Clinical studies with new drugs: My Indian experiences

Dr Krishan Maggon shares some of his not-so-good experiences while conducting clinical studies for new drugs in India

Dr Krishan Maggon

It may come as a great surprise to many that the first rules to regulate clinical trials were issued in Germany in the early 1920s. However, these rules were never enforced and everyone is aware of the Nazi atrocities and their experimentation on prisoners and Jews during World War II. To eliminate past practices of doing medical experimentation and radiation exposure on prisoners, blacks and tribal populations, Declaration of Helsinki and Good Clinical Practice guidelines and regulations came into medical use.

GCP guidelines have become part of medical practice because a few companies and investigators cheated and falsified data and patients records. A recent report in this paper concerning companies sponsored clinical trials with a breast cancer hormonal drug letrozole (estrogen synthesis inhibitors) for induction of fertility in premenopause women for which the drug is contraindicated, raises several issues and shows that GCP regulations in India only exist on paper and not in practice.

The promotion of unapproved uses and unapproved drugs by the industry is a controversial subject. If the pharma company has to substantiate claims of safety and effectiveness for an additional use by obtaining regulatory approval for that use. Proof does not consist of a single study, abstracts in meetings or a few journal articles or letters to editors supportive of a claim. Such proofs are later discredited because the sample size was too small. Lay consumers and physicians cannot conceivably evaluate such health claims independently.

My experience in India, during the period 1995-2002, about doing phase II-III clinical studies with several drugs and interactions with investigators is described. In case of red tape, delays or lack of interest/commitments by investigators I moved on to the alternative sites in Europe. I decided to include some negative experiences and not to sweep them under the carpet and has gained relevance now in the light of RCC and letrozole trials.

This is a snapshot of the general hostile attitude prevailing about five years ago to give better perspectives. The names of investigators, authorities and locations are not mentioned but can be provided under confidentiality. These real cases illustrate the problems encountered in the past.

One investigator asked for payments and help in opening a Swiss account and was excluded. During the past three years regulatory environment and growth of Contract Research Organisations (CROs) have improved the prospects for doing clinical studies.

Decapeptyl

The first protocol in 1995 was a comparative safety and efficacy study in endometriosis patients with the new three-month formulation (triptorelin pamoate) with marketed 1-month formulation (triptorelin acetate). The new formulation was marketed in France and is now approved by FDA. A list of Indian experts in endometriosis was obtained from contacts in WHO and a meeting was set up in Mumbai with an opinion leader. Our first meeting was held in the evening in the private clinic of the doctor. This person was a consultant in a top city hospital.

Information from the potential investigator covering CV, publications were obtained. I explained the obligations of the investigator and sponsor and the requirement of obtaining all approvals from Indian regulatory authorities and hospital Ethical Review Committee (ERC), import license and written informed consent. In the second meeting a few months later, we discussed the protocol, CRFs and Investigator Drug Brochure. I agreed to obtain approval from regulatory bodies for the protocol and import of the drug and run a training course in GCP for all trial staff. It was explained that the study would take place in a hospital setting only.

On my next visit, I was informed that the study was to be done in the private clinic only and not in the hospital. Because of the potential risk and lack of equipment in the private consultancy office, the study was cancelled. As a sponsor I had the moral and ethical obligations to ensure that the trial with new drugs was carried out in hospital setting where emergency help and other specialists were available in case of emergency or serious adverse event.

Oxaliplatin

The second study in 1996-97 period was about the possibility of studying the efficacy of oxaliplatin in some forms of cancer common in India like oral and GI cancer. The product was approved in France and EC approval was expected soon. Two investigators were identified and they had sufficient number of patients for the study and were participating in GCP trials for other companies. Many investigators in cancer had already done the GCP course and participated in GCP studies.

As we were getting ready to start the trial, the drug was licensed out to marketing partners in India and the West and the licensee discontinued the project. Extensive GLP toxicology data for registration in EU/USA with expert report and risk benefit assessment was already available. The head of the toxicology panel was against standard EORTC/NCI Phase I protocol, where new cancer drugs are tested in terminally ill patients with all tumour types who have failed prior therapy. He said he will not allow mixing of different tumour types and wanted the study to be limited to only one tumour type. As if he knew which tumour would respond to a new drug!

In Europe, phase I clinical studies in cancer patients are initiated after minimal toxicology studies in mice and a simple toxicity check in rats, the Indian law required extensive studies in rodents and dogs or monkeys. The law was to be changed in 2003 for cancer drugs, after almost seven years, to bring it in line with EORTC requirements.

Octastatin

I had a request from a professor based in USA for samples of octastatin. The idea was to link octastatin with a radioactive agent and use it as a nuclear imaging agent for diagnosis and therapy in a specific indication. He had collaboration with a hospital in India and was invited to initiate a pilot clinical Phase I/II study. Their plan was to get the local hospital management approval and proceed. I had some concerns about the availability of nuclear medicine equipment and facilities in India. Very few nuclear medicine departments had million-dollar PET and SPECT cameras or even the Tc 99m generating columns. My other objection was based on ethical considerations.

The study as planned was not likely to be approved in USA or Europe because it lacked proper safety and toxicology data in animals for the new diagnostic agent. I did not want to go to India to do studies, which raised questions about ethics and posed higher risk to patients. Request for samples and sponsorship was refused and the study plans were terminated.

This attitude probably avoided a major controversy like the Johns Hopkins Hospital/RCC cancer trial in India. An octastatin (vapreotide) study was planned in patients with cirrhosis and variceal bleeding, to compare the efficacy of the combination of vapreotide and endoscopic treatment to endoscopic treatment alone as a method of controlling acute bleeding.

A top rated world famous gastroenterology surgeon heading a department in a top medical hospital initially contacted us in Europe to do the study. He was identified as a potential investigator and contacted in India for Phase II clinical studies. This was as part of the multicentric study to be done in India and Hong Kong. Several visits were made over a period of the next two years to discuss protocol, CRFs, drug brochure, background information and start the trial.

The surgeon was extremely busy and often worked from early morning till late night and agreed to find a junior doctor to run the study. He agreed to get ERC/IRB and Drug Controller of India approval. The multicenter study was initiated simultaneously in several sites in Hong Kong. Another study in France was completed and published in the New England Journal of Medicine in early 2001, made headlines and editorials review and comments worldwide. The study in India had not yet started and no regulatory or ethical approvals were obtained. The professor missed a golden opportunity to put his name in a publication, which would have brought him additional funds and trials.

Several lives would have been saved and I strongly think that the patients in India were denied a real benefit. I do not know the reason for his inability to initiate the study but it is probable that the high death rate in such patient populations (with standard treatment) and its potential link to any investigational drug and media exposure may be one of the key factors. Now in the light of streptokinase trials, DCGI approval and the refusal of GEAC to approve the product shows that trials about life saving drugs in high mortality patient populations are likely to be controversial and media coverage is not in the best interests of high risk patients.

Procianidol

The last attempt for clinical study was made with procianidol for improving visual acuity in a reputed eye hospital. The protocol, drug brochure, CRF were discussed and handed to the investigator to get a cost estimate and his suggestions for improvements or changes. After additional 2-3 visits over the next year or so, things did not move and the project was terminated. Another product for AIDS wasting received no response from the investigators who were contacted.

Conclusions

The attitude of the sponsor is the key to running good GCP clinical studies on solid medical, scientific, ethical and moral basis. If I had allowed all requests for clinical studies in India, some of these would have generated RCC cancer trials or letrozole type of situation. The current letrozole trials controversy shows that the checks at the sponsor, regulatory, ethical and medical aspects of the clinical trial process have not worked. Sponsor has the responsibility to ensure that the study is conducted by medically qualified specialists in that field.

The objections to the protocol should have been raised at the Medical, legal and regulatory departments of pharma companies, DCGI office, Ethical committee or IRB, investigators, hospitals and even at the informed consent of patients (unless only poor and uneducated patients were used). The risk benefit assessment for the use of letrozole for infertility treatment raises ethical and moral issues for the medical, regulatory and social community.

In my view the risk benefit assessment will go against its use for infertility due to concerns about its toxicity. The use of FSH is well established for fertility induction in standard medical practice. After citalopram bioequivalence study and its probable link to the death of a subject several months later and a DCGI audit clearance last year, it seems that no lesson has been learned to prevent such episodes in future. On the other hand, I strongly feel that the media exposure and adverse publicity about clinical trials supplement regulatory system that aim to reduce health and safety risks by means of rules and enforcements. The writer is Pharma, Biotech R&D Advisor based in Geneva, Switzerland E-mail: maggonk@lycos.com

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