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Rare Diseases And Orphan Drugs Need Digital Innovation
More patient-centric study design, using mHealth for longer-term monitoring, will address many of the inherent challenges in conducting pivotal clinical trials in rare diseases, argues Elin Haf Davies.
Pharma companies are leveraging digital health data more than ever before to improve clinical trials, in a bid to develop drugs that could have a significant impact on patients' lives.
No area could benefit more from this disruptive approach than the rare disease sector and the development of orphan drugs: an area of high unmet therapeutic need and large financial investment.
There are estimated to be between 6,000 and 8,000 rare diseases affecting up to 60 million people across Europe and the US. The orphan drug sector is expected to experience strong growth over the coming years; EvaluatePharma (2014) estimates total orphan drug sales of $176 billion by 2020. There were 2,476 ongoing national or international clinical trials for 629 rare diseases in 29 countries (IDiRC/Orphanet) in 2014.
EvaluatePharma (2015) estimates that the average phase 3 clinical trial for an orphan drug costs $103 million and suggests that, based on the current pipeline of phase 3 drugs in development for orphan drugs, the total spent by pharma companies will be $6.9 billion on phase 3 trials alone.
In current clinical trials, a patient visits a doctor or researcher at fixed intervals during the trial and data is taken from them. However, as depicted in the diagrams below, a large amount of important information is completely missed or not observed during routine testing.
What the doctor sees:
What the patient experiences:
The choices of endpoints and outcome measures in many trials do not reflect the issues that are important to patients living their day-to-day lives. What patients consider relevant is an important criterion and, as such, patient perspectives on other aspects of their disease/treatment experience that are significant to other stakeholders should not be ignored.
In rare disease, where patient numbers are low, and both disease presentation and rate of progression are heterogeneous, relying on data from sterile snapshot assessments during clinic visits alone leads to inconclusive trial results, which is both unethical and uneconomical.
As a result of poor information gathered during clinical trials, a significant number of them fail – especially those involving children – at significant cost to the pharma industry. Recent research suggests that 42% of recently completed paediatric trials failed to establish safety and efficacy (Wharton, G T et al [2014]) and, out of 103 orphan drugs approved by the EU, 37% failed at the Health Technology Assessment (HTA) stage owing to insufficient effectiveness information for the payer (Brook, A. PPi Healthcare Consulting [2015]).
In light of these challenges, regulators and payers are increasingly demanding real-world data that demonstrates both the efficacy and the effectiveness of the drug. This is echoed in the recent adaptive pathway pilots conducted by the European Medicines Agency.
An obvious solution is to use the digital health revolution and tap into the global availability of smartphones and the rapid improvements in the size, appearance, usability, battery life and costs of wearables.
The regulatory and reimbursement pathways for mHealth and wearables are not clear, however – not only in terms of understanding which regulatory routes and demands apply for medical devices and apps, but also in understanding how generated data will be analysed by regulators and payers for drug evaluation.
Throughout Europe, standalone software and apps that meet the definition of a medical device must still be CE marked, in line with the EU medical device directives, to ensure they are regulated and acceptably safe to use and also perform as the manufacturer/developer intends.
Consumer–grade trackers
However, as of June 2016, there were 104 completed, current or pending Fitbit studies on the ClinicalTrials.Gov website, including studies in obesity, diabetes and cancer. Consumer-grade activity trackers, such as Fitbit, are not considered medical devices, and it is not yet clear how regulators will respond to the data generated. However their low cost and consumer-friendly functions make them a popular choice for pharma and patients alike.
Given the fact that patients' wellbeing between clinic visits is based on no objective data at all, and on what the patient can remember, does the fact that a Fitbit may record 70 steps when a patient has actually only taken 68 really matter? Will consistently misreading a heart rate by 2-3 beats per minute be important in chronic diseases?
Recent challenges encountered with using the Six-Minute Walk Test as a primary endpoint in Duchenne studies further highlight this issue. Is 12-18 minutes'-worth of data from a two-year study, generated during stressful and sterile hospital visits, really considered superior to continuous data captured in real time throughout the patient's trial experience using a consumer-grade wearable?
I would argue not.
The current drug development pathway for rare diseases is not sustainable, either in terms of addressing the high unmet therapeutic needs of patients through ensuring rapid patient access to innovative drugs, or in providing orphan drugs that are affordable to current healthcare economies.
A more patient-centric study design will address many of the inherent challenges in conducting pivotal clinical trials in rare diseases, allowing:
Objective data, captured passively and in real time with wearable technology, and contextualised with patient data input linked to medication adherence, side effects/adverse events and Patient Reported Outcomes, provides the platform to capture and analyse in-depth and meaningful patient data. Providing such a platform in accordance with regulatory and governance demands is one step towards enabling an adaptive and iterative pathway to drug development, such as that promoted by the enabling platform ADAPT SMART (see www.Adaptsmart.Eu)
ADAPT SMART works to accelerate development of appropriate patient therapies in a sustainable way. By assisting the coordination of Medicines Adaptive Pathways to Patients (MAPPs), it seeks to foster access to beneficial treatments for the right patient group at the earliest appropriate time in the product's lifecycle. Providing drugs at this stage introduces some uncertainty, which, in turn, will require a higher level of patient monitoring – but one that is conducive with patients' daily lives.
Many rare diseases are likely to meet the engagement criteria set for MAPPs. Introducing digital health innovations in this field will facilitate both the need for increased patient monitoring and the generation of real-world evidence.
Our studies in India, America and the UK, for example, introducing wearables and disease-specific apps for proof-of-concept and observational studies in Gaucher disease, Niemann-Pick C and Late Onset Tay Sachs, are based on such needs, and have been instigated in partnership with patient groups, physicians and pharma.
About the author:
Elin Haf Davies PhD began her clinical career at Great Ormond Street Hospital in London, UK. After 11 years of clinical, research and academic experience, she went on to work in the Paediatric Team at the European Medicines Agency, implementing the Paediatric Regulation in Europe. Six years later she left to become an Associate Fellow at CASMI (Oxford University) and to found aparito.
Read more on rare diseases:
Tunnah's musings: Rare diseases hold key to future of drug development
Human Genetics: Concepts And Application
Because of natural selection, different alleles are more likely to confer a survival advantage in different environments. Cycles of infectious disease prevalence and virulence often reflect natural selection.
Balanced PolymorphismIf natural selection eliminates individuals with detrimental phenotypes from a population, then why do harmful mutant alleles persist in a gene pool? A disease can remain prevalent when heterozygotes have some other advantage over individuals who have two copies of the wild type allele. When carriers have advantages that allow a detrimental allele to persist in a population, balanced polymorphism is at work. This form of polymorphism often entails heterozygosity for an inherited illness that protects against an infectious illness. Examples are fascinating.
Sickle Cell DiseaseSickle Cell disease is an autosomal recessive disorder that causes anemia, joint pain, a swollen spleen, and frequent, severe infections. It illustrates balanced polymorphism because carriers are resistant to malaria, an infection by the parasite Plasmodium falciparum that causes cycles of chills and fever. The parasite spends the first stage of its life cycle in the salivary glands of the mosquito Anopheles gambiae. When an infected mosquito bites a human, the malaria parasite enters the red blood cells, which transport it to the liver. The red blood cells burst, releasing the parasite throughout the body.
In 1949, British geneticist Anthony Allison found that the frequency of sickle cell carriers in tropical Africa was higher in regions where malaria raged all year long. Blood tests from children hospitalized with malaria found that nearly all were homozygous for the wild type of sickle cell allele. The few sickle cell carriers among them had the mildest cases of malaria. Was the presence of malaria somehow selecting for the sickle cell allele by felling people who did not inherit it? The fact that sickle cell disease is far less common in the United States, where malaria is rare, supports the idea that sickle cell heterozygosity provides a protective effect.
Further evidence of a sickle cell carrier's advantage in a malaria-ridden environment is the fact that the rise of sickle cell disease parallels the cultivation of crops that provide breeding grounds for Anopheles mosquitoes. About 1,000 B.C., Malayo-Polynesian sailors from southeast Asia traveled in canoes to East Africa, bringing new crops of bananas, yams, taros, and coconuts. When the jungle was cleared to grow these crops, the open space provided breeding ground for mosquitoes. The insects, in turn, offered a habitat for part of the life cycle of the malaria parasite.
The sickle cell gene may have been brought to Africa by people migrating from Southern Arabia and India, or it may have arisen by mutation directly in East Africa. However it happened, people who inherited one copy of the sickle cell allele had red blood cell membranes that did not admit the parasite. Carriers had more children and passed the protective allele to approximately half of them. Gradually, the frequency of the sickle cell allele in East Africa rose from 0.1 percent to a spectacular 45 percent in thirty-five generations. Carriers paid the price for this genetic protection, whenever two produced a child with sickle cell disease.
A cycle set in. Settlements with large numbers of sickle cell carriers escaped debilitating malaria. They were therefore strong enough to clear even more land to grow food- and support the disease-bearing mosquitoes. Even today, sickle cell disease is more prevalent in agricultural societies than among people who hunt and gather their food.
Glucose-6-Phosphate Dehydrogenase DeficiencyG6PD deficiency is a sex-linked enzyme deficiency that affects 400 million people worldwide. It causes life-threatening hemolytic anemia, in which red blood cells burst. However, it develops only under specific conditions- eating fava beans, inhaling certain types of pollen, taking certain drugs, or contracting certain infections. Studies on African children with severe malaria show that heterozygous females and hemizygous males for G6PD deficiency are underrepresented. This suggests that inheriting the enzyme deficiency gene somehow protects against malaria.
The fact that G6PD deficiency is sex-linked introduces a possibility we do not see with sickle cell disease, which is autosomal recessive. Because both heterozygotes and hemizygotes are selected for, the mutant allele should eventually predominate in a malaria-exposed population. However, this doesn't happen- there are still males hemizygous and females homozygous for the wild type allele. The reason again relates to natural selection. People with the enzyme deficiency- hemizygous males and homozygous females- are selected out of the population by the anemia. Therefore, natural selection acts in two directions on the hemizygous males- selecting for the mutant allele because it protects against malarial infection, yet selecting against it because an enzyme deficiency. This is the essence of balanced polymorphism.
PKUPhenylketnonuria is an inborn error of metabolism in which a missing enzyme causes the amino acid phenylalanine to build up, with devastating effects on the nervous system unless the individual follows a restrictive diet. Carriers of this autosomal recessive condition have elevated phenylalanine levels- levels that are not sufficiently high to cause symptoms, but that are high enough that they may have a protective effect during pregnancy. Physicians have observed that women who are PKU carriers have a much lower-than�average incidence of miscarriage. One theory is that excess phenylalanine somehow inactivates a poison, called ochratoxin A, that certain fungi produce and that is known to cause spontaneous abortion.
History provides the evidence that links PKU heterozygosity to protection against a fungal toxin. PKU is most common in Ireland and western Scotland, and many affected families living elsewhere trace their roots to this part of the world. If PKU carriers were most likely to have children than non-carriers because of the protective effects of the PKU gene, over time, the disease-causing allele would increase the population.
Tay-Sachs DiseaseCarrying Tay-Sachs disease may protect against tuberculosis (TB). In Ashkenazim populations, up to 11 percent of the people are Tay-Sachs carriers. During World War II, TB ran rampant in Eastern European Jewish settlements. Often, healthy relatives of children with Tay-Sachs disease did not contact TB, even when repeatedly exposed. The protection against TB that Tay-Sachs disease heterozygosity apparently offered remained among the Jewish people because they were prevented from leaving the ghettos. The mutant allele increased in frequency as TB selectively felled those who did not carry it and the carriers had children with each other. Genetic drift may also have helped isolate the Tay-Sachs allele, by chance, in groups of holocaust survivors. Precisely how lowered levels of the gene product, an enzyme called hexoseaminidase A, protect against TB isn't known.
Cystic FibrosisBalanced polymorphism may explain why cystic fibrosis is so common- the anatomical defect that underlies CF protects against diarrheal illnesses, such as cholera.
Cholera epidemics have left their mark on human populations, causing widespread death in just days. In the summer of 1831, an epidemic killed 10 percent of the population of St. Louis, and in 1991, an epidemic swept Peru. Cholera bacteria causes diarrhea, which rapidly dehydrates the body and can lead to shock and kidney and heart failure. The bacterium produces a toxin that opens chloride channels in the small intestine. As salt (NaCl) leaves the cells, water follows, in a natural chemical tendency to dilute the salt. Water rushing out of intestinal cells leaves the body as diarrhea.
In 1989, when geneticists identified the CF gene and described its protein product as a regulator of a chloride channel in certain secretory cells, a possible explanation for the prevalence of the inherited disorder emerged. Cholera opens chloride channels, letting chloride and water leave cells. The CFTR protein does just the opposite, closing chloride channels and trapping salt and water in cells, which dries out mucus and other secretions. A person with CF cannot contract cholera, because the toxin cannot open the chloride channels in the small intestine.
Carriers of CF enjoy the mixed blessing of a balanced polymorphism. They do not have enough abnormal chloride channels to cause the labored breathing and clogged pancreas of cystic fibrosis, but they do have enough of a defect to prevent the cholera from taking hold. During the devastating cholera epidemics that have peppered history, individuals carrying mutant CF alleles had a selective advantage, and they disproportionately transmitted those alleles to future generations. However, because CF arose in Western Europe and cholera in Africa, perhaps an initial increase in CF herterozygosity was a response to a different diarrheal infection.
Diagnosing Down Syndrome, Cystic Fibrosis, Tay-Sachs Disease And Other Genetic Disorders
Sometimes, a pediatrician will suspect that a child has a genetic disorder based on the child's symptoms or on the presence of dysmorphic features. For example, if a child has coarse facial features and developmental delays, a pediatrician may have reason to believe that the child has a form of mucopolysaccharidosis. Mucopolysaccharidosis is a family of diseases caused by an enzyme deficiency that leads to the accumulation of glycosaminoglycans (GAGs) within the lysosomes of cells. In one particular variant of this disease known as mucopolysaccharidosis I (MPS I), a deficiency of the enzyme alpha-L-iduronidase causes a build up of GAGs in tissues and organs, which in turn leads to a host of signs including skeletal deformities, coarse facial features, enlarged liver and spleen, and mental deficiencies. Because of the progressive nature of MPS I, a child might not exhibit noticeable symptoms until one to three years of age or even later, depending on severity.
There are a number of reasons that a pediatrician might refer a child to see a geneticist. Geneticists can confirm or rule out a physician's diagnosis based on the findings of a physical exam and various tests. In the case of a child with suspected MPS, if the enzymatic deficiency associated with the disorder is confirmed via testing, DNA analysis may also be performed to determine the exact genetic mutation causing the disorder. Because MPS I is inherited in an autosomal recessive fashion, identification of the mutation can allow the family to undergo carrier screening, as well as prenatal or preimplantation diagnosis in any future children.
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