Burn injuries account for a significant number of deaths and morbidities in India.1 According to the World Health Organization (WHO), around seven million people in India suffer from burn injuries each year that lead to approximately 140,000 deaths and leaves around 240,000 people with disabilities. Of every five burn victims, four are either women or children.2 Burns are the fifth most common cause of non-fatal childhood injuries and the eleventh leading cause of death in children aged 1–9 years.2,3 There are many reasons for this high rate including socioeconomic status, occupational hazard, overcrowding, underlying medical conditions for example epilepsy, alcohol misuse and smoking and use of paraffin as a fuel source.4
Burns are characterised by severe skin damage that causes the affected skin cells to die. Burns are generally classified on the basis of degree of severity; first, second and third-degree and if not appropriately treated can lead to infection at the wound site.
A wound is generally defined as a disruption in the continuity of the epithelial lining of the skin or mucosa.5 To prevent microbial infection and to facilitate the body's natural healing mechanisms, an optimal healing environment and an appropriate wound dressing are required.4
Reasons for death due to burns
The majority of burn injury deaths are caused by complications arising from burns, such as infections, rather than the burn injury itself.6 The majority of patients admitted to hospital due to burn injuries die due to infected wounds.3 There are many possible reasons that lead to wound infection, such as nonavailability of advanced dressings and their high cost which also impacts on their availability; burn injury is a long-term treatment requiring frequent dressing changes, thus further increasing the total cost of treatment. Factors also include lack of awareness in some patients of the need to maintain hygiene, change dressings and to attend doctor's appointments, as well as overcrowded hospitals and unhygienic conditions. Some of the other reasons are described below.7
Low blood volume:
burns destroy the blood vessels, triggering fluids to leave the body. This can lower the volume of blood, termed as hypovolaemia. A severe loss of blood and fluid would stop the heart from pumping adequate volumes of blood through the body.8
Respiratory failure:
large quantities of smoke and hot air inhaled during a fire leads to burning of the airways that cause difficulty in breathing.
Problems with bones and joints:
burn injury can also cause permanent disability as deeper wounds limit the movement of bones and joints. The healed scar tissue starts contracting and pulls together resulting in contracture that also prevent movement in bones and joints.
Burn shock:
occurs when the patient's body does not receive adequate oxygen supply. Treatment is often critical in the prevention of burn injury-related deaths. Burn shock may be caused by hypovolaemia or low blood volume due to damaged blood vessels, it may also occur as a result of sepsis, a response to burn infection.
Burn infection:
one of the leading causes of burn injury death and complication. This is because the skin plays a vital role in protecting the body from airborne bacteria, fungi and other pathogens. In patients with severe burns, open wounds create pathways for pathogens to enter the body and cause infections. Infection may also occur as a result of treatment, such as pneumonia from breathing tubes or urinary tract infections from bladder catheters.9
Wound and burn dressings
A dressing is a medical device that is used to cover wound and burn injuries, to promote healing and further prevent harm. They are also called surgical dressings or bandages but generally, they are different from bandages because they are designed to be in direct contact with the skin.10
Wound and burn dressings include a first layer which remains in direct contact with the wound and is made up of a material which should be bio-absorbable, porous and able to serve as a scaffold for cell attachment and proliferation. The second layer comprises an absorbent, gel-forming material, which serves as a barrier to cell adhesion and penetration.11
There are various types of wound and burn dressings, used for short-term or long-term application. They can be further subdivided by wound type, such as partialthickness until healing occurs, or full-thickness until autografting.
Dressings can be categorised in many ways but the most preferred dressing classification is based on the nature of the material used, either conventional, biological or synthetic dressings. They are subcategorised as:12,13
- Primary dressing: used directly on the injured skin
- Secondary dressing: used to cover the primary dressing
- Island dressing: made up of a central absorbent core surrounded by an adhesive portion, and is applied directly to the wound.
Advanced dressings are named according to the materials from which they are produced, such as hydrocolloids, alginates and hydrogels.
Various types of advanced dressings include: impregnated gauze; transparent film dressings; foam dressings; hydrogels; hydrocolloids; alginates; collagen dressings, and silver dressings.
An ideal dressing should have the following properties:
- It should maintain a moist wound environment
- Permit diffusion of gases as required for regeneration of skin
- Provide postural (mechanical) support to protect body part from injury or infection
- Help maintain temperature and pH
- Low in cost and commercially available
- It should be elastic and biocompatible with the patient's skin tissue
- Should be hypoallergenic and not irritate the skin
- Easily removable and require less frequency of change
- Help to reduce pain, such as being easy to remove without causing pain to the patient
- Easy to apply and remove during wound checks and dressing changes
- Protect the wound from external contamination and microorganisms
- Help manage exudate and prevent dressing saturation from the external environment, for example when the patient is showering.
Various types of wound and burn dressings are available that can help prevent infection and reduce mortality. Although many options are available, research is underway to discover more innovative solutions.12,14Table 1 describes some dressings that are, at the time of writing, under clinical trial.15–25
Table 1.
Dressings under clinical trials
| Product | Innovator/Company | Material | Clinical trail | Reference |
|---|---|---|---|---|
| Dissolvable dressing | Boston University (US) | Hydrogel | Under trial in laboratory rats with second degree burns | 15 |
| Colour change dressing | University of Bath (UK) | Hydrated agarose film | Funds granted for further trials | 16 |
| Fish skin dressing | Federal University of Ceara (Brazil) | Tilapia Fish Skin | Trials on-going on 56 burn patients in 2017 | 17 |
| Smart bandage | Massachusetts Institute of Technology (US) | Hydrogel and LED indicators | Under trials | 18 |
| Microlyte Ag wound dressing | Imbed Biosciences (US) | Ultrathin polymeric film with metallic silver coating | In 2017, FDA cleared MicroLyte Ag for use | 20 |
| Strata graft | Stratatech Corporation (UK) | Living tissue of human cells | Completed clinical trial on 28 patients | 23 |
| Omega3-rich fish skin | Keresis (US) | Omega3-rich fish skin | Under clinical trial since 2016 | 24 |
| Restorative oxygenation technology | Mednoxa (US) | Oxygenation in skin | Received funds to develop the technology in 2017 | 25 |
| Smart scar pad | Department of Rehabilitation Sciences, PolyU (China) | Pressure therapy and silicone gel | Clinical trial (2017) results showed the pads are effective | 53 |
| Wood based gel dressing | Indian Institutes of Technology Kharagpur (India) | Unique water-based gel, wood is main component | Under clinical trials | 54 |
Critical analysis
A critical analysis was conducted of 54 research and review articles, including regulatory guidelines in India. The purpose was to:
- Understand how traditional and advanced dressings are approved in India
- Understand the laws applicable to the import and export of dressings
- Understand the gaps in existing regulations
- Guide the manufacturers/innovators on how to file their applications under the right category for the approval of their product/devices/dressings to health authority.
Structured search of bibliographic databases (such as CFR 21, volume 8, subchapter H, United States Food and Drug Administration) for previously published peer-reviewed research papers, review articles and regulatory guidelines were explored and data was culminated to understand the regulatory status of surgical dressings.
Table 2.
Major imported advanced dressings
| Product | Product name (manufacturer) | Market share of the dressing in India % |
|---|---|---|
| Hydrogel | Aquasite, ReliaMed, Anasept, Flex derm, Nu-Gel (Dow Hickam, Johnson & Johnson) | 22% |
| Collagen | Prisma, Promogran, Stimulen (Systagenix) | 32% |
| Film dressings | Tegaderm (3M), Pro-clude, Polyskin II, ProCyte film (proCyte) | 10% |
| Foam dressings | Biatain, Tegaderm, Restore, Optifoam, Mepilex, PolyMem, Cura form (3M) | 17% |
| Alginate dressings | Bioguard Roll gauze, Kerlix AMD, Algicel, Melgisorb (Kendall) | 6% |
| Others combined total | 4% | |
| Hydrocolloid dressings | Biopad, Tegasorb, Comfeel, Hydrocoll, Varihesive E, Medihoney tube (Coloplast/Sween) | |
| Artificial skin and skin substitutes | Biobrane, TransCyte (Smith & Nephew) | |
| Fibrin-based sealants | Fibrin-coated wound dressing (3M) | |
| Collagen-based sealants | Regranex, Autogel, Multidex gel (Smith & Nephew) | |
| Anti-infective dressings | Silver dressing, Algidex, Aquacel Ag (DeRoyal) | |
| Conventional negative pressure wound therapy | Vacuum Assisted Closure (VAC) therapy, Vista Versatile (Boehringer Wound Systems LLC), Engenex | |
| Oxygen and hyperbaric oxygen equipment | OxyHeal (OxyHeal Health Group) |
Table 3.
Changes in registration process for dressings after 2017
| Point | Old regulations | New regulations |
|---|---|---|
| General overview | Largely unregulated. Tough challenges faced to place advanced dressings on market Only CE mark and US Food and Drug Administration (FDA) approved products allowed to enter the India market | Possibility of strong, sustainable and technically sound domestic industry. India has its own regulatory approval procedures. Manufacturers do not need foreign regulatory/marketing approval. Should limit the cost required for approvals to market in India |
| Regulatory perspective | Dressings are regulated as a ‘Drug’ under Drugs and Cosmetics Act 1940 and Drugs and Cosmetics Rules 1945. No specified dressings were listed. Nascent regulatory framework. Classified under notified medical device | Advanced dressings are now well defined in the new medical rules of 2017. Robust regulatory framework. Well defined categorised classifications based on risk as A,B,C and D, where A and B are low-risk devices |
| No Internet procedure for application filing | Entire process from submission to grant of permission/license processed through Internet electronic platform | |
| No defined approval procedure, no list of required documents, no audits and no renewal requirements | Defined approval procedure, list of documents per product classification and audits of the manufacturing facility and renewal requirements | |
| Quality-audit, registration and renewal | No audits of facility required | Audits required ensuring a standard quality of product reaches consumers. Facilities required to be in line with the new rules |
| Registration and renewal | No assessment required from the third party | Third Party Conformity Assessment and Certification through government-appointed notified bodies |
| High import dependency | Dressings can obtain marketing approval from Indian medical device regulating authority | |
| Unfavorable duty structure | All duties of the manufacturer, importer, exporter, auditor clearly explained | |
| Inadequate quality standards and most Indian made products found not in compliance with standards | Quality documents are required to be maintained at the manufacturing site and list of required documents defined to obtain approval | |
| Registration certificate and approval valid for three years | Fee payable every five years and no renewal required | |
| Application applied in Form 40 and registration issued in Form 41 | Selection of application form depends on the type of medical device | |
| Manufacture, distribution and sale, import and export | Not well defined | Well defined. Special forms are available to apply |
| Regulations applicable to drugs are applicable, unmet clinical regulations | Separate provisions for regulation of clinical investigation (clinical trials) of investigational medical devices (i.e. new devices) | |
| Periodic renewal is required | License is valid unless suspended, canceled or surrendered | |
| Labelling and shelf life | No evidence required | Not to exceed five years from the date it was manufactured unless the Central Licensing Authority extends it upon receiving satisfactory evidence. New labelling provisions are provided |
Market availability of advanced dressings in India
Market availability of good quality health-care products generally depends on the regulatory approval procedures and regulatory guidelines in the concerned country. Greater clarity on the guidelines and procedures involved in bringing a product to the market, may mean manufacturers and innovators would be more forthcoming in the launching of such advanced dressings.
The Indian wound care market is growing at a compound annual growth rate (CAGR) of 7.4% which is higher in comparison with the rest of the world.26 The year-wise growth in the number of companies manufacturing traditional and advanced dressings between 2005 and 2017 is shown in Fig 1. Advanced wound dressings constitute a major market share of the wound dressings market and the market in India is dominated by international companies, this is expected to rise.27 Key factors responsible for this growth are rising levels of chronic disease, a growing geriatric population, increased health-care expenditure and patient awareness about their health, rising incidents of wound infection and growing demands from emergency cases. Growing demands for more economic advanced dressings and an increasing focus on the development of combination dressings is projected to enhance the growth of India's wound dressing market.28
Market trends of wound care dressing manufacture
The wound care market in India is still in a growth phase and Johnson & Johnson has emerged as the market leader, in terms of revenue. Smith & Nephew and Datt Mediproducts are the next two leading companies.29 These companies have a strong portfolio and distribution system, supported by promotion strategies that enable them to keep hold of their market share.30–37 Thus, the wound care market is dominated by foreign-approved advanced dressings, most of which are imported, increasing the final cost of the product and putting it beyond the financial reach of people on low incomes.38 Manufacturing and approval of wound dressings in India is, therefore, required.
This article details approval procedures for developing wound dressings so that innovators can launch such products in India.
Dressings in India before and after the new rules
In 2017, India's Ministry of Health and Family Welfare published the Medical Devices Rules 2017 (implemented January 2018). It contains a total of 97 rules.39 Before its enactment, dressings were regulated by the Central Device Standard Control Organization (CDSCO) and followed the regulations laid down in the Drugs and Cosmetics Act 1940 and Drugs and Cosmetics Rules 1945.40 Some differences between the new and old rules are provided in Table 3.13,41–45 Previously, import and manufacturing registration application required only a few documents, however, this was revised by the Medical Device Rules 2017 (Table 4 and 5). The dressings have been classified as A, B, C and D, based on their associated risk (Fig 2 and 3).37 This will help manufacturers to more easily categorise their dressing easily.
Table 4.
List of application forms required to apply for dressings approval in India
| Description | Form number |
|---|---|
| Application for grant of certificate of registration of a notified body | Form MD1 |
| Application for license to manufacture for sale and distribution for Class A or Class B dressing | Form MD3 |
| For Class C or Class D or (ii) Class A or Class B, and Class C or Class D | Form MD4 |
| Application for grant of loan license to manufacture for sale or for distribution of Class A or Class B dressing | Form MD5 |
| For Class C or Class D or (ii) Class A or Class B, and Class C or Class D | Form MD6 |
| Application for license to manufacture for sale and distribution of (i) Class C or Class D or (ii) Class A or Class B, and Class C or Class D dressing | Form MD7 |
| For Class A or Class B or Class C or Class D dressing | Form MD8 |
| Form in which the audit or inspection book shall be maintained | Form MD9 |
| Application for issue of import license to import dressings | Form MD12 |
Table 5.
List of documents required for manufacturer registration and for importation of dressing
| Class A dressings | Class B, C and D dressings | Dressings other than predicate |
|---|---|---|
| For manufacturing | ||
| Device description | Constitution details of domestic manufacturer or authorised agent | Data analysis |
| Intended use | Site or plant master file | Design input/output documents |
| Specification | Device master file | Mechanical and electrical test results |
| Working principle and use of novel technology if any | Essential principle checklist for demonstrating conformity for safety and performance | Reliability test results |
| Label package inserts | Quality control data | Validation of software |
| User manual | Signed undertaking agreement stating the manufacturing site is compliant with schedule | Performance test results |
| Summary of alternative dispute resolution | Biocompatibility test results | |
| Site master file | Risk management data | |
| Firm details | Animal performance data | |
| Signed undertaking agreement | Pilot and pivotal clinical investigation data | |
| Regulatory status and restrictions in use | ||
| Proposed instructions for use | ||
| For importation | ||
| Copy of overseas manufacturing site or Free Sailing Certificate | ||
| Copy of quality of management system | ||
| Self-attested whole sale license | ||
| Copy of latest inspection report | ||
Classification of dressings Class A and B
Classification of dressings class C and D
Role of state and central government in the regulatory approval process
The State Drugs Controller serves as the State Licensing Authority. It is the competent authority for the enforcement of rules relating to the manufacture of Class A or Class B (low to low-to-moderate risk) dressings and the sale, stocking and exhibition of dressings and other related functions. Class C and D (moderate-to-high to high risk) dressings are regulated by the Central Licensing Authority (CLA), which oversees the clinical investigation and performance evaluation of dressings, as well as other related functions. If the manufacturer intends to produce dressings where safety and effectiveness are already well defined and the product is already a legally marketed dressing (a predicate dressing), the manufacturer must receive approval from the CLA before applying to the State Licensing Authority (SLA). Fig 4 and 5 present the requirements for receiving marketing and import approval.41
Regulatory approval process for manufacturing, sale and distribution
Discussion
Several leading research institutes in India (including the Indian Institutes of Technology, Birla Institute of Technology and Science, National Institute of Pharmaceutical Education and Research and other universities and colleges) are conducting pioneering research in an effort to develop improved dressings options. Despite several good publications and innovative research/patents filed by researchers in India, none of these were commercialised or lead to products.46 A barrier is the complexity of the regulatory approval process.13 Furthermore, critical input from inventors, manufacturers, doctors, chemists and patients make it clear that regulatory hurdles play a major role in denying the availability of advanced wound care and burns dressings to patients in an economical and affordable manner.13 Though Amendments to the Drugs and Cosmetics Act 1940 were made in 2017 and the Medical Devices Rules was introduced in India in January 2018 to simplify the approval of advanced wound care and burn dressings, challenges still remain and need to be addressed.
Some practical approaches to speed up approval for innovative dressings are suggested. E-filings, consisting of automated software enabling dossier preparation and Internet filing, based on the procedures used by US and European Regulatory Authorities, can be a cost-effective approach for individual inventors and manufacturers. Improving access to consultants or professionals trained in the area of regulatory affairs can greatly simplify the process and ensure quick commercialisation of innovative dressings.47 A similar approach could be followed by the regulatory authorities so that regulatory consultants/professionals are easily accessible and can facilitate rapid approval of advanced and innovative products, where appropriate. Lastly, the regulations and approval procedure should be harmonised to develop an effective mechanism that ensures those with the lowest incomes also have access to the best available wound dressings, in an affordable and cost-effective manner.
The Medical Device Rules 2017 has many unique features that favour the growth of the advanced wound dressings sector in India and are expected to fill the legislative gap that exists for dressings due to the absence of proper legislation in India. The Government's audit facility included in the 2017 rules will ensure higher quality products enter the advanced wound dressing market in India.13 Furthermore, the entire regulatory process, starting from the initial submission of a pre-market application or marketing authorisation, will be processed through an Internet electronic procedure.
An additional effect of the rule is the shortened timeline for new innovative products to gain marketing authorisation. Therefore, it is expected that many new products and multinational corporations will enter the Indian market.13 The streamlined regulations are expected to attract investors from around the world and because of the streamlined rules and improved government oversight, the quality and range of products and services should improve to better serve the citizens of India.
Importance of consultants/professionals trained in regulatory approval
The field of regulatory approval is a specialised field which requires extensive documentation, interaction with the appropriate technical staff to collect data, knowledge of rules, amendments and current procedures.48,49 Although the process could be carried out by anyone, it would be beneficial to manufacturers if trained professionals/consultants are available and duly empanelled by the approving agency. Furthermore, the approving agency can conduct training and certify people to assist with documentation and submissions, for example, to ease the process of approval. Recognising the importance and need for trained professionals in the field of regulatory approval, several universities in India introduced a specialisation in ‘regulatory affairs’ at postgraduate level.50,51
In the context of protecting innovations and inventions, for example, in the area of advanced wound care and burns, the inventors should have easy access to qualified and trained professionals who can draft the patent specifications and submit to the patent office for approval.
Such persons are duly empanelled by the Patent Office as ‘Patent Agents’ and their names and addresses are displayed on the Patent Office website.52 Furthermore, their qualifications for the work are well-defined. All patent agents must be graduates in science and must pass a patent agent exam, which tests their knowledge about the Patent Act and also the necessary skills in interpreting an invention and drafting patent specifications. Thus, a trained and skilled resource of professionals is available for inventors to assist them in protecting their innovations. Unfortunately, such resources are not available to manufacturers to navigate the regulatory approval process. There is no process for the empanelment of qualified regulatory professionals to ease and facilitate the approval process. Table 6 gives a comparison of resource availability for invention protection and invention regulatory approval.
Table 6.
Comparison of resource availability for invention protection and invention regulatory approval
| Description | Invention Protection | Invention Regulatory Approval |
|---|---|---|
| Mechanism | Patent under the Patents Act 1970 | Approval Certificate under the Drugs and Cosmetics Act 1940 (and rules thereunder 1945) |
| Human Resources | Patent agents- approved by patent office after examination. Prescribed qualifications include graduation in science and successfully qualifying a national level exam conducted by patent office. Exam consists of written test and interview | No system exists- for approving any regulatory professionals, who can assist manufacturers who want to manufacture innovative and advanced devices, indigenously e.g. by in-licensing technology from Indian Institutes of Technology, universities in India or even abroad. |
| M.Pharm (Regulatory Affairs) persons can be empanelled by Central Drugs Standard Control Organization (CDSCO), after conducting training and test. Further, fee structure can be streamlined and made transparent to facilitate budgeting in terms of expenses on regulatory approvals, as part of overall budget of innovation development | ||
| Academic Support | Nil but still qualified professionals available on public platform i.e. patent office website Patenting as a subject is not taught in medical, engineering and research institutes. It falls under Intellectual Property Rights which is a subject taught in law schools. Some universities have started basic courses/diplomas etc. for science professionals, to help them qualify the patent agent exam | Well-Established but not accessible to industry in easy and convenient manner on public platform. No listing on CDSCO website of qualified professionals Professionals passing out are either hired by multinationals or switch careers |
| Industry support/support from other qualified professionals | Existing patent agents also conduct coaching/classes for science professionals who want to become patent agents. They also act as adjunct faculty for universities/colleges offering courses in patent drafting etc |
Conclusion
At present, India lacks stringent guidelines to assess and regulate the quality of wound dressings being marketed. Major impediments to its successful implementation is neglect of this issue by the government, lack of input from physicians in the development process and lack of awareness among patients on the cost benefit of adhering to treatment. Hence, there should be industry-oriented guidelines, provided by the Indian government, that can inspire manufacturers to innovate and establish more manufacturing units in India to produce high-quality, less costly wound dressings.
A programme of patient education, such as shortterm courses, should be implemented for patients that supports them in taking the best possible care of their wounds, including information about the healing process, selection of the correct dressing for their type of wound or burn injury, its cost and the importance of keeping the wound area clean.
The Government in India should establish a research and development scheme to attract industry and academia to consider how best to innovate products that are produced locally, as well as develop a practical postgraduate curriculum or diploma syllabus on regulatory guidelines. This would increase the number of trained professionals in this field, potentially making them more accessible. Innovators and manufacturers would be supported in getting their product registered with the health authority, with the ultimate aim of reducing preventable morbidity and mortality as a consequence of burn injury.
Reflective questions
- Where and what type of applications should be submitted to state and central regulatory body?
- Why is there an urgent need of quality regulatory guidelines?
- How should the advanced dressings be classified - what are the key criteria?
Procedure for import of dressings