Introduction to biological medicines

Small molecule medicines: Most medicines, such as acetylsalicylic acid (aspirin), are small molecule products. This means that they have simple molecular structures with low molecular weight. These small structures are easy to produce or copy. Once a patent expires, other manufacturers can make copies of small molecule medicines by reproducing the exact same active ingredient, which they can then sell as a generic copy.

Biological medicines: By comparison, biological medicines are very large and have complex molecular structures, created by living cells, from specialised ingredients, using an intricate biotechnology process. It is impossible to produce an exact copy of a biological medicine without using the exact same ingredients, the same living cell lines, and identical manufacturing conditions. In fact, it is not even possible to demonstrate that a batch of any biologic is identical to previous batches of the same biologic.

Biosimilars: The first biological medicine of its kind is called the reference or innovator medicine. Once a patent expires for a reference biologic, other manufacturers are able to copy it. However, the innovator company doesn’t have to share its patented manufacturing processes (which may include the room temperature, the type of cells that produce the biologic, and the food the cells used to grow it), and since there is always variability in a live biological system, it is impossible to create an identical medicine. But they are able to create a copy that is highly similar, with a different brand name; these are known as biosimilars.

To be approved for use in New Zealand by Medsafe, the manufacturer must demonstrate that their biosimilar has no clinically meaningful differences to the reference medicine in quality, safety and efficacy.

Reference biologics and their biosimilars are all biological medicines. Biological medicines are the fastest-growing medicine type being developed internationally. Biological medicines that target specific receptors or proteins involved in disease progression in conditions such as rheumatoid arthritis, Crohn’s disease, multiple sclerosis and some cancers are already available in New Zealand. Some biosimilars are also funded for use in New Zealand and it is likely that the number of funded biosimilars in New Zealand will increase as the patents on reference medicines expire.

Patients receive biological medicines mainly subcutaneously or by intravenous infusion. Biological medicines cannot be taken orally, since they have limited permeation through the gastrointestinal tract and are rendered ineffective by digestive processes (eg, acidic stomach pH and digestive enzymes). New formulations allowing for buccal, sublingual and nasal administration are starting to come to the market and will continue to be developed.

Overall, the introduction of biosimilar medicines has the potential to widen patient access to effective biological therapy, to better accommodate restraints within healthcare budgets and improve overall patient outcomes.

This is because in most cases, biosimilars are less costly to develop than the reference biological medicine. For the biosimilar to be granted approval in one or more indications, the manufacturer must demonstrate their product is safe, effective, and of comparable clinical quality to the reference biological. However, they do not need to conduct extensive clinical trials, as the innovative manufacturer had to do. Further to this, at the end of a product’s patent life, most manufacturers are willing to lower their prices to compete in the biosimilar market space, creating more competition and driving down prices.

The availability of biosimilars in New Zealand could potentially:

• improve the cost-effectiveness of biological medicines in various conditions
• improve economic efficiencies by creating a more competitive market with a broader range of cost-effective treatment options
• contribute to ongoing Pharmac sustainability and allow reinvestment in new treatments
• expand access to medicines via broader eligibility criteria or broadening of approved indications
• improve the security of the supply chain, ensuring fewer consumers are affected by medicine shortages.

Some health professionals may have concerns about differences in adverse effects and/or allergic reaction profiles between a reference biological medicine and its biosimilar. However, biosimilar medicines are tested and shown to be as safe and effective, and of the same quality as the reference biological medicine.

All biological medicines (both the reference biologic and its biosimilars) have the ability to induce an immune response; this is known as immunogenicity. There are two types of immunogenicity in biological medicines:

• Wanted immunogenicity, as seen in vaccines, where the vaccine stimulates an immune response against the pathogen to create protective antibodies

• Unwanted immunogenicity, where the body has an immune response to the biologic and neutralises its biological activities or provokes an allergic reaction. These can result in adverse events, which may sometimes be very serious.

The immunogenicity of biological medicines is influenced by numerous factors. These may be related to the medicine used and to the patient's disease and individual characteristics, as well as the dosing schedule and route of administration.

Many studies and systematic reviews examining the safety profiles of biosimilars have been conducted over the last 10 years. These studies have found that the number and type of adverse effects and side effects are the same for biosimilar medicines as for the reference biological medicines.

Prescribers may decide with the patient to switch biological medicines to:

• improve treatment efficacy

• improve tolerability

• address issues relating to an administration device

• continue to receive funded treatment

• reduce the cost of treatment due to funding, availability or supply issues.

Interchangeability refers to the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect. This could mean replacing a reference product with a biosimilar (or vice versa) or replacing one biosimilar with another. Replacement can be done by:

Switching, which is when the prescriber decides to exchange one medicine for another medicine with the same therapeutic intent/clinical effect.

Substitution (automatic), which is when the pharmacist dispenses one medicine instead of another equivalent and interchangeable medicine at pharmacy level without consulting the prescriber. In New Zealand, biological medicine brands may not be substituted at the pharmacy without the prescriber's agreement.

It is recommended that biological medicines, including biosimilars, should be prescribed by brand name. Brand name prescribing ensures that inadvertent substitution of the biological medicine without the prescriber’s knowledge does not occur at dispensing.

It is good practice for both the brand name and the batch number to be recorded at dispensing to allow for tracing, pharmacovigilance and quality assurance processes.

There are many points to consider when starting a patient on a new biological medicine. You can learn more about the psychological aspects of starting new medicines in episode one (part 1) of our podcast series Legendary Conversations.