Human Plasma-derived Products - Protein Therapies for Rare Diseases

I recently listened to a podcast from NPR's planet money "Blood Money". It discussed why only the U.S. and a few other countries allow companies to pay people for blood (or precisely the plasma) - the materials for many life-saving protein therapy products for rare diseases. Please listen to the podcast or read the transcripts of the podcast. 

Blood Money

We all heard or experienced blood donation which is usually voluntary by the donor with no monetary incentives. The Plasma donation is different and donors are paid for donating their plasma. So the first question we need to know what the difference between the (whole) blood and the plasma. Here is a table for comparison:

Whole Blood	Plasma
This red bodily fluid is composed of red cells, white cells, plasma, and platelets. It supplies oxygen and essential nutrients to cells and tissues in the body and removes waste materials like carbon dioxide and lactic acid.	Plasma is the clear, straw-colored liquid component found in the blood. It is made up of 90% water and carries nutrients, minerals, hormones, and proteins to parts of the body that need it. Plasma also contains antibodies that help fight infections and proteins including albumin and fibrinogen that help maintain serum osmotic pressure.
With red cells, white blood cells, and platelets in it	With red cells, white blood cells, and platelets removed
	plasma is collected through a process known as plasmapheresis. Plasmapheresis is a method of removing and separating plasma from whole blood via an apheresis machine. After Plasma is separated from the whole blood, the red blood cells and other cellular components are returned to the doner’s body
Whole blood is commonly transfused in its original form in an effort to treat injuries and illnesses. It can be also be separated into its individual components and used to treat conditions including cancer and blood disorders.	Plasma, on the other hand, is typically used as a starting material to manufacture commercial drugs known as plasma-derived products. These plasma-derived products serve as lifesaving therapies for patients living with immune deficiencies and autoimmune diseases.

Human plasma is a treasure and contains many enzymes and antibodies that can be extracted and manufactured as medicines for many rare diseases. Human plasma products (also called plasma-derived products or fractionated plasma products) are highly regulated by the FDA - Office of Blood Research and Review under the Center for Biological Evaluation and Research (CBER). The drugs manufactured from human plasma (so-called plasma-derived products) need to go through the same process as other biological products and Biological License Application (BLAs) needs to be approved by the FDA for market authorization. Human plasma-derived products have been approved to be used in treating diseases in various indications in immunology area, enzyme replacement/augmentation therapies, neurology, pulmonary, hemostasis, ...... Some examples are:

• Alpha-1 antitrypsin deficiency (A1AD)
• Primary Immunodeficiency (PI)
• Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
• Guillain-Barré syndrome (GBS)
• Hemophilia
• Rabies
• Hepatitis B
• Kawasaki disease

The blockbuster product from the plasma fractionation is immunoglobulin (IVIG or SCIG). immunoglobulin is a life-saving product for primary immunodeficiency patients. Immunoglobulin is also thought to be a panacea for all kinds of neurological diseases (CIDP, GBS, Myasthenia Gravis, multifocal motor neuropathy) that some of which have no other efficacy treatments. 

Many of these diseases treated with plasma-derived products are orphan diseases or ultra-orphan diseases.

Theoretically, plasma-derived products have a risk of carrying bloodborne pathogens (viruses and other pathogens). However, these pathogens are destroyed or filtered out during the manufacturing process. The actual plasma-derived products are very safe - at least in the United States. 

For clinical trials with plasma-derived products, the following points are noted: 

• Similar to the oncology drugs, the plasma-derived products can not be tested in healthy volunteers. Even for the first-in-human trial, the plasma-derived products will need to be tested directly in the patients.  
• The study procedure will always need to include the virus tests at screening and possibly the following up visits. 
• Always include the immunogenicity assessment (because the plasma-derived products are large protein therapies)
• The design and analyses of clinical trials are the same as other drugs or biological products. For ultra-rare diseases, the single-arm design may be used as the pivotal study and the sample size can be very small. See FDA Approves First Ever Treatment for Plasminogen Deficiency Type 1 based on a single-arm study with 15 adult and pediatric patients with plasminogen deficiency type 1.
• For pharmacokinetic analysis, the pre-dose drug concentration is not zero since there are endogenous compounds (i.e., enzymes or antibodies that are generated by the patients). 

Useful Links: 

• FDA Websites: Blood and Blood Products
• FDA Approved 'Fractionated Plasma Products'
• Efficacy of intravenous immunoglobulin in neurological diseases
• Business is booming for the $24 billion plasma industry — but it may be putting vulnerable donors at risk
• Blood Business: How the Plasma Industry Works | ENDEVR Documentary