Blinkered View: Third World Medical Researchers Get Short Shrift
December 2003, marks one year since the US Food and Drug Administration (FDA) cleared the first U.S. clinical trial for laser reversal and treatment of presbyopia (the inability to focus clearly at short distance). A couple of months before, the clinical trial had moved very publicly in its 3rd phase to Canada in September 2002.
"Dr. Michel Pop successfully reverses Presbyopia", said Canada News Wire (CNW), of the Michel Pop Clinic and the doctor conducting these trials in Canada. The Las Vegas Review Journal (Dec 30, 2002) described Dr. Jon Siems' success with conducting trial surgeries at his clinic in Summerlin, Las Vegas while the principal investigator of the New York trials got similar coverage.
Amidst all the hoopla, no one acknowledged the pioneers Dr. Vivek Kadambi, eye surgeon from Bangalore, India and Dr. JT Lin, Chinese-American infrared laser specialist who came up with the hypothesis that designed the machine. Nor was credit given to the early doctors who conducted these trials in Venezuela, Argentina and India. The June 2003 issue of Ocular & Surgery News (OSN, Europe/Asia Pacific edition) writes, "Despite the early indicators of success, no one is quite sure exactly how the procedure improves near vision ". In apparent ignorance of the Lin-Kadambi hypothesis, it has Canadian doctor James Miller describing the theory without any mention of its developers.
"I think I have earned the right to be credited for my work," says an upset Kadambi who protested to the Ocular & Surgery News' editor-in-chief Joan-Marie Stiglich. He drew a 'blanket' response: "It is our policy that as techniques or technology gain acceptance in the mainstream we no longer mention the inventor of said technique or technology. " Stiglich's argument contradicts the very title of the article "Laser reversal of Presbyopia promising in Trials", the latter term itself defining the method's status.
One reason for the lack of due credit in this entire scenario of trials in North America is probably due to the marketing company itself not mentioning the early pioneers. Collette Cozean, CEO of Surgilight disagrees. Saying that 'early papers' and 'all videos' mention Lin as the inventor, she believes four doctors have published theories relating to this technique. "We had no proof for any of the theories, so the company refused to speculate to take sides between them."
While doctors based in US and Canada are gaining credit, the story behind the discovery is yet to be told.
Insights into Presbyopia
In 1998, an international group of ophthalmologists met in Florida, USA. Among them were an Indian eye surgeon and a Chinese-American physicist specializing in ocular laser technology. The two, with a common Asian heritage, quickly formed a bond. In between vain attempts at roulette aboard one of Florida's famous 'floating casinos' they debated techniques on correcting presbyopia. Previous attempts at correction had been to 'expand' by incisions the white of the eye (or sclera) the muscles of which in a normal eye are elastic and supple enough to allow the lens of the eye to 'accommodate' or 'flatten' itself to focus on near objects. But the cilary muscles attached to the sclera formed scar tissue over the incisions, causing vision to regress.
"If we could find a way of not allowing this scar tissue to interconnect", mused Dr. JT Lin, the infrared laser specialist. "Well, we could ablate [a laser technique that simply vaporizes tissue] the sclera which would allow sub-conjunctival tissue [which lies beneath the sclera and forms softer scar tissue than cilary ones, thus allowing the expansion needed] to mesh, we could then keep the incision from closing up", suggested Dr. Vivek Kadambi, the eye surgeon from Bangalore, India. Scraps of paper at the casino's bar were used to illustrate their discussions. Thus was born the Lin-Kadambi hypothesis.
As early as September-October 2000, Dr Lin presented the theory at a meeting of ECSRS (European Society of Cataract and Refractive Surgeons) in Cannes. According to Dr Kadambi, in 2001, Surgilight distributed a printed document of clinical trials where they mentioned the hypothesis. Says Kadambi, "Initially we too were not aggressively pushing our hypothesis since Dr. Schacher 'scleral expansion' hypothesis was more popular and Surgilight probably felt it best go with something which had more acceptance. Now the "Lin-Kadambi" Hypothesis is gaining more acceptance. Surgilight has changed its protocol from scleral expansion to "elasticity change" without mentioning Lin or Kadambi."
The hypothesis has since been published: ("The New Mechanism for Laser Presbyopia Reversal and Accommodation." JT Lin and Vivek Kadambi, in Presbyopia- A Surgical Textbook. Slack Inc. NJ, USA ) 2002. The technique is known as LAPR or Laser Assisted Presbyopia Reversal. The hypothesis works on the theory that sub-conjunctival tissue gives more 'elasticity' on healing than cilary muscles, thus allowing the eye most of its original flexibility or accommodation in seeing near objects. In short, it does away with reading glasses, ideal for people in the 40-60 age group.
Lin developed the specific laser beam needed for the ablation, and the machine now named IR-3000, was patented by Surgilight Inc., a company specializing in ophthalmic devices. Lin was founder-CEO of Surgilight when LAPR was devised, but now has Surgilight's previous Regulatory Consultant (for clinical trials) Dr. Colette Cozean as CEO. When contacted, Dr. Lin said due to legal constraints, he was unable to comment on why he was no longer CEO.
Outsourcing Clinical Trials: Wither Accountability?
Any company needs US FDA approval -entailing a regime of clinical trials-to be able to market a new machine or technique in the US. Surgilight outsourced to developing countries the first two phases of these clinical trials dealing with critical issues of safety and efficacy. The FDA's Medical Devices Advisory Committee's Ophthalmic Devices Panel, one of 18 separate expert panels dealing with specific areas of specialty, is responsible for overseeing trials such as Surgilight's. And though the panel's guidelines are as fastidious as the FDA's general ones, there appears to be no regulatory mechanism for conducting phase 1 and 2 of its trials in developing countries, though the FDA obviously does allow such outsourcing. There is in fact no collaborating regulatory agency in India for monitoring clinical trials; Surgilight, for instance, monitored its own trials in India and South America.
In June 1999, the first group of patients (age 60-65) was treated in Venezuela. Dr. Anthony Parasso and Dr. David Martinez together with Lin reported their successful results at the International Society of Refractive Surgery (ISRS) conference (Oct., 1999 and 2000). In 2000, Dr. Oscar Mallo of Argentina operated successfully on some 65 patients and was the first surgeon to demonstrate the technique live on television. This was followed by surgeries conducted in Bangalore, India by Dr. Vivek Kadambi and in 2001 in the Bahamas by Dr. Rogers. "These are the true pioneers," says Lin.
India is a prominent recipient in the present climate of outsourcing of skills and talent by developed nations, causing resentment in those countries at the loss of jobs. But enthusiasm for such jobs, highly visible in India's software industry, has paid scant attention to the exploitation in areas other than IT being tapped for their skills, or to their manner of conduct. There is now a growing international debate on the ethics of western pharmaceutical corporates and medical institutions using clientele from poorer countries without giving them access to the benefits of research. Yet, surprisingly little is still being made of the contributions of developing country doctors in clinical trials involving medical techniques.
India, for instance, saw a controversy on issues of safety, efficacy and ethics in 2001 when a non-medical scientist at the Baltimore, US-based Johns Hopkins University (JHU) conducted a clinical trial for an anti-cancer drug on Indian patients at the government Medical College Hospital at Thiruvananthapuram, Kerala, without proper authorization from any of JHU's regulatory institutional boards that ought to have considered if it was safe to use the drug on human beings. It also transpired that JHU had no knowledge of the scientist being granted $2m by a Minnesota-based start-up company called BioCure Medical for conducting the trials. The Indian government's Health & Family Welfare department brought out new guidelines thereafter on 'good clinical practices for conducting clinical research in India', but very little is written about medical techniques.
Small wonder then, that medical practices, well emphasized by Kadambi's case, are prone to exploitation. Lower costs, the country's mass of patients making for speedier trials and its excellent medical skills are proving attractive to foreign corporate concerns, says Dr. Prem Pais, Dean of the Bangalore-based St. John's Medical College Hospital. The College has approximately 20 clinical trials in process, both for academic research and market-based pharmaceuticals.
Developing country doctors themselves, the good ones among them more keen on international recognition than financial gain, are happy to undertake clinical trials from foreign companies, and as in the case of Kadambi, many naively sign off their rights under exploitative clauses, ignorant of what their rights should be.
"We don't know the proper way to document our work," concurs ophthalmologist Dr DP Prakash of Chennai's Appasamy Eye Hospital, who came up with a technique to avoid excessive splashing of the eye with liquids during surgery (Ocular & Surgery News, June 2003 ).
Surgilight's intellectual property clause, for instance, claims all rights to "Inventions, discoveries, ideas, improvements, processes, devices, products, know-how or the like whether patentable or unpatentable ("inventions"), and copyrightable material that the Institution, the Investigator, or the associated staff, alone or jointly with others, conceive, invent, make, produce ("conceive"), or reduce to practice" during the trials.
The company's approach to the conducting of these trials raises questions too. No move was made at getting the various investigators worldwide to discuss their work with each other, payment for the supply of fiber-optic cables (for the laser beam) ordinarily supplied gratis by a company seeking FDA approval during a study period, was tentatively asked from investigators; at $1500 inordinately exorbitant and thereby capable of making future surgeries very expensive for poorer nations, feels Kadambi.
Blurred Vision: Policy Guidelines Lacking
The Indian government's policy, or the lack of it, indirectly allows such questionable contracts. In 2001, Kadambi asked the Drug Controller General of India (DCGI) and the Ophthalmological Society of India (OSI) if FDA approval was needed by the authorities in India for conducting the LAPR clinical trials, and what was required of him for conducting laser trials for the first time in India. While OSI did not reply, the DCGI's response was an uninformative one-liner: "We do not deal with medical technology issues".
So then who does? Guidelines on good clinical practices by the Central Drugs Standard Control Organization under the Ministry of Health, issued recently after cases of gross ethical violations by the Johns Hopkins Institute in collaboration with an Indian medical college went public are still inadequate. Clause 7.3 of the "Clinical Trials with Surgical Procedures/Medical Devices" states that the concept [of regulating medical devices trials] is new and admits that these do not come under the "strict purview" of existing regulatory bodies and vaguely shelves that responsibility to equally nebulous committees to be set up for such cases.
The Indian Council of Medical Research, which supports new intellectual property development only for research it specifically funds, is currently drafting a proposal for the establishment of an Indian Medical Devices Regulatory Authority. It is hoped that some guidelines and mechanisms of redress will soon come about.
"Unfortunately medical-practices patents are not allowed in India. I agree this is an area that needs to be looked into", says Professor G. Padmanabhan, retired director of the Indian Institute of Science, involved in India's biotechnology IPR issues.
The US allows medical-technique patents, but the difficulty of monitoring them in the field has led to companies and individuals relying heavily on winning FDA approval for a product instead. The resultant cut-throat race to be ahead in the market has seen enormous lawsuits, involving misappropriation of trade secrets and financial misdeeds, as well as companies 'reinventing the wheel' each time they need FDA approval for new brands of the same technique.
'LASIK' (laser technique for correcting myopia or long-distance vision), for instance was approved by the FDA over 5 years ago, yet in October 2003, a similar machine called Wavelight for correcting myopia was granted FDA approval. Resources that could be used for aiding new technology and research are thus being pumped into trials for different brands of the same technical product. Commercial interests actually have an interest in deifying the FDA approval: they can then use that approval for boosting their sales, gaining a monopoly in the market as well as decide their own selling rates.
For developing countries seeking to emulate the US FDA system of approval, this poses an even bigger problem of wasting scarce financial resources on similar products.
Even more interesting is that FDA approval does not regulate the commercial use of any of its products in non-US countries. The Wavelight machine, approved only in October 2003 by the FDA, is being used for the last two years at least in various places worldwide, including at least one machine in Bangalore. Why then, is FDA approval such a benchmark, or measure of standard in India and elsewhere?
But Dr. Prem Pais, Dean of St. John's Medical College Hospital, Bangalore, which has over 20 completed and ongoing clinical trials, feels India can use the opportunity that foreign outsourcing provides to increase both scientific knowledge and working procedure. "It's not such a bad thing to be conducting foreign trials. The meticulousness that is required for them is not part of our normal work here, so we learn more", he says.
Pais adds that since most drugs used in India are tested outside, clinical trials are beneficial by giving Indians data on themselves. "The main intellectual output is in working out the protocol for conducting these trials, which comes from outside. So intellectual exploitation isn't really an issue here", he adds.
But Dr. Kadambi differs, saying matters are simpler with trials on drugs already in the market. Medical techniques are more complicated. "A protocol, even if from abroad, still has to be reviewed. For this you need initiative, 'gut feeling' or 'sixth sense', and a thorough knowledge of your subject to change the protocol if necessary." Interaction with other investigators is thus essential.
Dr. Dennis Xavier of St. Johns' in charge of conducting India's largest clinical trials, involving 69 hospitals and 120 investigators, says India and poorer countries' interests should focus on the benefit their own patients can get from such deals, an issue which remains sensitive from two angles mainly: the ethics involved in using these patients and the unaffordability and lack of access to such medicines once approved. Another disturbing trend is talk of unskilled or semiskilled professionals reportedly floating companies just to win such contracts.
What all doctors interviewed do concur on is that 'we should evolve into our own process and not become call-office operators doing work for others'.
Dr. Pais says St. John's is taking the lead in creating a network of reliable institutions and building up skills for India. "And we will get there. After all, Indian pharma companies have already started outsourcing their phase 3 trials to foreign countries. "
Dr. Prakash thinks doctors with techniques have that ultimate responsibility to publish in peer-reviewed journals and disseminate thereafter. "Whether the government has enough time and resources to authenticate each practice is debatable."
But meanwhile what happens to the inventive skills of our doctors? Will we 'get there' in time?
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