Subject Recruitment and Retention: Barriers to Success in Clinical Trial

The Success to the Clinical trial depends upon the subject Recruitment and Retention but at the same time, successful recruitment of participants for any clinical trial is a challenge.

The Barriers to Recruitment and Retention may be classified in four broad groups: 

1.  Subject-Related Barriers.
2.  Investigator-Related Barriers.
3.  Protocol-Related Barriers.
4.  “Other” Barriers.

 Subject-Related Barriers :

1. Appointment hours are not Flexible.
2. Uncertainty towards the trial.
3. Unrealistic Expectation from the trial.
4. Disease Status.
5. Age of the patient.
6. Level of education.
7. Socioeconomic circumstances.

Investigator-Related Barriers:

1. Logistical Factors.
2. Personal Factors.

Protocol-Related Barriers:

1. Protocol designs with eligibility criteria that are so tight that potential study subjects do not be eligible for entry.
2. Protocols that is too difficult for investigators to follow due to overly Complex study designs.

Other Barriers :

Research studies that fail to meet recruitment goals provide minimal scientific return and may have a negative financial impact on the institution.

Low rates of recruitment and retention:-In order to increase the rate of recruitment and retention

1. Direct advertising should be encouraged.
2. Subject should be give the relevant information during the informed consent process.
3. Subjects rights should  be protected by ensuring the review of documents by IRB/IEC.
4. Develop an understanding of the population being recruited.
5. Provide the clear insight of the inclusion/exclusion criteria.
6. Develop close working atmosphere.

As the clinical trial is increasing the patient recruitment and retention is also becoming challenging.

1. Increased public alertness through campaigns would eliminate the recruitment and retention barriers created by geographic, socioeconomic, and cultural factors.
2. Individuals must be extra alert when dealing with the majority of subjects, who are ignorant, poor, and have a deep respect for and perhaps a blind belief in the physicians treating them.
3. Community education and consultation.

Importance of IT in Clinical Research Industry

The process of drug development and approval process takes a lot of time and is an expensive process. Generally, this process requires millions of dollars in investments and takes many years to complete.

  

Why the drug does takes more than 15 years to be launched into the market?

Since the drugs goes through different stages staring from lead discovery till marketing and each stages of drug discovery takes almost more than 2-3 year as a result of which the total years of drug discovery gets extended to approximately 10-12 years

Successful process takes

•     More than 10 years
•     More than $800 million – $1.2 billion
•     More than 10000 tested compound
•     For one drug

 Figure 1

Pharmaceutical and life sciences companies are outsourcing more of their activities to the IT Companies in a proposal to improve Research efficiencies and shorten the drug development timeline.

IT Players in Clinical Trial:-

• Accenture
• HCL
• Reliance
• Cognizant
• TCS
• Wipro
• Infosys 

Roles of the IT player:-

The IT Companies play major role in reducing the cost of the clinical trial by decreasing the timeline of approval process and increasing the efficiency of the trial by delivering accurate and reliable data. 
So, Pharmaceuticals companies are increasingly looking for partners to sustain them in their revolution, to optimize costs, and to bring innovation to the field of clinical research.
In what ways the IT Companies provides support to pharmaceutical industry?

1. By designing electronic capture instrument which facilitates the capture of massive amount of data generated during the conduct of clinical trial.
2. By designing and ensuring the testing (UAT)and validation of each and every process involved in design of the database.
3. Designing different dictionaries based on the requirement of client to enforce standardization as per the regulatory.
4. Provide support for data communication.
5. Provides confidentiality by ensuring security.
6. Furnish a mechanism to ensure that only authorized users can have access to the database.
7. Providing the opportunity to the Pharma companies to implement the existing standards and regulation.
8. For example, Title 21 Code of Federal Regulations under the FDA defines the guidelines for.
•   Electronic records.
•   System validations.
•   Processing of electronic data and signatures to demonstrate compliance with paper records.
9. By Offering real time web based reporting to client. 
10. By offering online reporting system to enhance and fasten the reporting of any SAE appearing once the drug is being marketed.
11. By bringing efficiency to its US sales and marketing operation, through a range of solutions spanning commercial analytics, sales force planning, sales incentive compensation, customer relationship.
12. Furnish a mechanism for recovering the database if the database is damaged in any ways.

     

Conclusion:-

 The data management processing not only improves the overall cost of the clinical trial but also enhances the sharing and integrity of the clinical data .Henceforth reducing the redundancy.

Targeted delivery system is a niche scientific development, but is there an established delivery mechanism to handle it?

An absolutely novel way of anti-tumor drug delivery for the first time in human using “minicells” derived from bacteria is found to be safe, well tolerated and effective even in advanced stages of cancer. A biotech company in Sydney, Australia, designed the minicells created from small bubbles of cell membrane pinched off the surface of mutant bacteria[1]. These minicells, help to deliver anti-cancer drugs directly to tumor cells, thereby reducing the toxic side-effects that are seen when chemotherapy is given to patients systemically.

In chemotherapy,there are many toxic side effects like Fatigue,Skin Problems,Hair Loss,Loss of appetite, Lymphodema, Vertigo, Urinary tract infections,Hemorrhagiccystitis,hairloss (alopecia) etc..,, Hair loss is one of the most distressing side effect of cancer treatments. Hair loss happens because the chemotherapy affects many other cells in the body, not just the cancer cells. The lining of the mouth, stomach, and the hair follicles are especially sensitive because those cells multiply rapidly just like the cancer cells[2]. 

The chemotherapy drugs are transported through the blood and eventually access the cancer cells. The problem with chemotherapy drugs is that when they attack cancer cells, they can also attack the healthy cells. In most cases, the healthy cells can survive, but sometimes the attack on the healthy cells results in side effects[3]. Minicells acts only on the affected cancer cells because of special form of drug delivery system where pharmacologically active agent is selectively targeted only to the site of action and not to the non-targeted site which then minimizes the side effects caused due to chemotherapy.

The difference is that the normal cells will repair themselves, making these side effects temporary. Minicells acts only on the targeted cells without affecting the normal cells thus minimizing the side effects caused due to the chemotherapy which desperately damages the normal cells. Targeted drug delivery system is a felicitous method of delivering medication to a patient in a manner that increases the concentration of the medication in some parts of the body relative to others where only the affected cancer cells gets cured. The goal of a targeted drug delivery system is to prolong, localize, target and have a protected drug interaction with the diseased tissue[4].

Minicells are generally filled with anti-tumor drugs and encrusted with antibodies targeting the encumbered minicells to tumors expressing the Epidermal Growth Factor Receptor (EGFR) a protein that is found on the surface of many cancer cells. Minicells acts as the targeted release system helps in reducing the frequency of the dosages taken by the patient, having a more uniform effect of the drug, minimizes side effects of drug, and also helps in reducing fluctuation in circulating drug levels. This shows that the minicells reach the tumor cells averting normal cells which obviously don’t have the same receptors.

The tumor cell determines the bacteria from which this minicell has being derived and activates its defense by swallowing the minicell, which manifests cell nucleus to whichever tumor-killing drug the minicell is carrying [5].Each minicell is 200 times smaller in diameter than a human hair. This is the very promising and advanced treatment for cancer where there is a selective delivery of anti tumor drug at the targeted site which safeguards the normal cells from needless adverse effects.

In the future this will enable a truly tailored medicine approach to cancer treatment, as the million molecules of the drug can be attached to the targeting antibodies and delivered to the body in a secure manner[6]. Targeting of drugs to special cells and tissues of the body without their becoming a part of systemic circulation is a very novel idea. But there are no proper methods to administer into the human body.

Delivery mechanism of minicells is a desired pharmacological response at the selected sites without undesirable interaction at other sites; there by the drug have a specific action with minimum side effects and better therapeutic index[7]. But it is very expensive method and the main drawback is that the minicells will not get absorbed in the gastrointestinal tract when administered orally, moreover there is no much information regarding route of administration of minicells and how they act exactly. 

Although it is very effective in vitro, there is no established mechanism to deliver minicells in vivo. By which route these minicells are administered is not known properly and it is still remained a question, as how to deliver this minicells in best effective manner.

Reference:

• http://chemocare.com/chemotherapy/side-effects/default.aspx 
• http://www.inblackandwhitecopy.com/samples/chemo-side-effects.pdf
• Muller, R; Keck, C (2004). "Challenges and solutions for the delivery of biotech drugs – a review of drug nanocrystal technology and lipid nanoparticles". Journal of Biotechnology 
• http://www.medindia.net/news/first-trial-of-delivering-anti-cancer-drugs-in-humans-109842
• http://www.ecco-org.eu/Global/News/ENA-2012-PR/2012/11/9_11-First-trial-in-humans-of-minicells.aspx

ACRI Events For the month of November-2012

 

Opportunity in the field of Drug Development – Smoking cessation

Antismoking foundations have sprouted at regular intervals consistently in different parts of the world, with an objective of overcoming the addiction to smoking. Various products have been undergone clinical research for efficacy and safety. There have been abundant developments in the form of extraction and novel delivery of nicotine that is devoid of dangerous and hazardous chemicals that usually part of smoke. Developments have evolved and promulgated into electric cigar and Trans dermal patches etc. Novel products with the variation in delivery system such as these are acting on the same receptors where the active from smoke too act. i.e., nicotinic receptors. Hence, there exists a scope for products that are devoid of nicotine. 

Lately, Varenicline an active is indicated for Smoking cessation. It is found to be more effective than NRTs and nicotine agonists^1&2.  Among the recent developments, Champix found to be the best of the rest. Drug of this kind work through the mechanism of competitative inhibition and prevent the nicotinic effects.  Nowadays, Clinical trials are being focused on towards the development of antismoking vaccine³. 

Recent news suggests that around 4.1 milliion US dollors have gone in drain through an exhaustive clinical trial performed by Glaxo – Nabi collaboration for vaccine. The objective of that vaccine was supposed to induce the creation of an antibody; this in turn intends to prevent the transportation of nicotine through Blood Brain Barrier.  These concepts and drug targets are food for thought for those in the drug discovery and development fields. Currently, there are around 1.1 billion smokers in the world and these numbers are increasing steadily day after day; therefore, developments in the field of smoking cessation is the field that could be tapped by the pharmaceutical companies.

References:

1.   ^ ^a b Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR (2006). "Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial". JAMA 296 (1): 56–63. doi:10.1001/jama.296.1.56.PMID 16820547.

2.   ^ ^a b Mills EJ, Wu P, Spurden D, Ebbert JO, Wilson K (2009). "Efficacy of pharmacotherapies for short-term smoking abstinance: a systematic review and meta-analysis". Harm Reduct J 6: 25. doi:10.1186/1477-7517-6-25. PMC 2760513. PMID 19761618.

3.   http://www.naturalnews.com/033071_smoking_vaccine_clinical_trials.html

Is There a Hope For Type II Diabetes Patients ?? 

There are lots of clinical trials that are happening in the field of diabetes treatment. Most of the trials are focused on the adjuvant therapy and also on improving the existing delivery mechanism. Recently in the news about a phase II trial conducted for a product Imeglimin, a novel compound as an add-on therapy to Sitagliptin (Imeglimin-Sitagliptin Therapy Shows Significant Benefits In Type 2 Diabetes." Medical News Today. MediLexicon, Intl., 5 Nov. 2012. Web 6 Nov. 2012. For more info, visit Medical News Today).

                

             

As per the bulletin, the combination found to be effective in reducing the blood glucose. News of this kind is common nowadays and most of the results are from the early stage clinical trials. The sample size of this particular trial is just 150 and it is certainly not a size on which the decision can be made. The majority of trials fail in the 3rd phase of the clinical trial and mostly due to the increased number of variables and sample size. Hence, news of this kind is certainly not the answer for the long wait; however this can provide a glimmer of hope for the type II diabetic’s patients.

India A High Risk Country for Misconduct in Clinical Research

I) Introduction

Clinical Research is a scientific discipline wherein numerous data is getting generated in different location on a daily basis. There are various players who are responsible for the generation of these data. Moreover, these data do influence the decision of the sponsor and the regulatory authority in commercializing the tested product. It is significant to note that the data that is getting generated can be genuine or fraudulent and therefore will have an impact on the wellbeing of the society. The way and the manner in which the clinical trials are being conducted will have to be taken into serious consideration by each and every professional in the Clinical Research industry.

The point of discussion of this article is that, whether India is a high risk country for misconduct in Clinical Research or not.

When we mention misconduct, it is an “intentional wrongdoing” and in the case of fraud it is a “willful deception”. Does India carry out intentional wrongdoing in the field of Clinical Research, a question to be answered by the professionals working in CRO and Pharmaceutical Industry in India? It is true that India is an important destination for clinical trials but we can’t deny the fact that it is one of the most vulnerable countries for the fraud and misconduct. The reason why India is a leading destination for conducting Clinical Research is enumerated below:

II) Resource advantage

1) Investigators

• Large No. of specialists and super specialists in the field of science and research
• English trained medical professionals
• PG trained physicians from Europe/US
• Large no. of ICH/GCP trained individuals.

2) Patient population

• Large, Diverse, therapy.
• Advantage of having 6 out of 7 genetic varieties.
• Large amount of patient pool in acute/chronic disease segment.
• Increase in no. of cases like AIDS and cancer.

3) Clinical Research Infrastructure

• Over 200 Medical Colleges.
• Over 22,000 graduates per year.
• 15,622 hosp., 903,952 hosp.beds >75% in urban area.
• 14000 diagnostic labs.
• 700,000 scientists and engineering graduates / year.
• World class medical / lab facilities.

4) IT Support

• Highly developed IT / ITES
• Motivated & committed personnel

5) Connectivity

• High quality digital connectivity.
• Excellent transport facilities across country

III) Number of Clinical trials from India:-

(www.clinicaltrials.gov; 15 Apr08)

Clinical Trials	No. Of clinical trials from India
PHASE 1	32
PHASE II	165
PHASE III	394
PHASE IV	63

IV) Who is responsible for the fraud?

• This includes
• Sponsor or CRO.
• CRAs.
• Investigators and
• IRBs or ethics committees.

It’s not just the matter that who has been involved in the fraud but it’s the matter of negligence which can affect the lives of many innocent consumers.

In the clinical trial most of the activity is often delegated by the Principal investigator to the CRC or nurses .Many trials involve a regular dose of medication in which the patient will come to the investigator for administration of this product. A doctor will often examine the patient for serious side effects and leave it up to a nurse to administer the medication, although many of these nurses are very competent. However, nobody is perfect which can sometimes lead to the fraudulent activity.

Many companies offer recruitment incentives to doctors involved in studies, as they get more patients into the studies, the doctor receives more money. The main problems associated with recruitment incentives will cause a physician conflict of interest as a result of which doctor might recruit the subject that may not fit for the specific trial

Conflict of interest has been defined as “a discrepancy between the personal interests and the professional responsibilities of a person in a position of trust” (Orlowski and Wateska, 1992).

V) Why India A High Risk Country for Misconduct

1) Sites

• Low awareness of regulations, ethics and GCP amongst investigators, CRC,CRA and ethics committees.
• Lack of proper system to document the data.
• Scarcity of trained research staff.

2) Sponsor

• Dual quality in clinical trials – local vs. MNC
• Unnecessary focus on speed rather than focusing in quality and integrity of trial.

3) Regulators

• Lack of system of inspections and review procedures.
• Lack of awareness.
• Lack of proper Guidelines.

VI) Why Fraud in India:-

There is a school of thought, which says that the reason for misconduct in India is due to lack of regulation, lack of transparency and accountability.

In 2006, WEMOS and the Centre for Research on Multinational Corporations prepared an overview and found that out of 22 unethical cases around the world, 8 cases are from India.

The Indian examples of illegal and unethical trials

• Sun Pharmaceuticals and Novartis’s Letrozole for inducing ovulation when approved only for breast cancer.
• Novo Nordisks for diabetes treatment.
• Solvay Pharmaceuticals for treating diarrhea.
• Johnson and Johnsons for treating acute malaria.
• Pfizer’s for cardiac events.
• Otsukas for arterial disease.
• Indian companies Shantha Biotechnics and Biocon for diabetes and
• John Hopkins University’s trials for treating oral cancer.

In recent years, India has made some regulatory attempts

• Amending its drugs and cosmetics act
• Good clinical practices (GCP) guidelines
• The ethics committee that the ICMR has formulated.
• But there is still no compulsory compensatory payment, or penalty against the defaulting company. Ethics awareness in India is developing and the law superseding, but still there is deficiency in working out solutions for improving the act of fraud and misconduct.

VII) Dealing with Misconduct
Prevention

• Identify and eliminate risk factors for misconduct

Detection

• Increasing the period of monitoring and auditing can help detecting the fraud.

Correction

• Promptly investigate and report fraud and try to correct them as soon as possible to reduce the deviation from the truth.

VIII) Conclusion

Even if a new product doesn't work or we don't know how it works, there is pressure on managers to get it reviewed and approved.

The Clinical trial process takes up a lot of time and money on the part of the sponsor. Often the company has high hopes for a specific product that in reality the product just may not meet. No company wants to invest all of the required money for the trials if they are not going to make a profit from it. As a result there may be more fraudulent activity, even when the product has been reviewed and approved. In order to improve these fraud and misconduct, it is essential that has the broader objective that is overall well being of the society.