What are the main obstacles that a new compound must overcome to become a successful marketed medicine? With examples
An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London
Introduction:
Pharmaceutical medicine can be thought of as an area of medical specialty, describing the entire discipline that concerns drugs and pharmaceutics, with considerable overlap into other fields, for example, genomics, molecular biology, engineering, public health and epidemiology (Young & Stonier 2011). Pharmaceutical medicine also encompasses the profession more widely. Trade associations and professional bodies of practitioners are included. Drug Development concerns the specific process of taking a compound of interest and producing a marketable drug from it. This would include drug target identification, lead selection and pre-clinical testing. Within this, sits Clinical Development, which chiefly describes the process of taking a target compound and carrying it through the phases of clinical development (Phase I to IV) and its successful registration for marketing approval by the licencing authorities. The relationship between these areas can be illustrated in the diagram below.
Figure 1 – Diagram to show the relationship between Pharmaceutical Medicine, Drug Development and Clinical Development.
Once a compound has been identified there are significant barriers that need to be overcome for it to progress through drug development until it can be granted regulatory approval and then, to become a successfully marketed medicine. I will illustrate some of these obstacles using the example of simvastatin.
Cost will perhaps be the biggest barrier to drug development, but I will not be focussing on this for the rest of this assignment. The process of developing and successfully marketing a new drug can easily cost over £1b. In many cases, that can be inhibitory (FPM nd).
Organisational Barriers:
Due to the significant investment drug development requirements, there are often organisational barriers that must be overcome to finance the continuance of a drug through its development. For example, in GSK, the Global Safety Board must be presented with data from pre-clinical trials and approve the progression of this drug into the clinical setting. Equally, analysis must be carried out on the level of development in which competing drugs are in both internally - organisational resources are not unlimited and externally - market competition (GSK nd). While this is an interesting barrier to discuss, it is not within the scope of this assignment to discuss this further.
Drug Development:
During drug development, compounds of interest must be identified and optimised for their use. This takes place prior to clinical studies (Han et al. 2017). Following compound identification, they are tested for the Mode of Action (MoA), specificity and efficacy, these ‘lead compounds’ are most often identified through experimentation or computer screening that utilises already elucidated MoA and drug targets. (Kaehler et al. 2018). Lead compounds are further tested for their specificity, safety and MoA both in-vitro and in-silico. Often a range of compounds will be identified with similar MoA, each having been optimised to ensure negative pharmacokinetic (PK) properties are minimised. (Huber 2005).
Pre-clinical studies determine the toxicity, safety and stability of these drug candidates. Animal models are used to establish the likely effects in humans. Provided the drug candidate successfully demonstrates its PK, marketing authorisation is sought for clinical trials. (Loscher et al. 2013). Figure 2 shows a process overview.
Figure 2 – Diagram to show process of drug development up to the Preclinical stage (Image adapted from Katalin 2010).
In the case of simvastatin, chemists altered the structure of the existing drug, lovastatin, by adding a side-chain methyl group, making simvastatin an analogue. This meant that much of the pharmacology and biochemistry was already known (Hajar 2011).
There are significant issues with the reliance on animal models, aside from the ethical considerations. Animal systems do not always work in analogous ways to human systems. Disease-specific critical disparities may also exist, and the level of control utilised in these studies can be looser than that of studies involving human participants (Van der Worp et al. 2010). Further end-point measures should be relevant to patient outcomes. In the case of statins, all-cause mortality and Quality of Life were the primary end points. This is not considered to be best practise (Thompson & Temple 2001).
Drug Registration:
To register drugs for marketing approval, studies demonstrate the Proof of Concept (PoC), Proof of Mechanism (PoM) and Proof of Pharmacology (PoP). Large volumes of data must demonstrate these as well as, the safety of the drugs before they can be given to human participants. Phase I Trials are the First in Human Trial (FTIH). Here, the experimental drug is tested in a small group of healthy volunteers, to establish the side effects and safe dosages of this drug. Following this Phase II trials are carried out. Phase II trials are the first time the drug in question is tested for its efficacy in patients. Experimental drugs can be compared against placebo or active drugs already on the market (FPM nd). Phase II provides evidence of exposure and its relationship to dose, evidence of target engagement and its relationship to PK and evidence of the target related pharmacodynamic (PD) effect and its relationship to the dose and PK. This final step is a measure of clinical efficacy and is used to determine the dosing procedure for Phase III (Mohs & Grieg 2017). Only around 1/3 of test drugs can successfully pass the Phase II study (Han et al. 2017).
Phase III or, Full Clinical Development (FCD) is where the drug is tested in a larger group of volunteers. The efficacy of the drug is observed in a larger scale and drug safety can be better determined with a larger sample size. It is usual for the experimental drug to be tested against a drug that has established use in treating the condition. For marketing approval to be granted, a drug will require 2 studies with pivotal results. All safety and efficacy data along with data from all trials must be compiled in the Common Technical Document for review by the regulatory bodies. Figure 3 shows a comparison of the stages involved in the development of new drugs.
Figure 3 – Table to show the drug development process (Adapted from FPM nd).
In the case of simvastatin, statins were a generally new class of drugs, and many adverse effects were yet to be identified, despite receiving regulatory approval. This shows that the regulatory process is not fool-proof and drugs require extensive monitoring and treating post-approval to ensure patient safety and drug efficacy (Schmidt et al 1994, Hippisley-Cox & Coupland 2010).
Attrition rates throughout the drug development process are significant (see figure 4). Drugs may not progress through to the next phases as a result of data collection in toxicology, PK, PD, efficacy to name just a few barriers.
Figure 4 – Graph to show attrition rates from 812 small-molecule drug studies from a range of industry leaders (Adapted from Waring et al 2015).
Payer Approval:
Following regulatory approval, drugs must be successfully marketed to recoup the expenditure of the development companies. Aside from intellectual property challenges, the drug will seek reimbursement from agencies such as The National Institute for Health and Care Excellence (NICE) and Private Insurance Companies.
If the drug can demonstrate sufficient economic benefit to the NHS, it may receive approval from NICE. In this case, the drug should generate enough revenue to be considered successfully marketed. If it is unable to demonstrate the economic benefit to the NHS, it will have to rely on private medical insurance companies to purchase it (NICE nd). Just because a medicine has received marketing authorisation, does not necessarily mean that it will be purchased and be successful on the open market.
Pharmaceutical companies must consider the competitive environment of the market they wish to enter, the therapeutic competition, generic competition as well as public policy considerations which will all impact on the drugs marketability and the chance of generating a profit (Dickson & Gagnon 2004). Having said that, statins are an extremely successfully market medicine yet significant literature questions their overall effectiveness. One review succinctly states “The case for statin drugs..has not been made.” In this case, payer approval over efficacy has been the driving force of their success. As a reference point Simvastatin’s annual US prescription peaked at 107.26 million in 2011 (Clincal 2018).
References:
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An assignment by: Darren Wogman MSc. Completed as part of Pharmaceutical Medicine MSc at King's College London