What does “snake oil” mean and why?
A hoax or con.
Originated from an old Chinese remedy for RA which consisted of fatty acids including eicosapentaenoic acid (EPA). It was used by Chinese labourers on American railway in the late 1800s and was known as snake oil. It wasn’t long until an American “snake oil” was produced and passed off as the Chinese Snake Oil by “grifters”.
What 2 agencies are involved in drug development? What is an exception to this rule?
The government - promote health of citizens.
Drug/research companies - to make money.
In Cuba, major vaccine development is conducted and assessed by the state since the 1970s (i.e., not an R&D company).
What is antibody positive pure red cell aplasia?
A condition associated with erythropoeitin use where there is a lack of reticulocytes and erythrocytes despite presence of erythropoietin therapy due to an EPO-targeted antibodies and lack of erythroid progenitor cells.
What is a biosimilar?
A medicinal product which contains a version of the active substance of an already authorised original biological medicinal product
What are some differences between chemical and biological drugs?
Chemical drugs tend to be smaller and have a simple structure with well-defined composition. They usually have more than one pharmacological target (low specificity) and have minimal heterogeneity.
Biologic drugs have large complex structures and their composition is only defined to a certain extent. They are highly specific and have significant microheterogeneity (have several molecular variants).
What is the difference between generics and biosimilars?
Generics - chemical drugs. Can be marketed almost immediately after molecular identity and bioequivalence has been confirmed to the original drug, after its patent has run out.
Biosimilars - biologic drug. Molecular variant of the original biologic and requires the same development and clinical trial as the original. Much longer.
What are some advantages and disadvantages of biologics?
Pros:
* Health economics – low cost
* Increased access and choice
* Encouraging innovation
* Anticipated that biotechnology medicines will account for 50% of the market for pharmaceuticals all over the world.
Cons:
* Complexity and process specificity
* Regulatory agencies, require pre-clinical and clinical comparability studies to demonstrate safety and efficacy, and request additional post-manufacturing assays to look for immunogenicity of biosimilars.
* Bioanalytic and comparability assay development, the definitions of biological activity under clinical view, the global harmonization of acceptable data, and product commercialization strategies of biosimilars.
What is epoetin alfa?
A recombinant human erythropoietin identical to human erythropoietin. Used in treatment of anaemia associated with CKD and cancers.
What is Darbepoetin alfa?
A hyper glycosylated form of epoetin alfa which has improved biological activity and extended half life.
What were some issues in the development of darb=epoetin alfa?
- Expression in host cell – granulocyte stimulating factor expressed in Chinese hamster ovary cells is glycosylated but in E. coli is non-glycosylated.
- Fermentation – the size of tanks effects glycoside fingerprint (location of sugar attachment to protein).
- Purification – Eprex erythropoietin originally isolated from human blood and used for treating anaemia, but in 1998 EU asked for removal of human albumin from Eprex. This was done by solubilising the protein with Tween 80. Patients became sick and anaemic and it was found they had antibody positive pure red cell aplasia.
- Formulation – above applies.
What is the ethical issue with unregulated, private healthcare? Give 2 examples.
Pharma companies can charge whatever they want for drugs at the expense of patients.
AbbVie’s CEO received multi-million dollar bonuses due to the profits from Humira, a mAb used for RA and other autoimmune diseases, making it the highest profiting drug in the world.
The price of insulin increased 585% from 2001-2015 ($35-234 per vial (2 weeks treatment)). Total cost for patient = $6k. Total cost to produce = $34. Companies could charge $50 a year and still make a profit but don’t.
What are 5 issues associated with cost of biologics?
- Biosimilars (cheaper generics) are an unattractive investment as they require lots of testing and regulatory work.
- New indication, new patent - Biologics which have expired patents for a particular indication can patent for a new indication and give themselves another 20 years of protection, which means they can charge more and make more money.
- Pharma operates as a cartel – AbbVie paid off biosimilar companies to stop them marketing cheaper version of their biologics.
- Changes in manufacturing process require proof of equivalence – any change to the approved manufacturing process (e.g., change in supplier of raw materials, replacement of a piece of equipment etc) requires demonstration to the FDA of the comparability of the products quality attributes before and after the change to ensure the safety and effectiveness of the product is maintained.
- Patient groups become advocates – for various conditions, patient groups lobby to the government to demand more attention, support etc.
Give an example of a patient advocate group case?
Kidney Cancer UK advocates called for a “ban on kidney cancer drugs to be lifted” and wanted Avastin, as well as 3 other drugs, on the NHS but was denied by NICE. These drugs were licensed for advanced renal carcinoma and was targeted for 50% of 7000 patients diagnosed each year. NICE did not consider “end of life medicine” value for money, as it cost £70k per year with no guarantee for extension of life.
Give an example of where political and regulatory control reduced cost of biologic medicines.
In 2018, AbbVie agreed to an 80% price reduction in European countries on Humira after the introduction of biosimilars there.
Why do biologics not have a defined compostion?
The organisms from which the biosimilar and reference drug are produced may not be identical, and the production process of the reference drug remains confidential, even after the patent for the process expires. As a result, the biosimilar and the reference biologic are not exact duplicates.
What is the benefit of epoetin treatment in CKD and cancer-related anaemia?
- Fewer blood transfusions
- Improved exercise capacity
- May slow progression of kidney disease
- Potential cardiovascular benefits
What is a case that indicates the need for extensive testing of biosimilars?
In Asia and South America, testing for epoetin biosimilars is not done, and they are assumed to have a similar safety and efficacy profiles as the original product. However, upon testing against the EU quality specifications for epoetin afla, it was found that:
* 7 samples exceeded the pH specifications.
* 1 sample failed to meet the specification for total protein content.
* 2 samples exceeded EPO content.
* An in vitro bioassay found that 11 samples exceeded the specification.
* The in vivo potency in mice ranged from 48-163%. 7 samples failed to meet the specification.
* Bacterial endotoxin present in 2 samples.
