How to Conduct Clinical Research in India

Introduction:

The Clinical Research industry in India is about a decade old. The business has however gained momentum in the last three to four years. Now that India has subscribed to the TRIPS agreement and recognizes product patents, it is expected that the effect of this will be that the multinational industry will be more inclined to conduct clinical trials here, as the level of protection from generic copies has increased. This development should also stimulate more innovation within India’s own pharmaceutical industry as new molecules discovered will be protected.

The clinical research industry is touted by experts to be the next big outsourcing boom. The potential and pitfalls of India as a favored clinical trial destination is the subject numerous discussions in the Pharmaceutical and Clinical Research fraternity. Most articles on the subject focus on how India is an irresistible target for the Pharmaceutical and Biotech industry to conduct clinical trials.

Of course, not everyone shares this enthusiasm. Critics warn that venturing into India may be a risky prospect for Sponsors fraught with ethical issues. I shall however steer clear of this debate and attempt to provide via this article the framework within which clinical trials in India are conducted. I hope it will serve as road map to sponsors who are possibly – with much trepidation – considering taking the plunge and finding out if India truly lives up to its claims.

The key areas of concern to the foreign Sponsor while considering performing clinical trials in India are
1. Regulatory procedures
2. Functioning of Ethics Committees
3. Informed Consent process
4. Quality of Investigators
5. Hospital Infrastructure

I have provided below a summary of each of these areas and attempted to highlight the difference in procedures as compared to those in the west.

1. Regulatory Procedures: The Central Regulatory agency known as the DRUGS CONTROLLER GENERAL (INDIA) or the DCGI is responsible for all procedures related to New Drugs including Clinical Trial Application, Registration, and Import & Export. All clinical trial applications are submitted to the DCGI office for approval. The documents required as part of the clinical trial application are detailed in Form 44 under Schedule Y of the Drugs and Cosmetic Act. Permission to conduct trials is granted in approximately 3 months from the time of submission. The approval process takes longer if the DCGI’s office decides to refer the application for expert feedback to agencies such as the Indian Council of Medical research (ICMR). If the drug falls under the category of “genetically engineered” or “biologics” then the application is passed through to the Department of Biotechnology (DBT) and is reviewed by the Genetic Engineering Approval committee (GEAC). This approval process usually take anywhere between 5-6months.

As per current regulations, Phase I trials for molecules discovered “outside” India are not permitted. Exceptions are made only when the drug being tested is of “relevance” to the health problems in India or if it is a repeat phase I study. Phase II and Phase III trials can be conducted in parallel with the trials in the rest of the world as long as data from earlier phases is submitted with the application.

Along with the clinical trial application, an application for Import License is made by completing Form 12 of Schedule Y. The application should accurately quantify the drugs imported accompanied with appropriate justifications for the quantities imported. An import license number is issued about 2 weeks after the clinical trial approval is provided. This import license number should appear on all the individual subject drug supplies.

If biological samples need to be shipped out of India, an application for export needs to be made to the Director General of Foreign Trade (DGFT)

The Central Drugs Standard Control Organization first issued the Indian Good Clinical Practice (GCP) guidelines in year 2001. These guidelines were subsequently amended and made the law in the year 2005. Not many countries can boast of this achievement. These guidelines can be readily downloaded from the website cdsco.nic.in. There are also elements in Indian GCP that are not included in other GCP Guidelines, these include the following:

• Research on Special Groups (Paediatrics, or Pregnancy),
• The role of a foreign sponsor. A foreign sponsor may hand over responsibility to a CRO, and this transfer of responsibility must be documented. However, the sponsor is ultimately responsible for the drug and the trial
• Clinical Trials on vaccines, contraceptives, surgical procedures/medical devices, diagnostic products and herbal remedies.

The Guidelines also include specific details about the format for submitting data for rDNA based vaccines, diagnostics and other biologicals.

Indian GCP is modified in the following sections in comparison to ICH-GCP:

• Protocol- QC/QA methods, Finance and Insurance
• Ethics Committee- Composition
• Informed consent
• Compensation for participation

Sponsors need to be aware of each of these differences and ensure adherence to Indian guidelines at all times.

2. Ethics committees: Almost every large hospital in India has an Institutional Ethics Committees attached. These committees are formed in line with requirements of the GCP guidelines. Submissions for approvals are made as per the format requested by the Ethics Committee. At a minimum, the documents submitted to committee are Protocol and Investigator Brochure including all amendments, Informed Consent Forms along with translations as well as details of payment or compensation to subjects, if any.

Approval is received in maximum of six to eight weeks following submissions. Most ethics committees usually charge a fee of approximately 200 US$ or 170 Euros. Some ethics committees chose to provide conditional approval until regulatory approval is received. Once regulatory approval is received, a full approval is provided in a matter of few days.

In a reflection of the increasing number of clinical trials being performed in India, several Independent Ethics Committees have begun functioning in the last couple of years. Sponsors usually approach the Independent Ethics Committees when they need to work with potential investigators with a private practice that not attached to a Hospital or Institution

The regulatory and Ethics Committee approval process usually tae place in parallel. However, some Sponsors prefer to provide at least one Ethics Committee approval at the time of submitting the application to the regulatory authorities.

3. Informed Consent Process: Ever since the recent BBC documentary on clinical trials in India, the issue of informed consent has come under even more scrutiny than ever before. The “guinea pig” theory has been widely discussed in the national media as well. Illiteracy as well as the possibly blind acceptance of the doctor’s advice amongst semi-urban and rural populations naturally raises sponsors’ concerns about how truly “informed” the informed consent process is in India. A recent issue of the journal CRFocus published by the Institute of Clinical Research carried an article on this very topic. The authors who are auditors and have audited studies all across the globe concluded that that the informed consent process carried out in India is probably as good or bad as anywhere else in the world.

Most clinical trials are carried out in urban and semi-urban areas where the population is generally literate. India has a population of over 1 billion, and there are many languages spoken throughout the country. One source I found listed 387 living languages! The informed consent and patient information leaflet therefore need to be translated into the local languages. Any informed consent document is translated into a minimum of at least 8-10 regional languages. Being a multi-lingual society, most site staff are conversant with the languages in which the Informed Consent Document is provided to the site. The Informed Consent Document is always explained verbally in a regional language the subject is most comfortable with. In cases where the subject is illiterate, the subject is asked to return with a relative who is literate and can serve as the Legally Acceptable Representative during the informed consent process. If the subject is illiterate, a thumbprint impression is obtained in the Informed Consent Form; it is also accompanied by signatures of the Legally Acceptable Representative, an independent witness and the site staff conducting the entire informed consent process. As per the Indian guidelines, the subject can refuse to allow his biological material to be stored and used for future evaluations. The Indian GCP guidelines clearly define the content and format of the Informed Consent document and must be adapted for all clinical trials being performed in India.

4. Investigators: India has the second largest pool of qualified doctors, (after the USA) and probably over 500 investigators who have been GCP-trained and have the experience of participating in clinical trials. It is anticipated that India will need to double this figure in the next 2 years in order to deal with expected load of clinical trials to be performed in India.

Sponsors and CROs will invariably have to expand this database by approaching investigators who lack GCP awareness or have no prior experience. However, based on my personal experience these novice investigators more than make up for their lack of knowledge and experience with sheer enthusiasm and commitment and have been known to perform as well if not better as the sites with experience.

In any case, most sponsors ensure that the investigator and site staff undergo basic GCP training prior to the start of a study. Doctors in India are very well conversant in English and familiar with the standards and practice of Western Medicine. Besides the obvious financial reasons, an opportunity to participate in global trials, possibilities of authorship in journals international repute as well as the ability to provide patients with free treatment are some of the driving factors for investigators to participate in clinical trials. Access to latest treatment options and generous grant by sponsors by way of expensive equipments are compelling reasons as well.

5. Hospital Infrastructure: Most hospitals and Institutions have the minimum requirements necessary for a clinical trial to be undertaken. Specific equipment required for the study is usually provided by the sponsor and remains at site post-study as an institutional grant. Based on the requirements of the study the sponsor may need to provide the site with necessary equipment such as a refrigerator or deep freezer. At a minimum, a cupboard to store the study documents exclusively is requested by most sites.

In most hospitals, patient records are maintained with the medical records department. During the course of the study, these records are maintained with the study staff for the sake of convenience. Following the closure of the study, the original source documents are returned to the medical records department and photocopies of the source documents are placed with rest of the study documents such as Case Report Forms and Informed Consent document. These documents are not archived in the true sense of the word but rather stored in a secure locked metal cupboard for the required duration.

As opposed to the norm in the west, the pharmacies in the hospital do not play any role in the management and dispensing of study drug supplies. This activity is always managed by the study staff.

In general, the privately owned and run hospitals are better equipped as compared to government-run hospitals. However, it is the government hospital, which receives the bulk of the patient population. Sponsors should aim for careful balance of private, semi-private and government institutes while choosing sites in India.

With data generated to GCP standards, the quality of clinical trial data generated in India is on par with the rest of the world. The US FDA last year successfully audited two sites in Southern India and reported no serious findings. Clinical trials outsourced to India have so far performed well. The need of the hour is a collaborative effort the by the industry and regulators to position India as a global player in the field by ensuring quality in every aspect of clinical research.

Ethics in Clinical Research

 

Ethics: “a system of principles governing morality and acceptable conduct.”

As a society and as a race, we are individuals prone to subjective judgment. While this may hold true for various facets in society, scientific conduct is definitely not a subjective matter. As societal animals, we have the tendency to pin down anything objective as rebellious and defiant. But rebellion and defiance are what define out-of-the-box thinking, which is one characteristic science cannot survive without.

How do we relate the philosophical areas of ethical arguments with research? In fact, the discussion has become popular. Biomedical research, involving the use of human beings as subjects, is a prickly topic to deal with. As the discoveries of drugs and medicines related to human welfare grow in dimension and scope, so do the requirements for human experimentation in the field. It cannot be opined that the use of human beings as subjects is entirely unethical. Meanwhile, it cannot also be accepted that for the welfare of a population, a few hundreds are to be put at stake.

What then is the middle path? Neither can human experimentation be stopped, nor can it be made ideal.

There are various methods devised by researchers and people who are concerned with research conduct to keep the proceedings as ethical as possible. Practically speaking, a few loopholes are what we all expect in the course of a generalized conduct. But expectations and reality fall wide apart when we come under the purview of actual research. The incidents of various trials gone wrong, some deliberately and some accidentally, are too many to be ignored. Be it the Tuskegee Syphilis study in the U.S, or the more recent Cervical Dysplasia study conducted by none other than the Indian Council of Medical Research in India, researchers are apparently not able to resist treating human subjects as guinea pigs.

The infamous Nazi war crimes, which occurred during the Holocaust from 1939 to 1945, were indicative of the latent human tendency to be extremely objective about research. Here is where a contradiction of sorts arises. On one hand a physician has to be extremely objective about his patients and is supposed to have no feelings apart from the awareness that the patient is a body to be healed. But when physicians approach research with the same objective intent, there are more chances than one that he or she may be tempted into unethical conduct. Herein we can ask a valid question. Does being a physician and a researcher concurrently involve a paradigm shift? And if it does, then what defines it? Who defines the boundaries?

We can confront the issue from the various sides it exposes us to. Understanding points of view from all sides ensures some clarity, but we have to accurately judge the distance we have to travel to cover the space between ideal conduct and the presently followed line of conduct.
Maybe we can conclude here with the famous lines by poet Robert Frost:

And miles to go before I sleep, miles to go before I sleep.”

Chillibreeze’s disclaimer: The views and opinions expressed in this article are those of the author(s) and do not reflect the views of Chillibreeze as a company. Chillibreeze has a strict anti-plagiarism policy. Please contact us to report any copyright issues related to this article.

What Ails Clinical Research in India?

Clinical Research became a highly desirable bandwagon around 2005, when all was well with the economy around the world, and when some starry-eyed estimates pegged the future value of research projects in India at astronomical, and perhaps unrealistic, levels.

An unholy frenzy to climb on to this golden dream led to a clinical research boom which now threatens to go bust, leaving many dreamers holding the proverbial bag.

So what is going wrong? Does anything ail the sector?

When a noise is sufficiently loud, it naturally attracts attention – from the wary, the curious, the ignorant and the bold. Noise about clinical research opportunities offered by India woke up China, Malaysia, Australia and other players with similar attributes, and suddenly the pie was divided into many more segments than originally visualized.

With so much competition, Indian clinical researchers need to take stock of what interests the global clientele, and what may frighten them about India.

Clinical trials emerged from the dark shadows of World War II and the infamous US Tuskegee study with a commitment from the medical profession to always uphold the interests of the patient, above all commercial and scientific considerations of profit, fame, glory and so on.

The Helsinki Declaration of the World Medical Association is reviewed regularly to adapt to changing modalities of research and evolving medical needs. And yet, the term “clinical trials” conjures up a picture of torturous experimentation, which is in reality extremely closely observed and regulated by designated authorities worldwide, precisely in order to remove this aura. The spirit of the Helsinki Declaration is embodied into regulations governing and guiding the conduct of clinical trials, and has yielded a best practice guideline called Good Clinical Practice or GCP guideline.

GCP specifies the desirable process of conducting clinical trials, spelling out in great detail the steps to ensure ethical conduct and safeguard the interests of the patient or volunteer participating in the trial.

Now comes the worrisome part about trials in India.

Ethical issues in clinical trials in India are expected to be addressed through the appointment of an Ethics Committee or EC (called Institutional Review Board, IRB in other countries), which approves the protocol (plan) of the study, oversees the obtaining and recording of informed consent from trial participants, the actual conduct of the study, and the reporting of adverse events arising in the course of the trial.

The constitution of an Ethics Committee in an institution is seen as an assurance that all is well with the clinical trial process in that institution. Patient safety continues to direct the decisions pertinent to trials, and the quality of data generation needs to rationalize the means employed.

However, in reality, ECs work very differently and rarely follow the GCP guidelines. The following was observed in a teaching medical institution:
The members themselves did not meet the requirements in terms of experience or familiarity with the clinical trial process. The agenda was not circulated in advance to members. The honorary secretary was almost always too busy to circulate the minutes, which were noted by hand in a ledger book, and which were not signed on the spot by members present.

Meetings were scheduled at maximum permissible intervals and few members had scientific observations or queries to be resolved, as they had no desire to offend the investigators, who were seen as bringing research grants to the institution.

With such ECs in teaching institutes, what can be expected in terms of protection of patients’ rights?

The Human Rights Protection Bill 2005 was scheduled to be tabled in Parliament in January 2008, but there is no news of its fate as yet.

Worse yet, there is no awareness of these transgressions, or even an acknowledgement that they ARE transgressions. There is no interest in their impact either. Just a complacent smugness about clinical research opportunities, almost like they are simply commercial ventures on the lines of call centers.

Apart from the Ethics Committees, another important mechanism overseeing the GCP guideline compliance is the process of clinical trials auditing. This process is considered mandatory in the EU and the law has been changed recently to ensure that this is effectively accomplished. The USFDA too considers auditing mandatory.

Sadly, the Indian Drug Law merely mentions that an audit certificate should be included in a new drug dossier “if available”.

What then can possibly motivate a manufacturer to commission an audit (a source of added costs) of his products or services?

Unfortunately, for the most part in India, quality is only perceived in a very narrow sense as the quality of a manufactured item. The other crucial area of application, to a company’s services, are not considered worthy of quality checks or audits.

Clinical research, sadly, is one such neglected service within a pharmaceutical company. The quality of clinical research is a mission that is individually driven by the ethos and values in a given company, and sometimes only by the personal vision of the in-house scientists.

A recent article in a popular pharmaceutical business journal states, “Clinical trials auditing in India is a pressing need of the day and must be undertaken to ensure that the rights, safety and well-being of human subjects participating in the trial are protected and the reported trial data are accurate and complete. This would give a sufficient guarantee that the report of the clinical trial is credible and worthy of submission to the drug regulatory or licensing authority and publication in a medical journal”(1)

It is a sad commentary on the status of clinical trials in India today that the need for clinical trial auditing has to be emphasized to ensure the upholding of ethical values, scientific integrity or sheer credibility, for fear of taking a back seat in this bumpy ride to a global marketplace.

An old adage urges, “Physician, heal thyself”. Who should we urge now, for healing this ailment? Should we now call out, “Physician-Researcher, heal AND audit thyself” before it is too late to save clinical research in India?

For a start, he following simple processes can be adopted to make some form of headway into solving the problem.

1. Short term measures:
a. Heightened awareness through training and communication, of the imperative to measure, monitor, and thereby assess and improve the quality of clinical research at every level; sponsor, monitor, regulator, inspector, investigator, clinical coordinator etc.
b. More proactive interest in quality of clinical trials from the regulatory viewpoint, but unaccompanied by bureaucratic delays.
c. More critical assessment of manuscripts by medical editors for compliance with available guidelines such as the CONSORT Guidelines for publishing randomized clinical trials’ reports.
d. Registration of all trials in the Registry.
e. Greater involvement of Independent Ethics Committees unshackled by institutional hierarchical pressures.

2. Long term measures:
a. Providing formal training for quality auditors and inspectors to evaluate quality in research.
b. Providing training to investigators in research method
c. If necessary, curriculum changes at post graduate level
d. Amendments in Drug Laws to make GCP assessments mandatory in the dossiers compiled for New Drug Approvals

Is this just one more Utopian vision?
To quote the lyrics for a well known stage version of Don Quixote,
“To dream the impossible dream,
To fight the unbeatable foe,
To bear with the unbearable sorrow,
To go where the brave dare not go.
To fight the unrightable wrong,
To love, pure and chaste, from afar,
To try when your arms are weary,
To reach the unreachable star,
This is my quest”……. (From the Stage adaptation of Miguel de Cervantes’s“DON QUIXOTE”)
Come, together let us make Quality in Clinical Research a reachable star.

Chillibreeze’s disclaimer: The views and opinions expressed in this article are those of the author(s) and do not reflect the views of Chillibreeze as a company. Chillibreeze has a strict anti-plagiarism policy. Please contact us to report any copyright issues related to this article.