Therapeutic proteins are emerging as a new phase in disease management of important diseases like cancer, diabetes, rheumatoid arthritis, HIV infections and cardiovascular diseases. The conventional chemical entities carry a burden and risk of unknown ADRs and are unable to resolve the health issues to the satisfaction of the patients and other stakeholders.

In fact, the growth of biologics has stemmed out due to deficiency of the therapeutic outcomes and risks involved of chemical based drugs. For example, existing therapeutics in cancer and rheumatoid arthritis although address the symptomatic relief but are unable to resolve the long term morbidity. In addition, by using these drugs for long period extending to several years does have effect on vital organs like kidney, liver and heart.

The variety of therapeutic proteins includes hormones, enzymes and monoclonal antibodies (mAbs). The hormones and enzymes can be made by recombinant DNA technology whereas mAbs are made by Hybridoma technology. It is interesting to know that recent biologics are made utilizing human DNA and hence they are known as humanized insulin or humanized mAbs. The advantage of humanized proteins is reduction of immunogenic reactions which is a major concern of all therapeutic proteins.

Unlike the chemical drugs, the therapeutic proteins differ in having several thousand Daltons of molecular weight and are of complex structures which are usually described as quaternary structural entities. Hence the therapeutic proteins’ regulatory requirements are entirely different and complex. There are still many dark areas where in the regulatory frame for therapeutic proteins is under development even in USA and European countries.

The classification of therapeutic proteins:

• Hormones such as Insulin in case of diabetes and growth hormones in case of growth hormone disorder
• Monoclonal antibodies in case of autoimmune disorders and cancers
• Immunomodulators such as beta- interferon in case of multiple sclerosis
• Enzymes such as serratiopeptidase    
• Vaccines for prevention of infectious diseases

The biologics are not recent entities; their therapeutic potential was known from primordial times for example, the insulin and growth hormone. The problem with the biologics was manufacturing them in a large quantity so that it can be used on large populations. The breakthrough came when the recombinant DNA and Hybridoma technology became available for making therapeutic proteins on industrial scale. The human genome project gave a shot in the arm which discovered several proteins, peptides and the targets opening a plethora of opportunities to experiment and pave way for new therapeutics. Initially, the biologics were highly expensive and even the rich and developed countries had an issue of affordability; even today the problem of meeting the cost of treatment of biologics bothers and they have remained under-utilized.

biologics there were attempts to make similar molecules which are called Biosimilars. However, they differ from the conventional chemical generics in a way that they are entirely different from the originator product in terms of chemical similarity, the PK/PD profile and clinical efficacy. Hence the regulation of biosimilars differs with new challenges and tasks met in development of a new chemical entity.

The biologic/ biosimilar is usually a very big molecule with complex structure which relates to its clinical activity. There can be issues of reproducibility of clinical efficacy as the molecules are different however; they are similar to 80-95 per cent. The new term Biobetter was coined as sometimes the biosimilar was able to show an improved clinical efficacy over the biologic. There are instances where the altered response has yielded much unprecedented benefits in terms of cost and clinical efficacy.

Biosimilars are considered as biologic generics however there are issues of molecular and therapeutic similarity. These are rising regulatory issues as they cannot be same as generics of new chemical drugs. However, the regulators are demanding more proof in terms of clinical equivalence, safety and efficacy. Biosimilars are showing a variable response in terms of Pharmacokinetic and Pharmacodynamic profile in comparison to originator biologic. Sometimes biosimilars have shown significantly more improvement in terms of safety and efficacy. This has led to the new concept called Biobetters.

Biobetters are also deliberately altered molecules with an aim of improving disposition, safety, efficacy and ease of manufacturing. Biobetters are also patented as novel patents with improved Pharmacodynamics like less frequent dosing and side-effect profiles with sustained or slow release formulations. The distinction between the biosimilar and Biobetter is on their improved characteristics in comparison to originator biologic. The high developmental cost and application of high-end technology has made the biologics and Biobetters a high risk profile drug development activity.

Although many people have the technology are afraid of investing due to patent issues and risk of failure to perform in the market. In choosing the pre-clinical development of biosimilars or Biobetters, an investor would always prefer to go for Biobetter as the scope of filing a new patent and charging more price than the originator biologicis for Biobetter and not for a biosimilar. However, a manufacturer from developing economies like India and China may show some interest in biosimilars as these drugs can occupy the market share of an expensive biologic whose patent has recently expired.

Currently, bringing a biosimilar is extremely difficult as compared to a new chemical entity drug as developmental cost of biosimilars includes the preclinical data along with phase one to Phase four clinical trials.

This would cost heavily for developing a biosimilar or a Biobetter.

Different countries of the world have their unique approach as far the regulations of biologics, biosimilars and Biobetters are concerned. For example, regulatory guidelines are not yet established in USA for biosimilars and Biobetters whereas Europe or Asia has taken the first step towards regulation.

More biosimilars are available in Europe because the early molecules to go out of patent were simple molecules like growth factors that is why it was easy to establish a straight forward pathway for approval. In European Union, the clinical trials have to be done with comparator innovators in Europe. As a result, worldwide approval even for growth factors can be more expensive if every country regulator demands data from its own country. In many instances the market size maybe the constraint for developing a biosimilar or Biobetter however the mAbs having a large market like in auto immune diseases and cancer can have many players leading to several brands of biosimilars and Biobetters. There is a need to sit together and lay down the guidelines of harmonization for biosimilars and Biobetters as this would help in containing the cost of the development by avoiding the repetition of the preclinical and clinical data.