HORIZON LINES: A Yearly Review of NDAs – 2014

• Tara Innovations LLC

A total of 133 NDAs were approved in 2014. This column summarizes details on all the NDAs (New Drug Applications) approved in 2014. The details on individual NDAs can be obtained from the articles listed in the reference section.^1-4

There are three types of NDAs – 505(b) (1), 505(b) (2) and 505 (j). The 505(b) (1) application contains the full report on safety and efficacy. In 505 (b) (2), some of the information is taken from studies not conducted by the applicant but obtained from previously approved drugs or literature. A 505(j) application is an abbreviated new drug application (ANDA) that contains information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics and intended use, among other things, to a previously approved product - the reference listed drug (RLD).⁵ This review article does not cover ANDAs. From Figure 1, it is clear that a significant (31%) percent of NDAs were approved for old/previously approved molecules in 2014.

Figure 1. Percent of New Drug Applications as old and new molecules

A company gets approval for the NDA and with further research it is found out to be useful for various other indications or the doses are varied or the modes of drug delivery are altered over the period of time. In some cases, the patient population is altered on the basis of advanced clinical studies. All such NDA’s are included under “old molecules”. The reason being the drug molecule remains the same but other parameters in the same NDA are altered.

FDA CDER published a review article on the Novel New Drugs (NNDs), which is a subset of new approvals.⁶ These are truly innovative products that help advance clinical care to another level. The focus was not on the number of NNDs but the unique quality offered by these NNDs to enhance patient care. Figure 2 depicts the NNDs approved over the years and 2014 was one of the best years for NNDs.

Figure 2. Novel New Drugs approved over years

Figure 3 depicts the number of NDAs approved in every month in 2014. About 11 NDAs were approved per month, with an increasing number of NDA’s approved towards the end of the year. Maximum number (27) of NDA’s were approved in December 2014 (20.3% or 27 out of 133).

Figure 3. Number of New Drug Applications approved in 2014 over months.

In recent years, there has been an increased interest in large molecules. For the purpose of this article, large molecules were defined as those with molecular weight over 900 Daltons. It is obvious from Figure 4 that almost one third of NDAs approved were for the large molecules. A considerable number of large molecules (39.9%) were monoclonal antibodies and majority of which are used to treat cancer and related conditions.

Figure 4. Proportion of large versus small molecules in New Drug Applications in 2014.

The size of a company obtaining NDAs is also a crucial point for the analysis. Large companies have a strong R&D muscle for innovation and they are expected to be pioneers in the new research. Figure 5 shows the distribution of NDAs approved to large, medium and small companies. The size of the company can be defined based on the number of employees and revenues. Companies with revenues of <$100 million, $100 million - $1 billion and >$1billion were assigned as Small, Medium and Large, respectively. Small companies obtained 35% of NDAs, which was very significant. It proved a key point - It takes more than R&D budget to innovate new products. The key factors for success could be – motivation, management support, fast decision making (lack of bureaucracy), and a main focus on the goals. Many large companies tend to focus on marketing of drug products. These companies either acquire products from small companies or take over the small companies for their product line. Another major factor is the patent expiration date. Large companies need to acquire products to keep their robust pipeline intact and replace their lost “cash-cow” revenue. Currently, small biotech companies with late stage products are prime targets for take over.

Figure 5. Number of New Drugs Applications approved for Small, Medium and Large companies.

In pharmaceutical dosage forms, the mode of administration is critical and it is important to understand the trend. Delivering medicines only to the site of action is most desired. Still 42.8% NDA’s preferred oral route where the drug is delivered to the blood stream to reach the site of action. Tablets and capsules are still preferred for the delivery of the drug. Based on the information, even injectable formulations have gained a lot of importance in 2014 (Figure 6). Out of 133 NDAs, 55 (41.4%) NDAs were approved as injectable formulations. Injectables include intravenous, intramuscular, subcutaneous, intrathecal routes. Injection of microspheres for treating facial wrinkles and acne scars was found to be a novel approach. Developing and manufacturing injectable formulations has its own challenges. In spite of that, this mode of drug administration is very popular. The reasons could be – short Tmax to obtain an immediate action, higher profit margin, psychological factor for patients etc. Nasal (6%) and Ophthalmic (3%) delivery systems are chosen for localized delivery of drugs. Intranasal delivery has been attempted for systemic administration. Topical delivery (4.5%) is predominantly used to treat cosmetic disorders (acne). Topicals were also preferred for the treatment of toenail infections as well as transdermal patches for a systemic absorption.

Figure 6. Trend for the preferred modes of administration for the New Drug Applications approved in 2014.

Another important criteria to review is the target of action for the NDAs. It was not easy to divide NDAs in different categories and some targets were pooled. The details of each are available in the previously published articles in the same journal.1-4 The NDAs were evenly distributed over 13 categories based on the body system they act on, with a maximum being 18% acting on the nervous system (Figure 7). All the NDA’s for management of acute and chronic pain, Alzheimer’s, schizophrenia, seizures and conditions related to overuse of opioids were classified into the nervous system category. Companies have started focusing on lifestyle diseases like atherosclerosis, heart disease, stroke, obesity, type 2 diabetes, hypertension, cancers and diseases associated with smoking and alcohol and drug abuse. Almost 11% of NDA’s are classified in categories like circulatory system (Angioedema, hypotension, hypertension, hemophilia, etc.), endocrine system (type 2 diabetes, renal failure, hypogonadism, lipodystrophy, etc.) and skeletal system (various types of cancers and osteoarthritis), which are mostly affected by lifestyle diseases. Considering the current trend we are seeing in increases in lifestyle diseases, more and more companies will be seen shifting their focus to these categories. In fiscal year 2014, U.S. federal funding to combat HIV totaled $29.5 billion of which 9% was dedicated for research purposes.⁷ Approximately 3% of the total NDA’s were for treatment of HIV infection.

Figure 7. Number of NDAs targeted to different physiological systems to cure different diseases

Conclusion

Attempts were made to capture various trends observed in approved NDAs in 2014. It will be important to conduct such an analysis every year to understand year-to-year trends. The key trends are – an increased interest in large molecules and the large contribution by the small companies. It will be important to understand the productivity in R&D for the large versus small companies and encompassing factors. Oral and injectable routes are still the most preferred routes of administration.

References

1. Horizon Lines, A Quarterly Review of NDAs – 1Q14, Harshada Sant and Hemant N. Joshi, Pharmaceutical Outsourcing, May/June 2015, pgs. 48-xx (2015).
2. Horizon Lines, A Quarterly Review of NDAs – 2Q14, Harshada Sant and Hemant N. Joshi, Pharmaceutical Outsourcing, May/June 2015, pgs. 48-xx (2015).
3. Horizon Lines, A Quarterly Review of NDAs – 3Q14, Harshada Sant and Hemant N. Joshi, Pharmaceutical Outsourcing, May/June 2015, pgs. 48-xx (2015).
4. Horizon Lines, A Quarterly Review of NDAs – 4Q14, Harshada Sant and Hemant N. Joshi, Pharmaceutical Outsourcing, May/June 2015, pgs. 48-50 (2015).
5. Food and Drug Administration, www.fda.gov.
6. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/ DrugInnovation/UCM430299.pdf
7. http://kff.org/hivaids/fact-sheet/the-hivaids-epidemic-in-the-united-states.