Biological Orphan Drugs: what defines them and regulatory requirements

Orphan drugs are designed to treat disease conditions that are rarely observed in people. In the US, FDA’s Office of Orphan Products Development (OOPD) and in the EU, EMA’s Committee for Orphan Medicinal Products (COMP) authorizes orphan drug designation (ODD) to medicines for rare or orphan diseases.

Introduction to orphan drugs

Orphan drugs are designed to treat disease conditions that are rarely observed in people.  Rare diseases manifest only in 6-8% of the world population; hence such conditions are defined as orphan diseases. However, globally, the prevalence of rare diseases is seen to rise in the last couple of years. In the US, the Orphan Drug Act (ODA) came into existence in 1983 to facilitate research and development of products that exhibit promise for the diagnosis and/or treatment of orphan diseases. The FDA’s Office of Orphan Products Development (OOPD) is responsible for orphan drug development and authorization. Whereas, in the EU, the Committee for Orphan Medicinal Products (COMP) is the European Medicines Agency’s (EMA) committee responsible for recommending orphan designation of medicines for rare diseases. Both regulatory bodies authorize financial incentives to attract industry’s interest, market exclusivity and waive off tax for research and development-related expenses. Based on drug type, orphan drugs are categorized into biological and non-biological drugs. Since biologics elicit fewer side effects in the treatment; therefore, approval of biological orphan drugs for multiple indications steers the growth of the orphan drugs market.

Interestingly, the sales forecast of orphan drugs estimates a growth of 12.3% per year, reaching $242bn in 2024. And with respect to the overall prescription drug market, orphan drugs anticipated sales account for a little over a fifth of all prescription drug sales by 2024.


Regulatory Requirements of Orphan drugs

Firstly, in order to acquire Orphan Drug Designation (ODD), the drug or biologics should satisfy three major criteria as follows

  • The product must be intended for use in a rare disease or condition.
  • There must be adequate documentation or prevalence data to demonstrate that the intended condition is rare. For instance, in the EU, prevalence must not be more than 5 in 10,000.
  • There must be a scientific rationale establishing a medically plausible basis for using the product for the rare condition.

Importantly, ODD is applicable to both the active moiety and the condition but may be exempted for the product formulation. Also, derivatives of a given active moiety such as esters, salts, and other non-covalent categorize as the same drug when it comes to ODD.

In the US, the process is initiated when ODD requests are submitted to the FDA’s OOPD. In order to obtain the ODD status for the targeted drug and condition, submissions can be made at any time during drug development before New Drug Application (NDA) or biologics license application (BLA). A sponsor is not obliged to open an investigational new drug (IND) to request the ODD status since an ODD request is not submitted as an amendment to an IND. Orphan Drug Modernization Plan initiated in 2017 by the FDA facilitated responding to all new ODD requests within 90 days of their receipt.

Similar to FDA’s examination timeline, COMP assessment procedure includes 90 days from validation. As a part of the evaluation in the EU, companies categorized as micro, small, or medium-sized enterprises can benefit from further incentives. If COMP recommends issuing a license, the exclusivity period for orphan drugs marketed within the EU is ten years. The COMP also advises and assists the European Commission on matters related to orphan medicines, including:

  • Developing and establishing an EU-wide policy
  • Drawing up detailed guidelines
  • Liaising internationally

Number of drugs wit European ODD

In the case of both regulatory bodies, COMP and OOPD, the sponsor must submit orphan annual reports summarizing the status of development of the desired orphan drug or biologics every year until the marketing application is approved.


Challenges in Accessibility and Affordability of Medicines for Rare Diseases

The lack of or inefficient legal and policy frameworks in many countries make it challenging to access therapies for rare diseases. High cost for the therapies and insufficient funding is also the other factors contributing to the limited access and affordability of orphan drugs. However, such obstacles can be overcome through education towards payers, responsible and evidence-based pricing, and innovative contracting. Addressing these issues, especially in middle-income and emerging markets, will help contribute to the growth in rare disease therapeutic areas.


EMA-approved biologics with orphan drug designation (ODD)

The classification of orphan drugs may vary from country to country. Various regulatory authorities take different approaches to classify rare diseases. For example, the US- FDA mainly categorize an orphan disease based on the disease prevalence, that is, simply the number of people suffering from the disease. In comparison, the EMA calculates the prevalence proportion, which considers the proportion of people in the population that have the disease. The table summarizes some of the biologic drugs among various therapeutic areas that have been granted a European orphan designation according to Regulation (EC) No 141/2000 (updated on March 2021).

In addition, the EMA also mentions a list of drugs that have a European marketing authorization (MA) for one or more indications of use for a rare disease but have either not been granted a European orphan designation or the designation was withdrawn. These drugs may or may not have an ODD in other countries. For example, Pembrolizumab (Keytruda®) is an orphan drug in the US but does not hold ODD status in the EU. The US FDA has conferred an orphan drug designation for Keytruda for three separate indications for malignant melanoma from stage IIB through IV.

  • For the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection (Expires 02/15/2026).
  • For treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF-V600 mutation positive, a BRAF inhibitor (Expires 09/04/2021).
  • For treatment of patients with unresectable or metastatic melanoma (Expires 12/18/2022).


Therapeutic areas International Non-proprietary name (INN) Molecular class Target /MoA Therapeutic indications
Oncology Brentuximab vedotin Antibody-drug conjugate CD30 directed delivery of the cytotoxic agent CD30-positive Hodgkin lymphoma (HL),
systemic anaplastic large cell lymphoma (salcl)
Inotuzumab ozogamicin Antibody-drug conjugate Binds CD22 mediating ADC-CD22 internalization in tumor cells CD22-positive B cell precursor acute lymphoblastic leukaemia (ALL)
Blinatumomab Bispecific T cell engager that binds  to CD19 on B-lineage cells and CD3 on T-cells Refractory B -precursor acute lymphoblastic leukaemia (ALL)
Obinutuzumab Monoclonal antibody Targets CD20+ B-cells and induces ADCC Chronic lymphocytic leukaemia (CLL)
advanced follicular lymphoma
Moxetumomab pasudotox Antibody-drug conjugate CD22-targeted immunotoxin delivery Hairy cell leukaemia (HCL)
Gemtuzumab ozogamicin Antibody-drug conjugate CD33 directed delivery of cytotoxin CD33-positive acute myeloid leukaemia (AML)
Polatuzumab vedotin Antibody-drug conjugate CD79b-targeted delivery of
anti-mitotic agent
Relapsed/refractory diffuse large B-cell lymphoma (DLBCL)
Mogamulizumab Monoclonal antibody Binds to
CCR4 resulting in depletion of the target cells
Mycosis fungoides (MF) or Sézary syndrome (SS)
Dinutuximab beta Monoclonal antibody Targets disialoganglioside 2 (GD2) High-risk neuroblastoma
Siltuximab Monoclonal antibody Binds to IL-6 preventing IL-6 mediated signalling Multicentric Castleman’s disease (MCD)
Autoimmune diseases Belantamab mafodotin Antibody-drug conjugate Targets B cell maturation antigen (BCMA) on tumor cells, leading to internalization Multiple myeloma
Daratumumab Monoclonal antibody Binds to CD38 blocking CD38 mediated signalling Multiple myeloma
Hematology Eftrenonacog alfa Recombinant protein Recombinant human coagulation factor IX Haemophilia B
Crizanlizumab Monoclonal antibody Binds to P-selectin blocking P-selectin/PSGL-1 interaction Sickle cell disease
Caplacizumab Antibody fragment Targets von
Willebrand factor inhibiting its interaction with platelets
Acquired thrombotic thrombocytopenic purpura (attp)
Albutrepenonacog alfa Fusion protein Recombinant human coagulation factor IX Haemophilia B
Luspatercept Fusion protein Binds to selected
transforming growth factor-β (TGF-β) superfamily ligands
Transfusion-dependent anaemia associated eith low and intermediate-risk myelodysplastic syndromes (MDS)
and beta thalassaemia.
Eculizumab Monoclonal antibody Binds to the complement protein C5 Atypical haemolytic uraemic syndrome (ahus)
generalized myasthenia gravis (gmg)
neuromyelitis optica spectrum disorder (NMOSD)
Lanadelumab Monoclonal antibody Targets and inhibits
active plasma kallikrein
Hereditary angioedema (HAE)
Metabolic disorders and Neurology Cerliponase alfa Recombinant protein Recombinant human enzyme tripeptidyl peptidase-1 (rhTPP1) Neuronal ceroid lipofuscinosis type 2 (CLN2) disease
Sebelipase alfa Recombinant protein recombinant human enzyme lysosomal acid lipase (rhLAL) Lysosomal acid
lipase (LAL) deficiency
Velmanase alfa Recombinant protein Recombinant form of human enzyme alpha-mannosidase Alpha mannosidosis
Vestronidase alfa Recombinant protein Recombinant human beta-glucuronidase (rhGUS) Mucopolysaccharidosis VII (MPS VII; Sly syndrome
Parathyroid hormone Recombinant protein Recombinant human parathyroid hormone Chronic hypoparathyroidism
Cenegermin Recombinant protein Recombinant form of human nerve growth factor Neurotrophic
Pegvaliase Recombinant protein Recombinant Anabaena variabilis phenylalanine ammonia lyase Phenylketonuria (PKU)
Somapacitan Fusion protein Recombinant human growth hormone derivative with albumin binding moiety Adult growth hormone deficiency (AGHD)
Asfotase alfa Fusion protein Recombinant tissue-nonspecific alkaline phosphatase-Fc-deca-aspartate fusion
protein with enzymatic activity
Paediatric-onset hypophosphatasia
Elosulfase alfa Recombinant protein  Recombinant form of human N-acetylgalactosamine-6-sulfatase (rhGALNS) Mucopolysaccharidosis, type IVA (Morquio A Syndrome, MPS IVA
Velaglucerase alfa Recombinant protein Recombinant form of glucocerebrosidase Type 1 Gaucher
Bone diseases Burosumab Monoclonal antibody Binds to fibroblast growth factor 23 (FGF23) leading to inactivation X-linked hypophosphataemia
Infectious diseases Obiltoxaximab Monoclonal antibody Binds to protective antigen (PA) of B. anthracis Inhalational

Reference: Orphanet Report Series – Lists of medicinal products for rare diseases in Europe. March 2021



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Publishing Date:
Monday, 24 January, 2022
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