriate data that is meaningful to patients, physicians, regulators, and payers.

The optimal organization

Looney: We have not addressed the impact of size, scale, and internal organization in fostering a culture of excellence around rare diseases. Does the way a company manages its stake in rare disease therapy affect its capacity to be a successful competitor in this segment?

Rothera: There are issues with size. In the 17 years I have worked in rare diseases, I have seen multiple instances where large players simply abandoned work on an orphan drug when the initial trial results proved less than expected. What you need most in rare diseases is determination and resilience to stay the course. That means in turn a higher tolerance for risk, which is often absent in big Pharma, where multiple options force you to make tradeoffs.

Haack: Culture does count. I worked for Genzyme. I can say that a condition for being hired there is the ability to prove how well you think about the patient in your daily work. I also worked for Pfizer, whose culture is very customer-focused; it's the clinician and provider that is top of mind. You need to be both patient and customer focused in genetics now. Genzyme eschewed bureaucracy, while Pfizer had more resources to bring to a situation.

Rothera: Rare disease is very global. Being flexible, with ears close to the ground, is vital to keeping connected to the geographies where you choose to engage. Staying small means having fewer silos that thwart these connections.

Bagchi: When initially organizing our rare disease portfolio, Pfizer evaluated a number of potential approaches. These ranged from continuing the arrangement in which rare disease drugs had no special designation to various models of alignment and operational independence. We opted for a course designed to best align both to the shape of our portfolio and to the innovative core of Pfizer, with its own R&D and commercialization staff assigned to push specific targets forward and create better synergies with rare disease patients. This arrangement gives us the proper balance between scale and flexibility, while the enhanced focus allows for stronger links back to the patients that inspire our work.

I have asked payers-and structure and size do drive perceptions of the business. For example, when payers are asked if the same rare disease compound, with equivalent support data, was put to them for a reimbursement decision simultaneously by a big Pharma company and a small biotech, which one would they choose; many have said they would opt to go with the biotech, on grounds that it was smaller and presumably had more at stake in succeeding with the compound than a big Pharma. The sentiment was to "give back" to the biotech, assuming it had put more effort and skin in the game; it is a calculus that causes bigger companies to confront more negative risks than is commonly assumed.

McDonald-Everett: Discussion on company size or portfolio diversity ignores what really counts, which is whether the organization is a learning organization. The advantage for a company with a more diverse portfolio is the opportunity to leverage best practices from a broader portfolio and apply it to rare diseases, and vice versa. The requirement is you have to reinforce communication across functions and geographies. No silos.

Rare disease-future tense

Looney: As a final thought, what excites you about the future of science in rare diseases? In what therapeutic areas is our industry best positioned to help fight these conditions?

Ruff: Gene therapy holds significant promise, largely because it will serve as a pathway to cures, not just in our space but in other areas of medicine as well. I believe that we will see significant progress, in a 10-year time frame rather than over multiple decades.

Duttagupta: It is also going to drive enhancements in personalized medicine, which means these cures will lead to broader service and financing efficiencies because of the higher level of certainty attached to the treatment.

Danison: With an increased focus on personalized medicine, we will see treatments for cancer classified more according to the mutations that drive a tumors growth rather than the location where the tumor originated.

Rothera: mRNA biology will prove just as important as unlocking the secret of DNA many decades ago.

Editor's note: The views expressed by the Roundtable participants are their own and do not necessarily represent the official positions of their affiliated companies.