GCP and Clinical Trial Costs

Fundamentally designed to protect the rights and safety of human beings, the Good Clinical Practices (GCP) guidelines have recently been bearing the brunt of inflating clinical trial costs. In a pursuit of achieving the high quality and credibility that GCP imparts to clinical trials, the industry finds itself overwhelmed with the documentation and administrative set up required for establishing GCP compliance. While the issue of rising costs is usually brought to the forefront, benefits of GCP that could possibly outweigh these costs go unnoticed. Discussed herein are the numerous ways through which GCP by virtue of its implications offers to either save costs or presents opportunities that clearly offset the research expenditure.

Effective patient recruitment and retention

Failure to reach patient recruitment goals is undoubtedly a major cause of costly and increased risks of losing out to market competition. Over 85% of all completed medical research studies experience recruitment delays ¹ and more than half of U.S clinical trials experience enrollment delays between one and six months². The GCP stipulated process -a good quality informed consent; is adequately equipped to act as a precursor step to deal with this challenge. While concerns of safety and confidentiality may inhibit patients from enrolling, informed consent provides a comprehensive understanding of the trial to enable the subject to carefully weigh the pros and cons before entering a trial. An effectively performed informed consent assures the safeguard of rights, safety and well- being of a subject and could thereby encourage the subject to enroll for the study. Moreover, a subject’s realization of how valuable his contribution to research is to the overall benefit of the society, certainly improves the chances of retaining the subject into the trial.

Reduced risk of adverse events

Mounting pressure of recruitment targets may sometimes induce investigators to enroll subjects beyond the inclusion criteria described in the protocol. Risks entailed are jeopardized safety of the subject and high incidence of adverse events. A considerable extent of these risks could be avoided by GCP- prescribed clinical monitoring where qualified monitors at a frequency appropriate to the study, check the compliance of patient recruitment and other study procedures with protocol. It also saves the sponsor costs of medical care required for managing adverse events (costs of hospitalization etc) and costs of compensation and litigations. Furthermore, clinical monitoring is equally capable of detecting frauds and misconducts in the study which otherwise would result in costly implications for the sponsor and most importantly on the well being of the patient.

Improved quality of data

Successful outcome of a clinical trial is largely dependent on the quality and quantum of data collected during the course of the study. Through procedures of data verifications and clinical monitoring, GCP compliance ensures that the clinical trial data is credible, accurate, devoid of discrepancies and has minimal traces of missing data. High quality GCP compliant data has wider recognition and is crucial for facilitating acceptance with regulatory authorities. It empowers the sponsor to create a strong scientific basis for the research product and to successfully counter market competition.

Enhanced standard of health care

A few therapeutic segments which earlier presented with limited scope for conducting research, have now progressed to extending advanced research based health care to afflicted patients; only due to the provisions of Good Clinical Practices. Pediatric studies for example; shunned by researchers for many years are today considered acceptable and even mandated by law ³. In such cases the resulting benefits accrued to the industry and society at large, are far beyond those that would commensurate with the costs of research involved.

Conclusion

GCP apparently has a demanding effect on the clinical trial budget. Alternatives of adaptive trial designs and EDC systems have been offered and implemented to reduce clinical trial costs. A viable option would be to invest in GCP quality and reap the longstanding dividends of fruitful outcomes.  This will be accomplished when there is a change in approach from observing GCP as an ethical or legal obligation to GCP as a mutual advantage for all stakeholders of clinical research. 

References:

1. Gamache V. Minimizing Volunteer Dropout. CenterWatch Monthly. 2002;1:9-12.
2. Diana L Anderson. The Patient Recruitment Market: An overview of today’s issues. Applied Clinical Trials Online, Published Nov 2, 2003. Accessed 12 May 2010
3. Carl Naraynassamy. Maintaining good clinical research practices in paediatric studies. Paediatric and Perinatal Drug Therapy, 2007; 8 (3)

Raising the Bar for Dietary Supplement Clinical Trials

Dietary Supplement and Ingredient companies as well as regulators have long considered double-blind randomized controlled trials (DBRCTs) as the gold standard for clinical trials. While DBRCTs clearly can produce high quality data, it is important to question the quality of the trial design, the quality of trial conduct, and finally the quality of the clinical data management, statistical analysis, and interpretation.

Clinical Trial Sponsor, Investigators, and even the US regulators often miss critical points of evaluation of Trial Data quality. There is over-emphasis on peer review and number of studies. Acceptance of clinical trial data in a peer reviewed journal is still considered as proof enough of good quality clinical data. Out of 3 pillars on which a good clinical trial stands – Design, Conduct, Analysis – the one that is often the weakest is the quality of Trial Conduct or Trial Management. Sadly, journals also focus more on the robustness of the trial design and the interpretation of the results but do not ask enough pointed questions on the Conduct. Independent Review Board (IRB) approval is only approval of design and is grossly inadequate control over trial conduct.

Look beyond US Regulations and Markets

Clinical research in the US dietary supplement and ingredient industry is expected to meet the standards of claim substantiation and truthful advertising set by the Federal Trade Commission (FTC). Unfortunately, the regulatory control by FTC of such clinical research is limited and guidelines inadequate. The FTC states that all label claims must be substantiated with Competent and Reliable Scientific Evidence from studies that are designed, conducted, and evaluated

• With Professional Expertise
• In an Objective manner
• By Qualified persons
• Using Accurate and Reliable Procedures

While the FDA or FTC do not lay down further specifications for the above requirement, we need to consider each term used there carefully and may be draw from the other guidelines for  drug clinical trials available from the divisions such as the Center for Drug Evaluation & Research (CDER). FDA's Center for Food Safety and Applied Nutrition (CFSAN) in its latest document of Dec 2008 “Substantiation for Dietary Supplement Claims Made Under Section 403(r) (6) of the Federal Food, Drug, and Cosmetic Act”, stops short of what we would call adequate guidance.

But why go the extra mile when FTC is satisfied with the current level of science behind our ingredients and products? Research sponsors can best answer this individually based on their international sales aspirations. The companies that will survive the ongoing consolidation in the dietary supplement industry will be forced to become more global, suggests Jeremy Zhou, a senior analyst and director of healthcare at market research firm Revere Data, San Francisco, CA. “Sales for a successful company will have to be geographically diversified,” he said. “Herbalife, as a good example of this, derives 27% of its sales from the EU and the Middle-East/North Africa markets, 18% from Mexico and Central America, 20% from North America, 14% from South America and 21% from Asia-Pacific.”

If US companies wish to make health claims and compete in the international markets, then their supporting evidence for safety and efficacy needs to stand tall in front of tougher regulators like Health Canada, EFSA (EU) and TGA (Australia). Health authorities across the world are now concerned with the credibility of clinical evidence that is being presented to them for making health claims for foods and supplements.

Whatever the global business and regulatory plans of a firm, before investing in costly national marketing and communication programs for the brand, brand managers and top management need to be assured that they have high quality due diligence in place. A well-conducted, well-powered GCP clinical trial is the best assurance that can be offered on the probable market success of a new Nutraceutical brand. Nobody can deny this common business sense.

Once a clinical trial sponsor has decided to invest only in high quality clinical trials, the next obvious question is what this good quality is. In the rest of this article, we shall be previewing the definition of the terms GCP, good trial design, good conduct, good reporting, etc., a detailed review of this subject being beyond the scope of this paper.

Good Clinical Practices (GCP) is GXP for Clinical Trials

If one is told that a trial was compliant to GCPs by International Conference of Harmonization (ICH) and was audited by an independent group, then there is not much more to be asked about the quality of the trial. ICH-GCP encompasses various requirements from design to reporting of human trial data. The US, EU, and Japan are signatories to this universally accepted guideline for clinical trials. While GCP compliance requires dedication and discipline across the entire study team, the approach is simple and logical to a person skilled in the science. Basic tenets of GCP include trial subject rights, ethics, documentation, maintaining an audit trail, and independent monitoring of data. The largest number of audit findings FDA has when they audit drug trials are related to lapses in ethical conduct of the trials. One may wrongly conclude that since dietary supplements are safe and don’t pose the kind of risks that drug trials do to the trial subjects, it is all right to have slightly lower standards of ethical review of trial conduct. In the eyes of the regulators or experienced auditors, even minor concerns regarding the ethical treatment of trial subjects may completely jeopardize the entire study or at least data coming out of the specific study site. Such is the importance laid on subject safety, rights, and confidentiality by GCP and by the Declaration of Helsinki.

Regulations can help in Clinical Trial Design

A good start is a job half done. ICH-GCP elaborates on the roles of the Independent Ethics Committee (IEC), the Investigator, and the study team of the Contract Research Organization (CRO). However, the study protocol and related documents actually can sometimes decide how well the study has been designed and eventually the probable fate of the study. Some clinical trials are doomed to fail from start due to faulty or over-ambitious protocols. There is a wealth of information, regulation and guidance available from FDA, EMEA, ICH, etc that can help in study design. Sample size calculations, selection of subject population, treatments assignment, dose selection, efficacy outcomes, statistical planning and analysis, data management, and report writing are just some of the areas that sponsors need to be concerned about when designing trials that will stand up to the scrutiny of the authorities.

Registration of the Clinical Trial makes Research Transparent and Credible 

Clinical Trial Registry is as critical a prerequisite to clinical data acceptance by the scientific community as is IRB approvals and GCP. However, trial registration is still not widely prevalent in the supplement industry. Some sponsors obviously fear adverse publicity of potentially negative trial outcomes. Others are simply unaware about trial registration as an important credibility and transparency tool.

A CRO brings in “Objectivity” that is required by FTC

Going back to the FTC statement on clinical study quality, the element that is prominently missing is “objectivity” in trial design and conduct. Our observation of clinical trials for Nutraceuticals over the last one decade confirms our view that sponsor firms are unaware of the importance of a statistical plan set forth upfront in a study protocol, the criticality of a robust informed consent process, clinical trial site monitoring by personnel independent of the site, source data verification, third party audits, compliant data management, statistical analysis using Good Statistical Practices by a third party, and trained biostatistician, and finally the evaluation of the tables and graphs by a person with no conflict of interest in the product being studied. Objective trial conduct assumes greater significance in the light of the fact that most supplement studies measure the quality of life of the human subjects in the trial. If studies are not fully objective then errors or even intentional manipulations are likely to affect credibility of data. A CRO independent of the investigator’s site adds great value here. All these factors, if taken care of, can add enormously to the objectivity and transparency of clinical trial data. If trial conduct and evaluation lack this objectivity, then none of the other conditions listed by FTC (qualified and competent persons using accurate and reliable methods) matter much.

Clinical Research is a Marathon not a 100m Sprint

It must be noted here also that some sponsors do not understand their product fully, know little about its pharmacology or mode of action, dose-response relationship, possible side effects, etc., yet want to straightway embark on full blown “publishable” clinical trials. It doesn’t work that way. Clinical research is a set of experiments conducted in series, each one with a specific purpose that the other cannot serve. To expect one single clinical study to meet all the expected objectives may be unreasonable from a biological study involving human beings. Such expectations will only lead to a sponsor poorer in terms of R&D dollars and time/opportunity, and a frustrated CRO/Investigator. Clinical Development Strategy is a specialized subject, but it would suffice to say here that supplement brand-owners should consider clinical research for their brands as a marathon rather than a short sprint.

Globalize Your Clinical Trials

Quality costs, but it pays back. In fact good quality research does not necessarily require millions of dollars but a little bit of specialized training and mostly plain common sense. It’s best for supplement companies to focus on their core strengths of marketing and sales, and leave the R&D to experts like CROs. Clinical research in North America and Europe is expensive due to large number of on-going drug trials here. In contrast, Eastern Europe, Russia, China, and India offer the advantage of lower cost clinical research due to larger drug naïve patient pools and trained investigators. The drug industry has for long managed larger trials either partially or completely outside of the USA. Recognizing the need to offshore clinical research, the FDA has always allowed foreign clinical data to be submitted towards a New Drug Application as long as the data meets certain simple criteria. (FDA Guidance for Industry on Acceptance of Foreign Clinical Studies, March 2001)

When top players are facing pricing pressures and consumer losing faith in unproven commodity offerings, the worst decision that an industry can take is to curtail its innovation programs. Consumer confidence can be regained only by offering something that is novel but more importantly proven to be effective. Consumer can no longer be misled season after season with “clinically proven” labels using half-baked clinical research. It does not pay in the long run and the industry is now paying a price. It’s a wake up call.

In conclusion, a message for the industry: Raise the standards of Clinical Trial Conduct. Limit the cost of Innovation, but not Innovation itself. Build Credible Evidence and then build Brands. Offshore if needed.

Jayesh Chaudhary is Founder & CEO of Vedic Lifesciences, a CRO with offices in Redwood Shores, CA and Mumbai. He can be reached at jayesh.chaudhary@vediclifesciences.com

Misleading health related Vitamin Claims

Product Claims – Saying what you mean, meaning what you say.

Misleading Consumers with false Health Claims can lead to judicial inquiry and facing legal implications thereafter.

The Issue:

German Global Pharmaceutical giant is in the limelight for facing charges levied by The Center for Science in the Public Interest (CSPI), a leading consumer advocacy group. Their product One-A-Day multivitamins has come under rigid scrutiny for false claims with regards to its health benefits. ¹

The group maintains that the Pharmaceutical Company has been releasing misleading information about Selenium, a trace mineral found in their One-A-Day Multivitamin. It widely claimed that Selenium was able to “support prostate health” and “reduce the risk of prostate cancer.” This claim was questioned by the Advocacy Group who claimed that the trace mineral could in fact cause a lot more harm to the consumers than its proclaimed benefits.

Claims Tug of War:

The Pharmaceutical Company had earlier claimed that their One-A-Day mens vitamins could help to prevent prostate cancer because of its ingredient Selenium. They were now revising the verbiage in their advertising material and packaging claims to conclude that the inclusion of Selenium could ward off ‘certain types’ of cancers because of the perceived cancer fighting benefits.

A statement issued by the CSPI executive director, Michael Jacobson to the media brought out a startling discovery. He revealed that the Pharma Giant has been giving American men false hope about Selenium contained in their product, One-A-Day multivitamins. It was also brought to the notice of the Consumers that a trial study found that the so called benefits of Selenium supplements weren’t that accurate to be justified and clinically accepted. It could in fact have serious health complications and may cause more harm. The company still continued to run and display for sometime advertisements containing verbiage of highly disputable nature.

After the incident, The Company spokesperson was quoted saying that the Company indeed had reviewed the section on the U.S. Food and Drug Administration's permitted qualified health claim on Selenium. It was therein that it was mentioned that ‘Selenium may reduce the risk of certain cancers’. The company also confirmed that it was now channeling to adjust the claims in their advertising material and packaging.

The Vedic Way:

A successful product delivers successfully on all fronts. Right from Discovery, Development to Commercialization is a path filled with challenges. Overcoming Regulatory hurdles in the right and certified usage of Health related Claims is more complicated than it appears. Understanding the nuances of product claims and the government regulations surrounding its legal acceptability can be very daunting. A less regulated market can prove to be easy bait to Nutraceutical Divisions to launch product(s) without much research on the ethical and acceptable Health claims associated.

The Vedic way suggests beginning with identifying the nature of claims one wishes the product to be associated with. Knowing that markets and Regulatory bodies have absolute clear demarcation when it comes to soft claims or hard ‘drug’ claims. Ascertaining that the information accrued from Regulatory bodies is adequate and clinically compliant with the nature of claims one wishes to market Conducting trials in compliance with ICH-GCP Guidelines to fully substantiate your product claims is not an option, it’s a must, a necessity to highlight the authenticity of the product and the claims made likewise.

With professional help from Regulatory Clinicians, this incident could have been avoided. Correct data being analyzed for the development of the most relevant and clinically accepted Health Claims. Had the Data borrowed from FDA been checked to ensure its compatibility with the claims developed the result would have been definitely different.

Shefali Roy looks after International Marketing at Vedic Lifesciences Pvt. Ltd. For more information you can reach her at vedic@vediclifesciences.com or on +91 22 42025731

REF:

1) http://www.healthnews.com/natural-health/vitamins-supplements/bayer-one-a-day-men-s-vitamin-claims-lead-lawsuit-3738.html

Is My Product Ready for Clinical Trials?

(This article was published on Natural Product Insider magazine for November, 2009 Issue. http://www.naturalproductsinsider.com/articles/2009/11/is-my-product-ready-for-clinical-trials.aspx)

A clinical trial is considered low-hanging fruit in the dietary supplement industry, yielding immediate marketing value. Other types of data to support claims for a health ingredient or supplement are not as glamorous or accretive to the bottom line. Ideally, consumers want to know whether a product works on them and not just in animals. Regulators even specify controlled human studies are the gold standard for evidence of efficacy of health ingredients or drugs.
Before nutraceutical firms started to look at clinical trials in a big way, product marketers relied on testimonials from satisfied consumers and health care practitioners. Today, companies are increasingly dedicated to clinical trials; however, two types of preclinical research—“Formulation & Analytical Development” and “Animal Pharmacology & Toxicology”—are important, although the investment can seem costlier than the results.


Formulation & Analytical Development
As an example, suppose you have a novel compound from India that you want to market globally. Traditional knowledge and some in-house laboratory data substantiate certain health benefits. Ready to make that claim in most countries? Not without a passport.
The passport is a review of the finished product’s quality. Ingredient certificates of analysis (C of A) provide details on the ingredient itself; however, formulation and production steps ranging from granulation to tableting can impact the compound. Further, novel delivery systems and dosage forms also affect an ingredient’s bioavailability and stability.
On a global level, innovation in novel nutraceutical dosage forms has been slow, although some actives have been converted into forms suitable for food or beverage formulation.
There has been little innovation in new dosage form design such as sustained release or delayed release herbal products, patches, oral release sublingual tablets, etc. On a global level, Japanese firms have converted a large number of actives into functional food forms. But take our example from India. Curcumin, which has been studied for many health effects, has been shown to have poor bioavailability in humans, making innovative formulation or delivery technology a must.
The bottom line—if a finished product is not standardized as it leaves the production lines, stays stable on the shelf and is well available at the target sites of action in the human body, having a hot marketing claim won’t deliver results.

Animal Testing
Some firms may question the need for spending money on animal work if they are committed to investing in clinical trials. Perhaps it is less than ethical to test on animals when human research is equally possible for potentially harmless natural health products, right? Wrong. There is still plenty of research that is possible only in lab animals and not straight away or not at all in humans. Where there are specific safety concerns from traditional use or where the manufacturing process is likely to alter the ingredient dramatically, it is required by the regulators to perform some basic or extensive safety testing in animals before marketing or even human trials.
Even when animal studies are not required by regulations, in vitro and in vivo efficacy studies both offer advantages of screening several ingredients and doses of the same ingredient rapidly and more efficiently in the lab than it would be ever possible in a clinical setting. Moreover, some animal models are available that can elucidate mechanisms of actions which are difficult to reveal in simple human studies. Pharmacokinetic and bioavailability indicators can come out quicker and may be equally respectable as expensive human data.
Also, only having anecdotal data can hamstring the ability to design an appropriate clinical study protocol. Human studies can be expensive, even if off-shored. For clinical trials to be successful and cost-effective, the trial objectives need to be focused. Animal study results can provide this single-point focus to permit the development of a clinical study protocol that is likely to generate a positive outcome. This industry has a history of presumably good products failing in the clinic due to over-ambitious or poorly conceived trial objectives within the constraints of limited resources of time and money.
There are several possible approaches for nutraceutical product development, not one single path as is generally the case with pharmaceuticals. A balanced approach of doing some preclinicals before, during and after the clinical phase of research is prudent. But, each product is different. In some cases, it might be worth running a small pilot human study before doing any preclinical work; however, sample size being small in such a study, one must be prepared to forgo using this data for regulatory purposes. In certain cases, human studies may be more easily set up and in cases such as where “quality of life” is the research endpoint, only a human study will do. There can be many reasons for not doing extensive animal work before getting into clinical trials, but there are not many for avoiding formulation development totally. Typically clinical trials last for longer than a year. A non-uniform or an unstable product going out to human subjects in a study over several months has a potential to create chaos and not authentic and reliable data.
Clinical trial data can be a good tool for differentiating a new or existing product in the crowded market. But it may not be the right time to rush in and pluck this fruit yet. Discuss with your scientific team and outsourcing partners and time it right. An early start on a holistic approach to product development is more likely to yield results in the long run rather than ad hoc decisions on a clinical trial just because the competition has done one. A good dialogue between the preclinical and the clinical teams, set up at an early stage, can be a fair determinant of success. A regulatory expert to guide on research and business strategy can be an added benefit. In this light, contract research organizations (CROs) offering a single point management of the regulatory affairs and preclinical and clinical research programs offer a huge benefit.


Jayesh Chaudhary, is CEO of Vedic Lifesciences Pvt. Ltd., a contract research organization serving the pharmaceutical, phytopharma and nutraceutical industries; contact him at jayesh.chaudhary@vediclifesciences.com .

DESIGN THE STUDY RIGHT – MAKE YOUR SUPPLEMENTARY DREAMS COME TRUE

The story so far…….

Once upon a time, nutraceutical and functional food manufacturers lived and thrived in an unregulated world. Their products addressed a variety of health concerns and came with either implied or overt assurances of safety and efficacy. Sales were good and incidents of side effects or lack of efficacy went unquestioned. As these products did not fall into the ‘drugs’ category, they did not come under the purview of existing drug regulations which demanded proof of safety and efficacy of the drug before it reached the consumer. The creation of a ‘market’ for nutraceuticals was the next best thing that happened to manufacturers since sliced bread.

But now….

Unfortunately, like all fairy tales, this one too came to an end. Law makers stepped in and introduced systems for safeguarding the health and pockets of consumers. Writing a nutraceutical’s success story began to seem like a distant dream.

Dietary supplement (DS) and functional food (FF) manufacturers today are under scrutiny to ensure that they churn out products which really do what they say they do. Simultaneously, they have to race against time to reach the market as soon as possible. Given that the number of DS and FF products lining retail shelves is ballooning everyday, one can well understand their concerns.

As if getting adequate returns on investment on developing the product wasn’t difficult enough, DS and FF manufacturers today have to contend with grabbing a slice of the market. Add to it the fact that in premium markets like the US and the EU, because claim policing authorities are on a 24x7 vigil to trim or eliminate unsubstantiated claims, manufacturers can hardly afford to sit back and relax hoping their coffers would get replenished with no questions asked.

The problem - Regulatory Dragnets

In December 2006, EU decision makers adopted Regulation (EC) no. 1924/2006¹ to ensure that any nutrition and health claims made on a food label in the EU is clear and substantiated by scientific evidence which would be verified by EFSA (The European Food Safety Authority).

Under the Dietary Supplement Health and Education (DSHEA) Act of 1994, FDA has jurisdiction over the safety and labeling of dietary supplements while the FTC has jurisdiction over advertisements for dietary supplements² Section 403(r)(6) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 343(r)(6)) requires that a manufacturer of a dietary supplement making a nutritional deficiency, structure/function, or general well-being claim have substantiation that the claim is truthful and not misleading so as to help preserve consumer confidence in his product.³

FDA can either refuse to allow new ingredients into or remove existing ingredients from the marketplace for safety reasons. The label of a dietary supplement product is required to be truthful and not misleading. If the label does not meet this requirement, FDA may remove the product from the marketplace or take other appropriate actions.

The case is quite similar even in other markets around the world where regulators demand to see proof that such products work and are safe to use for the duration of the health condition they address.

If you thought getting regulatory go-aheads was easy, think again! Recently, the USFDA refused a claim for lutein (eye health) ⁴ EFSA too has a tough image regarding its role in assessing data for claim substantiation. In fact, industry experts feel it’s a notch tougher than even the USFDA. Apparently, only about 2% ⁵ of the scientific papers presented on clinical trials on nutraceuticals survive the regulatory check post. The reasons for rejection are many, some being poor study design, short treatment duration and too few compliant subjects to allow a sound statistical analysis. Lack of product standardization and other quality issues have also contributed to this failure of data acceptance. The amount of time and money lost due to lack of adequate foresight and planning is heart-wrenching since this could have been well avoided.

Thus DS and FF have to literally go on trial in the regulators’ courts and undergo cross-examination of their efficacy and safety. It is only the quantum and strength of scientific evidence derived from clinical trials that can help manufacturers either win or lose their case and put their products in the hands of consumers or face the penalty of holding back or withdrawing their products from the market.

The solution – CRO assistance

Facing such trials would become easier with the technical and operational support of a Contract Research Organization (CRO). CROs can design and undertake the necessary clinical trials to help DS and FF manufacturers successful in generating the necessary body of evidence to back their product’s label claims in the market they wish to enter.

Evaluating dietary supplements and functional foods requires a different approach as compared to pharmaceuticals in order to ensure that the data generated on the product’s safety and efficacy is scientific and adequate without being unduly excessive and untailored to cater to the need of backing the specific claims the manufacturer wishes to make.

The cost of researching and developing a nutraceutical is lesser than that of a pharmaceutical whether in India or abroad ⁶ However, the Return on Investment (ROI) on nutraceuticals is also substantially less as compared to that of the latter. One major strategy in maximizing profits then is to cut costs. This can be best achieved by ensuring that the cost of the clinical trial and the time required to generate the necessary evidence for backing claims is tightly controlled. This is easier said than done. Any manufacturer without adequate experience in conducting clinical trials is bound to find the hurdles involved in the process daunting, if not defeating. The costs of conducting studies can be enormous for the uninitiated sponsor. Similarly, the time spent in completing the whole project would put him at a disadvantage as compared to his competitors in reaching the market, not to mention the costs of lost opportunity he would have to bear.

The advantage of using a CRO lies in faster recruitment, and the flexibility it affords by providing additional capacity or expertise in different therapeutic areas. A CRO with strong capabilities and a rich experience in conducting clinical trials (CTs) on nutraceuticals can make all the difference in ensuring that the sponsor has a zero headache deal on obtaining the necessary data for his product within stringent timelines and costs. Vetting the product’s identity, purity and capability and the sponsor’s need to make specific claims requires a thorough understanding of the science behind herbal and other traditional forms of health supplements.

Maintaining your wallet’s health - Offshoring

Having extolled the virtues of CROs then, here is a piece of advice for DS and FF manufacturers in the US / EU and other countries in the West – offshore your clinical trials – it will translate into further savings in time and cost. Countries like India and China today are a hub for clinical trials.

India especially with its diverse patient pool, GCP-trained investigators with specialized knowledge in their specific therapeutic areas, English speaking Clinical Trial personnel, cutting edge laboratory and data capture technology and low man-hour costs are the best bet for a sponsor wishing to minimize costs in product research.
The cost of conducting clinical trials on pharmaceutical products in India is roughly 50% of the cost of the trial when conducted in the US ⁷ or probably even in the EU. One can then extrapolate this finding to nutraceutical research and development and expect similar if not more reduction in costs in India as compared to the western world.

The strategy – A robust trial design that keeps the end in view

The importance of a well planned, well designed trial in determining the ultimate success of the product cannot be emphasized enough. Only a CRO with expertise in CTs on nutraceuticals can know just how to tweak the study design and manage it operationally to ensure positive outcomes that when collated into a report at the end of the study provide loud and clear evidence on the product’s claims. All this, without compromising on the safety and welfare of the trial subjects and the quality of data generated. Generation of data which would be acceptable to regulators reflects the expertise of a well experienced CRO, as this focus is necessary right from the outset while planning and designing the study.

The design of a nutraceutical trial has a very important role to play in ensuring study outcomes which could have a bearing on the advancement of health and wellness therapies and quality of life standards for patients with various afflictions. Double blind randomized placebo or active comparator controlled clinical trials are the gold standard for generating evidence about the safety and efficacy of a product. Choosing such and closely modified study designs can provide invaluable insights in improving the quality of healthcare. Randomization introduces measures of eliminating bias in treatment allocations. However, a poorly designed randomized trial will not generate credible and useful data on the product as would a well-designed study.

The success of a research trial depends on many factors and the overall strategy that carefully takes them all into consideration. However, the strategy to designing a good trial should be based on the question that one needs to ask regarding the dietary supplement to be evaluated. In his article on research in clinical practice, Dr. Arun Nanivadekar, Former Medical and Research Director, Pfizer India, writes, “The process of research has two aspects: getting an idea is one, and verifying it is the other.” ⁸ Getting the idea equates with generating the question that would need verification via a trial. Although at times one might find that the research question that ought to be answered is a tough nut to crack, it is imperative that one avoids the easy way out by asking an easier but a useless or a less useful question. Having asked the right question is the first step to designing the trial to get the right answers and to ensure study success.

To quote Jayesh Chaudhary, Founder and CEO of Vedic Lifesciences, a CRO specializing in nutraceutical claim substantiation trials, “Determining the primary question to be asked in a clinical trial of a dietary supplement is critical to its success. Ask a wrong question and you end up with the wrong answer, no answer or an answer that has no market or regulatory value.” ⁹ Thus in a nutshell, a well designed study can provide the answers to support nutraceutical label claims while maintaining an optimal cost/ benefit ratio thus maximizing profits while minimizing costs.

Making your product’s fairy tale have a happy ending is possible without incurring financial nightmares. Choosing the right CRO and thereby the best study design, is the best way to go about it.

Dr. Aliya Shakeel is Medical Writer at Vedic Lifesciences Pvt. Ltd. For more information on growing yournutraceutical business you can reach her at vedic@vediclifesciences.com or on +91 22 42025703

References

1) Food Science and Technology Ireland Publication of the Institute of Food Science and Technology, Ireland
Volume 2, September 2008
www.icmsf.iit.edu/pdf/FoodScienceTechnologyIrelandVol2-2008.PDF

2) Brackett R. : The Regulation of Dietary Supplements: A Review of Consumer Safeguards
March 9, 2006
http://www.fda.gov/NewsEvents/Testimony/ucm112576.htm

3) Guidance for Industry: Substantiation for Dietary Supplement Claims Made Under Section 403(r) (6) of the Federal Food, Drug, and Cosmetic Act December 2008
http://www.fda.gov/Food/.../ucm073200.htm

4) Qualified Health Claims: Letter of Denial - Xangold® Lutein Esters, Lutein, or Zeaxanthin and Reduced Risk of Age-related Macular Degeneration or Cataract Formation (Docket No. 2004Q-0180) 
December 19, 2005
http://www.fda.gov/Food/LabelingNutrition/LabelClaims/QualifiedHealthClaims/ucm073291.htm

5) Berry P: EU health claims and accompanying legislation - time lines
Nutraceuticals International June 01, 2006
http://www.accessmylibrary.com/coms2/summary_0286-15771927_ITM

6) A G Pise, D Sreedhar, M Janodia, V Ligade & N Udupa : Changing paradigms in drug discovery
November 27, 2008
http://www.pharmabiz.com/article/detnews.asp?articleid=47207&sectionid=50

7) Clinical trials are now increasingly outsourced to developing countries like India
http://www.offshoringtimes.com/Pages/2006/BPO_news926.html

8) Dr. Nanivadekar A : On research in clinical practice Perspective in clinical research official publication of the Indian Society for clinical research

9) Chaudhari J: Selecting Health Claims for Nutraceutical Clinical Trials
Natural Products Insider 12/21/09 
http://www.naturalproductsinsider.com/articles/2009/12/selecting-health-claims-for- nutraceutical-clinical- trials.aspx

Maximizing Profit for Nutraceutical Firms

The Nutraceutical market worldwide is expected to reach USD 177 billion by 2013, growing at a CAGR of 7%, driven by the fastest growing category of dietary supplements.¹

Are the small/medium sized enterprises (SME) going to participate in this growth equally or will they be left out of the party? Having worked for the last decade with a number of such SMEs, Vedic Lifesciences has some insight to share. We shall discuss possible strategies to help Nutraceutical SMEs grow rapidly in the future.

Revenue growth by any firm could be achieved a) by going global, b) by growing sales within the domestic markets or c) by improving product life spans through constant investments in the value offered to the consumer. Bottom-lines can be improved by ensuring that at least some brands in the portfolio can command a premium pricing.

Growth by Going Global : 
There may be challenges to domestic sales growth as competition from similar brands becomes fiercer and/or the distribution network becomes a bottleneck. On the other hand, going global requires an understanding of the foreign regulations and market conditions and the ability to identify and grow partnerships. Its imperative to partner with foreign companies who have the required regulatory expertise and marketing muscle to smartly overcome the deficiencies of the brand-owner company. A big opportunity to maximize profits is by moving up the “regulatory value chain”, meaning getting the same brand approved in a tougher regulatory atmosphere using supporting R&D data. Example, a manufacturer of a dietary supplement that is able to make only health claims in US can get the same product approved as a Natural Health Product in Canada and make medicine like claims. Importers will always prefer a brand that is already established in markets elsewhere provided the product can meet higher regulatory requirements in the importing country. Having an R&D dossier that was planned and compiled well will go a long way in establishing newer and rewarding markets in economies that may be doing better than the home market.

Domestic Growth:
Relaunching old brands in the domestic markets is a tougher challenge without a new marketing partner or infusion of new value into the product through R&D. Several global economies are still recovering, yet consumer choices for supplements and health foods are huge. In such a scenario, brands that don’t offer value will be wiped out. The cost of a well-conceived preclinical or even clinical program is still lower than an advertising campaign that companies spend on. But an ad can be only as good as the product it sells. A good ad will sell a bad product too, but only for a while. Whereas a good product doesn’t require much ad spend at all in today’s highly democratic and networked consumer world of social media and Web 2.0. Hence companies that do their own domestic marketing of wellness products may consider setting aside at least 50% of their previous year’s marketing and promotional budgets for R&D for the next 3 consecutive years.

Growth by Lifespan Extension:
History of health and wellness brands in most of the regulated world has shown that brands that are well-entrenched in the minds of the consumer psyche had a strong value proposition for the consumer in the first years of their launch. Value can be created through multiple ways and a universal technique remains evidence of health benefit or clinical efficacy. Stronger brands always last a lifetime and sometimes span several generations of consumers. Age-old Nutra brands can be ever-greened through continual R&D.

Profit Growth through Premium Pricing:
Only with innovation and value addition can a dietary supplement or health food rise above the clutter of other me-too brands. Consumers clearly will pay a dollar more for any specific and proven value over the other brands available. Intelligent R&D and smart marketing: neither can do without the other. Investment in only one of them without concurrent focus on the other can lead to disappointments in the short or long run.

The Road to Success via Product Innovation:
When all roads to business success seem to be going via product innovation, it is imperative to have a highly efficient R&D process in-house or outsource it to the most experienced and effective partner. A big reason why SMEs have shied away from own R&D so far in the nutraceutical industry worldwide is the wrong perception that R&D is risky and costly. R&D success must be ensured and costs contained for SMEs to be able to participate fully in the market growth that we are likely to witness in the Health and Wellness markets worldwide in the present decade. Research methods used by pharma do not offer the promise of risk-reduction and cost efficiency that nutraceutical companies look for. Nutraceutical companies need special research methods ^{2 , 3}They must engage (early in the research program) a CRO that has the special skills and experience to handle such challenges specific to the natural product industry in order to participate in the competitive marketplace of wellness products today. Care must be taken that all research is compliant to the global regulations for such natural products. It must be further noted that the toughest global regulations for preclinical and clinical evidence for natural products are not difficult to comply with and are certainly not akin to drug regulations.

Cost-effective, speedy and compliant science is the starting point for building a great health and wellness brand for the world markets and maximizing ROIs in this sector.

Jayesh Chaudhary is Founder & Managing Director of Vedic Lifesciences Pvt. Ltd. For more information on growing your nutraceutical business you can reach him at vedic@vediclifesciences.com 
or on +91 9821086665

References:

1. Ernst & Young, FICCI: NUTRACEUTICALS - Critical supplement for building a healthy India.
     www.ficci-nutraceuticals.com

2. Chaudhary J: Is My Product Ready for Clinical Trials
    Natural Products Insider  Nov 23, 2009
   www.naturalproductsinsider.com

3. Chaudhary J: Selecting Health Claims for Nutraceutical Clinical Trials
   Natural Products Insider  Dec 21, 2009.
   www.naturalproductsinsider.com

Ethics Committees in India have come a long way

Around 2004 when I asked a friend from Pfizer Outcomes Research the hassles of conducting phase trials in India, top on his concern list was the weak ethical review climate that prevailed in India then. His company would bring in more trials to India if they felt confident that Indian Institutional Ethics Committees (IECs) and their review of project proposals would comply with international norms. As per our own admission on the FERCAP website (http://www.fercap-sidcer.org/home.asp), the Indian regulators were not confident of our Ethics committees in 2006. The web page on India has a posting that had confessed about the situation prevailing then:

“Transparency and accountability in (Indian Medical) research currently depends on individual institution which may have allegiance to different groups, and may be in need for benefits from Sponsors. (Indian) IECs are used to closed door meetings and generally communications from IECs focus on final decisions without specifying reasons or information on how to improve the research study to the researchers”

But that was 2006. In mid-2009, while the Medical Research Ethics Committees in India are still an evolving breed, they have clearly moved in the right direction since then. Two developments are worth noting. One, the Indian Council of Medical Research (ICMR) and the Indian chapter of FERCAP have made a move towards registration and accreditation of IECs. We also expect some oversight by the Indian regulator DCGI. Second, India’s clinical trial registry (www.ctri.in) is now operational and compliant with the WHO Trial Registration 20-item Data Sets (http://www.who.int/ictrp/network/ctri/en/index1.html) and other norms (http://www.who.int/ictrp/network/ctri/en/index.html)

FERCI

The Forum for Ethical Review Committee in India (FERCI) was formed in Dec 2002 as the Indian chapter of FERCAP. It was not very active for a few years after formation but has recently been rejuvenated and one of its recent initiatives is IEC accreditations in India (personal communication with ex-Deputy Director ICMR Dr. Nandini Kumar). Two leading Indian research sites - King Edward Memorial (KEM) Hospital and Tata Memorial Hospital, both in Mumbai - have invited audit teams and have been accredited under the SIDCER/FERCAP program. The audits went smoothly with only a few discrepancies and the Tata Memorial online approval process was also found to be acceptable. I see that many other IECs are to follow in this program. FERCI objectives include:

• Establish & foster communication between IECs in India
• Act as a national collaborating agency for ethics reviews
• Organize & facilitate meetings, trainings & symposia on ethical review processes
• Assist in the development & implementation of SOPs for ethical review based on WHO guidelines
• Co-ordinate national communications & issues with other global bodies

CTRI

The Indian Clinical Trial Registry is available / encouraged for all clinical research except Bioavailability and Observational trials. Registration is free and presently can be done for on-going studies also. CTRI registration requires some parameters beyond the WHO recommendation that may be essential from an Indian perspective. For example, name of the IECs/ Institutional Review Boards (IRBs) that have approved the study/sites and DCGI approval status are required. Later, CTRI may even insist on approvals from accredited IECs. Conversely, not all IECs in India currently insist on the WHO data set and CTRI registration while reviewing study proposals.

ICMR guidelines for IECs have existed since long and are by and large adopted as Standard Operating Procedures (SOPs) by most IECs in India including for-profit and non-profit IRBs. While Indian IECs have come a long way since the 2004 observation of my American friend, they still need to invest in further training of members and institute transparent functioning in order to avoid a Coast IRB situation in India.

Jayesh Chaudhary

CEO

VEDIC LIFESCIENCES P LTD

jayesh.chaudhary@vediclifesciences.com

Ethical concern and associated with Oncology Clinical Trial

Cancer is arguably the most fatal disease. It is estimated that one third of drugs under discovery or development are for Oncology, but still cancer is almost incurable. Many Cancer Drugs are themselves carcinogenic or toxic. So unlike other therapeutic area’s, it is unethical and unsafe to include healthy volunteers for non-therapeutic oncology clinical trials. That is the reason why non-therapeutic clinical trials are being conducted on patients who are already suffering from this disease, but I am not sure if it is ethical to keep even cancer patients on sub-therapeutic dosage.

There are lots of developments which are taking place around the globe to reduce the timeline and number of patients, which eventually reduce the risk & pain involved during non-therapeutic oncology clinical trial. One such development is Phase 0 clinical trials, which is developed in response to the United States Food and Drug Administration’s (FDA) recent exploratory Investigational New Drug (IND) guidance, to expedite the clinical evaluation of new molecular entities. It involves lesser number of patients for shorter duration and also promises to shorten the duration of non-therapeutic trial by three to six months, i.e. the timeline for taking anticancer drugs from the laboratory to the clinic. Unlike Phase I clinical trials which are designed to establish the MTD, the Phase 0 clinical trial’s maximum dose can be that at which a PK/PD response is observed or target modulation is measured, providing that no drug-associated toxicity is found. Although it does not give any Patient benefit but it gives a flexibility to conduct Phase 1 Clinical trials at much higher dose and with less patient population.

Another significant development which took place is modified study design. The designs which are more or less in use are Accelerated Titration Designs and simulation study designs. Current phase I trials often take a long time to complete and provide little information about inter-patient variability or cumulative toxicity. These designs are developed to get the necessary information by reducing the number of patients and duration in non-therapeutic Oncology clinical trials (http://linus.nci.nih.gov/~brb/AcceleratedTitration.pdf).

Still these developments will not eliminate the suffering a patient volunteer may endure in non-therapeutic trials. Although these study designs promise that the duration of risk will be less or the number of patient volunteers involved in such studies will be less, it can not be eliminated. The main problem in drug discovery & development of oncology drug is unavailability of laboratory methods which can accurately predict which entity will be effective against a particular class of human cancer.

The patients who are suffering from such a painful disease get involved in clinical trials for a variety of reasons, which I believe is unethical. However, the conduct of non-therapeutic Oncology clinical trials is necessary for the advancement of healthcare in society. Hence I believe that the conduct of non-therapeutic clinical trials is a necessary sin, which Pharma companies & CRO have to indulge in for the benefit of society.

Dhirendra V. Singh,

Business Development Manager,

Vedic Lifesciences Pvt Ltd

bizdev@vediclifesciences.com

Oncology Clinical Trial: Long Timeline and Breakthrough

Millions of dollars are spent on creating new treatment methods for cancer. The main reason for high cost of cancer treatment method is long time, complication and cost involved in Drug Discovery and Development process. Considering the timeline and cost involved in Clinical Trial, we developed a model. This model is based a disease surveillance on cancer and studying the trends of Cancer studies. This model is developed to reduce the timeline without compromising quality and by reducing the cost.

The major area’s which we have covered in this model are Long & Unethical early stages, failure at early stages, Study design related problem like end point & study criterion, General acceptance of report and Reasons for long time line like low recruitment rate, IND complications, multiple effects, low survival rate of patients etc.

V – Onco© model has been developed to identify exact input, process and output parameters, in order to bring an effective mechanism in place. Most important aspect of any mechanism is inputs. One cannot expect perfect results without accurate inputs. According to this model, the inputs have to be provided by CRO and Sponsor. Before looking for a CRO the sponsor should have definite plan to introduce modern models for conducting trial like Phase 0, New Phase I designs for reducing the timeline and getting early indication of investigational products. Considering the complications involved in study the sponsor should ease the inclusion exclusion criterion. While selecting a CRO the sponsor must consider the knowledge base, their patent & investigators database, regulatory environment and ability to absorb the SOP.

Once selected, CRO has to play role of partner and select a site not only with high disease prevalence, experienced investigator & favorable regulatory environment but also with clinical research supportive environment. If they are lacking in some area, they help the CRO as a guide or knowledge partner and help the sponsor in selection of right partners with high patient base and knowledge base with current industry patterns. CRO can provide their best inputs through accurate and innovative research methodologies (like translational research), site selection and site feasibility.

With accurate inputs, process becomes easier with boundaries of well defined SOPs and well trained monitor. It is the responsibility of CRO to empathize with the site personnel and patient volunteers for fulfilling their needs related to clinical study. There should be a system of patient follow-up by creating validating and updating the database. There should also be a system of IP administration if patient is unable to visit. Site effectiveness should be highest in order to conduct qualitative trials with 100% source data verification.

CRO support is most crucial aspect of this process which includes complete site based support and recruitment of ICH – GCP trained physicians.

Creating awareness and marketing of suitable clinical trial is also part of the process. All these process parameters are focused on faster subject recruitment with quality data, favorable regulatory environment & understanding of clinical trials among physicians and patients. This can not be done overnight rather a continuous effort is required to achieve this goal. CRO has to conduct a disease prevalence study to know the extent of disease spread. CRO should also maintain database of Primary health centers & general physicians and create awareness about Clinical research to get their support for Volunteer recruitment, which is very vital for Cancer Studies.

Last stage of this system is a suitable output which is directly dependent on above two steps. As per V – Onco© model, with precise inputs and efficient process, one tends to get desired output in terms of faster regulatory approval, quality data, shorter timelines and better return on investment.

As industry demands quality data in most cost effective manner, we have designed V – Onco© model. Industry trends and patterns have changed due to economic slowdown which suggests cost effective research and CRO can be best partner to achieve the same.Below is model for reducing the timeline of Oncology Clinical Trials:


V – Onco© Model:







Business Development Manager

Above V – Onco^© is copyrighted and property of Vedic Lifesciences Pvt Ltd. It shall not be used without written consent of Vedic Lifesciences Pvt Ltd.