During research for new drugs, some of the chemical molecules involved in the process of creating a treatment can be identified as having the potential to be developed into a novel drug that delivers therapeutic benefit in the form of a treatment or cure for a disease or disorder. These are called new chemical entities (NCEs): drugs or active molecules that are without precedent among regulated and approved drug products. The NCE label means that a drug in development is not an existing substance that has already been investigated and approved as a drug for a given therapeutic area.

NCEs are a great boon for the pharmaceutical industry as this is where many new ideas for treatments come from, but many new NCEs are also poorly soluble, leading to the problem of reduced bioavailability. The discussion of how the industry should move forward is a potentially controversial one, and there are many reasons why the procedures are being held up.

Count the costs

The cost of drug development is important to remember with any trend in the pharmaceuticals industry. While the past 50 years of data shows a reduction in absolute numbers of new drugs, critics of the pharma industry say it has become less productive as the number of new drugs launched has not increased relative to R&D time and expenditure, or the availability of more advanced technologies. The cost per new drug produced is estimated to have grown at an annual rate of 13.4% over recent decades.

These rising prices, coupled with a growing reputation for poor productivity, have led to widely voiced concerns that pharmaceutical innovation is declining overall. Worldwide data indicates a decline in NCE introductions between 1982 and 2002-03, and reports from the British Medical Journal show a trend that suggests a smaller number of new drugs have been launched over recent decades, despite increasing investment in research from pharma companies and other bodies. Is this because we have hit a wall in what our current technology and practices can achieve, or is it something else?

This problem is tied up with the fact that the drugs reaching the market now usually do so after a much longer wait: drug development times have been increasing greatly, and the time taken to bring a new drug to the market rose from approximately three to 12 years between 1950 and 2000. This all adds to the shortfall of NCEs as more may already be in laboratories, undergoing development. Such factors will seriously affect patients, who may not be treated adequately with the drugs that are already on the market.

These issues remain particularly important in the case of NCEs. Many think that regulations need to be changed in order to speed up the process of getting drugs from discovery to the laboratory and consumer, but another theory remains: perhaps we have simply reached the peak NCE market.

Some estimate that as many as 50% of NCEs are poorly water soluble and, as a consequence, prone to oral bioavailability problems, determined as Biopharmaceutics Classification System (BCS) Type II (high permeability, low solubility) or Type IV (low permeability, low solubility). This means patients will be unable to absorb the drugs effectively through the gastrointestinal tract (GIT), presenting a challenge to a formulator’s best intentions to deliver efficacious doses of BCS Type II and IV NCEs. There are many patients that are unable to get the therapeutic level of dose needed, so scientists are being challenged to develop tweaked versions that achieve a desired pharmacokinetic profile.

Poor solubility

Today, scientists working in pharma to create new drugs should have a good working knowledge of how to develop orally delivered formulations that can be used to improve the bioavailability of novel compounds. Creating new drugs is no easy process, taking years and potentially costing more than $1 billion. A trial-and-error approach to development is never easy and, with the number of NCEs shrinking, there is increasing pressure to make more development programmes succeed, rather than risking further expenditure on the development of drugs where GIT absorption and therapeutic effect are poor.

More than 70% of small-molecule NCEs, which will be taken orally, have poor solubility issues. This makes
absorption of the drug from the GIT into the patient’s bloodstream a challenge; often, these compounds also have poor bioavailability, requiring a high dose in order to see any therapeutic effect. Unfortunately, not using the right technology for formulation development of the compound could result in failure during preclinical or clinical testing, due to poor bioavailability of the compound and not seeing the desired therapeutic effect during the study.

Dr Elanor Pinto-Cocozza, technical project manager at drug manufacturer Catalent, has worked on the improvement of traditional drug formulations and the development of novel drug formulations in relation to stability, enhanced bioavailability and patient compliance.

"We do see a lot of NCEs coming through our pipeline," she begins. "Something new that’s proving to be an effective tool for the assessment and optimisation of these NCEs is a service that is designed to overcome development issues for poorly soluble compounds. One challenge we do see right now, especially at the research and preclinical stages, is that a lot of resources are invested to find compounds that are efficacious and have a positive therapeutic effect, but they become challenging to develop further."

Julien Meissonnier, vice-president of science and technology at Catalent, agrees: "30% of drugs in development do not progress past phase I, because the biopharmaceutical hurdles are not properly addressed. Many of these drugs are not properly formulated and come back to us because they repeatedly fail to achieve the desired effect in the clinic.

"This is why a parallel-screening approach is used that characterises a candidate molecule and matches the best formulation with the most appropriate drug delivery technology in order to expedite the development of bioavailability-constrained molecules."

Pinto-Cocozza adds: "There have been many challenges in the formulation development of NCEs. A lot of the compounds that are coming out are poorly soluble. These compounds are definitely effective in reaching the receptor or targeting certain areas to get the desired therapeutic outcome but, in order to do so, they have to overcome the limitations of poor oral bioavailability. This challenge creates the need for technological advances and formulation development expertise.

There are still hold-ups, however, that the industry is seeing from other areas. "These may be more than just scientific, and the success of an NCE is based on not only what gets approved by the regulatory authorities, but also what will get support from the health system or insurance companies – those who pay for the drug’s use," says Pinto-Cocozza.

"In order for a company to find success, the NCE needs to be demonstrably efficacious. If its cost is not justified by its efficaciousness compared with what is already on the market, the bodies paying for it may not fund it or many not provide sufficient financial support for every patient to receive it."

Market investment

The UK is the second-largest source of NCE development, accounting for 10.4% of pharmaceutical innovation worldwide – but the US is the dominant world player. "Most people can’t afford $1,000 a pill for medication," says Pinto-Cocozza, "so that may be one of the reasons why there are a smaller number of NCEs. The biggest challenge pharmaceutical companies are facing is getting approval not just from US Food and Drug Administration [FDA] but also from the insurance companies."

On the other hand, Pinto-Cocozza says, FDA is being very supportive in the US: it approved 45 novel drugs in 2015, up significantly from the 28-a-year average between 2006 and 2014. Meanwhile, insurance companies are challenged to determine whether an NCE is addressing an unmet need and evaluate the cost versus improvement in patients’ quality of life. Pinto-Cocozza is not worried, though. "There is strong interest in the pharmaceutical industry to support finding cures and treatments for rare and orphan diseases," she says.

The Global Genes Project estimates that Europe has 30 million people with rare diseases, and the National Institutes of Health estimates that around 6,800 rare diseases affect more than 25 million Americans alone. The National Organization for Rare Disorders estimates there are 7,000 orphan diseases but only around 500 approved treatments for these. There is evidently a vast unmet need for innovation in the global market, to find treatments or cures for these diseases.

The long-term trend, however, contradicts the widely held view that pharmaceutical innovation is declining and backs up Pinto-Cocozza’s optimistic outlook, suggesting that the annual numbers of newly launched drugs may have increased since the early 1970s. Although NCEs might not be coming to market as thick and fast as they once did, they are still being developed and released. Coming out with NCEs that fit into an unmet medical market is always a challenge and bringing to the market medication that is affordable to the general public is a necessity that can’t be ignored.