Clinical Trial vs Biomedical Research: Do we need a sorting hat?
New Drugs and Clinical Trial approval regulations 2019 have made a distinction between clinical research and biomedical research and the ethics Committees (EC) to approve the same.
To approve clinical research, we need to approach an Ethics Committee (EC) formed as per CHAPTER III- ETHICS COMMITTEE FOR CLINICAL TRIAL, BIOAVAILABILITY AND BIOEQUIVALENCE STUDY
To approve biomedical and health research, we need to approach an EC formed as per CHAPTER IV ETHICS COMMITTEE FOR BIOMEDICAL AND HEALTH RESEARCH. I will call them Ch3 and Ch4 for ease of typing
A definition has also been provided for Biomedical research: “biomedical and health research” means research including studies on basic, applied and operational research or clinical research, designed primarily to increase scientific knowledge about diseases and conditions
(physical or socio-behavioral); their detection and cause; and evolving strategies for health promotion, prevention, or amelioration of disease and rehabilitation but does not include clinical trial.
Why am I stating these facts?
I happen to be the chairman of a local EC. While discussing an observational study with some colleagues, who work for other ECs, it was suggested that I should register my EC under NAITIK too, since observational studies will fall under Ch 4. Just as we have to apply on the SUGAM portal for registering an EC under Ch 3, one registers on the NAITIK portal to register a study under Ch4.
I objected saying that any study where an intervention happens in a patient has to reviewed under Ch 3.
I was informed that only studies under the new drug category will come under Ch3, all the rest coming under Ch4. In case of doubt one has to enquire with the Drugs Controller’s office to receive a clarification.
I set about reading the new drug regulation and the frequently asked questions. I found the following that may have influenced my friends. Many decisions seem to revolve around the definition of a new drug mentioned in these regulations
In addition to prescribing the need for two types of ECs, the new regulation also mentions that “Any institution or organisation which intends to conduct biomedical and health research shall be required to have an Ethics Committee to review and oversee the conduct of such research as detailed in National Ethical Guidelines for Biomedical and Health Research Involving Human Participants.”
A couple of questions and responses from the FAQs are as under
Whether compensation, medical management in case of injury or death of trial subjects is applicable in case of academic clinical trial?
The academic clinical trial shall be required to be conducted in accordance with the approved clinical trial protocol, ethical principles specified in National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, notified by the ICMR with a view to ensuring protection of rights, safety and wellbeing of trial subject during conduct of such clinical trial. Therefore, ethical principles including compensation, medical management in case of injury or death etc. as prescribed in National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, notified by the ICMR are applicable for academic clinical trials.
Whether systematic clinical study of a drug (not covered under the definition of new drug) in human beings requires permission from the CLA?
……………. Therefore, in case the drug is truly not a new drug, in respect of composition, dosage form, indication, use, patient population etc. no permission from CLA may be required for conduct of such study of such drug in human beings. However, if such study is covered under category of observational study or non-interventional study, the same will be regulated as per the Fifth Schedule of the New Drugs and Clinical Trials Rules, 2019. Study of such drug in human beings if covered under the definition of Biomedical and Health Research, the same will be regulated as per the regulatory provisions prescribed under Chapter IV of the New Drugs and Clinical Trials Rules 2019 shall be applicable
The said ICMR guidelines “National Ethical Guidelines for Biomedical and Health Research
Involving Human Participants” has a chapter dedicated to “Clinical trials of drugs and other interventions”, and separate ones addressing “Public health research” and “Social and behavioural sciences research for health”
The combined definition of public, social and behavioural research is close to what is envisaged for Ch4 studies.
In the chapter on clinical trials of drugs, under phase IV studies it lists the following
In the case of Phase IV studies, the following are some examples of studies
that require EC approval:
(i) Phase IV clinical trials
(ii) Outcome research
(iii) Registries
(iv) Data that is used to answer any research question
(v) New use/route/dose/dosage form/combination/regimen of a marketed drug for non-commercial purpose such as academic research
In addition to EC approval, a Phase IV clinical trial on drugs with a market authorization of less than 4 years requires regulatory approval (CDSCO). (Again a reference to “new drug” but clearly demarcates the jurisdiction of the EC and the CDSCO)
In the ICMR guidelines, there is a general requirement given for an EC, but there is also a mention that if clinical trials are being reviewed, the basic medical scientist should be a preferably a pharmacologist; something close to Ch3 ECs
So, my simple segregation would be:
Any clinical study in whatever phase, involving patients where data is collected through investigations, scales or observation, after an intervention with drugs or otherwise will come under Ch3.
Studies on healthy individuals as in vaccine or Bioequivalence studies would also fall under Ch3
Those involving disease patterns, management, prevention could come under Ch4 as in a study establishing the prevalence of a disease in a given population through a screening test
But there would be fence sitters too.
Let’s say a serum marker is being ascertained in COVID patients. Since a patient is involved, this could come under CH3, but if the same was studied in cases who have recovered from COVID, this could go under CH4. But since it involves use of the individuals body fluids it may also fit under Ch3
Let me put forth some scenarios
• Genotyping patients to identify fast and slow metabolisers after administration of a drug would go to Ch3 because a patient and drug are involved, and one also needs permission for genotyping
• Genotyping in general population to identify prevalence of some disease marker would be under Ch4 since no patient or drug is involved
• A psychologist wishing to measure anxiety levels in COVID patients admitted to a hospital would be referred to Ch3 since a patients are involved
• A psychologist wishing to measure anxiety levels in COVID recovered cases in the population would fall under Ch4 since no patient or drug is involved
Well, I am certainly going to ask the licencing authority for a clarification (hope I get one with examples and not the routine nebulous response), but I do hope I receive their response on this blog itself. I also seek comments from my colleagues.
If nothing works, I will have to use the Harry Potter kind of “sorting hat” to decide.
References
• G.S.R.227(E) New Drugs and Clinical Trials Rules, 2019
• Frequently Asked Questions (FAQs) on New Drugs and Clinical Trials Rules
• National Ethical Guidelines for Biomedical and Heal th Research Involving Human Participants – ICMR
Dr Vishwas Sovani (November 2020)
I think the Categorization of Two iec’s in the ndcr is done with the purpose to Segregate clinical Studies requiring regulatory review. This could have beeN done to decrease the burdwn on The office of the dcgi By restricting studies which do not require reGulatory review ans monitoring.
Thanks
When an EC receives a research proposal for review, it may proceed as follows:
1. Is this a clinical trial of a drug or device controlled by the CDSCO? And are the data to be used for regulatory approval and marketing?
1.1. If yes, the data generated are subject to regulatory inspection and archiving for 5 years. The EC needs to be guided by Chapter 3, the ICMR guidelines, and ICH GCP.
1.2. If not, the data are not subjected to regulatory inspection and need archiving for 3 years. The EC needs to be guided by Chapter 4 and the ICMR guidelines.
2. Overlap may be found in several studies, in which case it would be prudent to follow Chapter 3. Possible commercial use of research initiated as academic is sometimes difficult to rule out because there may be vested interest, or conflict of interest, as a result of commercial support in the form of free or subsidized supply of materials and financial grant.
3. To be able to deal with § 2, it is advisable to register the EC for approval under both Chapters 3 and 4. The form of application is the same, CT-01, but registration is dual, in forms CT-02 and CT-03.
I think the status of participants, patients or non-patients, is not the principal criterion for segregation between chapters 2 and 3. Rather, it is whether the research is for generating data that need to be submitted to the regulatory authority for approval and marketing. Such data would be liable to inspection and audit, and would need to br archived for 5 years.
if the data and any publication resulting from them are not to be used for commercial purpose by a drug or device manufacturer, and hence not under the control of CDSCO, the research would be considered academic, the data would need to be archived for 3 years, and the CDSCO would not be in the picture.
The ICMR guidelines will apply to both types of research. And, of course, there will be proposals where the purposes will overlap to a greater or less extent, overtly or covertly. Hence, it would be prudent to register the EC under both chapters 3 and 4, applying in form CT-01 and securing approval in forms CT-02 and CT-03.
Thanks.
I understand what both of you are trying to say. But don’t you think that the decision about ch3 or ch4 should be based on science and not per convenience of DCGI? Even if an academic study were to be reviewed by Ch3 EC, the DCGI need not be approached, CTRI can be submitted and the DCGI need not monitor the study. Anyway the office does not review every single study. The only difference then is archival of 3 or 5 yrs which is not a big difference. Dr Sovani
I think Dr. Nanivadekar has given a complete response, but I am tempted to reply using a slightly different way to classify studies. Yet, before we go to that, I feel that this classification is not for the convenience of DCGI, but for separation of jurisdictions (if I may use the word) of DCGI and ICMR.
All clinical trials are under DCGI, and should be reviewed by EC for CT, BA & BE (Chapter 3), clinical trials are by definition of new drugs or investigational new drugs. If a drug is already cleared in India, and is over 4 years old, then mostly it is not a new drug (exceptions are vaccines, monoclonal antibodies etc). Why would a trial be conducted using an old drug? That would happen if one expects efficacy in a different indication, using a different form, route, dose etc, in which case it becomes an “academic clinical trial”. These may be conducted without DCGI approval, but then data obtained may not be submitted for requesting a new indication. The New Drug and Clinical Trial Rules provide a clause that if one wishes to use the data for filing an additional claim, then it should be referred to DCGI. In this case DCGI provides a no objection within 30 days, and if this does not come, one may assume that the DCGI has no objection and proceed. In my opinion any trial that involves an intervention (irrespective of whether it is observational or not) should go to the EC for CT, BA & BE(Chapter 3).
All other studies, that are basic research studies, do not involve an intervention should go to the EC for Biomedical and Health Research (BHR) or Chapter 4, Such studies should follow the ICMR Guideline of 2017 as its main guide.
Having said this, there are some studies where classification is difficult. Recently there was a surgical procedure using a tendon (not usually used) for ACL repair. This put me in an quandary, human tissues are not considered as drugs under the NDCTR (despite the widening of the definition of a drug). An intervention is used, but that cannot be classified as a drug, so where do we classify it. May be experts on this site will make some suggestions.
Dr. Sovani makes an interesting observation, let me reproduce his own words:
• Genotyping patients to identify fast and slow metabolisers after administration of a drug would go to Ch3 because a patient and drug are involved, and one also needs permission for genotyping.
• Genotyping in general population to identify prevalence of some disease marker would be under Ch4 since no patient or drug is involved
I disagree with this line of thinking, in both cases we are identifying fast and slow metabolizers, their status does not change if we give the drug (whose metabolism is being affected) or not. It matters little whether a healthy person or a patient is involved. After all how do you decide to call an individual a patient? I may be healthy in all other respects but suffer from alopecia, so am I a patient or not? Both the above cases, in my opinion belong to BHR Chapter 4.
I have yet another query, and let me take the opportunity of seeking clarification. In 2013 under Rue 122 DD ECs were classified as Institutional or Independent. An Institutional EC has wide powers to review CTs, BA, BE and BHR studies. An independent EC’s powers were limited and they could only review BA & BE Studies.
Classification of ECs under NDCTR was totally different. BA, BE was clubbed with CTs, and this EC is the one that is Chapter 3. WE have other type of ECs that review BHR studies. The classification as Institutional and Independent no longer exists. But those Independent ECs registered or re registered between Dec 2017 and March 2019, have valid registration (registration then was for 3 years), currently. I have no issue with this, but I have seen a recently re registration of an EC and the nomenclature used is Independent Ethics Committee, when such an animal does not exist under NDCTR. I am at loss to explain this. Will someone more knowledgeable please clarify?
I have enjoyed this exvhange of views. It reminds me of a comment by Bernard Shaw in the foreword to his play “Doctor’s dilemma”. He says, “… assent of the majority is the only sanction known to ethics.”
I have enjoyed this exvhange of views. It reminds me of a comment by Bernard Shaw in the foreword to his play “Doctor’s dilemma”. He says, “… assent of the majority is the only sanction known to ethics.”
Dr Ghooi,
Let me clarify on my examples of genotyping.
In the first instance ( actually a trial I planned) patients were administered a medication, PK studies were conducted and a genotyping was also carried out. Idea was to match the PK with genotype and estimate percentage of normal, fast and slow metabolisers. This naturally would go to CH 3
In the second instance, I am considering e.g prevalence of BCRA gene in the population by genotyping 5000 women across an area. No patient or drug is involved.we only need consent to use biological fluids, confidentiality . This I think will go to CH 4
Also , what about analysis of registry data? Since patients and drugs were involved possibility od drug related injury is real should it not go to CH3?
Where would a post marketing study for pharmacovigilance go?
Or a phase IV study trying to replicate a phase III trial in India, obviously for marketing purposes ?
I need to be educated on these examples
HI DR. SOVANI,
VERY THOUGHT PROVOKING BLOG. HONESTLY I DO NOT SEE ANY CONFUSION HERE. KEY DIFFERENTIATORS ARE THE OBJECTIVES OF THE STUDY AND THE REPORTING BODY. BIOMEDICAL HEALTH RESEARCH IS TO INCREASE SCIENTIFIC KNOWLEDGE WHEREAS CT/BA – BE IS TO EVALUATE CLINICAL, PHARMACOLOGICAL AND AE PROFILE. A GENOTYPICAL STUDY IN GENERAL POPULATION IS CERTAINLY CHAPTER 4 . REGISTRY TRIALS TO ASSESS SAFETY ARE CHAPTER 3.
POST MARKETING STUDIES FOR PHARMACOVIGILANCE ARE AGAIN CHAPTER 3.ANALYSIS OF REGISTRY DATA IS CHAPTER 4.prevalence of BCRA gene in the population by genotyping 5000 women across an area is chapter 4.
I AGREE WE NEED MORE EXPLICIT EXAMPLES FROM THE LAW MAKERS FOR EASE OF UNDERSTANDING. LET’S HAVE MORE SUCH EXCHANGES TILL WE GET COMPLETELY SORTED.