REQUEST FOR PROPOSAL RFP –  023731 – PHARMACOKINETIC STUDY FOR ORALLY INHALED MEDICINAL PRODUCTS

In connection with the co-financing of the projects entitled:

1. “Development, clinical confirmation of bioequivalence and implementation of a new generation ternary fixed-combination inhaled drug in the systematic therapy of COPD” –agreement no. 2022/ABM/04/00011 – 00,
2. “Development, clinical confirmation of bioequivalence and implementation of a new generation fixed-combination inhaled drug in the systematic therapy of COPD” –agreement no. 2022/ABM/04/00012 – 00,
3. “Development, clinical confirmation of bioequivalence and implementation of a new generation fixed-combination inhaled drug in the systematic therapy of respiratory diseases Asthma and COPD” - agreement no. 2022/ABM/04/00013 – 00,

financed by the Medical Research Agency pursuant to § 8 of the co-financing agreement, Adamed Pharma S.A. invites to submit tenders for the below-defined service.

Subject of the Tender:

Conducting a pharmacokinetic study comparing the exposure of two different batches of the reference product (used in the treatment of asthma and COPD) to two registered medicinal products (used in the treatment of COPD) containing the same active substances (one or two) as the reference product.

Study Sponsor (Contracting Authority): Adamed Pharma S.A.   

The company stipulates that disclosure of the full details concerning the subject (including Appendices no. 2-11) will be done after signing of confidentiality agreement which is attached to this inquiry (Appendix no. 1). Contractors with whom a confidentiality agreement has already been entered into must provide a signed agreement before full information regarding this request for proposal can be disclosed to them.

On order, the execution of which is planned in accordance with the timeframe presented in the point 9, consists of:

1. Realization of requested pharmacokinetic study (including submission of application along with the study documentation for obtaining legal approvals, clinical, bioanalytical, pharmacokinetic (PK) and statistical part, data management, medical writing, preparing a report and study management).
2. It is assumed to conduct the following study:     ​

   Pharmacokinetic study
   Investigational products	The reference product (two different batches) - inhalation powder at one strength which contains two active substances, administered by inhalation Registered medicinal product (I) - inhalation powder at one strength which contains three active substances, administered by inhalation Registered medicinal product (II) - inhalation powder at one strength which contains two active substances, administered by inhalation
   Study design	Randomized, open-label, single dose, four-period, cross-over pharmacokinetic study under fasting conditions.
   Study objectives	Evaluation of pharmacokinetics parameters: AUC(0-t) i Cmax (primary), tmax (secondary), AUC(0-∞), AUCres,  λz, and t½ (additional) of active substances. Intra-subject variability evaluation (Intra-CV%) of active substances. Based on the actual variability observed in the study, adjusting the size of the group of subjects in subsequent planned clinical trials. The obtained results can be used to perform the in vitro - in vivo correlation.

3. It is assumed to conduct the following activities: 

   • to prepare the study design according to EU requirements for orally inhaled products and other EMA guidelines,
   • to prepare the essential study documentation (Protocol, ICF, CRF, Instruction for use of IMPs, Instruction for training with the In-Check Dial, and other documents required for study approval),
   • to prepare the redacted version (blinded) of essential study documentation for publication (if applicable),
   • to prepare Investigator`s Brochure (if necessary),
   • to represent the Sponsor in Competent Authorities (CA) and Ethics Committee (EC) (if applicable),
   • to submit the study documentation and obtain CA and EC (if applicable) approvals, including fees,
   • to submit study documentation`s Amendments on the request of CA and EC (if applicable), including fees (if applicable),
   • to translate CA/EC approval and comments into English (if applicable),
   • to conduct of the clinical part of the study including study subjects training in IMP administration, all medical, safety and laboratory assessments, PK sampling and remuneration to subjects and study personnel,
   • to prepare randomization schedule,
   • IMPs labelling per individual subjects according to the randomization schedule and dispensing (Sponsor will provide IMPs in multi-subject packs),
   • to return IMPs to the Sponsor or destruct at the CRO (certificate or confirmation of destruction is required),
   • to ship PK samples to the analytical laboratory,
   • to conduct the analytical method development and validation (in accordance with the current EU guidelines, in particular with ICH guideline M10 on bioanalytical method validation and study sample analysis (EMA/CHMP/ICH/172948/2019, 25 July 2022) including preparation of Validation Report – if the Tenderer does not have a validated analytical method for active substances,
   • to conduct the samples analysis according to the analytical methods validated in accordance with the current guidelines, in particular with ICH guideline M10 on bioanalytical method validation and study sample analysis (EMA/CHMP/ICH/172948/2019, 25 July 2022) (the validation report has to be delivered to the Sponsor),
   • study and data management, Quality Control and Quality Assurance including internal audits of documentation and processes during the study (the internal audit certificate has to be a part of the Study Reports),
   • to perform pharmacokinetic and statistical analysis (ANOVA) and prepare the statistical report, (if the study will be conducted in groups, additional calculations including group effect assessment should be conducted for informational purposes only),
   • to provide the pharmacokinetic data in a suitable electronic format (e.g., Excel format),
   • medical writing and preparing of the Clinical Study Report according to ICH-E3 guideline: Note for Guidance on Structure and Content of Clinical Study Reports (CPMP/ICH/137/95, July 1996),
   • to provide to the Sponsor the paper version of the Clinical Study Reports along with CRFs (if only electronic version is included, please specify),
   • to provide the electronic version of the Clinical Study Reports and CRFs, 
   • to prepare and submit to the Sponsor the study summary (part of module 2.7.1) as required by Appendix IV of the “Guideline on the Investigation on Bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1): Presentation of Biopharmaceutical and Bioanalytical Data in Module 2.7.1.”,
   • to archive the study documentation for at least 25 years after the study completed,
   • to store the back-up plasma samples for at least 3 months from the date of the Clinical Study Report,
   • to ensure COVID-19 epidemiological safety measures e.g., study related RT-PCR testing for volunteers, gloves, disinfectant etc., (if applicable),

4. The offered study should be designed and conducted in accordance with current European Law and EMA guidelines:

   • Good Clinical Practice (ICH GCP (R2)),
   • the basic principles defined in the EU Clinical Trials Directive 2005/28/EC, 2001/83/EC and Regulation (EU) No. 536/2014 of the European Parliament and of the Council (if applicable),
   • Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1/Corr**, 20 January 2010),
   • Guideline on the requirements for clinical documentation for orally inhaled products (OIP) including the requirements for demonstration of therapeutic equivalence between two inhaled products for use in the treatment of asthma and chronic obstructive pulmonary disease (COPD) in adults and for use in the treatment of asthma in children and adolescents (CPMP/EWP/4151/00 Rev. 1,  22 January 2009),
   • the principles enunciated in the World Medical Association Declaration of Helsinki (Fortaleza, Brazil, October 2013),
   • the principles of GLP,
   • ICH guideline M10 on bioanalytical method validation and study sample analysis (EMA/CHMP/ICH/172948/2019, 25 July 2022),
   • Note for Guidance on Structure and Content of Clinical Study Reports (CPMP/ICH/137/95, July 1996).
5. The Contracting Authority proposed the study design including the number of blood samples and the minimum number of subjects to include in the study in Appendix no. 4. The Contracting Authority reserves the right to change the study design in case new data related to study design becomes available. The Tenderer may also propose his owns study design, specifying relevant parameters with justification to change.
6. The Tenderer has to complete information included in section III. GENERAL INFORMATION ABOUT THE STUDY (please refer to Appendix no. 3).
7. The contract between the Contracting Authority and the Tenderer must cover the entire service provided in the Subject of the tender. Contracts for part of services will not be accepted.
8. The contract concerning the realization of the requested study will be signed with maintaining the proposed conditions presented in the current tender procedure.
9. The offer shall take into account the following timeframe:           ​

Deadlines indicated above are counted based on the estimated availability of IMPD/certificates of analysis. The Contracting Authority may change the timeframe for the implementation of the research adopted in the request for proposals, taking into account the progress of work in the project.

Conditions for participation in the proceedings:

1. Orders cannot be awarded to entities affiliated personally or financially with the Contracting Authority. Through financial or personal connection, we understand the interactions between the Contracting Authority or persons authorized to enter into commitments on behalf of the Contracting Authority or persons performing on behalf of the Purchaser activities associated with the preparation and the procedure for selecting Suppliers and Supplier, in particular by:
   1. participation in the company as a partner or partnership,
   2. owning at least 10% of the shares,
   3. the functions of a member of the supervisory or management, proxy,
   4. remaining married in consanguinity or affinity in a straight line, second-degree consanguinity or affinity of the second degree in the collateral line or by adoption or guardianship.
      ​In order to fulfill this condition a Tenderer is obliged to send with the offer signed statements about the lack of connections (Appendix no 2 to this RFP).
2. Orders cannot be awarded to:
   1. a Contractor referred to art. 7 sec. 1 indicated in lists specified in Regulation no 765/2006 and Regulation no 269/2014 or entered in list on basis of a decision on entry in the list deciding on application of measure referred to article 1 point 3 of the Act of April 13, 2022 on special solutions in field of counteracting supporting aggression against Ukraine (Polish Journal of Laws no 835).
   2. a Contractor whose beneficial owner within meaning of the Act of 1 March 2018 on counteracting money laundering and financing terrorism (Polish Journal of Laws no 593 and 655) is a person indicated in lists specified in Regulation 765/2006 and the Regulation 269/2014 or entered on  list or being such a beneficial owner from February 24, 2022, provided that it was entered on list on the basis of a decision on entry in the list determining application of measure referred to in art. 1 point 3 of the Act of April 13, 2022 on special solutions in field of counteracting supporting aggression against Ukraine (Polish Journal of Laws no 835);
   3. a Contractor whose parent undertaking or subsidiary entity within the meaning of Art. 3 sec. 1 point 37 and 39 of the Accounting Act of 29 September 1994 (Polish Journal of Laws no 217, 2105 and 2106) is an entity indicated in the lists specified in Regulation 765/2006 and Regulation 269/2014 or entered on the list or being such a parent undertaking from February 24, 2022, provided that it was entered on list on the basis of a decision on entry in list determining application of measure referred to in art. 1 point 3 of the Act of April 13, 2022 on special solutions in field of counteracting supporting aggression against Ukraine (Polish Journal of Laws no 835).
      In order to fulfill this condition a Tenderer is obliged to send with the offer signed statement (Appendix no 10 to this RFP)
3. This offer is addressed to Entities:                                                                                                     
   1. Declaring conducting offered study in accordance with current European Law for orally inhaled products and other EMA guidelines. The Tenderer is obliged to send a relevant statement (Appendix no. 5).
   2. Having capability to recruit male and female subjects, capable of using one of contraceptive methods, to the offered pharmacokinetic study. The Tenderer is obliged to send a relevant statement (Appendix no. 6).
   3. Having certificates confirming conduct of their work in accordance with GCP/GLP requirements or list of the positive GCP/GLP results of EU inspections with short summary of the outcome (number of the findings and their category). Certificates or the list should be sent with the offer.
   4. Having inspection history of the European Regulatory Authorities with lack of the critical findings in the last 4 years. List of the inspections with a short summary of the outcome (number of the findings and their category) should be sent with the offer.
   5. Having the necessary knowledge and experience in bioavailability studies for orally inhaled products (including bioequivalence studies). The Tenderer is obligated to send relevant statement and list of conducted at least 6 bioavailability studies for orally inhaled products in the last 3 years.
   6. Having the experienced staff competent for conducting the study. 
      • CV of the Principal Investigator and CV of Pharmacokinetic/Statistician should be sent with the offer. CVs should include list of trainings which they took part in the last 3 years.
      • For the Principal Investigator and Pharmacokinetic/Statistician it is required to have experience in conducting of at least 6 bioavailability studies for orally inhaled products in the last 3 years (list of the studies is required). 
      • The Principal Investigator must have GCP training which should be documented in CV or by GCP certificate.
   7. Having capability to supply the required services in accordance to all RFP requirements. To prove it, Tenderer shall send: company’s organigram and information on the facility (number of beds, number and qualification of the personnel and list of clinical and bioanalytical equipment).
   8.  If it is necessary to conduct the study in groups, the cost of additional statistical analysis including the group effect (conducted for informational purposes only) should be presented in Appendix no. 3.
   9. Having a validated analytical method or being able to validate analytical method (before the start of the clinical part of the study) for determination of the active substances contained in investigational medicinal products in human plasma. The validation should be done in accordance with the current guidelines, in particular with ICH guideline M10 on bioanalytical method validation and study sample analysis (EMA/CHMP/ICH/172948/2019, 25 July 2022). The Tenderer is obliged to send a relevant declaration (Appendix no. 7).
   10. Having an insurance policy and submit documentation confirming the validity of the insurance.
   11. Having a Quality Assurance system compliant with GCP/GLP requirements. The Tenderer is obliged to send a relevant statement (Appendix no. 8) and a list of current Standard Operating Procedures (SOPs).
4. The Tenderer may use the services of subcontractors to perform all, or part of the services presented in this request for proposal. The Tenderer is obliged to ensure that his subcontractors meet the requirements contained in this request for proposal. In order to confirm the qualifications of subcontractors, the Tenderer must provide documents confirming their ability to perform the services entrusted to them as stated in section II.3. Subcontractors must have a current GCP/GLP certificate or present the inspection history of relevant authorities in the field of GCP/GLP with a brief summary of their results (number and categories of findings). The Tenderer is obliged to conclude an appropriate contract with subcontractors.
   Supplementary orders may be submitted to the selected Tenderer only if they are consistent with the main purpose of this contract, with a value not exceeding 50% of the value of this contract.

Terms and methods of offer submission 

1. The title of each correspondence should include the number of the procedure
   RFP - 023731– Company name
   
   Deadline for submitting Offer is 10.05.2023 at 23:59 CET. The deadline may change, all Suppliers will be informed by e-mail from the Procurement System. 
   
   Questions may be submitted to the Adamed Procurement System at https://supplier.ariba.com, using the sheet Appendix_9_RFP_023731_Questions_ [Company Name]. Questions will be answered until the end of the procedure. Late submission of questions from the point of view of the closing date of the procedure may result in a lack of time to provide the required answer. In order to ensure equal access to information to all Bidders participating in the procedure, questions and answers (concealing the author of the questions) will be sent to all Bidders
2. Any Supplier may submit only one offer. 
3. Partial bids are not allowed. 
4. The offer should be prepared on the excel spreadsheet which constitutes Appendix to this offer: Appendix_3 _RFP_023731_Proposal [CompanyName]. If Appendix 3 is not filled out, the offer will not be considered.  All unit costs in Appendix no. 3 should be completed if they make up the total cost of the study.
5. All required appendices, declarations and documents must be attached to the tender - the Bidder also attaches a completed and signed checklist (Appendix 11) to the enquiry to confirm that all required documents have been provided.
6. Offer along with the required attachments, may be submitted to the Adamed Procurement System at https://supplier.ariba.com.
7. In addition, the Bidder may also prepare an offer in his own preferable format and upload it into the system. 
8. Access to the Procurement System SAP Ariba Network the Supplier obtains through the registration to verify the existence of the company. Basic information such as country, tax identification number, postal code, contact details, etc. should be provided. 
9. Supplier's Offer should be comprehensive in Polish or English, electronically. 
10. The offer should include at least the following information: Supplier name, address, TAX / registry number, bid inquiry number, date of proposal, price net (PLN/EUR), payment terms, timelines).
    The Tenderer should provide in Appendix no. 3. the detailed timeframes for study realization, specifying an estimated time required for obtaining of CA and EC (if applicable) approvals, proposed dosing dates, preliminary results delivery and draft of the clinical study report delivery (including all required appendices). The cost as well as the timelines are important in the selection of the most advantageous offer. The documents for orally inhaled products (OIP) which are required by Competent Authority and Ethics Committee for submission should be listed in Appendix no. 3. 
11.  If the prices in the offer are expressed in EUR they will be converted using the exchange rate of 4,4536 PLN/EUR, in accordance with the Notice of the President of the Public Procurement Office of 3 December 2021 on the current EU thresholds, their PLN equivalent, PLN equivalent of amounts expressed in EUR and the average PLN / EUR exchange rate constituting the basis for converting the value of public contracts or design contests. 
    ​In the case of another currency than PLN or EUR, the average NBP exchange rate from the last day of submitting offers will be accepted for conversion.
12. Prices in the offer should be expressed as net prices in Polish zloty (PLN), Euro (EUR). The offer should include the total cost of the requested study, including pass-through costs (if applicable). 
13. Tenders submitted after the deadline will not be considered. 
14. The Supplier before time-limit for receipt of tenders is entitled: 
    1. to withdraw the offer by written notification by e-mail indicated for the submission of tenders, 
    2. to change the offer – notification of the changes must be submitted by the same rules as the submitted offer, appropriately marked with the note "CHANGING THE OFFER". All required appendices and statements with updated date (date of submission of the changing offer) should be provided.

Selection criteria and evaluation methods:

1. The Contracting Authority is entitled to reject the tender submitted by the Supplier who does not meet the conditions for participation in the proceedings, or if the offer is incomplete or incompatible with this request.

2. Formal compliance, the degree of compliance with the RFP requirements.

3. Possibility of realization of service within the above presented timeframes (Section I.9). 

4. Selection criteria:
   1. Net price (weight criterion – 80%); 

   2. Total timelines (in weeks) (weight criterion – 20%). The total timelines are counted in weeks as a sum:
      - from the availability of IMPD/certificates of analysis for the pharmacokinetic study to the availability of the preliminary results from the study.

5. The Contracting Authority shall evaluate offers based on the result of the accumulated number of points calculated on the basis of above criteria and scores:

   Criteria	Weight criterion[%]	Method of evaluation in accordance with the formula
   Price	80%	net price of the offer with the lowest price / net price of tested offer x 100 x 80%= number of points
   Total timelines (weeks)	20%	timelines (in weeks) of the offer with the shortest timelines / time (in weeks) of the tested offer x 100 x 20 % = number of points

6. The amounts of points for each criterion after summing up will be the final number of points awarded by each tender. As the most advantageous offer will be considered that which obtains the highest number of points. 
7. The results of the mathematical calculations carried out in the evaluation of tenders are rounded to the second decimal place. In case of equal scores for at least two offers the Contracting Authority will make the final choice of the offer more favorable when it comes to the impact on the environment i.e. treatment of wastewater and process exhaust gases and/or transfer of solid residues to specialized companies for disposal (e.g. unused drugs, biological samples, other materials). For this purpose, the Contracting Authority shall have the right to call the Suppliers, whose tenders have obtained the highest final points, to complete the offer by giving indicated by the Contracting Authority information about an impact of the offer on the environment. The deadline to complete the offer will be determined by the Contracting Authority, but it cannot be less than 3 working days from receipt of the request. 

The choice of Supplier and way of announcing:

1. The Contracting Authority will select the most advantageous offer on the basis of the selection criteria defined in this request for proposal.
2. Information on the results of the procedure will be sent by the Contracting Authority to each Tenderer who submitted his offer and will be published on the Adamed Pharma website www.adamed.com.pl.

General provisions

1. The contracting authority reserves the right to cancel the procedure at any stage without giving any reason.
2. In the case of cancellation of the contract the Suppliers are not entitled to claim for reimbursement of the costs of participation in the proceedings.  
3. Submission of the application for registration in the process or tender implies acceptance without reservation all the conditions of the proceedings. 
4. Withdrawal by the Contracting Authority from the conclusion of the contract after the notification the Supplier about the selecting the offer, cannot be the basis for claims of incurred costs of participation in the proceedings. 
5. In the process of evaluating Offers the Contracting Authority may seek information from the contractors concerning the content of their documents.  
6. If the application does not contain all the required elements, the Contracting Authority may in justified cases call the Supplier to complete it. 
7. The Contracting Authority reserves the right to record sound during technical meetings with suppliers. Submission of the offer will be treated as giving consent to the recording of the meeting. 
8. The Contracting Authority reserves the right to audit the Tenderer before the conclusion of the contract. In case of obtaining not satisfactory results of the audit Sponsor may withdraw from signing the contract. 
9. The Contracting Authority allows negotiations of the contract terms and conditions with the Bidder. 
10. The Contracting Authority reserves the right to negotiate the proposal with all the Bidders. Negotiations may have several consecutive  rounds with the possibility to invite  Bidder to submit the updated quotation after each round of negotiations.
11. Terms of contract change: The contracting authority envisages the possibility of introducing significant changes to the contract concluded as a result of the conducted contract award procedure in relation to the content of the offer, on the basis of which the contractor was selected, in the event of the necessity to change the indicated scope of works specified in the offer: 
    1. necessary or justified changes in the project documentation resulting from unforeseeable reasons, which may be caused by, among others, amendment of legal acts, guidelines, the result of "Scientific advice" in Regulatory Agency, publication of new scientific data and for other reasons that affect the scope, changes imposed by statistical methods applied in the study, type or design of clinical trials, the scope of analytical methods and their validation, and other aspects related to clinical development of the medicinal product;
    2. delays in the manufacturing or delivery of a medicinal product for a clinical trial resulting in the change of the clinical trial schedule for unforeseeable reasons or circumstances beyond the control of the contracting authority; among others, the necessity to make changes in the formulation of the medicinal product, changes in analytical methods and their validation, changes in product quality documentation, delays in the delivery of raw materials and packaging, production failures and downtimes, delays in the production schedule resulting from the availability of production workers due to the Covid epidemic, transit delays, delays in customs clearance or any other reasons;
    3. the necessity or justification for introducing changes to the clinical study design during the work on the study protocol or as a result of the Authority's recommendation at the stage of the clinical study approval;
    4. delays or postponements in the clinical study schedule caused by the Authority's request to supplement the gaps in the documentation, make changes to the study protocol or correct the study documentation at the stage of the study approval;
    5. the need to increase the sample size after the exclusion of study subjects due to an epidemic (e.g. COVID-19) or for other reasons (e.g., voluntary resignation, side effects, etc.), resulting in the need to recruit additional study subjects;
    6. the need to divide the clinical trial participants into smaller groups due to the epidemic (e.g. COVID-19) or issues related to the study organization for orally inhaled products;
    7. perform necessary or justified additional activities in connection with the conducted clinical study to ensure the conduct of the clinical study with appropriate quality and diligence, in accordance with the principles of ICH-GCP;
    8. financial constraints on the part of the Contracting Authority or changes in legal requirements limiting the scope of work included in the offer;
    9. obtaining study results that do not justify conducting the next study;
    10. other necessary or justified changes in the delivery time and conditions of the contract subject resulting from unforeseeable reasons.

Any changes and additions to the contract concluded with the selected Tenderer will be made in the form of written annexes to the contract signed by both parties, under rigor of invalidity.

Additional information

1. Any questions should be submitted using Messages in the SAP Ariba Network Platform – questions (Appendix 9).
2. Answers will be provided to all the participants via Messages from Procurement System SAP Ariba Network.  
3. The person authorized to contact the Bidders (Monday-Friday between 08:00-16:00 CET) is Aleksandra Stojak: [aleksandra.stojak(at)adamed.com].

Appendix No 1  (download)

Ariba Supplier's users guide – SAP Ariba Network Registration (download)

Ariba Supplier's users guide - Creating an offer on the AN Portal  (download)