Introduction

The drug development process for pharmaceuticals and biologics is strictly regulated across the globe by different regulatory authorities.

The process of drug development comprises of following stages

Stage 1:- Target and lead identification, in-vitro testing of tissues, plasma, etc. for bench testing of the product.

Stage 2:- Non-clinical testing in live animals (in-vivo testing).

Stage 3:- Filing of IND (Investigational new drug) to get approval to test on humans. If approved, the clinical trial begins with Phase I clinical trials which are also known as first in human studies.

Stage 4:- Filing of NDA (New Drug Application) after successful Phase II trial completion. If approved, the clinical trial begins for Phase III.

Step 5:- Submission of the document to request approval to market the product after a successful Phase III clinical trial.

Phase I Clinical Trials

Phase I studies are designed to investigate the safety/ tolerability i.e. identifying Maximum Tolerable Dose (MTD), pharmacokinetics, and pharmacodynamics of an investigational drug in humans. Right Drug to the Right Patient with Right Dose at the Right Time is the ultimate goal or objective of Phase 1 Clinical Trials.

To achieve the objective of Phase I studies, scientists carry out studies in the following sections:-

• • Clinical Pharmacology of the Drug

It involves studies like First-in-Human, SAD and MAD PK studies, Healthy vs Patient Population, ADME (Mass Balance), Specific population, Drug Interaction, Population PK, Biomarkers, Pharmacogenomics, and other special safety studies

• • Exposure-response (PK/PD) of the drug

It involves dose selection and optimization, efficacy vs. safety, and clinical trial simulation.

• • Biopharmaceutics of the Drug

It involves BA/BE and Food Effect studies

• • Invitro studies carried out with the drug

It involves protein binding, Blood to Plasma Partitioning, Invitro drug metabolism, transport, and drug interactions.

• • Bio-analytical methods

It involves validating assays and generating performance reports

• • For Biologics, scientists carry out immunogenicity and comparability studies.

This article is all about the ADME studies involved in Phase 1 Clinical Trials.

What is Pharmacokinetics?

Pharmacokinetics is the study that involves the action of the human body on medicines. Absorption, Distribution, Metabolism, and Excretion are the major steps involved when a drug enters human body. Physicochemical properties of the drug, the administration route, intrinsic and extrinsic factors of the subject like diseases, organ dysfunction, concomitant medications, and food are the factors that affect the PK profile of an investigational drug.

Efficacy, Toxicity, C_max, and T_max are some of the important terms that we generally come across in PK studies.

ADME study is also known as mass balance study. ADME studies are important because it helps to determine other clinical investigations that might need to be conducted in support of regulatory approval for a new drug. The ADME is determined by attaching a radioactive isotope (radiolabel), such as carbon 14 (14C) or tritium (3H) to an investigational new drug and following the radiolabel in human subjects.

Human ADME studies are carried out by the sponsor to obtain valuable information about the investigational new drug which includes:

• • Determining the routes of elimination and clearance mechanisms of the drug
• • Identifying metabolites and determining the relative exposure of parent drug and metabolites
• • Confirming that the human metabolite profile is covered by the metabolite profile in animals from toxicology studies

What is the type of study design carried out in ADME studies?

ADME studies are typically single-dose studies with healthy males (4-6 in numbers) at the intended route of administration.

What are the Primary and Secondary Outcome Measures Considered in an ADME study?

The primary outcome measures of ADME studies in Phase 1trials include

• 1) PK Parameters

Maximum observed concentration (Cmax), time to reach maximum observed concentration (Tmax), area under the concentration-time curve from hour 0 to the last measurable concentration (AUC_0-t), area under the concentration-time curve extrapolated to infinity (AUC_0-inf), apparent terminal elimination rate constant apparent terminal elimination half-life (t_1/2), apparent clearance, and apparent volume of distribution.

• 2) Urine and Feces PK Parameters

Amount excreted in urine over the sampling interval, renal clearance (CLR), and the percent excreted in the urine, amount excreted in feces over the sampling interval, and the percent excreted in feces

• 3) Metabolites

Metabolites of [14C]-DRUG MOLECULE and their PK parameters will be identified and calculated as deemed appropriate, based on plasma and urine concentration levels.

The secondary outcome measures involved in Phase 1 Clinical Trials include

• • Signs, symptoms, incidence, and severity of adverse events (AE)

• Abnormalities in clinical laboratory assessments, vital signs, electrocardiograms (ECGs), and physical examinations.

How are ADME studies conducted in Phase 1 trials?

Mass Balance or ADME studies are carried out with male healthy volunteers by administering them with a single dose of the investigational drug labeled with Carbon-14. The cumulative radiolabeled dosage used in these experiments is approximately 50-100 μCi. It is based on the predictions of real tissue exposures from tissue distribution studies performed during preclinical trials involving animals. The volunteers are then kept in the clinical pharmacology unit (CPU) after administration until the radioactivity linked to the radiolabeled drug is quantitatively retrieved in the excreta (thresholds prescribed in the study protocol, normally in the range of 95% total and < 1Bq/ mL in the blood). Blood samples collected during the study are analyzed for the PK properties of the parent medication. The samples collected from this analysis are used in circulation and excrete metabolite profiling.

Conclusion

The human mass balance study is an essential study of the drug development process. ADME is also being carried out in the preclinical stage but the safety and efficacy of the investigational drug can only be validated after determining the absorption, distribution, metabolism, and excretion (ADME) properties of the investigational drug on healthy human volunteers. It can be rightly said that the human ADME (hADME) study provides a correlation between clinical observations and preclinical safety studies. The key objective of the hADME study is to quantify, characterize, and identify drug metabolites present in the systemic circulation.

References

1. 1. Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development, US FDA.
2. 2. What is a Human Mass Balance Study? Accessed at

https://www.nuventra.com/resources/blog/what-is-human-mass-balance-study/

3. 3. Why, When, and How to Conduct ¹⁴C Human Studies. Accessed at

https://www.sgs.pt/~/media/Global/Documents/Technical%20Documents/SGS-Clinical-14C-ADME-Clinical-Trials-EN-09.pdf

 

Advancement in medical sciences has benefited humanity in many ways. However, in the process of conducting clinical trials, incidences of scientific, moral, and ethical misconduct have been unearthed that have shaken up the scientific community and public. This led to the formation of a formal organization in 1979 by the United States (US) namely the “International Ethical Guidelines for Biomedical Research Involving Human Subjects” to protect and safeguard the interests of trial subjects. Following this, many countries drafted their own guidelines for Good Clinical Practices (GCP). However, with increasing number of clinical trials being conducted at sites in multiple countries, it was necessary to have a uniform guideline for conducting clinical trials. This gave rise to the International Conference on Harmonization (ICH)-GCP guidelines in 1996 with the objective of providing a uniform standard that facilitates the acceptance of clinical trial data by the regulatory authorities of the respective countries. Over the course of time, many countries adapted the ICH-GCP guidelines to frame their own guidelines. India too followed suit with the Indian Council of Medical Research (ICMR) introducing the “Ethical Guidelines for Biomedical Research on Human Subjects” that is continuously revised and amended to ensure that clinical trials are conducted with utmost quality, giving priority to the welfare of the subjects involved.1

India – A global destination

India is emerging to be a favorite destination for clinical trials for many international companies due to several factors:

☉  Conducive Regulatory Environment: Internationally harmonized and favorable regulatory processes such as fast track approval of investigational new drugs making the Indian clinical research environment more amenable to conducting clinical trial. Market trends show a compound annual growth rate (CAGR) of approximately 12% (US dollars 987 million) in the Indian clinical trials industry from US dollars 500 million in 2017.1,2,3,4,5

☉  Trained Manpower: Availability of skilled healthcare professionals who are specialists in different therapy areas, well-versed in the English language and who ensure compliance to ICH-GCP guidelines.1,2,3

☉  Technology Infrastructure: World-class technologies in data management and information technology and related services.1,2,3

☉  Patient Pool: Large population who are treatment naïve and have a diverse genetic and ethnic makeup. With India becoming increasingly urbanized and with greater connectivity between the urban and rural areas, it becomes convenient to recruit patients from different geographical areas. In addition, there is a high incidence and prevalence of acute and chronic diseases due to lifestyle changes leading to diseases such as diabetes, cancer, and so on. Such lifestyle-related disorders open up the possibility of conducting more clinical trials in these disease areas.1,2,3,6

☉  Ease of recruitment: In countries such as the US, approximately 86% of the clinical trials fail to recruit the required number of subjects leading to delay of almost a year. This delay costs the sponsor company several million dollars. Some of the reasons for delayed recruitment are unwillingness of patient to participate, stringent safety requirements, and hefty compensation packages. India provides the possibility of recruitment of patients with relative ease with due to increased trial compliance and transparency especially with the recent release of the New Drugs and Clinical Trial Rules 2019 that consists of updated rules and regulations for fast tracking approval of clinical trials. Among countries with fast growing economies, it has been noted that India has a growth rate in recruitment sites of approximately 22.6% with the highest growth rate seen in China (≈36%).1,2,7,8

☉  Competitive costs – Cost effectiveness is a pushing factor for many trials being shifted to India. The cost to develop a new drug is estimated to be almost 50% less than what would be required in the US or in the European Union. 1,2,3

Future of clinical research in India

Specific guidelines are being worked upon by the Central Drugs Standard Control Organization (CDSCO) for stem cell research, biosimilars, and medical devices to protect patients as well as to encourage clinical research and development in the country. After a lull period in the Indian clinical industry before 2015 due to ethical and quality concerns, open communication between sponsor representatives and the regulatory team of CDSCO has helped in reconsidering India once again as a potential global destination for enrolling a diverse population in clinical trials that adhere strictly to ICH-GCP guidelines.6

Sources

1. Das NK and Sil A. Evolution of Ethics in Clinical Research and Ethics Committee. Indian Journal of Dermatology. 2017 Jul-Aug;62(4):373-9

2.Burt T, Sharma P, Dhillon S et al. Clinical Research Environment in India: Challenges and Proposed Solutions. Journal of Clinical Research and Bioethics. 2014;5(6):1-8.

3.Bajpai V. Rise of Clinical Trials Industry in India: An Analysis. Hindawi Publishing Corporation. Review Article. ISRN Public Health. 2013:http://dx.doi.org/10.1155/2013/167059

4.Melissa Fassbender. India poised to become ‘one of the largest clinical trial hub’ says CRO. (2018). https://www.outsourcing-pharma.com/Article/2018/08/13/India-poised-to-become-one-of-the-largest-clinical-trial-hubs-says-CRO?utm_source=copyright&utm_medium=OnSite&utm_campaign=copyright Accessed on May 12, 2015.

5.https://www.medgadget.com/2019/01/india-cro-market-growing-at-an-impressive-cagr-of-12-by-2023-says-recent-study.html Accessed on May 12, 2015.

6.Reconsidering India as a Clinical Trial Location. Pharm-Olam. https://cdn2.hubspot.net/hubfs/4238150/PharmOlam_March2018/PDF/pharm-olam_india_clinical_trials_white_paper_1.pdf?t=1524594556831 Accessed on May 14, 2019.

7.Pathan IK, Nuthakki S, Chandu B et al. Present Scenario Of Clinical Trials In India. International Journal Of Research In Pharmacy And Chemistry. 2012;2(2):ISSN: 2231-2781

8.Luo J, Wu M, & Chen W. Geographical Distribution and Trends of Clinical Trial Recruitment Sites in Developing and Developed Countries. Journal of Health Informatics in Developing Countries. 2017;11(1). http://www.jhidc.org/index.php/jhidc/article/download/157/211

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Veeda through its V-Konnect series interacted with Dr. Susobhan Das and discussed about

“Current outlook of Biosimilar Development”

About the V- Konnect

V-Konnect interview series, is a program to get in touch with specialized industry experts to know their views on opinions on current relevant subject matters.

About Dr Susobhan Das – Founder & CEO at Amthera Life Sciences

Dr. Das is a Founder & CEO of Amthera Life Sciences Pvt. Ltd which is a preclinical stage Biosimilar Drug development company based at Bangalore.

Dr. Das has extensive techno-commercial experiences in early stage Biologics Development. He has 20 years of experience in advanced biotechnology research and Biopharmaceuticals development. He has served as a member of USP Biologics and Biotechnology Expert Panel and also worked as a Director at United States Pharmacopeia, India site. Dr. Das has also worked at
senior management level at Intas Pharmaceuticals developing Biosimilar for global markets.

Dr. Das has worked as member of Expert committee on Biologicals and rDNA Products: Indian Pharmacopeia Commission (IPC); Govt. of India. He has authored research papers which are published in peer-reviewed National and International journals

Transcript.

1. What are the key international developments with respect to EU and
USFDA biosimilar requirements?
A: One key development towards biosimilar acceptance has been the issuance of guidance on “interchangeability” by US-FDA in May this year. This will pave the way for the substitution of one product for the other without a prescriber’s involvement, as is the case for generic small molecule pharmaceuticals. This I believe, is a significant action and will promote competition in the biologic market in the US.

Another development is the issuance of a revised guidance by FDA titled “Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality Considerations” also in May this year. This is the revised version of an earlier guidance titled “Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product,” published on April 30, 2015. FDA says this revision is to reflect on agency’s recommendations on the design and evaluation of comparative
analytical studies intended to support a demonstration that a proposed therapeutic protein product is biosimilar to a reference product and in anticipation that this will provide additional clarity and flexibility for product developers on analytical approaches to evaluating product structure and function.

For Europe, although approval rate of Biosimilars are much higher that the US, uptake of biosimilars are somewhat country specific, with the large EU5 countries still do not have interchangeability options. However, payers have significantly employing various tools which may lead to higher biosimilar uptake. For example introduction of prescribing target i.e. prescribing biosimilars to a predetermined percentage of patients. NHS of UK introduced biosimilar adoption framework with the idea that switching of patients to a
biosimilar may be inserted into clinical practice with incentive offerings for staff to offset switc hing costs. This year in May, NHS has published a document titled “what is a biosimilar medicine” for clinical and nonclinical stakeholders about the role of biosimilars in the healthcare system. The document explains among many others aspects, on the overall savings from Biosimilars as well as suggest that a prescriber can switch from a reference to a biosimilar product. However, switching at the pharmacy level is still not permitted without the consent of the prescriber as of now.

2. What are the main attributes for higher market approvals of Biosimilars in Europe compared to the US?
A: The first biosimilar, Zarxio, approved in the United States only in 2015 whereas Omnitrope, another biosimilar was approved by the European Medicines Agency (EMA) way back in 2006. Since then, the EMA has approved more than 40 biosimilars as of 2019. Essentially this shows that EMA as the pioneering agency to advance biosimilars approval
and uptake for the world. To understand this one may refer the concept paper on the development of a guideline on the comparability of biotechnology-derived products published in 1998 which led to the introduction of a directive in EU legislation with the idea of “similar biological medicinal product” in 2001. Therefore, definition and a legal framework for market authorization for Biosimilars was first introduced in the world by the EU and is monitored and updated on an ongoing basis which is key for larger market approval rate of biosimilars in the EU. By now the EU has already an experience of over a decade of Biosimilar use and established the fact that biosimilars have similar efficacy and safety concerns as that of the reference products and can save a significant portion of healthcare costs. Only three official biosimilars is in the market in the US, although around 15 are approved and their uptake has been slower than anticipated. For example less than 15% for filgrastim biosimilar and 3% for the infliximab biosimilar holds as market share. This is partly due to the lack of pricing incentives from biosimilars as well as more attractive contract offers from the innovator product. A host of other reasons for this slow approvals and uptake could be considerations on overall quality, safety, and clinical efficacy of the biosimilar plus manufacturer reliability (supply without disruptions), reimbursement rates set by insurance companies or commercial payers, and support services for health care professionals and patients. In other words, assurance on the efficacy and safety from the providers as well as less out-of-pocket expenses is key to most US patients. Currently this is yet to happen in the US, although progress has been made to achieve these goals. On the contrary, a range of different policies to generate
pricing pressure, drive adoption, and ultimately yield cost-savings for their healthcare systems have been implemented in the EU countries which somewhat led to higher uptake rate for the biosimilars.

3. What is the scenario of prescribers’ acceptance of biosimilars over the
innovator biological products?
A: In the beginning of biosimilar era, it was the differences between lots in quality characteristics were cited to be reason enough for great concerns on efficacy and safety of the product. From this we have come to a stage where regulatory agencies have formalized acceptable changes of quality characteristics in the “innovator products” with no impact on efficacy and safety. We also have for more than a decade of real world
experiences of biosimilar use with comparable efficacy and safety concerns in the EU. Moreover, we now have the outcome of NOR-SWITCH trial which demonstrated that “switching from infliximab originator to CT-P13 [a biosimilar] was not inferior to continued treatment with infliximab originator”. All of these experiences I believe, has led to higher prescribers’ acceptance of biosimilars over the innovator product given there is incentives attached all through the stakeholders chain (for example for the provider, prescriber, payer and insurer). The EU is clearly way ahead in implementing policies with
the above considerations and will reap benefits hugely in the healthcare cost savings. Although slow, the US has finally initiated action that may eventually allow biosimilars to be interchangeable with the innovator product. First to this idea was the finalization of the guidelines on interchangeability this year in May.

4. What is your opinion on Indian biosimilar industry, whether it attained its
potential or this just the beginning of the journey?
A: Indian biosimilar industry has now been very firmly established with defined
regulatory path and a number of large and medium manufacturers with more than 70 biosimilars approved. India is also the first country to approve a biosimilar monoclonal antibody to Rituximab in 2007 and interestingly without having a published guideline which first appear in the year 2012 and in a revised form in 2016. This approval has tremendously helped the patients to have access to the product with almost half the cost of the innovator product. Interestingly, another mAb, Trastuzumab indicated for HER2 positive breast cancer is now available at almost 65% less than the innovator price, due to the launch of an Indian biosimilar. Moreover, 3 companies from India has biosimilar
products registered in the US, the EU and Japan. This shows the maturation of Indian biosimilar industry as a global player. These facts although very positive, India still has huge gaps in filling up the affordability factor with its very low per capita income populace.

On the contrary, India has very high number of incidences and disease burden in most therapeutic segments such as Cancer, Diabetes, Infections, Arthritis, Blood factor disorders etc. Therefore, affordable and quality biosimilars is a big opportunity for India. However, what is critically needed is a policy framework somewhat similar to that is being followed in the EU which incentivizes all the stakeholders involved with biosimilar use including the insurance sector. Unfortunately, medicine costs in India is largely an out-ofpocket expense and this needs to change very rapidly. Given these policies are implemented, Indian biosimilar industry has tremendous potential to impact healthcare in a significant way.

5. Where does China stand with biosimilar approvals and the regulatory
requirements?
A: This year in February Chinese regulators approved their first biosimilar. A biosimilar Rituximab indicated for non-Hodgkin’s Lymphoma. Although biotherapeutics development in China continue to grow exponentially over the past decade, no biosimilar drug however was approved until 2019. This is primarily because of lack of a national regulatory guidance which was first published in February 2015. This guidance document followed the same principles and requirements consistent to that as formalized by FDA and EMA. Some other changes also happened simultaneously to foster pharmaceutical
approvals and market authorizations such as China Food and Drug Administration (CFDA) is now National Medical Product Administration (NMPA) which falls under the State Administration for Market Regulation (SAMR). The Centre for Drug Evaluation (CDE) which reviews applications under NMPA remains without change in function. China currently has more than 200 biosimilars under clinical development. Interestingly two key recent development in policy setting by NMPA can be seen either as a barrier to biosimilar growth or bring serious competition : One is listing of foreign made drugs for urgent unmet medical needs which can be approved for registration without any clinical trials being conducted in China. 48 such drugs have been listed for public review, out of which 11 are biologic drugs. The second one is reduced or no import cost of new cancer drugs or drugs for hard to treat cancer. Another very interesting development is the Market Authorization Holder [MAH] program implemented by the Chinese regulatory agency as
a pilot program which allows holders of a NMPA biologics approval will have an option to manufacture the drugs on their own or use any contract manufacturer. This policy has given significant boost to the CMO industry inside China and will surely foster growth in the Chinese Biosimilar industry along with new drug development.

6. How switching and interchangeability affect biosimilars access and its
market size?
A: EMA and EU commission defines 3 terms related to biosimilar switching:
interchangeability, switching and automatic substitution. Interchangeability is a general term which includes both switching, when the prescriber decides to use one over another and substitution when this exchange happens at the pharmacy level without the consultation of the prescriber. In the US though FDA designated interchangeability may refer to automatic substitution at the pharmacy. Europe has been at the fore front in terms of interchangeability and currently allow physician guided transitions of biosimilars restricting pharmacy level substitution and this is without any separate or additional
regulatory guideline or drug development criteria. As a result we see a very high uptake of Biosimilars in some select EU countries. Therefore, we may envisage that interchangeability or substitution will surely bring competition as well as uptake and cost savings. Indeed a follow-on-biologic to Lantus like Basaglar has gained a market share of around 30 percent and the Neupogen market share is down by 20 percent from the competition of Zarxio a biosimilar.

Disclaimer:

The opinions expressed in this publication are those of the Interviewee and are not intended to malign any ethic group, club, organization, company, individual or anyone or anything. Examples of analysis performed within this publication are only examples. They should not be utilized in real-world analytic products as they are based only on personal views of the Interviewee. They do not purport to reflect the opinions or views of the VEEDA CRO or its management. Veeda CRO does not guarantee the accuracy or reliability of the information provided herein.

Individual Case Study Report (ICSR) is a source of data in pharmacovigilance that contains information on the adverse events caused by medications.

It is reported by an individual or an individual’s physician. Reports from member countries of the WHO Network are the primary target of ICSRs.

The Uppsala Monitoring Centre (UMC), on behalf of the WHO, manages and produces a worldwide individual case safety report database called the VigiBase.

Medical coding aims to translate information on adverse effects into terminology that can be defined and analyzed quickly, as the terminology used for a similar event may vary from region to region.

As a part of medical coding, a generic terminology from a medical coding dictionary, such as MedDRA (the most widely used medical coding dictionary), is used for an adverse event. UMC has updated MedDRA 23.0 to capture the ICSRs for COVID-19 treatment, and the current MedDRA version in use is 23.1.

It should be noted that there are insufficient safety details about the multiple therapeutic options for COVID-19 infection.

It is important to exchange information on suspected adverse effects from all of the drugs that are used to treat COVID-19, as well as how the virus and the medications used to treat it affect patients with co-morbidities that are already on various medicines for managing conditions like hypertension, diabetes, etc.

Given the global scale of the pandemic, all attempts should be made to reduce delays in reporting events related to COVID-19 so that countries can benefit as early as possible from each other’s experience.

Data points other than demographic details (sex and age of a patient) that are particularly useful for analyzing and identifying COVID-19-related cases include:

• Medical history of the patient, inclusive of the concurrent medications
• The therapeutic reaction of the drug
• Laboratory tests results
• If there is death, then the reason behind death
• Patient narrative, diagnostic reports, and comments from the healthcare provider

EMA has recently released complete guidance on the processing and submission of ICSRs in the context of the global COVID-19 pandemic.

The detailed guidance document refers to the updated MedDRA version 23.0 for getting the terms related to COVID-19 and also notifies the release of a COVID-19 SMQ with MedDRA version 23.1.

It calls upon organisations to comply with their legal obligations to disclose reported adverse drug reactions in compliance with the provisions of Articles 107 and 107a of Directive 2001/83/EC.

It also requests the organizations to comply with the guidelines laid down in GVP Module VI, ICH E2B Guidelines, and the current version of MedDRA term selection.

The important points from the document regarding capturing ICSRs for COVID treatment include:

• Complete information that includes the medical and administrative data for a valid ICSR should be submitted in a standardized manner in the relevant ICH-E2B data elements and in the narrative section for serious adverse event cases.

• No report should be documented for the misuse of non-medicinal products that may contain substances that are also found in the medicinal product.

• The guidance stated to discuss the reports of drugs having off-label use with no associated suspected adverse reactions in the Periodic Safety Update Report or in the product Risk Management Plan. These reports should not be submitted to EudraVigilance as ICSR.

• If a pharmaceutical product is used to prevent or cure COVID-19 infection after getting approval and no possible adverse effect is recorded for lack of therapeutic effectiveness, then it should be sent to EudraVigilance as an ICSR within 15 days. The reason being that COVID-19 is a potentially life-threatening illness.

• If any medication has a valid Adverse Drug Reaction (ADR) and demonstrates a lack of clinical efficacy for the treatment of COVID-19, an ICSR should be requested regardless of whether or not the application of the drug as off-label.

• ICSRs should be considered as spontaneous reports. If ICSRs are of named patient programs having an active collection of adverse events, then they will be considered as solicited reports.

• Given the substantial rise in the number of publications related to COVID-19, the marketing authorization holders should abstain themselves from creating duplicate ICSRs in the EudraVigilance. Those AE reports should be submitted by the Medical Literature Monitoring Service.

• For every single identifiable patient, one case should be generated when respecting the exclusion requirements given in GVP module VI.C.2.2.3.2.

• Specific COVID-19 terms have been included in MedDRA version 23.1. Stakeholders should ensure that when coding ICSRs in compliance with the MedDRA, they choose the correct specific COVID-19-related word.

• If the COVID-19 condition is found to aggravate, then usually the ‘Reaction (MedDRA)’ field should be populated with either the MedDRA LLT “COVID-19 aggravated” (LLT Code 10084657) or MedDRA LLT “COVID-19 pneumonia aggravated” (LLT Code 10084658) term.

• If a suspected adverse reaction befalls in the off-label use environment, the guidance provided in GVP Module VI chapter VI.C.6.2.3.3 should be followed for coding AE in the ICSR.

• The medicinal drugs that are used in the treatment of confirmed or suspected COVID-19 infection should be populated with the most precise COVID-19-related MedDRA LLT (Low-level term).

• If any approved medication is used as a prophylaxis against COVID-19 infection, the indication “COVID-19 prophylaxis” (LLT code 10084458) should be filled as MedDRA LLT.

• If the medicine is used as immunization against COVID-19 infection, it should be filled in MedDRA under the PT as “COVID-19 immunization”.

• If the medication is used as a cure for COVID-19 infection, the indication under the PT ‘COVID-19 treatment’ should be filled with the most appropriate MedDRA LLT unless a more accurate code word is available.

• If a patient has reported COVID-19 infection, the patient’s medical history data should be filled with the most reliable MedDRA LLT COVID-19 terms.

• The most accurate MedDRA LLT codes, such as “Exposure to SARS-CoV-2” or “Occupational exposure to SARS-CoV-2,” should be entered for ICSRs where the alleged medicinal agent was not used to treat COVID-19 infection and where it is specifically stated that the patient has documented exposure to COVID-19 without contracting an infection.

• The code for the name of the test should be populated under the most accurate MedDRA LLT, as applicable. Code like PT’s ‘Coronavirus test,’ ‘SARS-CoV-2 test,’ or ‘SARS-CoV-2 antibody test’ can be used.

The updated MedDra Version 23.1 contains 50 new COVID-19-related LLTs/PTs. Similarly, a revised guideline on post-marketing adverse case reporting for prescription drugs and nutritional supplements during COVID-19 has been released by the FDA.

Formance should be maintained as far as possible, but to ensure business stability, the FDA agrees that consistency in adverse event reporting responsibilities would be required.

The post-marketing notice on the Mandatory Reporting Requirement of COVID-19 from Health Canada also aligns with the views of the FDA.

The MHRA has also included a new section on PV in its guidance on regulatory flexibility during COVID-19.

REFERENCES

• COVID-19 impact on Pharmacovigilance. Accessed at COVID-19 impact on Pharmacovigilance

• Detailed guidance on ICSRs in the context of COVID-19. Accessed at https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/detailed-guidance-icsrs-context-covid-19-validity-coding-icsrs_en.pdf

• ICSR in Pharmacovigilance. Accessed at https://www.idmp1.com/wiki/icsr/

• How to capture ICSRs for COVID-19 treatments. Accessed at https://www.who-umc.org/global-pharmacovigilance/covid-19/how-to-report-icsrs-for-covid-19-treatments/

• EMA DETAILED GUIDELINES ON VALIDITY AND CODING OF ICSR IN CONTEXT OF COVID 19. Accessed at https://allaboutpharmacovigilance.org/ema-detailed-guidelines-on-validity-and-coding-of-icsr-in-context-of-covid-19/

• What’s New MedDRA Version 23.1. Accessed at https://admin.new.meddra.org/sites/default/files/guidance/file/whatsnew_23_1_English_1.pdf

Medicine research and clinical trials are crucial to the success and growth of the healthcare industry. However, it is also the segment that faces varied economic challenges and fluctuations.

Furthermore, the looming expiry of their products’ patents keeps the industry constantly on its toes and working on its operational efficiency to survive and grow.

Clinical Trials – The Cost Factor!

Clinical trials are one of the largest cost drivers in the healthcare industry. These trials are sponsored by healthcare and/ or biotech companies.

According to an article published in the clinical trials arena in 2018, “the average cost of moving from phase 1 to phase 3 is over $79.1 million and is as high as $52.9 million for single phase 3.”

This cost may go up anytime due to various factors, and it impacts the industry’s performance in a big way. Hence, it is imperative to work on cost-control strategies for clinical trials.

Factors to Be Considered:

• Stretching Timeline

Delays affect clinical trial budgets to a great extend and can be financially damaging too. One of the most common reasons for delays in clinical trials is patient recruitment and retention, which is quite a complicated and tough aspect of the trial.

A research claims, “69% of patients final pre-screening, 58% decline consent and 8% drop out after the enrolment.” Researchers are adopting a patient-centric approach, wherein patients’ point of view is considered.

The approach would aid in patient recruitment and retention and control the delays in the trial. It also emphasizes on the importance of site selection.

• Logistics Decisions

Most of the clinical trials in phase 3 or 4 are conducted on a large scale at a global level. And hence logistics cost comes into the picture. More often than not, product shipment decisions are based more on previous experiences and less on the feasibility of the site.

It is best to take a pragmatic approach to it and analyze if it would be feasible to ship the product to the clinical site directly or make sense to have a local depot there.

Prior studies may be factored in, although they may have less or zero relevance to a new trial. Instead, a study must be conducted on demand and supply for the site, and the logistics and operational costs must be evaluated before deciding.

• Interactive Response Technology (IRT)

Automating the processes through IRT can bring down the costs significantly. It reduces manual oversights and the risks of stock outages and aids in supply management.

IRT systems can be programmed to monitor depot inventories and batch expiries and keep supply managers updated about the it through alerts. IRTs can be custom-built to provide real-time feed on varied aspects of operations in clinical trials, including stocks, supply chain, shipment, etc.

This small investment can optimize operations greatly and aid in cost control. It also simplifies the entire complexity of the tedious processes.

Cost control and increasing operational efficacies are the keys to the profitability of any clinical trial. And there are several opportunities to pursue this goal.

A tactical approach and its successful execution would mean saving millions of dollars and improving the worth of the drug in the investigation.

Contract Research Organization (CRO) plays a vital role as a service provider for the pharmaceutical industries.

The market size of the global contract research organization (CRO) services was estimated at USD 38,396.4 million in 2018. By the end of 2026, it is expected to hit USD 90,926.3 million.

It should be noted that in terms of the number of generic drugs, 20% of global exports are from India. This makes India the biggest global supplier of generic medicines.

It is very much obvious that to get marketing approval for generic drugs on foreign soil, manufacturers from India have to clear all the regulatory parameters.

Thus BA/BE studies are of great importance, and conducting them needs due planning and experience. Generic companies have the R&D for product development, manufacturing, and its quality testing.

Many of the bigger pharmaceutical firms have their own clinical and bioanalytical units. They are capable of carrying out Phase 1 and BA/BE studies.

However, because of the desire to produce more compounds in shorter time periods, there comes the point when the internal resources become saturated.

Often several smaller firms, virtual companies, and generic companies do not have the privilege of performing BA/BE trials with their own dedicated clinical unit or full in-house capability.

They may not have the clinical and bio-analytical capability. Thus the role of CRO or outsourcing of BA/BE studies comes into the picture. They reduce the cost of BA/BE study, help pharmaceutical companies to file ANDA applications, and bring new medicines to market quickly.

The typical services outsourced for BA/ BE studies from a pharmaceutical company to a CRO may include Bioanalytical Analysis, Bioanalytical Site Selection and Qualification, Clinical Study Design, Clinical Protocol Development, Clinical Site Selection and Qualification, Clinical Conduct, Clinical Monitoring, Data Management, Pharmacokinetic Analyses, Statistical Analyses, Pharmacokinetic Report Writing, Integrated ICH Report Writing, Project Management, and FDA/Regulatory Consultation.

How to Select a CRO?

The first step before outsourcing a study to a CRO is to develop a list of potential CROs that are involved in conducting BA/BE studies. CROs that have good experience in conducting BA/BE studies and can meet the sponsor’s timeline should be given first preference.

The list should include the CROs that provide all services and also the ones that provide only clinical or analytical services.

CROs that have a proven record of carrying out BA/BE studies with appropriate clinical conduct, laboratory analysis, data management, biostatistics, pharmacokinetics, and medical writing should be given priority.

They should be in compliance with Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and other applicable regulatory practices and guidelines.

How to Assess the Qualification of a CRO?

The sponsor company should assess a CRO on different parameters before finalizing to outsource the project. The parameters include Clinical Capabilities, Bioanalytical Capabilities, Pharmacokinetic capabilities, and quality deliverables on time.

The sponsor should obtain copies of past FDA inspection reports (483s and Establishment Inspection Reports {EIRs}) through the Freedom of Information (FOI). The client should also request any FDA warning letters (if any) that have been issued against the CRO.

The ability to recruit volunteers for both small and large sample studies is a major assessment criterion for the qualification of any CRO. The CRO should be able to recruit the entire study population at a single center, preferably as a single group.

The client should make sure that the Bioanalytical team is well-experienced in analyzing the analyte or metabolite of the drug as appropriate.

The client should also check that the facility follows cGLPs and have clean inspection history from regulatory bodies. The Bioanalytical team of the CRO should be able to provide a written validation report.

The CRO should have validated pharmacokinetic and statistical programs in place and should be compliant with 21 CFR Part 11 (especially concerning change control).

The CRO should also provide performance metrics used for monitoring the timelines and financial metrics. The client should request ‘‘references’’ that include those companies which outsourced studies and, in return, had successful ANDA or NDA approvals.

After evaluating the credentials and performance metrics of each CRO, the sponsor should physically visit the site and audit the clinical, bioanalytical, and pharmacokinetic capabilities of the CRO.

The audit should include the evaluation of the:

• Procedure for the CRO to handle an unexpected and serious adverse event (AE) investigation.
• Training records for the clinical team
• CRO’s capability to synchronize plasma urine deliveries to different bioanalytical facilities
• CRO’s ability to coordinate functional handoffs
• CRO’s clinical project management capabilities
• Validation of the data collection system
• SOPs, CRF and database correction, change control
• Deliverables like CRFs (CRO or sponsor format), transport procedures to the bioanalytical unit, Content of the written clinical report

The client should also asses the capability of the laboratory project management with regard to their coordination with the clinic, pharmacokineticist, and the sponsor during the study.

Finally, to support the BA/BE study, the CRO should provide written documentation of the final analytical report that should contain supplementary project-specific validation data.

Thus, in a nutshell, it can be said that factors like the number of years in the business, qualified team of scientific, medical, and statistical experts, the ability of CRO to recruit volunteers, a sufficient number of beds for in-housing, calibrated laboratory equipment with suitable SOPs, location of the CRO, duration of getting IEC/IRB approval, employee training on SOPs, adherence to GCP and GLP, correct volunteer database, appropriate ambulatory service, clean kitchen facilities with maintained hygiene, recreation rooms for volunteers, working QAU system, facility management, and accurately designed scientific organization charts assess the qualification of a CRO to conduct BA/BE studies.

Conclusion

A generic manufacturer outsources a BA/BE study so that their product can be proved bioequivalent with that of a Reference Listed Drug (RLD).

The key elements for the success of the BA/BE study between the client and the CRO are transparent Communication at all levels, Sensitivity to the requirement of the project, the Timelines, and Flexibility to recognize and adjust to unexpected events throughout the project timeline.

Work culture compatibility between a sponsor and CRO is also a substantial merit, as it leads to a more aligned relationship in the future.

REFERENCE

1. Outsourcing Bioavailability and Bioequivalence Studies to Contract Research Organizations, Patrick K. Noonan. Generic Drug Product Development Solid Oral Dosage Forms Chapter 13, Pg. No. 299-321.