It is Time to Make a Move! Ensure the Safety and Overall Wellbeing of the Human Subjects Involved in Clinical Research

Introduction:-

Subject/Trial Subject is an individual who participates in a clinical trial, either as a recipient of the investigational product or as a control.

The clinical trial is incomplete without the participation of an eligible human subject. It is known that Clinical trial is the heart and soul of the modern drug development process. It has become the necessity to evaluate the safety and efficacy of the drug in the human participant.

Many events and incidents occurred in the past clinical trial processes have an impact on both the researcher and the participant involved in clinical trial. Therefore, the question remains, how can we ensure the safety and overall well being of the human subjects?

Ethical principles that guides safety in Clinical Research

There are established guidelines and processes that monitor and ensure the safety of the human volunteers.

 According to Belmonte there are 3 ethical principles that guides the clinical research

• Respect for person
• Beneficence
• Justice

Patient autonomy or respect for the person is an important principle in the medical ethics; in actual practice, especially in the context of developing countries, this important principle is usually disregarded or misrepresented or only partially acknowledged.

Role of Investigator, Clinical Research Coordinator and Other staff;

• The investigator should understand that clinical research is not only valuable for the society but it is also ethically challenging. It requires an able and adept handling of both the science and human values.


• The investigator has to be aware of the tension that could arise as a result of balancing the science and protection to the subject.


• The investigator has to inform subject accordingly.


• Take an opinion from other members, physicians who are involved in the clinical trial to minimize the risk to the subject.

Responsibility of IRB/IEC in assuring the safety of human subjects

An IRB is defined as a committee which is responsible for the review, approval, disapproval, modification and suspension or termination of trial related to human subject

IRB is responsible for:-

• Review of important documents like informed consent form, protocol.
• Investigator brochure update, financial document and advertisement.
• Review research to ensure that benefit outweighs the risk.
• Review reports related to death, serious unexpected adverse event sent by the investigator.
• Conducting periodic review of all the documents, benefits, risks and informed consents etc

Common Problems associated with IRB:-

• Advertisement not reviewed and approved prior to conduct of clinical trial.
• Investigator qualification like CV not reviewed.
• Various document like protocol, Informed consent form not review prior to the conduct of clinical trial.
• Informed Consent.

Informed consent is defined as “Subject willingness to participate in the clinical trial after being informed about all the aspects of the clinical trial’.

It demonstrates that

• Person has freely given conformation without any coercion.
• Person knows that this is research but not a treatment.
• Person has been given all the important and relevant information related to the trial.

Must include important information:-

• Objective and purpose of the research.
• Benefit and risk associated with the research.
• Duration of the research.
• Any alternative treatment available.
• Can withdraw from the treatment.
• Compensation of unexpected injury.

Common Problems associated with Informed Consent

• Consent may not correct.
• Proper signatures are not obtained.
• Poorly written consent form.
• Missing required elements.
• Amended form is not signed.

Subject protection in U.S:-

There are different methods which are followed in the U.S to protect the rights of the study subject:-

Office for Human Research Protections which came in existence in the year June18, 2000, has a considerable power over the conduct of clinical trials.

The Office for Human Research Protections (OHRP) provides leadership in the protection of the rights, welfare, and wellbeing of subjects involved in research conducted or supported by the U.S. Department of Health and Human Services (HHS).

OHRP helps ensure this by 

• Providing clarification and guidance.
• Developing educational programs and materials. 
• Maintaining regulatory oversight.
• Providing advice on ethical and regulatory issues in biomedical and social-behavioral research.

In addition to inaugurating the OHRP, Education and training of clinical investigators and IRB staff.

Improved monitoring to quickly detect problems in Patient’s  safety and penalties of up to $250000 per clinical investigator and up to $1 million per institution for violations of patient protection agreements.

Subject protection in developing countries

With a population of more than a billion of people and prevalence of disease like cancer and HIV, and excellent pool of investigator, CRA and CRC, makes India an attractive location for foreign companies. Nevertheless, the subject enrolled in India is more vulnerable .Why?

1.Poor public health and educational system in Developing countries:-

Due to which the participant may not fully understand about the rights while participating in the clinical trial.

2. Inadequate dissemination of information

3.Unemployment:-

The unemployed and people below poverty line choose to be part of clinical trials to get free treatment.

4.Corruption in the public and private sectors.

In the context of developing countries, informed consent was nonexistent till the Consumer Protection Act came into existence.

Informed consent is very important before any medical treatment. Such consent can be implied, as in the case of a general physician’s treatment, when physician is trying to administer any drug or to perform any surgical procedure. In developing countries, where informed consent is infancy, most important elements of the trials are hidden and particularly in hospitals they are expected to sign the Informed consent form with a rider stating that they are willing for any kind of treatment.

           

5.Lack of facility and coordination among regulatory agencies

In August 2008, according to a report there are: "Fewer than 40 ethics committees in India are properly constituted and functioning”.

Ironically there is no proper linkage between Director Control General of India and Ethics Committee which are the governmental and institutional level of regulatory respectively .The DCGI fully depends upon the EC to implement the ethical principles. The DCGI neither cares for the proper functioning of ECs nor take care of how the rules and regulations are implemented. It’s been 30 years of EC in India but still there is no effective review process in India.

This is the time to break the silence and improve the ethical challenges that India is facing today.

Medical Coding and Coding Process

Coding is the translation of medical information relating to a patient's encounter with a health care provider into alphanumeric code.

Coding plays a very important role in establishing and converting the clinical and medical information into a code which helps us to save time and space.

Different Types of Coding System are:-

1. MedDRA-Medical Dictionary for regulatory activities.
2. WHODRL- WHO Drug Reference List .
3. COSTART- Coding Symbols for the Thesaurus of Adverse Reaction Terminology.
4. WHO-ART- WHO Adverse Reaction Terminology.
5. HARTS- Hoechst Adverse Reaction Terminology System.
6. ICD- International Classification of Diseases.
7. ICD-9-CM International Classification of Diseases, 9th Revision, Clinical Modification.

The Medical Dictionary for Regulatory Activities (MedDRA) Terminology is the international medical terminology developed under the sponsorship of the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use.

The MedDRA terminology applies to all phases of drug development, excluding animal toxicology.  It also applies to the health effects and malfunction of devices. 

The Categories of terms Classified as medical for these purposes are as follows:

• Signs.

• Symptoms.

• Diseases.

• Diagnoses.

• Therapeutic Indications.

• Names and Qualitative Results of Investigations.

• Surgical and Medical Procedures.

• Medical / Social/ Family History.

The five-level structure of this terminology provides options for retrieving data by specific or broad groupings, according to the level of specificity required.

Structural Elements of the Terminology

Coding Process:   

1.   Auto coding:-The term recorded by investigator gets coded automatically.

2.   Manual Coding:-When autocoder fails to code the term. All terms has to be coded manually.

Computer supported step

Uses Autocoders to try and match at least some codes automatically :

1.   Autocoder provides minimal support and company does not update dictionary tables when making a manual assignment. 

2.   Autocoder makes all the updates to the data record and the company updates dictionary tables when making a new assignment of a code to a term.

Coding Process Steps:

A .Coding process with minimal Autocoder support:

• Collect and store the reported term.
• Run Autocoder.
• If a code is found, Autocoder stores the result.
• If a code is not found, Autocoder flags the term for manual coding.
• Manual review of uncoded terms either assigns a code by updating the record.
• Registers a discrepancy on the reported terms.

B. Coding process with heavy reliance on Autocoder:

• Collect and store the reported term.
• Run Autocoder.
• If a code is found, Autocoder stores the result.
• If a code is not found, Autocoder stores the term for manual coding.
• Manual review of uncoded terms assigns a code in a separate table.
• Registers a discrepancy on the reported term.
• Rerunning the Autocoder, then finds a match.

   Advantages

• Saves Time.
• Saves Money.
• Fastens the approval process. 
• Standardize the reported term.
• Multilingual Terminology. 
• Facilitates communication between Industry and Regulators.

Challenges:-

• Illegible verbatim.
• Spelling errors. 
• Use of abbreviation. 
• Multiple medications recorded. 
• Non-contributing words which would require common text transformation.

The More Common text Transformations are:

• Capitalization.
• Removal of selected punctuation, symbols, and extra spaces.
• Removal of numbers and numeric words.
• Removal of dates and date words.
• Removal of noncontributing words.
• Replacement of words with standard terms.
• Alphabetizing the phrase.

Reference:

MedDRA Introductory Guide.

Subject Recruitment and Retention: Barriers to Success in Clinical Trial

The Success to the Clinical trial depends upon the subject Recruitment and Retention but at the same time, successful recruitment of participants for any clinical trial is a challenge.

The Barriers to Recruitment and Retention may be classified in four broad groups: 

1.  Subject-Related Barriers.
2.  Investigator-Related Barriers.
3.  Protocol-Related Barriers.
4.  “Other” Barriers.

 Subject-Related Barriers :

1. Appointment hours are not Flexible.
2. Uncertainty towards the trial.
3. Unrealistic Expectation from the trial.
4. Disease Status.
5. Age of the patient.
6. Level of education.
7. Socioeconomic circumstances.

Investigator-Related Barriers:

1. Logistical Factors.
2. Personal Factors.

Protocol-Related Barriers:

1. Protocol designs with eligibility criteria that are so tight that potential study subjects do not be eligible for entry.
2. Protocols that is too difficult for investigators to follow due to overly Complex study designs.

Other Barriers :

Research studies that fail to meet recruitment goals provide minimal scientific return and may have a negative financial impact on the institution.

Low rates of recruitment and retention:-In order to increase the rate of recruitment and retention

1. Direct advertising should be encouraged.
2. Subject should be give the relevant information during the informed consent process.
3. Subjects rights should  be protected by ensuring the review of documents by IRB/IEC.
4. Develop an understanding of the population being recruited.
5. Provide the clear insight of the inclusion/exclusion criteria.
6. Develop close working atmosphere.

As the clinical trial is increasing the patient recruitment and retention is also becoming challenging.

1. Increased public alertness through campaigns would eliminate the recruitment and retention barriers created by geographic, socioeconomic, and cultural factors.
2. Individuals must be extra alert when dealing with the majority of subjects, who are ignorant, poor, and have a deep respect for and perhaps a blind belief in the physicians treating them.
3. Community education and consultation.

Importance of IT in Clinical Research Industry

The process of drug development and approval process takes a lot of time and is an expensive process. Generally, this process requires millions of dollars in investments and takes many years to complete.

  

Why the drug does takes more than 15 years to be launched into the market?

Since the drugs goes through different stages staring from lead discovery till marketing and each stages of drug discovery takes almost more than 2-3 year as a result of which the total years of drug discovery gets extended to approximately 10-12 years

Successful process takes

•     More than 10 years
•     More than $800 million – $1.2 billion
•     More than 10000 tested compound
•     For one drug

 Figure 1

Pharmaceutical and life sciences companies are outsourcing more of their activities to the IT Companies in a proposal to improve Research efficiencies and shorten the drug development timeline.

IT Players in Clinical Trial:-

• Accenture
• HCL
• Reliance
• Cognizant
• TCS
• Wipro
• Infosys 

Roles of the IT player:-

The IT Companies play major role in reducing the cost of the clinical trial by decreasing the timeline of approval process and increasing the efficiency of the trial by delivering accurate and reliable data. 
So, Pharmaceuticals companies are increasingly looking for partners to sustain them in their revolution, to optimize costs, and to bring innovation to the field of clinical research.
In what ways the IT Companies provides support to pharmaceutical industry?

1. By designing electronic capture instrument which facilitates the capture of massive amount of data generated during the conduct of clinical trial.
2. By designing and ensuring the testing (UAT)and validation of each and every process involved in design of the database.
3. Designing different dictionaries based on the requirement of client to enforce standardization as per the regulatory.
4. Provide support for data communication.
5. Provides confidentiality by ensuring security.
6. Furnish a mechanism to ensure that only authorized users can have access to the database.
7. Providing the opportunity to the Pharma companies to implement the existing standards and regulation.
8. For example, Title 21 Code of Federal Regulations under the FDA defines the guidelines for.
•   Electronic records.
•   System validations.
•   Processing of electronic data and signatures to demonstrate compliance with paper records.
9. By Offering real time web based reporting to client. 
10. By offering online reporting system to enhance and fasten the reporting of any SAE appearing once the drug is being marketed.
11. By bringing efficiency to its US sales and marketing operation, through a range of solutions spanning commercial analytics, sales force planning, sales incentive compensation, customer relationship.
12. Furnish a mechanism for recovering the database if the database is damaged in any ways.

     

Conclusion:-

 The data management processing not only improves the overall cost of the clinical trial but also enhances the sharing and integrity of the clinical data .Henceforth reducing the redundancy.