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Case Studies


Real-World Data (RWD) and Real-World Evidence (RWE) are extremely promising assets as complementary sources of information that sometimes might be crucial in clinical studies such as CDG clinical trials, which is a growing area. RWD/E can be applied in different sections of clinical world, some of which we will not only underline but also exemplify with some case studies:

  • Drug Discovery
  • Preclinical Development
  • Clinical Development (Phase I,II, III)
  • Drug Review and Approval by regulatory agencies
  • Post-marketing Evaluation (Phase IV)

Myelodysplastic Syndrome

Myelodysplastic syndrome is a rare disease that is characterized as a group of blood disorders in which an individual has an abnormal development of blood cells within the bone marrow, having a low blood cells level. The symptoms that come with this disorder usually include dizziness, shortness of breath, bruising, bleeding, headaches. This syndrome in some cases may progress to acute leukemia (a type of blood cancer).

In a case study published in 2018 (1), it was analysed the cost-effectiveness of applying lenalidomide, an orphan drug, for treating myelodysplastic syndrome. While utilizing Real-World Evidence (RWE) to address the uncertainty of this method, they understood "the usefulness and relevance of the application of Real-world data (RWD) when trial data are limited". This study used RWE to validate some outcomes such as the meaning of treatment cycles in the people who are receiving lenalidomide, as well as predicting how many people would be able to reach the number of cycles desired (32% when compared with the 28% from the database acquired) (1). The authors state that "The weakness of this analysis lies in the limited amount of data available in terms of patient numbers, length of follow-up and availability of data for BSC". This increases the need of external databases and incentivises ways to generate useful data. Moreover, this case study also reflects the importance of RWD and RWE in research where simple Randomized Controlled Trials (RCTs) evidence is inherently limited.

CL2N disease

CL2N is a rare autosomal recessive pediatric neurodegenerative disease caused by the gene encoded lysosomal enzyme tripeptidyl peptidase 1 (TPP1) (2). Individuals with this disorder will require assistance from a wheelchair with their late childhood and have an extremely premature death. The approval for this rare disease is very difficult if the standardised procedures are followed, such as a control group and randomized clinical trials set. However, these hurdles were overcome with the use of RWE as the main key factor in the regulatory decision-making.

In 2017, the FDA approved the first pharmacological treatment for this disorder called cerliponase alfa (Brineura) an enzyme replacement therapy (2). This was only possible because of the design of non-randomized clinical trials, single arm study, dose escalation, open-label conducted to 24 symptomatic pediatric individuals for a 96 weeks study. Furthermore, the application of synthetic external control arm was another important factor in this approval because of the lack of candidates in which was regarded 42 untreated individuals who live with CLN2. This data was collected from the DEM-CHILD NCL database (2). A complex statistical analysis was used in order to match the historical control group with the people who are candidates in this trial. The criterias used to create the algorithm were genetics, age and timing of data collection between the clinical study population and historical control population. The comparison in the decline of motor skills between the people who are in the trial and the control was one of the most robust arguments to support the efficacy of the approved orphan drug.

Hypophosphatasia (HPP) disease

HPP is a rare genetic metabolic, chronic, progressive bone disease caused by a mutation in a gene called ALPL which regulates the production of an essential enzyme named tissue nonspecific alkaline phosphatase (TNSALP). This disorder is characterised by low alkaline phosphatase (ALP) which is accompanied with several symptoms such as respiratory complications (3). This condition at perinatal is almost always lethal near birth, in contrast with infantiles that have a 50% of survival.

In 2015, The FDA approved asfotase alfa (Strensiq) for therapeutic means for this disease in two distinct age groups such as perinatal and juvenile. This was another orphan drug where the clinical trials were designed as a single arm study, with an external control group. The candidates enrolled in the trial were 37 and compared with 48 selected outside individuals with similar age and HPP symptoms from a prior natural history study. The criterias used for candidate selection were, besides being diagnosed with HPP before 6 months of age, the following(3): 

  • “TNSALP gene mutation;"
  • “Serum ALP bellow the age-adjusted normal range and either plasma pyridoxal 5′-phosphate or urinary phosphoethanolamine above the upper limit of normal;” 
  • “Serum ALP below the age-adjusted normal range and HPP-related radiographic abnormalities.”

It was additionally put into consideration in candidate selection another set of parameters in order for further comparative analysis(3):

  • “respiratory compromise requiring supportive measures and/or medication and/or other pulmonary complications;”
  • “vitamin B6–dependent seizures;”
  • “rachitic chest deformity.”

The asfotase alfa results show an exponential increase in the survival rate of treated people by 91.2% in comparison to the historical control group with 27.1% (4). it is important to stress that these findings were only accomplished with the use of RWE.

Hereditary Oroticaciduria (HOA)

The HOA is an extremely rare autosomal recessive disorder in infants and children which is caused by a defect in uridine 5’ monophosphate (UMP) synthase gene. This condition has numerous repercussions to their bearers, such as hematologic abnormalities, developmental delays, etc (4). This disease was only registered on 20 diagnoses which is an extremely low number (5).

In 2015, the FDA approved uridine triacetate (Xuriden) for the treatment of this disease. The study consisted in the monitorization of the health status of the 4 individuals while being treated with 60mg/kg which was altered for 120mg/kg daily intake for 6 months (6).The design of it was a single arm study with only 4 people and an external natural history group composed with 19 individuals. The chosen drug (Xuriden) was selected for this study due to the fact that 3 out of 4 candidates had already been treated with it (6). 

Metastatic Uveal Melanoma (MUM) 

Alternatively, observational studies might create natural history data with the potential of becoming an external control group in a future study. A clear example of this is an article of 2017 (7) the authors made an analysis of RWD from an official diagnosed cohort of more than 2000 people who are living with uveal melanoma (UM) and 501 MUM. The data examined from HES database had similarities with other published related content to the subject which implies a consistency between real world and clinical status. This study helped to enlighten insight regarding UM and MUM incidence and might be used as a control in a future investigation. Moreover, the aggregated data will be an essential asset in assisting to identify possible individuals with this rare disorder and leveraging a personalized treatment for UM and MUM.


For a better understanding, the following articles that explained in more depth each rare disease case study are available:

  • The PharmacoEconomics has issued the study that was explained briefly in this section. Their paper is entitled “The Role of Real-World Evidence in UK Reimbursement: Case Study of Lenalidomide in Myelodysplastic Syndrome Deletion 5q” this ideal if you want to understand better the realized study of this rare disease: Myelodysplastic Syndrome.
  • The New England Journal of Medicine has issued the study that was explained briefly in this section. Their paper is entitled “Study of Intraventricular Cerliponase Alfa for CLN2 Disease” this ideal if you want to understand better the realized study of this rare disease: CL2N disease.
  • The Journal of Clinical Endocrinology and Metabolism has issued the study that was explained briefly in this section. Their paper is entitled “Asfotase Alfa Treatment Improves Survival for Perinatal and Infantile Hypophosphatasia” this ideal if you want to understand better the realized study of this rare disease: Hypophosphatasia (HPP) disease
  • The center for drug evaluation and research  has issued a summary review regarding the approval of the rare disease orphan drug Xuriden that is ideal to everyone who wants to understand better the realized study of this rare disease: Hereditary Oroticaciduria (HOA). Access here.
  • The journal “Value in Health” has issued information regarding Metastatic Uveal Melanoma (MUM)  that is ideal to everyone who wants to better understand this disease specifically. From the same rare disease (MUM), watch this video that provides a simple explanation of the condition in question. Watch the video here.



  1. Lee, D., Brereton, N., Dhanasiri, S. et al. (2019) The Role of Real-World Evidence in UK Reimbursement: Case Study of Lenalidomide in Myelodysplastic Syndrome Deletion 5q. PharmacoEconomics Open 3, 351–358 .
  2. Schulz A, Ajayi T, Specchio N, et al.(2018). Study of intraventricular cerliponase alfa for CLN2 disease. New England Journal of Medicine. 2018; 378:1898-1907.
  3. Whyte MP, Rockman-Greenberg C, Ozono K, et al. (2016). Asfotase Alfa treatment improves survival for perinatal and infantile hypophosphatasia. J Clin Endocrinol Meta N Engl J Med.101:334-342.
  4. Wu J, Wang C, Toh S, Pisa FE, Bauer L. (2020). Use of real-world evidence in regulatory decisions for rare diseases in the United States—Current status and future directions. Pharmacoepidemiol Drug Saf.1–6.
  5. Al Absi, H. S., Sacharow, S., Al Zein, N., Al Shamsi, A., & Al Teneiji, A. (2021). Hereditary orotic aciduria (HOA): A novel uridine-5-monophosphate synthase (UMPS) mutation. Molecular Genetics and Metabolism Reports, 26.
  6. Acessed March 2021
  7. Schwenk Links, M., Alamgir, G., Cheng, C., Adams, E. J., & Toward, T. (2017). A Real World Evidence (RWE) Approach To Characterising An Ultra-Rare Disease (URD) Cohort of Metastatic Uveal Melanoma (MUM) Patients Within National Health Service England (NHSE). Value in Health, 20(9), A730.
  8. Accessed March 2021

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Alexandre Gil and Pedro Granjo from Sci and Volunteer Program Nova School of Science and Technology 2021.


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Page modified at Tuesday, May 11, 2021 - 05:55