POTENTIAL CHALLENGES AND PROACTIVE APPROACH FOR SAFE HERBAL PRACTICE

Herbal medicinal practice existed either as standard treatment or as adjuvant with conventional medicine since long back. Ayurveda is well known as oldest treatment system ever existing. Safety concerns with toxicological effects and purification of plant product are mentioned in Ayurveda textbook also. Here I’m going to discuss some challenges faced by herbal practitioner, experts as well as global scenario. This article will be  centered around Ayurveda system of medicine, but similar concepts applies for other complementary and  alternative medicines:

Challenges faced during safety monitoring of herbal medicines:

Self-medication: The commonest myth regarding herba medicines s that these medicines are completely safe and can therefore be safely consumed by the patient on his/her own, without a physician's prescription. This belief has led to large-scale self-medication by people all over the world, often leading to disappointing end-results, side-effects, or unwanted after-effects.

     Improper quality control:  A majority of the adverse events related to the use of herbal products and herbal medicines that are reported are attributable either to poor product quality or to improper use. Inadequate regulatory measures, weak quality control systems, and largely uncontrolled distribution channels (including mail order and Internet sales) may have been contributing to the occurrence of such events.

    Complex natural constituents: No any single herbal medicines are synthesized. They are used either as crude or extracted form.  Detail understanding and description of clinical, pharmacological and toxicological effects of Chemical constituents present within every plant used as medicines is ambiguous. Moreover, combined herbal preparation are more in use than single herb.

°   Ambiguous prescription: Mostly herbal medicines are used in conjunction with conventional medicines as adjuvant therapy. Study on interaction of herbal product with synthetic medicine is meagre. Issue can also arise by such interactions between different  potential chemicals present within other medicines or food.

°   Contaminations and adulteration: The herbal based OTC products may be contaminated with excessive or banned pesticides, microbial contaminants, heavy metals, chemical toxins, and for adulterated with orthodox drugs. Excessive or banned pesticides, heavy metals and microbial contaminants may be related to the source of these herbal materials, if they are grown under contaminated environment or during collection of these plant materials. Chemical toxins may come from unfavourable or wrong storage conditions or chemical treatment due to storage. The presence of orthodox drugs can be related to unprofessional practice of manufacturers

°   Improper implementation of pharmacovigilance system: lack of knowledge on pharmacovigilance within practitioner of herbal medicine is another cause of improper reporting of safety issue, which ultimately leading to underreporting and repetition of similar inconveniences. The existing pharmacovigilance system is more based on understanding of synthetic medicines.  Lack of proper terminologies for coding of herbal medicines and adverse effect is causing problems in implementation of pharmacovigilance system.

  

°   Governmental ignorance: Although its being a primary care for health issues in every society, vigorous study couldn’t happen on its safety, potency and efficacy. Without Priority of government and qualified human resource, evidence can’t be collected. That’s why most of the issues and quarries are unresolved yet.  

Proactive approach and Recommendations to overcome safety issue:

°  Quality control and quality assurance: While Overcoming the issues step by step,  quality of final product can be maintained by implementing Quality control system. standard operating procedures (SOP), leading to Good Agricultural Practice (GAP), Good Laboratory Practice (GLP), Good Supply Practice (GSP) and Good Manufacturing Practice (GMP) for manufacturing these medicinal products from herbal or natural sources. The public's belief that herbal and natural products are safer than synthetic medicines can only be ascertained by imposing regulatory standards on these products that should be manufactured using these Good Practices. Government of Nepal also made GMP compulsory for manufacturers of Ayurveda medicines also.  

°  Clinical research: Even small voice with authentic reference is always louder than yelling without facts. Vigorous research activity should be conducted to collect sufficient evidence for crystallization of useful herbs as medicine. Available research methodologies can be used in Ayurveda practice also. Proper data on level of efficacy, safety, dose, dosage and interactions with other medicines will also be known during research process.

°   Use of pharmacovigilance system: The recommended approach is to include herbal medicines in the existing national pharmacovigilance systems or, where such systems have not yet been developed, to establish comprehensive national pharmacovigilance systems, which incorporate coverage of herbal medicines. Regional and national reporting centres are the same, databases used to analyse adverse reaction in herbal medicine is also same, but coding system might be different. Appropriate name for different Ayurveda terminologies are required.

° Professionalism: Clear recommendation of professional competency should be made for herbal medicine practitioner. Those with certified practice license should also be provided knowledge and training on understanding and reporting any expected or unexpected adverse reactions. Ethics of any practitioners comes at the primarily than any law and enforcement.

°  Enhancing reporting system: Report of adverse events is found mainly based on voluntary physician reporting. Other health professional like pharmacist, nurses are normally excluded. This largely led to underreporting. It should be established to report suspected event by all health professional not only for medicinal product but also for nutritional supplements.

°  Consumer consciousness: Consumers are mainly responsible for reporting event to their physician and any practitioner who prescribed medications. Patient and consumer education for prompt reporting will also help to generate signal.

° Use of prescription drug: Prescription based treatment system should be enforced from government level as compulsory in herbal medicine also. It will discourage self-medication and finally controls underreporting.

Member States of the World Health Organization (WHO) including Nepal are therefore encouraged to strengthen their national regulation, registration and quality assurance and control of herbal medicines. In addition, the national health authorities should give greater attention to consumer education and to qualified practice in the provision of herbal medicines.
                                                          thank you!!!

CURRENT STATUS OF SAFE PHARMACEUTICAL PRACTICE IN NEPAL.

Medicine safety is one of ever debating agenda universally since history of medicine itself . In Nepal large number of population is directly under any kind of medication or medicinal product currently. strengthening of healthcare system has taken rapid progress all over the country, specifically since last ten years. in order to achieve ambitious goal of safe pharmacological practice, proper understanding of relevant subject matters is of upmost importance.

Pharmacovigilance is the branch of science that deals with detection, assessment understanding and prevention of adverse effect with pharmaceutical products. This system deals with all medications which are given as treatment, diagnosis or prophylaxis of disease and any kind of medicine safey regardless of  rational or irrational use. 

What is signal detection in pharmacovigilance;

• Signal simply means information about relationship between use of drugs and adverse event after its use. In order to be a signal any reported information should go through validation by subject matter expert based upon other relevant data and scientific analysis. 
• Individual case safety reports (ICSR) are reported through medical practitioners as spontaneous reporting system. it should be valid where detail information about patient, suspected medicinal product, suspected event and reporter should be mentioned. 
• Interpretation of future health impact, reporting to  Uppsala monitoring center (UMC) WHO. here further analysis happens and final report is acknowledged to national centers for implementation of action. for this whole activitirs UMC uses a database called "vigibase" and all member country follows is sub-part "vigiflow". 

The global pharmacovigilance system:

World heath organization has a common goal of safe use of medicine globally. for that purpose,  worldwide PV networks is expanding and currently   more than 150 countries has been actively participation and working toward it. 

• Till date, 134 countries are member of international drug monitoring and 30 associates member countries are in early stages of establishing their PV system , preparing themselves for full membership
• All member countries share a common vision of safe and more effective use of medicines, working nationally and collaborating internationally.
• Nepal is full member since 2006, responsibilities taken by Department of Drug Administration

Current status of PV  in Nepal:

• Department of drug administration (DDA) is working as national authority of pharmaceutical regulations and reporting center  of  pharmacovigilance, under which immediate directions 12 different Regional PV centers are working, Only three of them are out of Kathmandu valley.
• US$ 137 is the per capita expenditure of each Nepalese in health sector, mainly for pharmaceutical product consumption either conventional or alternative
•  According to fiscal year 2018-19 budgeting, 4.13% of total bujget is allocated for health care system, which is third highest in ranking  after education and energy. but still, percentage is lesser than previous allotment. 
• currently 23,108 of registered health practitioners are working (among them 15.671 are doctors only), for prescribing medications including all level level
• according to DDA official website, only 547 adverse reactions are reported so far. 

This data shows a major pitfall of safety concern in practitioner as well as consumer. neither number of regional centers are enough, nor total reported cases. Such condition is refereed as Underreporting in pharmacovilange (PV) science. Quality of reports will be part of another discussion. 

Postive changes for PV system in Nepal

• Release of  Reporting form by DDA: since 2018, adverse event reporting form has been released, it certainly brings quality of data provided and increase easy excess  for reporting
• Expanding number of regional centers: recently two more centers were added. 
• Increasing discourse of safe medicinal practice and consumer consciousness, 

Recommendations to strengthen the PV system in Nepal

1. Incorporation into clinical practice: Every health practitioner should make aware of spontaneous reporting system about what to report, how to report, where to report. adequate  information at academic level and through training should be provided. 
2. Expanding of reporting centers: only 12 regional centers are not enough more centers should be expanded   in each provinces and local level.
3. Consumer education : use of prescription medication, rational use of pharmaceutical products and alertness about reporting system can help to combat underreporting.
4. Design and follow proper SOP (standard operating procedure)
5. Independent pharmacovigilance unit with adequate subject matter experts eg: pharmacist, doctors, researchers, IT experts etc.
6. National guideline for Pv management should be generated from DDA to make harmonization in practice
7. National leveled program by government of Nepal only can make large difference.  For example: India was working in pharmacovigilance since 1997, but result was very unsatisfactory. Since 2004 they initiated PvPI (pharmacovigilance program of India) along with suspected adverse event reporting form and national guideline on  PV management. this program became very effective took a huge leap

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Why Ethics Committee Reviews Research Proposal ?

Institutional Review Board is there in place for  reviewing, approving and providing favorable opinion on research proposal submitted by investigator or sponsor. Purpose and Intention behind all is scientific validity of study and safety of the study participants as research subjects. Members of ethics committee have full authority to probe researcher at any time regardless of progress of study, even they terminate study if continuation of such study found to be more detrimental to the subjects and science. Since, any research activities start after approval from IRB or IEC (independent ethics committee), lot of investigations about the study itself happens at the earliest before providing nod to conduct it. Judgments are made basically on the basis of following factors: 

• Qualification of Investigator in terms of his education and experience. 
• Scientific and safety appraisal of study protocol and other supportive documents
• Informed consent form and Patient information sheets designed to provide to the participants to observe how researchers are providing room for voluntariness over the decision of participants
• Compensation and other benefits provided to the participants
• Advertisement method adopted by the researcher to see if any claims are being made or not. 

 Documents to be Submitted before Study Initiations                  

1. A current curriculum vitae (CV) that includes qualification of investigator and sub-investigator, including education, training and experience.
2. Protocol of  study, which basically describes purpose of study, expected benefits, scientific background for research 
3. Investigators brochure which basically describes about clinical and non- clinical finding on the investigational medicine which is going to be studied
4. Proposed informed consent form which contains all appropriate element
5. Subject advertisement and recruitment method
6. statement of investigator form 1572, which includes all FDA- regulated studies conducted under an investigational New Drug Application (IND) 
7. Grant applications if the study is federally funded
8. Any other specific form or material required by IRB, such as application form

Once application is received  with attached necessary documets, members of IRB/IEC should review them within a reasonable time, make appraisals after enough discussions and final verdict should be  documented in the form of written document. This written statement should clearly mention about the details of the study, documents received and decision taken along with rationality behind it and date of decisions made. Generally decisions of ethics committee can be summerised as follows: 

• Approval to conduct study as per the documents submitted
• Any changes deemed necessary to take the project forward in the form of favorable opinions
• Objection to conduct the study by defining rationale behind the decision
• Termination/ suspension of any previously approved ongoing study

It's always the duty of Investigators and Sponsor to make sure ethics committee that their study is needed for the science and the public in the form of appropriate documents as well as way of conducting it. 

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UNDERSTANDING THE CONCEPTS OF IRB / IEC IN CLINICAL TRIAL. WHY ETHICS COMMITTEE IS CRUCIAL FOR CLINICAL RESEARCH ?

                                       

While conducting clinical trial, the safety of the human subjects comes first. The main two safeguard for human subjects are

• institutional review board (IRB)
• informed consent form

by regulatory definition, IRB is," any board, committee or group formally designated by an institution to review, approve and initiation of and to conduct periodic review of  biomedical research involving human subjects. the primary purpose of  such review is to assure the protection of the rights and welfare of human subjects. " 

International council of harmonization (ICH) defines IRB as, "an independent body constituted of medical, scientific, nonscientific members, whose responsibility is to ensure the protection of the fights , safety and well-being of  human subjects involved in a trial by, among other things, reviewing , approving and providing continual review of trial protocol, and amendments and of the methods and materials to be used in obtaining and documenting informed consents of the trial subjects."

independent ethics committee (IEC) is the body analogue to IRB outside the united state. the former one provides favorable opinions where later gives actual approval of study. 

         Fundamental purpose of establishment of IRB/IEC

• To protect the right, safety and well being of  human subjects participating in research.
• To provide approval of conduct of trial and give favorable opinion.

         Responsibilities of institutional review board (IRB)

1. IRB members must have assurance that the study is scientifically valid, i.e. there should be a properly designed protocol. however, it is not the responsibility of them to judge scientific merit/ worth of trial.
2. IRB should always look for sound research design. only properly designed program helps to minimize risks to human subject. 
3. IRB must compare anticipated benefits in terms of treatment and knowledge gained by research with possible risk might subject have to face. 
4. Should go through selection process of subjects and advertisement plan for study. this review insures that selection is equitable and that no group are excluded / included based on non- study related characteristics. 
5. Informed consent form should be reviewed properly. this should provide basic information related to trial and should state participation is voluntary and not influenced by any claim, greed or threat.
6. special care should be provided to vulnerable subjects. these subjects are those whose voluntariness can be influenced by other non study related factors. these group of specially has diminished autonomy. eg: children, pregnant women, old age patient, hospital staff, military force etc. 
7. consideration of state and local regulations. these are particular to population where study is being conducted and can influence recruitment and retention of  subjects throughout the study. 

DIFFERENCES BETWEEN IND AND NDA SUBMISSION TO FDA. LEARN HOW THESE TWO HELP SPONSOR TO DEVELOP RESEARCH PROGRAMME

Discovery and development of drug is very much systematic and law guided activity. FDA submission and getting approval to conduct drug development activity is what sponsor place on topmost priority. FDA has been enforced rule for submission of pre-clinical safety study data before conducting trial in human subjects and clinical efficacy data for marketing approval. the formal one is called investigational new drug (IND) and later, new drug application (NDA).

here we are going to discuss about some basic characteristics and  differences between these two regulatory submission

• Contents: IND is detail description of all the pre-clinical findings of animal study on particular Investigation new drug (IND) whereas NDA basically requests for permission for marketing of that drug. IND is intended to justify importance of further research in human subject by referring toxicological studies and safety finding, while IND exactly defines how marketing of drug is important for particular disease condition taking into considerations of efficacy finding in human subjects. 

• Time of submission: IND application is submitted after toxicological study, to get permission of administering drug in human, while NDA is submitted after closure of multicentric phase III randomized control clinical trial. 

• extent of regulation: NDA is tightly regulated in comparison to IND. loose regulation in a sense that sponsor can conduct human study at least after 30 days of IND submission even without response from authority. but after once NDA application, regulatory body has to go series of observation and  analysis at multiple level which may take more than a year. duty of manufacturer is within this period is confined to just being available at the time summoned by FDA.  US has developed and enforced a separate code of  federal regulation ( CFR 21 part 314)  for NDA regulations, which every applicants ought to follow. 

NOTE: in case FDA gives authority, one can conduct human study before completion of  animal study, where IND keeps updating with new safety finding.

• Format for content:  this is how IND is formatted:

- single dose toxicity finding in two mammalian species

          - safety pharmacological studies to include assessment of effects on vital functions
          - pharmacokinetic studies  (ADME)
          - repeated dose toxicity studies in two species for two or four weeks, providing phase I studies              will  not exceed two weeks 
        -   local tolerance studies using route of administration relative to proposed clinical                                  administration
          -  Invitro test for evaluation of mutations and chromosomal damage ( Genotoxicity )
          -  carcinogenicity studies only if there is cause for concern

    major scientific evidences in NDA form: 

• formal request for marketing in standard format
• statement that phase III study is completed and necessary safety and efficacy standards are maintained
• summery of final study report
• details of medicinal product, all the site documents along with investigators and sites involved, regulatory procedures followed during study, study protocol, data generated from site. 

  for further information on 21CFR part 314, please refer to this link; https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=314