Breakthrough Business Models: Drug Development for Rare and Neglected Diseases and Individualized Therapies: Workshop Summary (2009)

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7 Strategies for Facilitating Clinical Trials There are three common misperceptions about clinical trials for thera- pies for rare and neglected diseases: (1) there is a lack of interest in these conditions and research to address them, (2) there is a lack of informa- tion on these conditions, and (3) there is a lack of access to clinicians with salient experience. In fact, however, tremendous progress has been made. Investments in research and development on therapies for rare and neglected diseases are being made around the world, stimulated in large part by the interest and action of patient advocacy groups. Contrary to popular belief, there is considerable information available on these condi- tions, and one responsibility of the rare and neglected disease community is teaching the public and patients how to search for that information. Patients should not feel isolated or stigmatized by the diagnosis of such a disease. All therapies must be proven safe and effective in clinical trials with human subjects before they can be approved for broad use, regardless of the size of the target population. The three speakers in this session discussed strategies for streamlining the clinical trial process. Highlights of these strategies are presented in Box 7-1.   This introductory section is based on the presentation of session moderator Stephen Groft, Pharm.D., Director, Office of Rare Disease Research, National Institutes of Health. 82 

STRATEGIES FOR FACILITATING CLINICAL TRIALS 83 FDA Review and Regulation of Small Clinical Trials: Successes, Barriers, and Directions for the Future, From the regulatory/legislative perspective, there are special challenges associated with Food and Drug Administration (FDA) review and approval of products to treat rare diseases. The majority of New Drug Applications (NDAs) for orphan drugs are based on small clinical trials, some with as few as 20 patients. As noted by Coté earlier in the workshop, the Orphan Drug Act provides for predominantly financial incentives for orphan drug development. Orphan drugs are not held to different or less stringent stan- dards than other drugs. Marketing approval for all drugs requires, by law, “substantial evidence of effectiveness” (21 CFR § 314.50). But exactly how that evidence is provided is negotiable, and communications with FDA can help ensure the most effective use of the sponsor’s limited financial and human (i.e., patient) resources. Regulatory Tools The Orphan Drug Act has been successfully implemented, resulting in the approval of 326 products to treat rare and neglected diseases over the past 25 years. There are additional tools pertaining to the regulation of nonorphan drugs, such as the Prescription Drug User Fee Act (PDUFA) and the FDA Modernization Act of 1997 (FDAMA), that can also help advance the development of orphan products (see Box 7-2). For example: • Fast-track designation can be given to a drug product that is both intended to treat a serious/life-threatening condition and claimed to address an unmet medical need. Fast-track designation allows for more involvement with FDA through scheduled meetings and permits rolling review, whereby the NDA can be submitted in sections. • Accelerated approval is based on a surrogate end point rather than a clinical outcome. For example, a surrogate end point for treatment of HIV could be a decrease in viral titers rather than demonstration of clinical improvement or extension of patient life span. Proof of a clinically meaningful benefit, which can take a   This section is based on the presentation of Anne Pariser, M.D., Medical Team Leader, Inborn Errors of Metabolism Team, Division of Gastroenterology Products, Center for Drug Evaluation and Research, FDA.   Dr. Pariser’s presentation focused on conducting clinical trials for drugs to treat rare dis- eases and drugs that have been designated as orphan products. It is important to note that some of the discussion may not apply to drugs for neglected diseases.   he Orphan Drug Act is discussed in detail in Chapter 3. T 

84 BREAKTHROUGH BUSINESS MODELS BOX 7-1 Examples of Disease Foundation Strategies for Facilitating Clinical Trials Multiple Myeloma Research Foundation (MMRF) Founded in 1998 by a newly diagnosed multiple myeloma patient, Kathy Giusti, and her sister, Karen Andrews, MMRF’s mission is to urgently and aggressively fund research that will lead to the development of new treatments for multiple myeloma. As part of its long-, mid-, and short-term research strategies, MMRF funds a portfolio of research worldwide comprising the basic science of multiple myeloma, validation, and Phase I and II clinical trials (conducted by MMRC; see below). http://www.multiplemyeloma.org Multiple Myeloma Research Consortium (MMRC) A sister organization to MMRF, founded in 2004 by Kathy Giusti, MMRC has as its mission accelerating the development of novel and combination treatments for multiple myeloma by facilitating clinical trials and correlative studies. MMRC integrates the research efforts of 15 member institutions that represent the lead- ing myeloma centers in the United States and the world. Centers are bound by a common membership agreement. MMRC is designed to operate like a drug development organization. Its leader- ship team includes: • A chief executive officer with 10 years of experience in drug commercializa- tion at two major pharmaceutical companies (also the founder and a myeloma patient). • A chief scientific officer with 16 years of industry experience in drug and target discovery. • A chief medical officer who is a trained hematologist/oncologist with more than 20 years of clinical research and drug development experience in industry. The MMRC Progress Review Committee comprises experts from the member institutions, and selects and prioritizes targets. The MMRC Tissue Bank integrates myeloma tissue samples with corresponding genomic and clinical data. To facili- tate accrual, MMRC has a program in place to allow patients to donate tissue directly. The MMRC Data Bank enables sharing of standardized data among consortium member institutions. 

STRATEGIES FOR FACILITATING CLINICAL TRIALS 85 Metrics and reward systems are implemented to improve processes and to enforce accountability: • A scorecard tracks the number and quality of tissue samples provided to the tissue bank, the time required to open and accrue clinical trials, and the engagement of principal investigators (monitoring activities such as participa- tion in monthly calls and face-to-face meetings or bringing new ideas to the consortium). • Tier one centers, those performing in the top one-third, receive funding to cover the full salary of a clinical research coordinator who provides dedicated oversight of all MMRC clinical trials (100 percent full-time equivalent [FTE]). The second tier receives 50 percent of an FTE and the third tier 25 percent. http://www.themmrc.org Muscular Dystrophy Association (MDA) MDA was founded in 1950 by a group of patients and parents of young patients with muscular dystrophy and a researcher studying the disease. MDA is an u ­ mbrella organization covering 40 rare neuromuscular diseases and is the largest nongovernmental sponsor of neuromuscular disease research. It also provides numerous services to patients (such as buying and repairing wheelchairs and leg braces and running free summer camps for children), facilitates meetings of MDA support groups, and sponsors public and professional education programs. MDA is funded almost exclusively through individual, private contributions. MDA has more than 200 offices nationwide, sponsors 230 hospital-affiliated clinics across the United States, and supports nearly 400 research projects worldwide, distributing funding across basic research, target identification, proof- of-principle testing in animals, translational research and preclinical development, and clinical research. MDA is also working to develop, validate, and standardize end points. MDA works through private–private partnerships with other nonprofit organi- zations, such as the TREAT-NMD neuromuscular network in Europe, the Interna- tional Coordinating Committee for Spinal Muscular Atrophy Clinical Trials, and the Duchenne Research Collaborative International. http://www.mda.org 

86 BREAKTHROUGH BUSINESS MODELS BOX 7-2 FDA Review: Opportunities to Facilitate the Drug Development and Approval Processes FAST-TRACK DESIGNATION • Drug product must be intended to treat a serious/life-threatening condition and address an unmet medical need. • Allows for: – Scheduled meetings to obtain agency input on development plans – Rolling review option to submit NDA in sections rather than all at once • Allowed by law under Section 112 of FDAMA. • FDA guidance available: Guidance for Industry Fast Track Drug Development Programs—Designation, Development, and Application Review (http://www. fda.gov/Cder/Guidance/5645fnl.pdf). ACCELERATED APPROVAL • FDA approval is based on a surrogate end point (e.g., a laboratory measure or physical sign rather than a clinical outcome). • Allowed by law under agency regulations: – Drugs: 21 CFR § 314.500 (Subpart H) – Biologics: 21 § CFR 601.40 (Subpart E) PRIORITY REVIEW • Sets the goal date for FDA action on the marketing application at 6 months, rather than the standard review goal date of 10 months. • Designation is made after the marketing application is submitted. • Must be requested by the sponsor. • Allowed by agency procedure: – Drugs: CDER MaPP 6020.3R (http://www.fda.gov/cder/mapp/6020.3R.pdf) – Biologics: CBER SOPP 8405 (http://www.fda.gov/CbER/regsopp/8405.htm) COMMUNICATIONS • Early and frequent communication with FDA is encouraged by the agency to “aid in the evaluation of the drug and in the solution of scientific problems. . . .” Includes “free, full, and open communication . . .” (21 CFR § 312.47). • The Review Division should be contacted for information; must be requested by the sponsor. long time, is not required at the time of the accelerated approval, and verification studies are conducted post-approval. • Priority review can be requested at the time a sponsor submits a marketing application and if granted, commits FDA to a PDUFA goal date of 6 months, rather than the standard 10-month review cycle. 

STRATEGIES FOR FACILITATING CLINICAL TRIALS 87 • The consistent point of contact for the sponsor is the regulatory project man- ager (RPM). FORMAL MEETINGS • FDA guidance available: Guidance for Industry: Formal Meetings with Spon- sors and Applicants for PDUFA Products (http://www.fda.gov/cder/guidance/ 2125fnl.pdf). • Type A – Immediately necessary for a program to move forward. – For dispute resolution (e.g., Clinical Hold, Refuse-to-File). – To occur within 30 days of FDA’s receipt of sponsor request for meeting. • Type B – Held at specified clinical stages or milestones. - Pre-IND (21 CFR § 312.82) - End of Phase II (21 CFR § 312.47) - Pre-NDA/BLA (21 CFR § 312.47) – To occur within 60 days of FDA’s receipt of sponsor request for meeting. • Type C – Any meeting that is not type A or B. – To occur within 75 days of FDA’s receipt of sponsor request for meeting. SPECIAL PROTOCOL ASSESSMENTS • FDA’s evaluation of the adequacy of a protocol’s design, conduct, and analysis relative to regulatory requirements for approval. • FDA response issued within 45 days. • Available only for certain types of protocols. • Allowed by law under Section 119(a) of FDAMA 1997. • FDA guidance available: Guidance for Industry: Special Protocol Assessment (http://www.fda.gov/cder/guidance/3764fnl.pdf). INFORMAL MEETINGS • Usually response to a limited number of specific questions that may require only yes/no answers, or brief clarifications of previous responses. • Arranged through the RPM and usually involve only a few members of the review team. • No written communications are issued. Communication with FDA Regardless of whether a product is designated as an orphan drug or has fast-track designation, early, frequent, and quality communication between FDA and the drug developer is crucial. There are a variety of opportunities for communication with FDA; however, small companies and individual 

88 BREAKTHROUGH BUSINESS MODELS academic investigators often do not realize that they are entitled by law to these communications. It is important to note that FDA cannot initiate such a meeting; the party developing a new drug must request it, following the procedures detailed in guidance documents (see Box 7-2). Opportunities include formal meetings, informal meetings, and special protocol assess- ments (SPAs). An advantage of formal meetings is that FDA will issue written minutes, usually within 30 days of the meeting, documenting the advice given and verifying agreements that are reached, helping to speed the process and offering a better likelihood of success. There are three types of formal meetings—A, B, and C (see Box 7-2). Note that type B meetings, which are clinical-stage or milestone meetings, can be requested even before the initial Investigational New Drug (IND) protocol is submitted. Such early communication can make the clinical process run more smoothly and help prevent delays. Pariser urged applicants to request meetings with FDA, noting that the agency is usually very willing to grant such requests. Pre-IND Challenges In the pre-IND stage, problems arise that, while not unique to orphan drugs, are due to the limited resources of the small companies and academic institutions that sponsor the drugs. Before a sponsor can initiate an IND, much often expensive work must be completed. Chemistry, manufacturing, and controls (CMC) of the drug must be adequately characterized. This is especially challenging for biologics, which are generally large molecules that are difficult to characterize. Working assays, such as immunogenicity assays, must be in place during development. While CMC can be outsourced to contract organizations, funding for such services can be a nearly insur- mountable barrier for small companies and academic investigators. Animal pharmacology studies are also required before a product can be adminis- tered to humans in clinical trials—another topic that should be discussed during a pre-IND meeting. And if there is previous human experience, it must be of sufficient quality to support safety and proposed dosing. Pivotal Study Design Another common roadblock to approval is an inadequate pivotal study. The studies for orphan drugs are usually small. For a given product, FDA may see one Phase I/II study addressing safety, pharmacokinetics/­ pharmacodynamics (PK/PD), and exploratory efficacy that might include just 8–12 patients. There may then be only one pivotal trial, as opposed to a pivotal trial followed by a confirmatory trial, as is typically the case for nonorphan drugs. On occasion, a sponsor will initiate an IND, not com- municate with the agency for 5–7 years, and then submit an NDA with a 

STRATEGIES FOR FACILITATING CLINICAL TRIALS 89 pivotal trial that is inadequate. For a nonorphan indication, the study may have to be dis­regarded, and the sponsor may have to begin over again. But for an orphan drug, this is a heartbreaking situation, Pariser said, given that conducting a second pivotal trial may be an almost insurmountable prob- lem because of a lack of funds, of trial participants, or even of additional drug product. One way to overcome these obstacles is to maintain regular communication with the agency throughout the development process. What constitutes an adequate and well-controlled study will vary depending on the disease in question, and there may be more flexibility for rare diseases as a result of the small populations and lack of statisti- cal certainty involved. The best approach is to work with FDA to deter- mine what the acceptable end points are and agree on the study design in advance. Accelerated approvals that rely on surrogate end points are also a possibility, but these approvals require a postapproval verification study that demonstrates clinically meaningful benefit (a postmarketing or Phase IV study). “Well-controlled” does not necessarily mean a placebo control. The choice of control groups is determined on the basis of avail- able standard therapies, other available therapies, adequacy to support the chosen design, and ethical considerations. The control arm of a study is unique to the disease. In general, randomized controlled trials include control and test groups chosen from the same population treated concur- rently, and the controls may be placebo, no-treatment, dose-response, or active com­parator controls. In some circumstances, it may be possible to use a historical control, although this is an unusual situation, and such studies must be carefully designed. NDA/BLA Issues Some of the issues FDA encounters frequently with NDAs and Bio- logical Licensing Applications (BLAs) for orphan drugs arise from mis- understandings about what is required for an orphan drug. Incomplete submissions, from both large and small companies, are relatively common. Sponsors have told the agency they thought a particular component of the submission was not required because their product was an orphan drug. As noted earlier, all drugs are held to the same standard of “substantial evidence of effectiveness.” All components of the NDA or BLA must be completed unless there is an agreement from FDA in writing to the contrary. An incomplete application will not always be prevented from moving for- ward, but it can result in an unwanted delay. Again, the components of the application can be discussed at a pre-NDA meeting, or earlier. 

90 BREAKTHROUGH BUSINESS MODELS FDA Recommendations to Sponsors Based on FDA’s experience in working with sponsors of orphan drugs, Pariser offered the following recommendations: • Meet with FDA early and often. Sponsors should take advantage of all opportunities for meetings and communication. The agency favors open communication with both drug developers and patient groups. FDA does meet with patient groups, either alone or with the drug developer; however, all information regarding a drug product under IND is confidential, and FDA cannot discuss it with patient groups without permission from the drug developer. • Formulate the clinical program as early as possible. Understanding the natural history of a disease and determining whether there are biomarkers that can be used can aid in designing the pivotal study, especially since there is a limited patient population available for study, and many orphan diseases are not well understood. • Do not overlook the value of early-phase trials. Sponsors should consider animal models, exploratory end points, PK/PD ­parameters, and surrogate end points/biomarkers in the design of early-phase studies. • Submit an SPA for the pivotal study. FDA will review it and pro- vide comments. An agreed-upon SPA is a binding agreement, so if the sponsor’s trial meets the predetermined end point, the likeli- hood of approval is increased. • Rigorously control study conduct. Training study personnel and developing a comprehensive study manual can decrease variability in study-related procedures. This can be accomplished more easily for small trials in a limited number of centers, with experts in the field or specialists as principal investigators. • Conduct a natural history study. Such a study can be either r ­ etrospective or prospective. Given a limited number of patients, it is important to recognize end points, preferably ones that are apparent in the shorter term. Patient groups can facilitate natural history studies. The published literature, such as case reports, is often inadequate for rare diseases. The most severe cases tend to be published and may not be representative of the broader affected population and/or attenuated presentations. • Be attentive to the rights and welfare of medically vulnerable patients with no (or few) other treatment options. Among its patient protection provisions, the Declaration of Helsinki addresses vulner- able populations who need special protection. Sponsors should 

STRATEGIES FOR FACILITATING CLINICAL TRIALS 91 consider using an independent safety monitoring board or other oversight committee when conducting the pivotal study. • Remember that the drug will be labeled only for the populations/ indications studied. Orphan drugs can be very expensive, and insur- ance will not pay for them unless their use is approved by FDA and they are labeled for that particular population and indication. Since FDA needs substantial evidence of benefit before it can approve a label indication for a population, it is important to be as inclusive as possible early on. The target population and how the drug will be used should be carefully defined to ensure that patients will have access to the drug. • For biologics, discuss characterization, assays, and antibody testing with FDA’s Office of Biotechnology Products as early as possible. Sponsors can contact the review division for help in setting up a meeting with that office if necessary. Directions for the Future FDA is sharing knowledge with international regulatory agencies such as the European Medicines Agency (EMEA) and Health Canada and working to increase international collaboration. The agency is also attempting to increase the involvement of patient groups. For example, review divisions may have patient consultants participate in meetings, or patients may serve on advisory committees as special employees of the government. As discussed earlier, patient advocacy foundations have con- tributed significantly to the funding of clinical trials. Patient groups can also play an active role in planning studies, advising on barriers to enroll- ment, or addressing safety concerns related to a study. Post-approval, drug developers often collect data on patient safety and efficacy through orphan drug registries, which are often required by FDA as a condition of approval for a product.  Approaches to Accelerating Clinical Trials An oncology compound that is entering Phase I has about a 5 percent chance of ultimately achieving FDA approval (Sharpless and DePinho, 2006). In addition, oncology trials tend to be inefficient. Dilts and Sandler at Vanderbilt University reviewed 300 oncology trials conducted at their center and found that on average, almost 10 months elapsed between final protocol and first patient dosed (Dilts and Sandler, 2006).   This section is based on the presentation of Anne Quinn Young, M.P.H., Program Director, Multiple Myeloma Research Foundation. 

92 BREAKTHROUGH BUSINESS MODELS For multiple myeloma, four new drugs have been approved over the past 5 years, and there are nearly 40 additional compounds in devel- opment. The importance of collaboration in moving drug development forward was highlighted throughout the workshop. Bringing four new myeloma drugs to patients has been the result of a successful collaboration between the Multiple Myeloma Research Foundation (MMRF) and the Multiple Myeloma Research Consortium (MMRC), working with partners in industry; academia; government, including the National Cancer Institute (NCI) and FDA; and most important, the patients who participate in trials, donate funding to disease foundations, and provide tissue so that correla- tive studies can take place. MMRF and MMRC are sister organizations. MMRF funds a portfolio of research worldwide, including investments in the basic science of mul- tiple myeloma; validation of targets; translational research; and Phase I and II clinical trials, which are conducted by MMRC. Early on, MMRF determined that to accelerate drug development, it needed to operate like a drug development company. The leadership team consists of the CEO and founder, who is a myeloma patient with 10 years of experience in drug com- mercialization at two major pharmaceutical companies; a chief scientific officer with 16 years of industry experience in drug and target discovery; and a chief medical officer, who is a trained hematologist/oncologist with more than 20 years of industry experience in clinical research and drug development. MMRC integrates the research efforts of 15 leading academic ­centers, with the common goal of facilitating and accelerating Phase I and II clini- cal trials and banking tissue. These are the leading myeloma centers in the United States and the world, and are bound by a common member- ship agreement. MMRC is focused on high-quality trials of drugs and combinations. Targets are prioritized by a committee of experts from the 15 centers, and new projects undergo a stringent review process. MMRC brings expertise to small biotechnology companies that often have limited resources and clinical experience, working with the company to develop a strong regulatory plan. MMRC also has a Good Laboratory Practices (GLP)–quality tissue bank, which enables correlative studies to be con- ducted with all of the trials. Speed and efficiency are a priority, and MMRC has set aggressive goals for the timing of protocol development (3 months); contracting, which is often the biggest factor in delaying trials (2 months); institutional review board (IRB) approval (3 months); and patient accrual (8–14 months). Metrics and reward systems are implemented to improve processes and enforce accountability. MMRC has instituted a scorecard that is used to track the number and quality of tissue samples provided to the tissue bank; the time required to initiate clinical trials and accrue patients; and 

STRATEGIES FOR FACILITATING CLINICAL TRIALS 93 the engagement of principal investigators, including such activities as par- ticipating in monthly calls and face-to-face meetings or bringing new ideas to the consortium. Use of the scorecard has led to improvements. Following the release of the first scorecard results at the end of 2007, 100 percent of principal investigators participated in the monthly call for the first time. Using the scorecard, MMRC ranks the centers in three tiers and links finan- cial rewards to performance. The top third of the 15 centers are placed in tier one and receive funding to cover 100 percent of a full-time equivalent (FTE) clinical trials coordinator. The second tier receives 50 percent of an FTE and the third tier 25 percent. The top center, which in 2007 was Emory University, also benefits from the publicity and enhanced credibility gained from being designated Center of the Year. To date, MMRC has initiated 14 clinical trials. The portfolio is bal- anced in terms of Phase I and II trials, as well as independent investigator and industry-sponsored studies. MMRC is now in a position where it can be more selective about the trials that are undertaken, ensuring that only those that advance its objectives are selected. MMRC has assessed and devised solutions to barriers commonly encountered in the clinical trials process. During concept and protocol development, for example, MMRC brings sponsors and centers together in weekly teleconferences, and it is developing a standard protocol template. With regard to site selection, MMRC knows the number of its own trials that are open at each site, as well as the total number of myeloma trials and the number of myeloma patients seen by each center. As a result, MMRC can work with sponsors to identify the best sites for an expeditious trial. For the contracting stage, MMRC has a standard membership agreement for those institutions that are part of the consortium and a standard clinical trials agreement. It negotiates with companies on behalf of all of the centers as a single entity, as opposed to companies having to negotiate contracts with each center independently. In-house counsel and an outside attor- ney work closely to facilitate contracts. MMRC recently brought together industry partners and academic attorneys to review the clinical trials agree- ment and revise it as necessary to address the needs of both industry and academia and make the process even more efficient. As noted above, MMRC fully or partially funds coordinators at each site based on the site’s performance tier. For the IRB approval process, these coordinators ensure that consortium trials receive priority, even hand-delivering the IRB submission from one desk to another as needed, significantly reducing the duration of the process. The MMRC-funded site coordinators also facilitate patient accrual, aided by the MMRF database of almost 30,000 patients. In terms of FDA approval and com- munications, MMRC holds roundtables in collaboration with the agency, bringing biotechnology companies together the day before the roundtable 

94 BREAKTHROUGH BUSINESS MODELS to discuss real and perceived barriers to drug development and approval. MMRF also conducts continuing medical education and patient educa- tion programs. MMRC is now focused on ensuring that 100 percent of the trials con- ducted within its purview have a correlative science component. To date, this has been the case for about two-thirds to three-quarters of the trials. The resulting information can help companies understand who the target population is and who is most likely to benefit from the drug, and bring drugs that truly work in a given population to the market more quickly. Muscular Dystrophy Association’s approach to Maximizing Assets in Clinical Trials The Muscular Dystrophy Association (MDA) is an umbrella organiza- tion addressing 40 rare neuromuscular diseases, ranging from muscular dystrophy, to spinal muscular atrophy, to amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Dr. Hesterlee said that MDA faces the same challenges as single-disease organizations, but multiplied 40 times over. It cannot take the same approach as those other organizations to managing clinical research networks and clinical trials because it is dealing with so many different diseases. MDA’s mission is to develop therapies or cures for all of these diseases, so it seeks creative ways to leverage its resources. It operates on a program budget of $120 million per year, distributing fund- ing across basic research, target identification, proof-of-principle testing in animals, translational research and preclinical development, and clinical research. Currently, basic research receives the largest share of the funding, but in the next year MDA plans to shift its focus and spend significantly more money on translational and clinical research. Barriers to Clinical Trials of Drugs for Rare Diseases When a company has a promising therapeutic candidate, one of the first steps it takes is to calculate the net present value of the therapy going forward, looking at cash flow and applying a discount rate to account for inflation during development. Data inputs for this kind of model include revenue and the factors that influence it, such as patient flow (which for a rare disease is going to be low), price, length of therapy, and number of disease episodes per year. It also includes expenditures, such as develop- ment, sales force, cost of goods sold, NDA application costs, and milestone payments. Risk is an additional factor considered.   his T section is based on the presentation of Sharon Hesterlee, Ph.D., Vice President of Translational Research, Muscular Dystrophy Foundation. 

STRATEGIES FOR FACILITATING CLINICAL TRIALS 95 Clinical trial costs are a key component of development expenditures. These costs may include study and protocol development, site and patient enrollment, statistical analysis, report writing, and CMC. Even with a promising product and knowledge of what costs must be considered, issues often arise of not knowing how many patients have a particular rare disease or what the burden of disease is. The sponsor of the drug may find that the natural history data are inadequate, or that the academic community has been running clinical trials with end points that have not been validated or that the FDA does not accept. All of these issues add complexity to the development of an economic model. Finding trial participants is critical in a small market, and may require identifying every patient with a rare disease to make the economic model viable. Another common barrier is ownership of or access to data, net- works, methodology, funding, or patient populations on the part of those who are unwilling to share resources. Solutions: Partnerships and Collaborative Structures While there has been much discussion about public–private partner- ships, MDA functions primarily through private–private partnerships, col- laborating with other nonprofit organizations, notably those with which MDA competes for funding. Hesterlee described three examples of collab- orative partnerships in which MDA is involved. The TREAT-NMD neuromuscular network in Europe links 21 part- ner organizations and more than 300 doctors, researchers, and other p ­ rofessionals throughout 11 European countries. This European Union– funded network enables experts to work together to share best practices and develop consensus in diagnosis, standards of care, validated outcome measures, uniform patient databases, and a clinical research network. The member countries are currently establishing registries of patients with D ­ uchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). A key aspect of these registries is that they contain core data elements agreed upon by those who maintain the various national databases, and there are specifications regarding what data are to be collected and how. Beyond these mandatory data are data that are highly encouraged, and countries may also collect whatever additional data they desire for their own regis- tries. The ultimate goal is for all of the national patient registries to provide the core data to a central, global database. An industry drug sponsor would then be able to run a quick search of the database to determine how many eligible patients exist in multiple countries across the world. Another collaboration in which MDA is involved is the International Coordinating Committee for Spinal Muscular Atrophy Clinical Trials. The group includes academic and National Institutes of Health (NIH) investiga- 

96 BREAKTHROUGH BUSINESS MODELS tors and representatives of at least four patient advocacy groups (Families of SMA, Fight SMA, MDA, and the SMA Foundation), working on com- mittees to address outcome measures, clinical trial design, biomarkers, standards of care, and a patient registry, as well as a patient advisory com- mittee. Begun by Families of SMA, the organization was transitioned to joint ownership by the group of SMA disease organizations, and funding for the patient registry is divided among them. MDA asked the SMA groups to ensure that all of the core elements of the registry would be compatible with the TREAT-NMD standards so it would be able to join the global r ­ egistry. To date, the organization has published and disseminated stan- dards of care and launched a biomarker initiative. A third collaboration example is the Duchenne Research Collabor- ative International, comprising four organizations: MDA; the Associa- tion ­Française contre les Myopathies (AFM, the MDA sister organization in France); Parent Project Muscular Dystrophy (PPMD), based in the United States; and United Parent Project Muscular Dystrophy, based in the ­ Netherlands. Together, these organizations have identified a series of projects, including a clearinghouse for research investments and resources, a global clinical trial network, and a global patient registry. The clearing­ house, a “Research Crossroads” site, will be a for-profit website that aggregates data on funding and research. The vision is that from this joint grants database, researchers and patients will be able to access research grants from NIH, MDA, AFM, PPMD, and other groups, cross-referenced with listings for patient registries and other research resources. One of the difficulties encountered has been reaching agreement on a single contract among the four organizations and their lawyers and the lawyer for the website company. In addition to these collaborative efforts, MDA funds 230 clinics across the United States, where a neuromuscular specialist will see anyone with one of the 40 neuromuscular diseases covered by the program. These are primarily medical clinics, but some of them participate in research as well. Given that clinical research networks already exist for such diseases as ALS, SMA, and DMD, MDA decided that it would work with these net- works, augmenting their efforts by funding an FTE clinical coordinator at 10 ALS and DMD centers. MDA plans to expand this funding to include five ­ clinics focused on SMA next year, with the ultimate goal of funding 50 clinics in the network. Finally, MDA is actively working to develop, validate, and standardize end points. Two meetings have been held for this purpose, in 2005 and 2007. These meetings brought together stakeholders, including FDA, NIH, academic investigators, and companies, to discuss the current state of end   Since the workshop was held, five ALS centers and five DMD centers have received fund- ing for this purpose. 

STRATEGIES FOR FACILITATING CLINICAL TRIALS 97 points for particular diseases, whether the natural history of the diseases is known, and steps that need to be taken to move forward. Based on the results of those meetings, MDA has issued requests for applications and is funding projects to fill the identified gaps. For example, MDA funded a project at the University of Rochester to develop a survey instrument on the natural history of myotonic dystrophy. Open Discussion The open discussion in this session expanded on the concept of collabo- ration among disease foundations that compete directly for funding, and on the importance of considering issues of affordability and access when foundations fund the development of new drugs. Collaboration Among Foundations Hesterlee noted that collaborating on the same disease can be difficult because of fundraising issues. It is easier, however, to collaborate across different diseases—for example, looking at common mechanisms. Young pointed out that MMRC recently announced a collaboration with the Leukemia and Lymphoma Society, an organization with which MMRC competes directly for funding. The collaboration is focused on stem cell research, identifying and targeting the myeloma stem cell. Young suggested that collaboration works best in a high-risk area, an area that is unlikely to lead to any therapies in the near term, and one that is somewhat outside of both organizations’ direct missions. With regard to exploring common mechanisms, Pariser stressed the need for caution in designing trials. Dis- eases such as the muscular dystrophies may look the same, and some, such as progressive muscular weakness, may have a great deal in common, but if their etiologies differ, responses may differ as well, and the desired end points may not be achieved. Affordability and Access So inquired how MMRC and MDA are handling the issue of afford- ability at the end of the pipeline. Hesterlee responded that MDA is con- sidering this issue, and internal discussions are focused on whether the association is going to advocate for Medicare and Medicaid coverage. Part of the plan is to address affordability from the outset by absorbing some of the infrastructure costs. Young noted that there is a limited number of new and expensive drugs for myeloma. Until 4 years ago, patients were treated with chemotherapy and steroids that were all generic. The mission of MMRC is research, and while access has not yet been an issue, it will have to be considered as more drugs become available.