Abstract
The chapter describes briefly, but as much as is reasonably possible specifically, the key steps in therapeutic product development, starting with an invention and its patent protection and ending with the resulting product pricing and commercialisation. The chapter also addresses certain nanotechnology-specific aspects of such development, and draws attention to the importance of quality control and quality assurance in the process. Explaining the rationale for and current good practices in the tests conducted with animals and human test subjects leads to a concise description of the regulatory framework for developing and launching new (nano)therapeutic products. The chapter closes with some remarks on risk management and general recommendations.
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Notes
- 1.
Notable exceptions are such third parties that have signed a non-disclosure agreement with the inventor in spe, and lawyers.
- 2.
The cost for filling a full fledged patent application with 50 pages, five independent and ten dependent claims was in the USA in 2012 around 1,518 $US; the corresponding cost of an international, PCT, application was 2,755 $US, in either case excluding lawyers and examination fees.
- 3.
The European patent office defines this as “a skilled practitioner in the relevant field of technology, who is possessed of average knowledge and ability and is aware of what was common general knowledge in the art at the relevant date”.
- 4.
The latter number is proportional but not identical to the given condition prevalence, which is the proportion of the total number of cases to the total population, but often includes an estimated number of non-diagnosed cases.
- 5.
An official course on finding and using the US health statistics is available at http://www.nlm.nih.gov/nichsr/usestats/index.htm.
- 6.
The technical term for this is the Net Present Value (NPV), which can moreover be adjusted for risk.
- 7.
Zero risk assumption is ultimately not tenable and can be overcome by multiplying the risk-free NPV with the specific risk factor for the given product at the given development stage. Table 21.2 specifies the development risk typical of the latter for the clinical stage medicinal products.
- 8.
Most of the overall therapeutic development costs originate from clinical, especially from the large phases II and III, studies. With some experience, one can extrapolate the likely cost of the planned study by multiplying the cost per patient, which depends on the study design, with the scheduled number of patients in the study, which are derivable/estimatable from the published best practice/previous comparable approval studies.
- 9.
Product regulators can afford some extra protection time. Examples are the product-related data protection in EU (presently 10 years for an innovative EMA approved product, plus 2 years for a paediatric indication) and in the USA the corresponding Hatch/Waxman or New Drug Product Exclusivity under sections 505(c)(3)(E) and 505(j)(5)(F) of the Federal Food, Drug, and Cosmetic Act (presently 5 years for a new chemical entity (NCE) and for significant changes in already approved drug products, such as a new use). For a drug product that contains an active moiety that has been previously approved but was then approved again based on new clinical investigations (other than bioavailability studies) the Agency grants 3 years of extra exclusivity under sections 505(b)(1), 505(b)(2) of the Act.
- 10.
GLP also requests receipt and storage of the test items and reference items in separate rooms and areas that are also different from the space for mixing of the test items with a vehicle, to prevent contamination or mix-ups.
- 11.
An analytical instrument (or apparatus) qualification (AIQ) is the collection of documented evidence that an apparatus performs suitably for its intended purpose. It is typically performed by the apparatus manufacturer and must be repeated partially (→ Change Control) after any moving of the apparatus to a new location, even within the same room. More generally, AIQ comprises design qualification, installation qualification, operational qualification, and performance qualification, the last of which must be repeated periodically. If an apparatus relies on software, one must also validate the latter (and, in case, the network of which the software is a part). Changes to instruments, including software, or defects correction are subject to Change Control, a formal process ensuring that changes of/to an apparatus are introduced in a controlled and coordinated manner that does not adversely affect the results of measurements with the apparatus. It is also necessary to regularly inspect, clean, calibrate, and generally well maintain any apparatus used in the GLP setting.
- 12.
Test validation is the collection of documented evidence that a test procedure is suitable for its intended use. It involves assessment of accuracy, precision, specificity, detection and quantification limits, linearity, range, and robustness. Regulators accept only results of the fully validated tests and measurements in the registration relevant (i.e. typically Ph III and toxicity) data sets. Pre-validated tests are acceptable for Ph I/II studies, however.
- 13.
Before actually starting to use certain test or method, one must confirm, by conducting a method suitability test, that the product does not obstruct the method and that the method is working for the product.
- 14.
Since 1999, the International Conference on Harmonisation (ICH) issues GMP recommendations for Active Pharmaceutical Ingredients that by now apply in the countries signatories to ICH (the EU, Japan, and the USA) as well in some other countries (e.g. in Australia, Canada, Singapore) that adopt ICH guidelines for the manufacture and testing of active raw materials.
- 15.
Observing GLP principles automatically ensures an appropriate selection, as it requires confirmation of any experimental method suitability for the given tests set or purpose.
- 16.
Possible examples include, but are not limited to, binding to certain receptor, special mechanical or electromagnetic properties, etc.
- 17.
The term ‘Monitor’ is equivalent to ‘Clinical Research Associate’.
- 18.
The Study plan is also called the Clinical Study Protocol.
- 19.
The average time from synthesis of a compound to initial human testing is according to DiMasi et al. 2003 for self-originated drugs 52 months. The corresponding analysis of clinical phase lengths and phase gaps and overlaps indicates a period of around 70 months for the overall duration of clinical development.
- 20.
Under the USA law, a drug may be transported or distributed across state lines only with an approved marketing application. The IND is the means through which the sponsor obtains an exemption from this law.
- 21.
Biological products are approved for marketing under the provisions of the Public Health Service (PHS) Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a licence for the product. A biologics licence application is a submission that contains specific information on the manufacturing processes, chemistry, pharmacology, clinical pharmacology, and the medical affects of the biologic product.
- 22.
In this chapter, I collectively use the term “Product” for both IMP and IND.
- 23.
Preclinical data that permit an assessment of the Product likely safety for initial testing in humans, including any previous experience with the drug in humans and not excluding foreign use.
- 24.
This means esp. information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. The U.S. FDA assesses this information to ensure that the sponsor can guarantee adequate production of the Product and supply consistent batches of the drug.
- 25.
Detailed protocols for proposed clinical studies allowing an assessment of whether the initial-phase trials will expose subjects to unnecessary risks. The clinical part of IND must also provide information on the qualifications of clinical investigators overseeing the Product administration allowing the FDA to assess whether they are qualified to fulfil their clinical trial duties.
- 26.
One submits such an IND for promising experimental drugs in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.
- 27.
A physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed, is entitled to submit such an IND, for example, with the intent to study an unapproved drug, or an approved product for a new indication or in a new patient population.
- 28.
Such IND allows the FDA to authorise use of an experimental drug in an emergency that does not allow time for submission of a regular, treatment IND. An emergency IND is also useful for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.
- 29.
This includes the “Decentralised procedure” and the “Mutual recognition procedure” and relies on the principle that member states recognise marketing authorisations issued in another (EU) member state. The assessment report of the country that had granted the first marketing authorisation for the medicinal product in question is thus made available to the other member states. Mutual recognition procedures are coordinated by the Coordination group for Mutual recognition and Decentralised procedures (CMD(h)).
- 30.
In Europe, one can exceptionally submit a dossier with (strong) positive clinical results from just one study for a new medicinal product with a well known drug (already approved in a different formulation or for a different indication). One positive clinical study generally suffices to support CE marking of a medical device, however.
- 31.
Rules and procedures used by the Health Canada (HC) resemble more closely FDA than EMA practices.
- 32.
Pharmacoeconomic research is the process of identifying, measuring, and comparing the costs, risks, and benefits of programmes, services, or therapies and determining which alternative produces the best health outcome for the resource invested (Trask 2011).
- 33.
A health economic evaluation normally includes direct medical costs (esp. cost of medications, supplies, laboratory tests, healthcare professionals’ time, or hospitalisation) and direct nonmedical costs (e.g. for transportation, food, family care, home aides), indirect costs (such as lost wages due to morbidity), or income forgone (owing to premature death), intangible costs (such as pain and suffering, inconvenience, grief), and opportunity costs (such as lost opportunity, forgone revenue) (Trask 2011).
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Glossary
- BfArM
-
Bundesinstitut für Arzneimittel und Medizinprodukte (Germany)
- CFR
-
Code of federal regulations (USA)
- CTD
-
Common technical document
- CAMA
-
Community application for marketing authorisation
- CHMP
-
Committee for medicinal products for human use (EMA)
- EMA
-
European Medicines Agency (until 2009: EMEA)
- FDA
-
U.S. Food and Drug Administration
- GCP
-
Good clinical practice (also known as current good clinical practice, cGCP)
- GLP
-
Good laboratory practice
- GMP
-
Good manufacturing practice
- HAS
-
Haute Autorité de Santé
- ICH
-
International Conference on Harmonisation
- IMPD
-
Investigational medicinal product dossier (EMA)
- IND
-
Investigational new drug (USA)
- INDA
-
Investigational new drug (IND) application (USA)
- IQWiG
-
Institute for Quality and Efficiency in Healthcare (Germany)
- IRB
-
Institutional Review Board/ethical review board (see subsection)
- MEB
-
Medicines Evaluation Board (The Netherlands)
- MHRA
-
Medicines and Healthcare Products Regulatory Agency (UK)
- MPA
-
Medical Products Agency (Sweden)
- NDA
-
New drug application to FDA (USA)
- NICE
-
National Institute for Health and Clinical Excellence
- NPV
-
Net present value
- SPC/SmPC
-
Summary of Product Characteristics (EMA)
- SPA
-
Special Protocol Assessment (by the FDA, USA)
- QALY
-
Quality Adjusted Life Years
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Cevc, G. (2013). Nanotechnology-Based Therapeutic Product Development and Commercialisation. In: Uchegbu, I., Schätzlein, A., Cheng, W., Lalatsa, A. (eds) Fundamentals of Pharmaceutical Nanoscience. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9164-4_21
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