Drug Development

A question-based process

Rajendra Talele,  Head of Clinical Development Services Accutest Research Laboratories Pvt Ltd, India

Drug development is a complex, time consuming and expensive process involving numerous stakeholders, activities and regulatory authorities. Broadly it can be classified in six steps, starting from identification of lead molecule till submission of reports for marketing authorisation. This process evolved and technology has changed over development in last two decades.

1. With over two decades of experience within the realm of Drug Development behind you, what are the milestones of your career journey that you would like to share with us?

Last two decades was really wonderful and exciting journey working in drug development industry. Though I cannot claim, but have experienced almost entire process of drug development together in my professional career and college days. My experience goes from the first step of identification of lead and synthesis of a drug till the last stage of submission of documents to regulatory authorities for marketing approval of a drug in the drug development process.

The drug development is a complicated process involving various activities. On a broader level we can categorise these activities in six steps: (1) identification of a lead and target for new chemical entity (NCE), (2) synthesis of the identified NCE, (3) developing a suitable formulation, (4) conducting pre-clinical and toxicology studies of developed formulation, (5) clinical study and last one is (6) submitting data to regulatory authorities for approval to market the drug in prescribed format. I studied Pharmacy, specialised in Pharmaceutical Chemistry; hence in my post-graduation dissertation I experienced first two steps of drug development. I synthesised a non-opoid analgesic compound based on fentanyl, requiring 14 steps synthesis. That was my first experience of drug development process. Being a Pharmacy student I theoretically studied all six steps of drug development, but was not sure whether will get a chance to experience them. Luckily, after completion of post graduation, and at the start of my professional career, I got an opportunity to work in Formulation and Development (F&D). After F&D I joined Clinical Research and since two decades I am conducting trials, compiling data, and submitting to Regulatory Authorities for marketing approval. So all in all after completing more than two decades, I experienced all the six steps of drug development.

In F&D department, which I joined immediately after completion of my post graduates I experienced third step of drug development, i.e. how to develop a formulation. I was handling solid dosage forms, where I learned Physio-chemical characteristic, compatibility studies of drug powder with other ingredients, the stability studies of developed formulation. It was fun and exciting working with powders and making a stable solid oral dosage forms. After 4 years of experience in F&D, I moved to emerging stream and jumped into Clinical Research. It was in 1996 when I took a decision to move to clinical research when this industry was nascent in India. In those days we did not have many options  as only handful of companies was doing clinical research. I remember my classmates questioning and giggling at my decision and were laughing at me. However, I was determined. The clinical trial experience helped me to understand remaining steps in drug development. I understood different pre-clinical studies, their importance and also testing methodology and how drug acts on your body, as well as how body reacts to the drug. This experience covered the next two steps, i.e. steps four and five of drug development. The last step of documentation any way was part of my clinical trial activities; where last step of trial is usually compilation of the documents in prescribed forms by regulators and then submission. In clinical research I monitored, managed and handled number of clinical studies for New Chemical Entities (NCEs); New Biological Entities (NBEs), or for modified Generic compounds. Therefore, as said earlier, I effectively experienced all the steps of drug development, and thoroughly enjoyed every steps of drug development.

In last two decades, I witnessed number of technological and regulatory changes in this process. Every change in this industry was a milestone in itself. In this period the research has moved from person dependent to process dependent; from manual methods to the technological driven and from local to global. Technology literally changed the entire drug development industry, such as introduction of Computer Aided Drug Designing (CADD) systems for identification of lead molecules; new method and new technique for formulation, sophisticated instruments for analysis, use of high speed internet, highly developed communication system from manual printed reports or letters to electronic submissions. These changes brought a sense of confidence and transparency in the entire drug development process. These are all milestones in this process which I witnessed in last two decade.

On the other hand Regulators also changed their way of working, across the globe they become more vigilant, stricter in scrutinising the clinical trial reports and became more technology savvy. Regulators also adopted new methods and new technique to evaluate the result of clinical studies.

All these changes are made the drug research more attractive and accurate, but on the other side these changes also increased overall cost for development to many folds.

2. Being an integral part of a Contract Research Organisation like Accutest, in your opinion, how much of an impact does research make on the functional output of a medication?

Research has great impact on functional output of the medication, research provides answers to the question whether medication is a safe  and efficacious for use or not. Research has both positive and negative impact in the drug development process. Many times due to poor efficacy or safety the development of new discovery has to stop in between and developing Pharmaceutical company suffers a big loss; but on the other side you may get some wonderful discoveries or accidental discoveries  during research that may result in block buster!

Ancient civilisations relied on medical observation to identify herbs, drugs and therapies that worked, but beginning in the early twentieth century, therapeutic reformers in various countries including United States began to develop the concept of the "well-controlled" therapeutic drug trial, which was through research such as laboratory analysis and clinical studies.

In general, medication is a foreign material for the body, and whenever any foreign material enters in the body, it reacts to that material and tries to defend itself by different means.  Excess consumption of any foreign material is also harmful; hence it is important to know safety level for consumption of such material. Research helps in understanding safety level of medication and gives us an idea about the maximum tolerated dose or level of any particular medication.

Medication should not only be safe, but should be effective, and effectiveness of any medication is evidenced through different experiments. A worldwide drug disaster in 1961 resulted in the enactment of the 1962 Drug Amendments of US FDA, which explicitly stated that the US FDA would rely on scientific testing and that new drug approvals would be based not only upon proof of safety, but also on "substantial evidence" of a drug's efficacy, i.e. the impact of a drug in a clinical trial setting. To know the efficacy of the medication, various experiments are carried out to find the therapeutic window of the medication based on their efficacy. Hence, research is only the way we prove medication is the safe and efficacious.

Moreover, as an impact of research many newly synthesised / discovered molecules are dropped in the process of development. It is a known fact that when 10,000 molecules are synthesised in the lab to test for the hypothesis, only few of them make it to clinical trials and couple could complete entire process till submission to regulatory authority for marketing approval. The rest thousands may get dropped due to either poor safety or efficacy during the preclinical or clinical trial stages. I remember in 1997, when we were part of one of the global Phase III oncology studies, our study was called off midway due to poor response of the drug. It was a Phase III study enrolling breast cancer patients; and, in interim analysis it was observed that the newly developed entity was not showing any significant benefit to the patients when compared with placebo. The product was failing in efficacy, and hence, sponsor decided to call off the study. This was identified or noticed only because of research. Every year number of studies are failing because of poor safety or efficacy, which can be identified only through research.

Research also gives accidental discoveries turning new entity into a blockbuster. The classical example of this is Sildenafil (Viagra (R)) . Initially, Pfizer started life of this drug as UK92480, a new treatment for angina. Pfizer was looking for a new medication that would relax these blood vessels; however its trial results  in people were disappointing. Pfizer was about to abandon further trials when  few volunteers of the trial started coming back and reporting an unusual side effect: which was penile erections. This gave  new direction to Pfizer scientists and they started experimenting use of sildenafil on relaxation of penile blood vessels. In these experiments scientists found restoration of the erectile response, which they confirmed in clinical trials. Before the launch of Viagra, which was in 1998 there was no oral treatment for erectile dysfunction; and available options were either injections or a fairly gruesome prosthetic implant, but Viagra provided oral option. And, now, Viagra is one of the most prescribed drugs in the world, thanks to a failed angina treatment. This is a positive impact of research.

3. Kindly take us through the formative stages of a new medication, for instance, at the onset of a clinical study conducted by you. What course of action is taken once the concept of an introduced drug is proven?

Once the concept of the drug is proven in Phase I or Phase II astudies, that means the drug has shown expected response in pre-clinical, toxicological and early phases of the studies, indicating the drug is now ready to take bigger leap in clinical studies.  Often Proof-of-Concept (PoC) studies give idea on pharmacokinetic and pharmacodynamic pattern / behaviour of the drug molecule; it also answers the question of selection of dose for higher clinical studies. Therefore, the subsequent step after completing PoC is Phase II b, if required, and then a big Phase III trial involving investigational sites from various countries.

The planning of Phase II b or Phase III study is initiated well in advance.The documentation part, conducting feasibility, and decision on selection of the countries are all kept ready before getting results of a Phase II study are in. During this period, the pharmaceutical company also collects information from different CROs on their capabilities, with regard to experience, resources, and global reach. This is the Request for Information (RFI) stage. List of eligible CROs are identified well in advance for further phase(s) of the trial. This helps to reduce overall timeline for Phase III study and then submission to authorities. On receipt of favorable results of Phase II a study, the pharmaceutical company sends a Request for Proposal (RFP) to already identified CRO. At the RFP stage, the pharmaceutical company tries to select BEST FIT solution for their study. This selection process and decision depends on various factors and differs from company to company. The final decision on selected CRO is intimated through the Letter of Authorisation issued in the name of the CRO.

The association with this newly identified partnered CRO starts with a kick -off meeting, where project teams from both side meet face-to-face and discuss operational points as well as timelines and expectations. The kick-off meeting is crucial, as the entire road map for execution of the project is defined in this meeting. After getting a clear understanding of what is expected and when it is expected, the CRO plans the study, and then exchange of relevant documents starts between both the sides.

The start up phase / activities for the project initiated with the first step, i.e. development of study protocol or protocol synopsis (if not available), followed by identification of investigational sites in the countries, followed by . detailed feasibility of the project, performed Site Selection visits and record the observations and come to the realistic execution plan. All of this information is shared with the sponsor Pharmaceutical Company as per contractual obligation in defined frequency and methods. The selected sites are conveyed about their selection in the study, and then collection of Essential document process initiated. As a parallel process to be of collection of essential documents, a separate team at CRO starts preparing applications for Regulatory Authority (RA) and Institutional Review Board (IRB) or Institutional Ethics Committee (IEC). After collection of required essential documents and application, and depending on requirements for that country, the CRO or sponsor Pharmaceutical Company or the Principal Investigator apply to obtain approval from respective RA and IRB/IEC for conducting the planned study in that country. In many countries this application process to RA and IRB/IEC is parallel; whereas in some of the cases it is sequential. In some countries RA demands an approval from IRB before considering the application for processing and in some other countries IRB / IEC demands an approval from RA to give their opinion. After receipt of the respective approvals, the drugs get imported and sites are initiated. Meanwhile, depending on the complexity of the study and requirement of the study, the Investigators’ meeting may take place. This completes the start up activities of the project. This process is followed by Active Phase of the trials.

Active Phase of the project starts from enrolling the eligible patients. Once the sites are initiated, investigators are allowed to screen and enroll suitable and eligible patients in the study after taking valid written consent from each patient. A protocol process is followed for screening and enrolment of the patients in the study. During the process of enrolment and treatment of patients as per the protocol, CRO monitors (CRAs) either visit the hospital, or do remote monitoring or perform risk-based monitoring activities, as specified in the contract to check quality and compliance of the investigational sites. Often the sponsor pharmaceutical company also carries out the audit of these sites making sure that the study is conducted according to protocol and regulatory requirements. During this entire process of Active Phase data collection process takes place, which is either through electronic data capture technique, or through a manual paper recording system. The collected data is transferred to the Data Management team of the CRO or sponsored pharmaceutical company or third party agency. The data from patients is compiled and collated in the already developed database using various software; queries, if any, are fired to correct the data. Once entire study is over, i.e. all patients get enrolled and treated as per the protocol, and data for all patients getsstored in the database, the data base is called as locked. Once the database is locked, the monitors start closing the investigational sites. This ends the Active phase of the trial. Now the trial enters the last phase i.e. close out phase.

In this phase, the locked data base is transferred for statistical analysis or extracting various tables, listings and graphs. On completion of the statistical analysis, the data is then moved to medical writers for writing the final clinical study report. After completion of this report, the sponsor pharmaceutical company files the report to the regulatory authority.

During this entire process the sponsor pharmaceutical company is involved at various stages and interacts with the CRO as and when required.

4. Considering the dynamism in federal and government policies as well as regulations, how challenging is it to procure permissions in a compliant manner?

Federal and government policies are in favour of drug research if it is conducted in ethical and regulatory complained manner. All governments in the world seek new, effective and safe medicines for their country, and as a result several governments proactively came up with various initiatives to facilitate this drug development process. Almost all the governments in the world have a certain timeframe in approving application for the various processes involved in drug development. However, sometimes these set timelines may get altered due to different reasons. Some of them are: incomplete application, inadequate documentation, or some time unavailability of competent staff at government offices. Overall the process is not a complicated process and the permission is obtained easily from federal and government agencies.

5. While developing a drug, what is of a more critical importance: the compound’s favourable effect in terms of the disease or its clinical pathophysiology?

It is difficult to answer and differentiate the critical importance of drug development. Whether a drug should show excellent results, i.e. show great efficacy, or should have results in clinical pathophysiology depends on targeted disease. If the drug is developed as an anti-infective or anti-tuberculosis or anti-malarial, then the critical factor is to show greater efficacy. However, if the drug is developed to treat cancer or to treat neurological disorders such as Parkinson’s or Alzheimer’s disease, then having significant changes in pathophysiology would be the critical. No patient suffering from an infection would like changing only pathophysiology and not getting cured from infection. At the same time it is really difficult or nearly impossible to cure diseases such as cancer if detected at last stage; and patients suffering from such diseases will be happy to change their pathophysiological conditions.

6. Are there any pre-emptive measures taken to mitigate the possibility of a poor drug response which may find fault with the clinical analysis?

If it would have, then drug development would have been a smooth ride and less expensive, but this is not the case. Drug development remains complex and becoming more and more expensive. But a number of different ways were tried to reduce unnecessary drug exposure of patients and also reducing overall cost of development. One of the ideas is conducting smaller studies that expose fewer patients to understand the behaviour of a new drug early in development. However, it is not necessary that the behaviour observed in one set of patients will repeat when same drug and conditions are exposed to larger group. Therefore, it is difficult to suggest any pre-emptive measures to mitigate the risk. There are concept of ‘adaptive trial design’ or Phase Zero trials, pilot studies or pivotal studies well in discussion and in use, but again at a larger level the results may be different. There are numerous examples indicating a promising drug candidate failing when exposed to the larger patient population. Scientists are working on pre-emptive measures to mitigate the possibilities of poor drug response, but I have not heard of any major break through in this direction.

7. Would you say that the clinical evaluation of drugs is a question-based process?

Yes indeed. The entire clinical evaluation process is developed to satisfy specific objectives — either single or multiple — for the newly developed molecule. And these objectives are based on certain hypothesises that are either identified in early development or targeted. Hypotheses are questions, and you have to prove the set hypothesis right or wrong through experiments. Clinical evaluation is one type of experiment; and in this experiment the researchers try to satisfy their hypothesis. In other words the clinical evaluation process is nothing but to find answer or answers for pre-defined question or questions.

8. What are the challenges faced in ensuring utmost safety and confidentiality when it comes to documentation and recording clinical research procedures? Is every piece of information chronicled on a study stored for potential reference?

Not really. Safety and confidentiality of documents are important in clinical trials, but at the end of the study when results are out the drug developers provide all this information to the authorities. Often developers publish articles on their discovery and during this publication certain confidential information about the study is shared which then comes into public domain. Moreover, the molecule under development is anyway under patent protection which means a large amount of information is already in public domain. Therefore, the confidentiality is protected in one or other way. The most confidential part of the clinical trial process is the information relating to the enrolled patients. By ICH GCP guidelines, we are not allowed to discuss patient information openly and therefore in clinical research very minimal information is collected from participating patients beside the study-relevant details. The challenges to protect this patient confidentiality are numerous, but researchers do take precautions, such as patient names do not get reflected anywhere on any document; the records of participating patients are revealed to only the study personnels. If an outsider wants to review patient data then the confidential part is required to black out. According to the international guidelines, no one except an investigator can see participating patient details.

9. Finally, as the Head of Clinical Department at Accutest Global, what would you advise pharmaceutical companies who are swathed in controversial conferences about drug toxicology and counterfeiting?

Drug toxicology and counterfeiting are really two major issues facing the pharmaceutical industry. Toxicology is nothing but the safety of the drug. Often, the toxic effects of a drug are observed after repetitive use of medicine for a longer period. Clinical trials are certainly used to identify any untoward effects of a drug on the body; however, these trials have limitations, such as, either they are for shorter time or they expose limited number of patients in the study to satisfy a statistically significant result. Therefore, to understand the prolong side effects of the drug one approach is to keep exposing animals for longer period while clinical trials are on-going. Some of the companies are doing this, but if such practices is made mandatory in toxicological studies, then it will help minimise issues arising afterword due to toxicity. Counterfeiting is a vast and burning issue; however, general public education, creating awareness among the people regarding safe use of drugs, its side effects, its importance towards our health, harm caused by counterfeit medicines, etc. are the only remedies I can suggest here to control counterfeit.

Author Bio

Rajendra Talele