J Mol Neurosci (2016) 58:374–378 DOI 10.1007/s12031-015-0700-9

Drug Development and Challenges for Neuromuscular Clinical Trials Mohamed El Mouelhi 1

Received: 25 September 2015 / Accepted: 10 December 2015 / Published online: 21 December 2015 # Springer Science+Business Media New York 2015

Abstract Drug development process faces many challenges, including those encountered in clinical trials for neuromuscular diseases. Drug development is a lengthy and highly costly process. Out of 10 compounds entering first study in man (phase 1), only one compound reaches the market after an average of 14 years with a cost of $2.7 billion. Nevertheless, according to the Centers for Medicare and Medicaid services, prescription drugs constituted only 9 % of each health care dollar spent in USA in 2013. Examples of challenges encountered in neuromuscular clinical trials include lack of validated patient-reported outcome tools, blinding issues, and the use of placebo in addition to lack of health authority guidance for orphan diseases. Patient enrollment challenge is the leading cause of missed clinical trial deadlines observed in about 80 % of clinical trials, resulting in delayed availability of potentially life-saving therapies. Another specific challenge introduced by recent technology is the use of social media and risk of bias. Sharing personal experiences while in the study could easily introduce bias among patients that would interfere with accurate interpretation of collected data. To minimize this risk, recent neuromuscular studies incorporate as an inclusion criterion the patient’s agreement not to share any of study experiences through social media with other patients during the study conduct. Consideration of these challenges will allow timely response to the high unmet medical needs for many neuromuscular diseases.

Keywords Drug development . Neuromuscular clinical trials . Health care dollar spent

Introduction In a recent survey conducted by Kaiser Family Foundation Health Tracking Poll (Kaiser Family Foundation Health Tracking Poll 2015), more than two thirds of the Americans feel that drug costs are unreasonable (72 %). On the other hand, participants in this poll largely value the role prescription drug companies play, with most (62 %) saying that prescription drugs developed in the past two decades have made the lives of people in the USA better, including about 4 in 10 (42 %) who say a lot better. The process of drug development appears to be a Bblack box^ for the majority of people, including patients, who are the main stakeholder for this process. To develop a drug, it goes through lengthy and costly scientific, medical, and regulatory processes. The main objective of developing drugs is to respond to unmet medical needs. The ideal objective is to cure the disease. However, another scenario—cessation or slowing down the disease progression—is more common. A last resort is to provide some symptomatic relief. Of course, disease aggravation should be avoided at all cost. The real challenge in the medical field is to achieve cure with more effective medicines after getting an earlier diagnosis.

Drug Discovery and Development * Mohamed El Mouelhi [email protected] 1

Translational Medicine, Musculoskeletal Diseases, Novartis Institutes for Biomedical Research, East Hanover, NJ, USA

Many people are surprised when they go to the pharmacy to get their prescriptions. A common question is why just a month supply of tablets or capsules cost that much? In fact, in order to reach the consumer, to develop any drug

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it takes about 15 years and the average cost is around $ 2.7 billion. The average cost to bring a new drug to the market has become more expensive over the years. Recently, costs more than doubled compared to the last estimate 13 years ago. Approval of a drug requires proving that it is safe, effective, and the dose proposed is the optimal one for the intended use. The process starts with pre-clinical phase including research where animal and laboratory studies are conducted to identify the proper target, characterize it then test the proper molecule. Usually around 10,000 compounds are identified in the beginning, out of which 1000 compounds are chosen for in vitro testing. Superior compounds are selected based on many factors including animal toxicity, chemical stability, and in vivo handling (such as absorption and elimination). This pre-clinical and research testing step takes about 5 years. At the end of this pre-clinical testing phase, an Investigational New Drug Application known as IND in the USA and Clinical Trial Application (CTA) in EU is submitted to the Health Authority (FDA in US; and EMA in EU) prior to any clinical testing in human. As a next step, 1 to 10 compounds are selected for clinical testing in man. For most of neurological drugs, they need to cross the blood-brain barrier (BBB) to get into the CNS to cause their effect. However, some neurologic-related targets are also present in the periphery such as heart, gut, and skin. These compounds do not have to cross the BBB in order to hit their targets. In addition for the management of spinal and bulbar muscular atrophy (SBMA), drugs do not have to cross BBB as it is associated with destruction of motor neurons outside the central nervous system. During the pre-clinical and early exploratory clinical phases of drug development (phases 1 and 2), a large number of programs do not reach the registration phase. This is what has been called as BTranslational Gap and Valley of Death^ (Paul et al. 2010; Zurdo 2013). More than 90 % of the development programs fall into this valley of death. The clinical testing is composed of three phases, namely phases I, II, and III. Phase I generally tests the investigational compound in a small group of individuals (around 50) with the goal of identifying how the drug behaves in the body and a first assessment of its tolerability. It could be conducted in healthy volunteers or patients with the intended disease indication. Based on phase I findings, this investigational compound may proceed to phase II, where a larger number of patients with the intended disease indication (usually several hundreds) are enrolled to evaluate the proper dosage and preliminary e ff i c a c y. T h e l a s t c l i n i c a l p h a s e ( p h a s e I I I ) i s Bconfirmatory^ in nature. A large number of patients, usually between 1000 and 3000 (but fewer for rare diseases and perhaps over 10,000 for some indications, like

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diabetes and heart disease), participate in this phase to confirm the preliminary efficacy observed in phase II. Phase III studies generally use either a proper comparator or placebo and to provide a large data base for safety of the investigational drug. These three clinical phases take approximately 9 years to complete. At the end of the clinical phases, preparation and submission of data (depending on drug nature either New Drug Application: NDA; or Biologic License Application: BLA) to the Health Authorities for drug registration approval. The registration process could take up to 1.5 years. On average, it takes testing 10 compounds in humans to yield one marketed drug. There are several reasons that a compound fail during the development process. These reasons include animal toxicity, lack of chemical stability, human pharmacokinetic properties, intolerance, lack of efficacy, poor differentiation from available treatments, or lack of long-term safety. One final reason for a drug not reaching the market is non-approval by the health authority. Interestingly, some drugs are approved in USA and not in Europe and vice versa. In certain cases where thousands of patients are included in pre-registration studies, rare adverse events may not be detected until after approval. The Health Authorities (HAs) in these cases request a post-approval testing that is known as BPostapproval Commitment.^

Health Care Dollar and Cost of Prescription Drugs The Centers for Medicare & Medicaid Services assessed the proportion of each health care dollar being spent for prescription drug in the USA in 2013. Hospital care constituted the highest portion, reaching 32 % of health care spending, followed by physicians and clinics with 20 %. Interestingly, prescription drugs constituted only 9 % of health care spending (Fig. 1) (Centers for Medicare, and Medicaid Services, Office of the Actuary, National Health Statistics Group 2013). Nursing care facilities and elderly communities contributed the lowest percentage of spent health care dollars (5 %).

Challenges with Clinical Trials Clinical studies are crucial for any new drug approval where its safety and efficacy need to be established. Current regulation by the health authorities usually requires two phase III studies for any marketing approval. More than three fourths of clinical studies fail to meet their timelines. Patient enrollment in these studies represents a major challenge and is considered the leading cause for missed deadlines resulting in a delayed availability of potentially life-saving treatments to the overall patient population.

376 Fig. 1 How each health care dollar is spent?

J Mol Neurosci (2016) 58:374–378 Government Dental Services and Administraon and Net Other Professionals Cost of Health Insurance 7% Prescripon Drugs 7% Investment1 9% 6%

Other 14%

Physicians and Clinics 20%

Nursing Care Facilies and Connuing Care Rerement Communies 5% Government Public Health Activies Durables 3% Home & Other Health 2 Non-durables Care 3% 3% Other Health, Residenal, and Personal

Hospital Care 32%

Challenges for Neuromuscular Clinical Trials Clinical trials in neuromuscular diseases have some specific challenges. The use of placebo has been one of the main concerns for patients. Understandably, they prefer to be on the active arm. However, because most of measured endpoints are subjective, the placebo arm is crucial for these studies to minimize bias by the patients and investigators. In addition, placebo arm inclusion allows comparing adverse events (AEs) in the active arm versus placebo arm, as some of the reported AEs could be related to the studied disease and not related to the investigational drug. Blinding of the investigational drug is another important feature, especially when a comparator is being used. Blinding increases cost and complexity. For example, some of these comparators are available in a dosage form such as a capsule or pre-filled syringes while the investigational drug is only available as pills or in vials. Furthermore, most neuromuscular studies are being conducted in the outpatient setting, often with a self-administered study drug that makes the blinding matter more difficult but even more important. The duration of clinical study represents another challenge. Usually shorter studies are preferable by patients, investigators, and sponsor. However, the speed with which a disease is expected to respond to treatment drives the duration of most studies. Most of the neuromuscular diseases are slowly progressing. Thus, neuromuscular disease trials usually require longer treatment duration to show efficacy, in addition to the need to collect long-term safety data as well as maintained efficacy on chronic term usage of the investigational drug. Identification of relevant biomarkers or acceptable surrogate endpoints would be crucial in guiding the drug development process and providing supporting evidence of efficacy. This will facilitate the Bgo no-go^ decision and will dedicate long-term studies for confirmatory purposes. Of course, these biomarkers and surrogate endpoints will need validation

as well as ongoing discussion with HAs for acceptance. The oral route of administration is the easiest one for most disease conditions. This is followed by the subcutaneous route (s.c.), which can be self-administered with some training. The intravenous route (i.v.) is the hardest, generally cannot be selfadministered, and usually requires to be administered by a health care professional. However, based on the nature of the investigational compound, the i.v. route may be the only feasible route of administration. This would require either a clinical site visit or a specialized visiting nurse. Of course depending on the degree of efficacy and benefit from the investigational drug, patients are willing to go with chronic intravenous treatments. For example, myasthenia gravis patients receive IgG i.v. infusion every 2 weeks for their disease. As described earlier, the majority of endpoints assessed in neuromuscular studies are subjective. However, there are very limited acceptable tools in this domain. Those tools are known as patient reported outcome tools (PRO). For any new PRO adopted, there should be alignment and acceptance from the Health Authorities to use this tool in the study. This acceptance usually takes some time and requires validity data for this new tool. Recent efforts were directed to identify relevant PROs in the neuromuscular diseases. Among others, Voet et al. (Voet et al. 2010) studied the effectiveness of aerobic exercise training and cognitive behavioral therapy to reduce chronic fatigue and to optimize physical activity and capacity in patients with facioscapulohumeral dystrophy (FSHD) that could lead to potential change in existing guidelines for physical training and to improve the quality of life in patients with FSHD. Fernandez-Rhodes et al. (Fernández-Rhodes et al. 2011) and Shrader et al. (Shrader et al. 2015) used Adult Myopathy Assessment Tool (AMAT) as a performance measure in SBMA patients. Recently, Heatwole et al. (2015) provided supporting evidence toward the validation process and development of a disease-specific patient-reported outcome measure for myotonic dystrophy. The Myotonic Dystrophy

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Health Index (MDHI) provides clinicians and researchers with an option to assess a myotonic dystrophy type 1 patient’s perception of their health. These great efforts are just the beginning to establish tools in the neuromuscular disease arena that would need further validation and discussion with HAs to become acceptable. We live in a new era when social media and technology play an important communication role. This novel technology had been embraced by many patient advocacy groups and had been a valuable communication tool among patients, caregivers, and support groups. However, the risk to clinical trial integrity is increased by the use of this tool to share personal experience during the actual participation of patients in an ongoing study. Here is one scenario: In an ongoing study, one patient is randomly assigned to placebo and the other to active treatment. The first patient does not observe any benefit (+/− worsening of his condition). The second patient experiences some adverse events. These two patients communicate through social media and share their experiences. At this stage, you can imagine the impact and consequences of this interaction. Would you be confident in the collected data or would you expect some bias, either falsely reported AEs or low/lack of efficacy? Because of the serious consequences to the integrity of study data introduced by this social media interaction, many neuromuscular study protocols incorporated as an inclusion criterion the patient’s agreement not to share any of study experiences through social media with other patients during the study conduct. Obtaining early input from patient advocacy and support groups is becoming a more common practice. It is important to check the patient’s willingness to participate in any study at an early stage, as study logistics may not be practical from patient perspective. For example, an impractical assessment schedule requiring too many visits would interfere with patient’s working schedule and makes the study less attractive. It is very useful to get this important feedback early rather than late. A lack of patient enrollment will result in study failure and termination. Keeping patient’s interest in a study would ensure faster enrollment. The last step for any drug development program is the submission of all data for registration and approval by health authorities (HAs). Frequent interaction and communication with HA during the conduct of drug program is very important. One peculiar fact about neuromuscular diseases is for most of them there are no regulatory guidance and no clear path to approval in place, because their causes and therapies are poorly understood. Most neuromuscular diseases are orphan indications, with a prevalence of <200,000 cases in the USA. For these rare conditions, patients need to be the center for any drug development. Natural history of these diseases and awareness of the patients’ need to maintain their activities of daily living are valuable elements for developing treatments for these diseases. A close interaction with patient advocacy

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groups will ensure identification and ranking of these patient needs. Therefore, it is advisable for the drug industry to establish close interaction with patient advocacy groups and to gain alignment from the HA at an early stage of the program to facilitate approval process when reaching the final phase. Having a safe and effective drug available to all patients is a common goal for both regulators and sponsors. With this in mind, adopting a collaborative approach between regulators, sponsors, and patient advocacy groups would ensure smoother and faster interaction to achieve their common goal. Regarding SBMA disease condition, the disease was described by William Kennedy in late 1960s (Kennedy et al. 1968). There is no approved treatment for this slowly progressing and devastating orphan disease. The recent description of AMAT as a tool for assessing muscle performance in SBMA patients is a great step toward identification of a relevant performance tool; however, still more work is needed to validate it and to become acceptable to HAs (FernándezRhodes et al. 2011; Shrader et al. 2015). The need for longterm safety and maintained efficacy is among the challenges shared with most neuromuscular diseases.

Conclusions The drug development process is becoming lengthier and more expensive. The rate of new drug approval fluctuates, depending on the research pipeline and targeted disease entities. The area of neuromuscular diseases is a complex one, and is one of the most challenging therapeutic areas in drug development. Among the challenges encountered by neuromuscular studies are the use of placebo, lack of proper PRO in addition to long-term safety, and study duration. With time, HA guidance and experience with orphan diseases are improving and more efforts are directed to identify and validate PROs as well as relevant biomarkers. The concept of collaborative work between regulators, sponsors, and patient advocacy groups should prevail and lead to achievement of their common goal that is having effective and safe treatment available for all patients.

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