In past few years, potential of treating many chronic incurable conditions using stem cells has garnered a lot of interest among researchers, physicians and patients. But before we reach that stage, we have to study the science behind it and objectively assess its safety and efficacy on patients in a clinical trial setting. Only after critically assessing benefits over risks, can we consider stem cells as a successful treatment modality.

Stem cell research and clinical trials to establish their safety and efficacy are quite different from that of traditional drug development process. In stem cell therapy there are chances of infection, immune reaction, and abnormal and unwanted growth of transplanted cells leading to tumors etc. Recognizing this, United States Food and Drug Administration (US FDA) scientists are creating suitable techniques for characterization of these products, developing suitable animal models for pre clinical testing and biochemical signals which can be used for assessing safety and efficacy of such products. Such complex drug development also requires new regulatory approaches.

Regulatory framework for stem cell research includes:  

• US -IND regulations (21 CFR 312), biologics regulations (21 CFR 600), cGMP (21 CFR 211), CFR Part 1271  
• EU 3 Directives - Directive 2003/63/EC (amending Directive 2001/83/EC), Directive 2001/20/EC and Directive 2004/23/EC
• Guidelines from International body such as The International Society for Stem Cell Research (ISSCR)
• Central Drugs Standards Control Organization (CDSCO) Guidance Document for Regulatory Approvals of Stem Cell and Cell Based Products (SCCPs)

Regulatory framework of India
ICMR and the Department of Biotechnology (DBT) released “Guidelines for Stem Cell Research and Therapy” in 2007 and revised in 2013. These have been included in the Guidance Document for Regulatory Approvals of SCCPs released by CDSCO in 2014. This guidance considers stem cell as a research and not an established therapy except hematopoietic stem cell reconstitution for approved indications. Thus use of stem cells in patients outside an approved clinical trial is malpractice.

The CDSCO guidance is applicable to all the institutions and investigators carrying out clinical trials and commercial usage of SCCPs. The document is aimed to provide necessary guidance in all the aspects of the usage of SCCPs, from technical aspects of handling the stem cells, to licensing, regulatory submissions, non clinical studies and clinical studies to establish safety and efficacy. Now, all the related activities to stem cells i.e. manufacture/isolation, characterization, culturing, processing / collection, storage and transplantation into patients, sale and distribution of SCCPs are permissible only with required approval/license granted by Drug Controller General of India (DCGI) / CDSCO. All the clinical trials with SCCPs will require approval of the clinical trial protocol from the CDSCO.

The four categories of licenses/approvals issued by CDSCO are:
Category 1: License for collection, processing, storage of SCCP for the purpose of test and analysis
Category 2: Approval of Clinical Trial Protocols for generation of safety and efficacy data
Category 3: Approval/permission for manufacture or import of SCCP as IND/New Drug
Category 4: License for manufacture or import for storage, sale and distribution

Non clinical trials
Non clinical study’s designs and outcome will serve as a basis for designing clinical studies. Based on the clinical indication and characteristics of administered SCCPs, appropriate animal disease model and duration of the study should be used.  The study should ascertain potential mechanism of action, optimized route of administration and dose levels required for attaining efficacy.  

Animal toxicology studies (single dose and repeated dose toxicity) should be carried out in GLP certified facilities as per Appendix III of Schedule Y guidelines, in healthy animals preferably rodent. The study should also assess local toxicity, immune mediated toxicity, pro-inflammatory response, hypersensitivity and developmental toxicology (pregnant and lactating mothers) if needed as per intended clinical use.  A study of at least 6 months should be conducted to check tumorogenicity potential in immune-deficient mice to understand inappropriate cell proliferation and differentiation if any.

Clinical studies specific to stem cell
Because of inherent differences in SCCPs, alternative approaches to Phase I to Phase III clinical trials can be accepted after appropriate justification. Sometimes non clinical studies along with previous clinical experience of the treated pathology and initial clinical studies can be used to demonstrate proof of principle, provided endpoints of non clinical studies can justify safety and efficacy evaluation.

Pharmacodynamics
Exact mechanism of action of SCCPs in a condition may not be known, but the effects of SCCPs needs to be ascertained using suitable pharmacodynamic markers (microscopic, histological, imaging techniques or enzymatic activities). Based on the intended use in patients, functional tests or structural/histological assays can be used. When non cellular component is present in SCCPs; compatibility, degradation rate and functionality also has to be evaluated clinically.

Pharmacokinetics
Schedule of repeated dose administration should be decided after considering expected in vivo life span of SCCPs. They should monitor viability, proliferation/differentiation, body distribution / migration and functionality during the intended viability of the products.

Dose finding studies
The non clinical studies should form the basis of selection of the dose. Phase I/II studies should be designed to ascertain minimum effective dose, optimal effective dose and if possible, also safe maximal dose.  Dosage of SCCPs tested in confirmatory trials (might vary depending on individual characteristics of the intended patients i.e. cell mass density per body weight/volume of missing tissue/missing surface) is based on the results of these dose finding studies.

Clinical efficacy studies
These studies should be able to demonstrate efficacy in target population, appropriate dose schedule required for therapeutic effect, duration of therapeutic effect and benefit-risk assessment. All the general guidelines for confirmatory trials and specific to the disease condition should be followed.

Endpoints for confirmatory trials shouldn’t be different than usually used as per the current disease specific guidelines. All previously validated endpoints including surrogate markers can be used successfully to establish efficacy. In case of long term follow up studies to establish efficacy, surrogate markers or novel meaningful endpoints may be used after sufficient justification. If there is limited guidance available for the new therapeutic indication, then consultation with regulatory authorities, experts from ICMR should be done.  

Clinical safety studies
Being invasive process, safety and risk of the complete therapeutic procedure including the required surgery to administer SCCPs has to be evaluated in the target population. All safety concerns which arose in the previous studies including pre clinical development phase should be addressed in the safety studies. The size of the population should be adequate to assess safety and detect common adverse events as seen in previous clinical experience with similar products.

Long term follow up studies should be conducted to establish long term safety and efficacy. Post marketing studies should have emphasis on biological processes including immune response, infections, malignant transformation, teratogenic effects and concomitant treatment. In case of possibility of repeated dosing in patients, a safety study should also be performed taking maximal safe dose into consideration.

Pharmacovigilance
Long term safety monitoring including lack of efficacy and traceability in the donor-product-recipient axis is required to establish SCCPs as a safe viable treatment modality.

Thus, special safety studies and special pharmacoepidemiological studies may be needed. The specific requirements of such studies should be based on the biologic characteristics of the SCCP. These studies may assess infections, immunogenicity /immunosuppression, teratogenic effects and malignant transformation as well as the in vivo durability of the associated medical device/biomaterial component.

An independent data safety and monitoring process is required for all clinical studies. Complete adverse event reporting, safety update along with appropriate statistical analysis as per Schedule Y and ICH E guidelines should be made available for peer review committee.

Conclusion
CDSCO’s guidance document for SCCPs in adjunct with other applicable guidelines of India should be used for all the clinical trials of SCCPs. The guidelines however don’t give us solutions to many problems. Not all animal models may be applicable for SCCP. Also traditionally used randomized trials with placebo or comparators may also be not possible. The duration of the study and the follow up also may be arbitrary as we may not have sufficient experience with a particular condition/product. We may still be lacking in many aspects but a start in regularizing these studies is definitely a welcome step. We should look into similar guidance documents by other countries to serve as a reference point for us. As the science and research in this field evolves, the legislation and regulatory framework should also change to adapt the changes to come in future.