Challenges in the Pharmaceutical Industry/Development Process
How are medications developed?
The development of a medicines or medical devices is a highly complicated and costly process. The most important steps will be briefly outlined here /1/.
In the first step the potential active ingredients will be synthesized. Modern high-throughput facilities manufacture up to 300,000 substances per day. A fraction of those substances show positive effects, and are then identified as “hit-substances.” These substances are starting points for the development of better substances, and are not ready to be used for the treatment of patients. The molecule will be chemically modified until a compatible active ingredient is found.
In the pre-clinical development the active ingredient will be extensively reviewed and chemically and physically characterized. Furthermore, the substance will be reviewed toxicologically and tested to see if the drug has adverse affects such as causing damage to embryos, triggering cancer, or inducing changes in genetic make-up.
When an active ingredient candidate has passed all pre-clinical tests it can be applied to humans. The clinical studies will be divided in to three phases:
- Phase I – Trial with few healthy subjects
- Phase II – Trail with few sick subjects
- Phase III – Trial with many sick subjects
Afterwards, when the results are good, the medication can be considered for approval /1/.
What are the documentation requirements?
The documentation requirements are divided in to three sections – pre-clinical research, clinical research, and manufacturing. For this there are the following rules and standards:
- Good laboratory practice (GLP) – pre-clinical research
- Good clinical practice (GCP) – clinical research
- Good manufacturing practice (GMP) – manufacturing
The GLP is a guideline and provides a formal framework for the safety tests of a chemical product. The following aspects are in the foreground /2/:
- How can laboratory testing be planned?
- What conditions must be given for laboratory testing?
- How will the organizational process look?
- How will laboratory testing be recorded?
- How and to whom will it be reported?
The GCP identifies internationally recognized and ethnically and scientifically constructed rules for the execution of clinical studies. At the center are the protection of study participants, their informed consent, and the quality of the study results /3/. In Germany, clinical studies must be approved by the Paul-Ehrlich-Institute (Federal Institute for Vaccines and Biomedical Products) /4/. Some of the most important documents for the GCP documentation are /5/:
- Test plan
- Financing of the study
- Verification of insurance
- Resume/qualification of the tester
- Randomization list
- Shipping documents of the test substance
- Medical/ technical tests and laboratory procedure
The GMP describes standard procedures to ensure quality in the area of manufacturing. Medical products, drugs, active ingredients used in medicine, as well as food products are all included. The following components comprise the GMP guidelines /6/:
- Quality management
- Room and furnishings/equipment
- Complaints and product recall
- Special test procedures for drug groups (for example liquid and part-liquid dosage forms, aerosols, application of ionized radiation, and much more)
What legal requirements must be fulfilled?
The GxP Regulations originated in the USA, represented by the Food and Drug Administration (FDA). The greatest goal of the FDA is to protect and maintain the health of the population and to prevent the manipulation of studies. The FDA oversees the following areas /7/:
- Human and animal medicine
- Biological and biotechnological medicines
- Radiation-emitting and medical devices
- Food products
The FDA inspects all pharmaceutical manufacturers that produce approved medications as well as the facilities that are required for the production of the medicines, drugs, and medical devices.
Many of these formalities have also been put in place in other countries as law. The requirements for participating countries have been stated by the Organization for Economic Cooperation and Development (OECD). The member countries of the OECD are required to monitor compliance with the basic principles of the GLP in test facilities.
The FDA-based GCP rules are manifested in Germany through the GCP Act. The act regulates in detail the approval and execution of clinical studies involving medicines used on humans /8/.
The GMP is understood as guidelines for the quality insurance of manufacturing processes and surroundings in the production of drugs and active ingredients, but also in cosmetics and food products. The according guidelines for the medicine area are specified by the European Commission, and represented by the Pharmaceutical Inspection Co-Operation Scheme (PIC/S), the FDA, as well as on a global level through the “International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use” (ICH) /9/.
What happens when the regulations are not complied with?
Scenario: Temporal shift
Until a medicine is ready for the market it costs on average 1 billion euros. The medicine Xarelto (a blood thinner) manufactured by the company Bayer AG costs more than 2 billion Euros. The necessary patents generally last 20 years. The development lasts 10 years and the market launch 2 years. There is therefore 8 years remaining to re-earn the investments and generate a profit.
One year delay
When the necessary documents are not acquired in a timely manner and the market launch of the medicine must therefore be delayed, the profit of 800,000,000 Euros would be missing, and matter would be made worse by the running yearly cost of 166,666,667 Euros. This yields a loss of 966,666,667 Euros. In addition would come the damage to image that cannot be quantified. The damage to image can also negatively affect the popularity and demand.
Scenario: Sampling inspection
Sampling inspection can become a problem for the pharmaceutical groups when the necessary documents are not acquired in a timely manner, or when the acquisition makes great demands for time and money. In the worse case documents that should have been printed in paper form would be untraceable and the tests would have to be re-executed.
When the tests last half a year this leads to a drop in sales from 400,000,000 Euros, in addition to the running costs that amount to 80,000,000 Euros. With this comes the loss of 480,000,000 Euros with the added momentous damage to image.
Scenario: Medicine has (for example) deadly side effects
Assume a medicine must be recalled from the market because (for example) unknown side effects have appeared. If the company is not able to prove that it has complied with its documentation requirements in the development phase, this could mean a loss in the billions.
In this case the company would suffer a loss in the in the amount of the development costs at 1,500,000,000 Euros. Additionally, they would be missing profit amounting to 4,800,000,000 Euros. Unobserved remains additional potential fines that they would need to pay to the victims or plaintiffs. These totals are usually negotiated in millions. For example, the drugmaker GlaxoSmithKline reached a consensus with plaintiffs totaling 460 Million USD, because the relationship between use and risk of the medication “Aviada” was classified as questionable.
The penalty for violations of the GxP guidelines is carried out mildly. Next to /13/, which imposes a 3-month prison sentence, there are no penalties. In /14/ it is written that violations against good scientific practice, such as the falsification of entire studies, will not be punished. Generally falsifiers are able to continue in their professions without further ado.
Concrete Case Example
In the past in some Indian transport service companies there has been diverse GMP findings that have lead to bans on imports and temporary suspensions of approval. European and American monitoring authorities ascertained that the affected companies had repeatedly implemented non-conforming GMP guidelines since 2006. These anomalies appeared especially in the documentation, for instance through the manipulation of data. There were also shortfalls in the GMP-conforming equipment and maintenance of machines and manufacturing sites /10-12/.
The following GCP violation caused quite a stir: After the French approval administration found considerable shortcoming in the implementation of new bioequivalence studies of CRO GVK Biosciences in May 2014, the validity of the data in all studies by the company came into question. In the criticized electrocardiogram (EKG) study between 2008 and 2014 the CRO claimed the EKG of one person to be the EKG of all study participants, and thus violated the GCP. The European approval administration (European Medicines Agency, EMA) reviewed over 1,000 medicines that were tested by GVK Bio. For 700 of these medications the EMA recommended a suspension of approval until new clinical data were available /10/.
Steve Eaton of Britain was an employee at the contract research organization “Aptuit” and had sugarcoated data regarding the effectiveness of cancer medications. The substances he had tested showed better effectiveness than really was the case. He was the first person in England since 1996 who was convicted to a 3-month prison sentence under the effectively tightened GLP law /13/.
What is the condition of IT?
How will the procedures be handled at present?
In current systems the data will be saved on local hard disks, on central servers, or in paper form. Central servers mirror hard disks, so that the data are on hand twice.
Where are the weaknesses?
The classic memory techniques are not prepared to save the data in a read-only format over a long period of time. In the paper version the documents can be lost, for example, if a disaster were to occur. Furthermore, the ink could be smudged, making the document unreadable. The local hard disks on the measuring computers are not secure in themselves, since the lifespan of a hard disk is always limited. Also simultaneous saving in two servers is not secure. A technical defect can affect both sets of equipment. For example a fire, disaster, sabotage, or natural disaster could destroy the servers. This is an essential critique of such central data bank solutions.
Functional principle of a blockchain
What are advantages of the blockchain?
A blockchain is a data bank with two primary characteristics. On the one hand, because of a very elaborate encryption procedure (the hash function), it can be considered secure from tampering. On the other hand, many copies are distributed throughout the overall data bank, in which 51% of all instances must be changed in order to successfully forge a data bank entry.
The core units of the blockchain are the transactions. This can be a bank transfer, a contract, or a certificate. At a certain point in time the transactions will be gathered and grouped in to one block. A further important perspective is the decentralized nature of the blockchain. In a classic databank if the server fails, the data bank can no longer be used. With a blockchain in case one part of the nodes fails, the remaining nodes can be used further.
With today’s computer technology billions must be invested in order to tamper with just one single unit in a blockchain. This is completely uneconomical and thus leads to a higher lever of tamper security for the blockchain.
What cost savings arise?
The read-only format saving of GxP relevant data is a key factor in the survival of researching pharmaceutical companies. A documentation mistake in this complex development process can lead to the refusal or suspension of an approval. In the best case the studies must then be repeated, incurring costs equal to 10 % of the overall development. The damage would amount to an assumed cost of 2 billion Euros in addition to the cost of the delayed launch amounting to 200 million Euros. The risk also exists that other firms could surpass the development, which would result in the complete loss of the invested money. The GxP regulations state that no improper investigation has taken place. Improper documentation can entail enormous economic damage und endanger the survival of the company.
In contrast are the costs for the implementation of a blockchain. This is also not free of charge, since the costs of transactions and mining must be paid. The mining process, in which the block is constructed and encrypted, expends a large amount of energy. But the costs of the construction and operation of a tamper-proof blockchain for the pharmaceutical industry are nevertheless unlikely to exceed a single digit million amount. The potential investment would be written off in a short period of time.
The GxP regulations are an important and effective tool for guaranteeing quality assurance in the area of medicines and medical products. Thus, rules exist for the preclinical (GLP), clinical (GCP) and manufacturing practices (GMP). An import point to consider is the tamper-proof saving of accumulated data, which is the basis for an approval of a medicine. The current storage technologies do not suffice for the need for manipulation and loss security. Normally data are saved twice on a central ad vulnerable data bank server. To remedy this situation, blockchain technology can be considered tamper-proof because of its extensive encryption, distribution across a network, and decentralized nature. It can be assumed that blockchain saving technology will be implemented in the pharmaceutical and chemical industries.
/4/ Paul Ehrlich Institut (PEI)
/5/ ICH GCP
/11/ Pharma Fakten
/14/ Zentrum der Gesundheit
Published by: R & D faizod, Dresden, Dr. Thomas Kaltofen